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Polymeric Surface Modification of Metallic Medical Implants for Enhanced Stability and Delivery of Therapeutic Agents


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POLYMERIC SURFACE MODIFICATION OF METALLIC MEDICAL IMPLANTS FOR ENHANCED STABILITY AND D ELIVERY OF THERAPEUTIC AGENTS By MARGARET W. KAYO A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2005

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Copyright 2005 by Margaret W. Kayo

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This dissertation is dedicated to my family and the close friendships I have made here

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iv ACKNOWLEDGMENTS I thank my advisor, Dr. Eugene Goldbe rg, for his support and leadership, in addition to his confidence in my abilities. My thanks are also ex tended to my advisory committee, Dr. Anthony Brennan, Dr. Chris Ba tich, Dr. James Seeger and Dr. Kenneth Wagener. I would also like to acknowle dge the expertise of Eric Lambers, Gary Scheffeile, Paul Martin, Dr. Won-Seok Kim, Dr. Mike Olli nger, Dr. David Norton, Mat Ivill, Dr. Harmut Derendorff, Dr. Vipul Ku mar, Dr. Samuel Farrah and Dr. George Lukasik. Thanks are extended to the following people for their technical support and friendships: Dr. Daniel Urba niak, Amanda York, Adam Re boul, Adam Feinberg, Dr. Chris Widenhouse and Jennifer Wrighton. I thank the following people for their fr iendship and humor Samesha Barnes, Dr. Brett Almond, Dr. Clayton Bohn, Iris Enriquez, Jim Schumacher, Anika Odukale, Jompo Moloye, Tara Wahsington, Amin Elachchabi, Michelle Carman, Leslie Wilson, Thomas Estes, and Jim Seliga. Finally, I would like to thank my mother, Cecilia Kayo Bressan, father, David Kayo, stepfather, Ronald Br essan, sister, Rebekah Kao and brother, Jonathan Kayo for their confidence in my ability to succeed.

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v TABLE OF CONTENTS page ACKNOWLEDGMENTS.................................................................................................iv LIST OF TABLES...........................................................................................................viii LIST OF FIGURES.............................................................................................................x ABSTRACT.......................................................................................................................xv CHAPTER 1 INTRODUCTION........................................................................................................1 2 BACKGROUND..........................................................................................................4 Introduction...................................................................................................................4 Endovascular Stents......................................................................................................5 Sirolimus (Rapamycin) Eluting Stents................................................................10 Paclitaxel Eluting Stents......................................................................................11 17 -estradiol Eluting Stents................................................................................12 Dexamethasone Eluting Stents............................................................................13 Drug Release from Silicone.................................................................................14 Keratome Blades.........................................................................................................15 Materials for Coatings and Implantable Medical Devices.........................................15 Significance................................................................................................................20 3 METAL ALKOXIDE TREATMENTS AND LOW DOSE GAMMA SURFACE MODIFICATION OF STAINLESS STEEL..............................................................21 Introduction.................................................................................................................21 Metal Alkoxide Treatments........................................................................................21 Materials and Methods........................................................................................23 Preparation of 316L stai nless steel substrates..............................................23 Treating 316L stainless st eel with metal alkoxides......................................23 Chromium alkoxide degradation study........................................................24 Analysis........................................................................................................24 Results and Discussion........................................................................................24 Summary..............................................................................................................31

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vi Low Dose Gamma Irradiation Grafting of Polymers to Metal Alkoxide Treated Substrates...............................................................................................................32 Materials and Methods........................................................................................33 Preparation and treatment of 316L stainless steel substrates.......................33 Preparation of monomer solutions...............................................................34 Gamma irradiation of substrates..................................................................34 Analysis........................................................................................................35 Results and Discussion........................................................................................36 Summary..............................................................................................................52 4 PULSED LASER ABLATION DEPOSI TION (PLAD) AND RF PLASMA POLYMERIZATION DEPOSITION........................................................................55 Introduction.................................................................................................................55 Pulsed Laser Ablation Deposition (PLAD)................................................................55 Materials and Methods........................................................................................57 Preparation of silicone targets and substrates..............................................57 Pulsed laser ablation deposition chamber....................................................58 Analysis........................................................................................................59 Results and Discussion........................................................................................59 Summary..............................................................................................................66 RF Plasma Surface Modification................................................................................67 Materials and Methods........................................................................................68 Preparation of substrate, monomers, and comonomer.................................68 Monomer RF plasma....................................................................................69 Analysis........................................................................................................70 Results and Discussion........................................................................................70 Summary..............................................................................................................74 5 SOLUTION POLYMERIZATION COAT ING SURFACE MODIFICATION........76 Introduction.................................................................................................................76 Materials and Methods...............................................................................................77 Preparation and Treatment of 316L Stainless Steel Substrates...........................77 Preparation of Monomer Solutions.....................................................................77 Preparation of Silicone Component Solutions....................................................77 Solution Polymerization (SP) Coating of Substrates...........................................78 Analysis...............................................................................................................78 Results and Discussion...............................................................................................79 Summary.....................................................................................................................89 6 LOADING AND RELEASE OF THERAPUETIC AGENTS FROM SURFACE MODIFIED METAL ALKOXIDE TREATED STAINLESS STEEL......................91 Introduction.................................................................................................................91 Materials and Methods...............................................................................................92 Preparation of Substrates and Coatings...............................................................92

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vii Post Loading Ofloxacin and Dexamethasone......................................................93 Drug Loading Solution Depletion Study.............................................................94 Release of Drugs from Surface M odified 316L Stainless Steel..........................94 Preparation of Bacterial Cultu res for Zone of Inhibition....................................96 Analysis...............................................................................................................96 Results and Discussion...............................................................................................97 Summary...................................................................................................................105 7 CONCLUSIONS......................................................................................................107 8 FUTURE WORK......................................................................................................110 LIST OF REFERENCES.................................................................................................112 BIOGRAPHICAL SKETCH...........................................................................................118

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viii LIST OF TABLES Table page 2.1 Metal alkoxide chromi um complex constituents......................................................18 2.2 Silicone curing systems............................................................................................19 3.1 Volan L solution and Silver Acrylate mixed solvent solution composition..........24 3.2 XPS analysis for air dried samples w ithout rinsing: % Cr2p3 and % C1s relative to % O1s, Fe2p3 and Cl2p. All conditions were examined on 316L stainless steel.......................................................................................................................... .27 3.3 MPC XPS elemental surface composition (%) and rehydrated contact angle of surfaces for dose of 0.1 Mrads. MPC* refe rs to theoretical concentrations of elemental composition..............................................................................................49 3.4 NVP XPS elemental surface composition (%) and rehydrated contact angle of surfaces for dose of 0.1 Mrads. NVP* refe rs to theoretical concentrations of elemental composition..............................................................................................49 3.5 KSPA XPS elemental surface compositi on (%) and rehydrated contact angle of surfaces for dose of 0.1 Mrads. KSPA* refe rs to theoretical concentrations of elemental composition..............................................................................................51 4.1 Contact angle of MED 6820 depositions at various fluences on untreated 316L stainless steel............................................................................................................60 4.2 XPS elemental analysis (%) of PLAD coated samples on untreated 316L stainless steel............................................................................................................64 4.3 XPS elemental analysis (%) of PLAD coated samples on Volan treated 316L stainless steel............................................................................................................65 4.4 XPS elemental analysis (%) of 5 mi nute monomer RF plasma modification of untreated, Volan L and Quilon L treated 316L stainless steel.............................74 5.1 XPS analysis of SP coated Volan L and untreated 316L stainless steel................89

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ix 6.1 Coating and metal alkoxide treatment conditions investigated for drug release where Oflox and Dex refers to ofloxaci n and dexamethasone, respectively. 2% V-L refers to 2 % v/v Volan L...............................................................................94 6.2 Ofloxacin depletion UV-Vis absorption measurements in term s of concentration with adjustments for surface area and conversions, all values are reported as averages....................................................................................................................97 6.3 Dexamethasone depletion UV-Vis absorption measurements in terms of concentration with adjustments for surf ace area and conversions, all values are reported as averages.................................................................................................98

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x LIST OF FIGURES Figure page 2.1 Illustration of balloon angioplasty and stenting. Adapted from ADAM, Inc............6 2.2 Histological section of restenotic arteries follo wing balloon angioplasty and stenting.10 Indolfi et al. 2003.....................................................................................8 2.3 Various stents. A) CYPHER sirolimus-eluting coronary stent by Cordis Corporation, B) Stent by Boston Scientif ic Corporation, C) Stent by Medtronic, Inc............................................................................................................................ .11 2.4 Volan and Volan L bonding agent, chromium (III) methacrylate........................17 2.5 Quilon L bonding agent, chromium (III) fatty acid where R=C14-18......................17 2.6 Hydrophilic monomer structures: 2-methacryloyloxyethyl phosphorylcholine (MPC), N-vinyl pyrrolidone (NVP), N,N-dimethylacrylamide (DMA), and potassium 3-sulfopropyl acrylate (KSPA)...............................................................19 2.7 Silicone vinyl addition curing system......................................................................20 3.1 Silver Acrylate (Geles t, Inc., Morrisville, PA)........................................................23 3.2 XPS survey of PET..................................................................................................26 3.3 XPS spectra of Ag3d5 of silver acr ylate treatment on 316L stainless steel............28 3.4 XPS C1s and O1s spectra of: A) Previously-opened 2% Quilon L treatment on 316 L stainless steel, B) Newly-opened 2% Quilon L treatment on 316 L stainless steel, and C) 316L stainless steel control...................................................30 3.5 XPS C1s and O1s spectra of: A) Previously-opened 2% Volan treatment on 316 L stainless steel, B) Newly-opened 2% Volan treatment on 316 L stainless steel, and C) 316L stainless steel control.................................................................31 3.6 60Co gamma irradiator and rotating sample stage....................................................35 3.7 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% NVP / Ultr apure water solutions...........................................36

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xi 3.8 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% MPC / Ultrapure water solutions..........................................37 3.9 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 2.5% DMA / Ultrapure water solutions........................................37 3.10 Contact angle stability of untreated 316L stainless steel i rradiated to 0.1 and 0.15 Mrads in 10% KSPA / Ultrapure water solutions........................................38 3.11 Contact angle stability of untreated 316L stainless steel i rradiated to 0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DMA / Ultrapure water solutions....................38 3.12 Contact angle stability of untreated 316L stainless steel i rradiated to 0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DMA / Ultrapure water solutions...................39 3.13 Contact angle stability of untreated 316L stainless steel i rradiated to 0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / Ultrapure water solutions..................39 3.14 Contact angle stability of Quilon L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% NVP / U ltrapure water solutions..............................40 3.15 Contact angle stability of Quilon L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% KSPA / Ultrapure water solutions............................40 3.16 Contact angle stability of Quilon L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DM A / Ultrapure water solutions.......41 3.17 Contact angle stability of Quilon L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / Ultrapure water solutions.....41 3.18 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% NVP / Ultrapure water solutions....................................42 3.19 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% KSPA / U ltrapure water solutions..................................42 3.20 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DMA / Ultrapure water solutions.............43 3.21 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DM A / Ultrapure water solutions...........43 3.22 Contact angle stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% NVP / U ltrapure water solutions..............................44 3.23 Contact angle stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% KSPA / Ultrapure water solutions............................44

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xii 3.24 Contact angle stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DM A / Ultrapure water solutions.......45 3.25 Contact angle stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / Ultrapure water solutions.....45 3.26 Contact angle stability of Quilon L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% MPC / U ltrapure water solutions.............................46 3.27 Contact angle stability of Quilon L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DM A / Ultrapure water solutions.......46 3.28 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% MPC / Ultrapure water solutions...................................47 3.29 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DMA / Ultrapure water solutions.............47 3.30 Contact angle stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% MPC / U ltrapure water solutions.............................48 3.31 Contact angle stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DM A / Ultrapure water solutions.......48 3.32 MPC grafted on treated and untreate d 316L SS. XPS elemental spectra for N1s and P2p. A) 2% Volan L treated, B) 2% Quilon L treated, and C) untreated...................................................................................................................50 3.33 SEM of cleaned 316L stainless steel at 5000x.......................................................51 3.34 SEM of 10% v/v MPC gamma irradi ation grafted (0.1 MRads) coating on Volan L activated 316L stainless steel at 5000x....................................................52 4.1 Illustration of PLAD system setup.60.......................................................................57 4.2 FTIR-ATR spectra of MED 6820 deposited at a fluence of 400 mJ/cm2 on silicon wafer.............................................................................................................62 4.3 FTIR-ATR spectra of MED 6820 deposited at a fluence of 400 mJ/cm2 on 2% Volan treated 316L stainless steel............................................................................62 4.4 FTIR-ATR spectra of MED 6820 deposited at a fluence of 200 mJ/cm2 on 2% Volan treated 316L stainless steel............................................................................63 4.5 FTIR-ATR spectra of MED 6820 deposited at a fluence of 125 mJ/cm2 on 2% Volan treated 316L stainless steel............................................................................63 4.5 SEM of 316L stainless steel at 500x........................................................................65

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xiii 4.6 SEM of MED6820 PLAD coated at fluence of 300 mJ/cm2 onto untreated 316L stainless steel at 500x...............................................................................................66 4.7 Initial contact angle measurements for NVP, DMA and NVP/DMA RF plasma surface modifications on untreated 316L stainless steel..........................................71 4.8 Initial contact angle measurements for NVP, DMA and NVP/DMA RF plasma surface modifications on 2% v/v Quilon L treated 316L stainless steel................71 4.9 Initial contact angle measurements for NVP, DMA and NVP/DMA RF plasma surface modifications on 2% v/v Volan L treated 316L stainless steel.................72 4.10 Rehydrated contact angle measur ements for NVP, DMA and NVP/DMA RF plasma surface modifications on unt reated 316L stainless steel..............................72 4.11 Rehydrated contact angle measur ements for NVP, DMA and NVP/DMA RF plasma surface modifications on 2% v/v Quilon L treated 316L stainless steel....73 4.12 Rehydrated contact angle measur ements for NVP, DMA and NVP/DMA RF plasma surface modifications on 2% v/v Volan L treated 316L stainless steel.....73 5.1 Initial contact angle measurements for 10% and 25% v/v monomer SP coated untreated 316L stainless steel...................................................................................80 5.2 Initial contact angle measurements for 10% and 25% v/v monomer SP coated Volan L treated 316L stainless steel......................................................................80 5.3 Contact angle measurements immedi ately after dehydration for 10% and 25% v/v monomer SP coated untreat ed 316L stainless steel...........................................81 5.4 Contact angle measurements immedi ately after dehydration for 10% and 25% v/v monomer SP coated Volan L treated 316L stainless steel...............................81 5.5 Rehydrated contact angle measurem ents for 10% and 25% v/v monomer SP coated untreated 316L stainless steel.......................................................................82 5.6 Rehydrated contact angle measur ements for 10% and 25% v/v monomer solution coated Volan L treated 316L stainless steel.............................................83 5.7 Contact angle measurements for 10% and 25% v/v NVP SP coated untreated 316L stainless steel...................................................................................................83 5.8 Contact angle measurements for 10% and 25% v/v NVP SP coated Volan L treated 316L stainless steel.......................................................................................84 5.9 Contact angle measurements for 10% and 25% v/v MPC SP coated untreated 316L stainless steel...................................................................................................84

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xiv 5.10 Contact angle measurements for 10% and 25% v/v MPC SP coated Volan L treated 316L stainless steel.......................................................................................85 5.11 Contact angle measurements for 10% v/v KSPA SP coated untreated 316L stainless steel............................................................................................................85 5.12 Contact angle measurements for 10% v/v KSPA SP coated Volan L treated 316L stainless steel...................................................................................................86 5.13 FTIR-ATR spectra of ME D 6820 medical grade silicone.....................................87 5.14 FTIR-ATR spectra of MED 6820 SP co ated untreated 316L stainless steel.........87 5.15 FTIR-ATR spectra of MED 6820 SP coating on Volan L treated 316L stainless steel............................................................................................................88 6.1 Molecular structures for ofloxacin and dexamethasone..........................................92 6.2 Ofloxacin release from 25% v/v NVP SP coated Volan L and untreated 316L stainless steel compared with unmodified controls................................................100 6.3 Ofloxacin release from 25% v/v MPC SP coated Volan L and untreated 316L stainless steel compared with unmodified controls................................................100 6.4 Dexamethasone release from 25% v/v MPC SP coated Volan L and untreated 316L stainless steel compared with unmodified controls......................................101 6.5 Dexamethasone release from 10% v/ v MPC gamma irradiation graft coated Volan L and untreated 316L stainless steel compared with unmodified controls.102 6.6 Dexamethasone release from 45% v/v MED6820 SP coated Volan L and untreated 316L stainless steel comp ared with unmodified controls......................103 6.7 Zone of inhibition of ofloxacin re lease from 25% NVP solution coated Volan L treated 316L stainless steel. Le ft-S.Aureus. Right-S.Epidermidis....................104 6.8 Zone of inhibition of ofloxacin rele ase from 25% NVP solution coated untreated 316L stainless steel. Left-S.A ureus. Right-S.Epidermidis...................................104 6.9 Zone of inhibition of ofloxacin rele ase from 2% silver acrylate functionalized 316L stainless steel. Left-S.A ureus. Right-S.Epidermidis...................................104

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xv Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy POLYMERIC SURFACE MODIFICATION OF METALLIC MEDICAL IMPLANTS FOR ENHANCED STABILITY AND D ELIVERY OF THERAPEUTIC AGENTS By Margaret W. Kayo August 2005 Chair: Eugene P. Goldberg Major Department: Materials Science and Engineering Complications associated with implantable devices have led to research focused on enhancing surface properties to improve device biocompatibility. Implants such as endovascular stents and surgical contact devices such as keratome blades are examples of medical devices that can potentially benef it from enhanced surface properties. Drug delivery from stent surface modifications has been shown to reduce or control wound healing response to such implants and enhance wound healing with inhibition of restenosis. Surface modifications that provide therapeutic effects through the incorporation and localized act ion of drugs represent an important area of research for improved medical devices. In the study reported here, novel surface modifi cations of 316L stainless steel have been prepared with surface functionalized metal alkoxides. The general objective has been to develop new surface treatments pertinent to metal stents and surgical blades. The surface modification techniques use in this re search included gamma radiation grafting,

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xvi solution polymerization coating, thin film deposition by pulsed laser ablation deposition (PLAD) and radio frequency plasma (RF plas ma). The monomers used in these metal coating systems were designed to produce stable hydrophilic surfaces; Nvinylpyrrolidone (NVP), 2-methacryloyl oxyethyl phosphorylcholine (MPC), N,Ndimethylacrylamide (DMA), and potassium 3-sulfopropyl acrylate (KSPA). Medical grade silicones were also studied as coa tings on 316L stainless steel using PLAD and solution polymerization coating methods. Emphasis of the research was on the evaluation of new metal alkoxide activated stainless steel surfaces with untreated stainless steel to enhance surface modificat ion stability. Improved hydrophilic surface modifications of metal alkoxide treated stainles s steel were demonstrat ed to be stable and lubricious. Surfaces were characterized by contact angle goniometry, FTIR-ATR, XPS and SEM. Various conditions were also investigated to develop methods for incorporating therapeutic agents into modified device surf aces. The drugs studied included ofloxacin, an antimicrobial agent, and dexamethasone, an anti-inflammatory agent. Loading and release of these drugs into PBS and human blood plasma were examined by UV-Vis and HPLC. In summary, new coating systems and pract ical process procedures were developed to enhance the coating stability on 316L stainl ess steel surfaces and to effectively deliver therapeutic agents.

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1 CHAPTER 1 INTRODUCTION The manufacture and sale of implantable devices, such as endoluminal stents and keratome blades, represent a growing industr y in medical treatments that extend and enhance the quality of life fo r patients. While manufacturi ng continues to advance, many complications remain associated with the bi ocompatibility of these devices. Materialtissue interactions play a central role in the bioacceptance of a device. Surface modification of a medical device is an e ffective approach to reducing and controlling post-interventional complications such as inflammation, thrombosis, and restenosis and to enhance biocompatibility between de vice materials and local host tissue. The research presented here was aimed at exploring various new coatings involving several hydrophilic vinyl monomers and resin reinforced sili cone applied in conjunction with an assortment of metal alkoxide coup ling agents through se veral novel coating techniques that have been shown to modify surfaces effectively. 316L Stainless steel is widely used in the medical device industry due to its desirable mechanical properties, low carbon content and high corrosion resistance. Despite these beneficial characteristics, 316L stainless steel surfaces elicit an inflammatory and thrombotic cascade when im planted in a blood rich environment in the human body. For this reason, surface modifica tion is an ideal method to improve the biocompatibility of 316L stainless steel. Several approaches to modifying metallic substrates have been investigated and will be presented in this body of work as will the problems associated with va rious coating techniques.

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2 A problem inherent to most coatings for medical devices is stability of coatings over time and when exposed to a variety of storage environments and inadequate adhesion of the coatings to substrates. The use of a novel coupling system for biomedical device applications to enhance binding at the polymer and metal interface may resolve these issues. Metal alkoxides with either me thacrylate functionality or fatty acid pendant groups were investigated in this research. The research presented here used metal alkoxide coupling systems to enhance the binding of polymer coatings to metal substr ates employing a wide variety of surface modification techniques. Because these coupl ing systems have not been used in the biomedical device industry, their incorporat ion into medical device surface modification techniques is a novel approach for developing st able coatings with th e potential to release therapeutic agents from the coatings. Chapter 2 presents a review of the biologi cal complications associated with medical implants, examples of device complications fr om clinical studies and the materials and technologies that have led to this work. Backgrounds of individual surface modification techniques will be addressed at the beginning of each respective chapter. Chapter 3 focuses on the development of metal alkoxide coupling and coating systems and the use of gamma irradiation fo r initiating surface reactions in monomer solutions for modification of metal substrat es. The incorporation of metal alkoxide pretreatments is shown to enhance the stabili ty of the hydrophilic m onomers investigated when grafted by gamma initiation. Chapter 4 covers the use of Pulsed Laser Ablation Deposition (PLAD) and monomer RF-plasma. Both techniques require vacuum systems and rely on ionizing the

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3 surfaces with laser and radio frequency gene rated plasma, respectively. In PLAD, the influence of chamber oxygen content on coating composition is explored. New coating conditions are investigated with RF-plasma u tilizing individual monomers as well as a combination. Additionally, the effectiveness of these surface modification techniques are investigated with metal alkoxide coupling systems. Chapter 5 describes the effectiveness of metal alkoxide treatments with solution polymerization coating. In addition to vinyl monomer solutions, dilute reactive resin reinforced silicone solutions were also i nvestigated in these coating systems. Chapter 6 highlights sustained release studi es demonstrating th e potential of metal alkoxide coupling systems to enhance coating stability for drug delivery applications. Release of both an antimicrobial and anti -inflammatory drug was investigated with various gamma irradiated and solution coated systems. Chapters 7 and 8 review the conclusions drawn from the studies in each chapter and identify avenues for fu ture studies, respectively. This body of work is intended to advan ce the understanding an d application of chromium alkoxide coupling systems to enhance polymer coating stability on stainless steel surfaces with the potential to release dr ugs. Biocompatibility is not tested in this work, while demonstrating biocompatibility is the long-term goal fo r the coating systems developed here.

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4 CHAPTER 2 BACKGROUND Introduction The manufacturing of implantable medical devices has revolutionized treatment and quality of life for patients. The strides made in implantable medical device research have led to a focus on developing surfaces that afford these devices greater biocompatibility in the human body. Fo r example, surface modifications and compositional developments of endoluminal st ents have reduced restenosis rates. Additionally, developments in keratome blade sharpness a nd composition have decreased trauma after intraocular lens implantation. However, most materials are not readily accepted by the body and often cause a foreign body response in addition to inflammatory trauma associated with the process of implantation.1 How well a device is accepted by a patients biology is largely gove rned by chemical or structural surface interactions between the implan ted material and surrounding tissue.1 Immediately after a device has been implante d or is in contact with live biological tissue, an inflammatory response ensues be ginning with the adsorption of a protein monolayer.1 Monocytes, leukocytes, macrophages, cytokines and other chemical mediators are signaled to migrate to the injured site and serve to heal or rebuild the tissue. This initial response can last from minutes to several days depending on the host response to the implant or type of trauma followed by a chronic response and granulation. When injured tissue cannot be healed or rebuilt often due to the presence of a foreign body

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5 (implant), local inflammatory cells begin fusi ng together forming giant cells in an attempt to wall off the site, which is an end stage healing response.1 Thrombosis is a blood compatibility complication associated with most intravascular implant materials that may othe rwise be inert. When these materials are used for implantable medical devices, plat elet activation coupled with inflammation begins the thrombotic cascade. Thrombosis is initiate d by protein adsorption onto a surface in contact with blood, which causes an i rreversible platelet aggregation releasing a host of factors to essentially coagulate and plug an injured site to prevent excessive blood loss.1-4 Material surfaces that are thrombogenic can be modified to have more compatible material-tissue interactions for a variety of different surgical instrument and implant applications. Furthermore, inflammatory re sponse can be controlled without systemic toxicity through localized release of therapeuti c agents. Presented here are two examples illustrating the clinical needs to enhance material surface properties for increased biocompatible medical devices for implantat ion: endovascular stents and keratome blades. A discussion of materials for coati ng implantable medical devices will conclude this background. Endovascular Stents Percutaneous transluminal coronary angiopl asty (PTCA) is a technique used for the treatment of coronary atherosclerosis a nd heart disease, where procedures for revascularization of coronary arteries involve flattening fa tty plaques in the blood vessel against the vessel walls by a balloon catheter, see Figure 2.1.5 From 1987 to 2001, the number of PTCA procedures has in creased 266% in the United States.6 In 2001, approximately 571,000 PTCA procedures we re performed on 559,000 patients. Also,

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6 475,000 of these procedures incl uded cardiovascular stenting, which has been shown to significantly reduce re stenosis as compared with balloon angioplasty alone.6, 7 Figure 2.1 Illustration of ba lloon angioplasty and stenting. Adapted from ADAM, Inc. Restenosis is a phenomenon marked by an occluding lesion occurring after balloon angioplasty or stenting.5 Restenosis can require repeat su rgeries and can lead to death. For patients undergoing percutaneous ba lloon angioplasty, 3040% will develop restenosis in the first 6 months while stenting decreases the incidence to 20%.7 Although there have been vast stent t echnology improvements, the prob lem of in-stent restenosis has not been resolved and remains as relevant as the issue of restenosis after PTCA. Recent studies suggest atherosclerosis, a diso rder that causes fatty plaque to deposit along arterial and vessel walls, involves seve ral factors including inflammation, vascular smooth muscle cell (VSMC) proliferati on/migration, endothelial dysfunction and

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7 extracellular matrix alteration.8 Similar factors are asso ciated with the molecular mechanisms of restenosis and in-stent restenosis.9-11 Restenosis after balloon angiopl asty was found to be distin ctively different from instent restenosis from a histological standpoint.10 Indolfi et al. suggests that the mechanism for restenosis af ter balloon angioplasty is pr edominantly due to negative vessel remodeling, while the proliferation of smooth muscle cells only accounts for 25% of the phenomenon, as illustrated in Figure 2.2.10 Indolfi et al. noted that there was no evidence of vessel remodeling with cardiovascu lar stenting; however, restenosis was still observed. The in-stent restenosis mechanism appeared to be due entirely to the proliferation of smooth muscle cells. Consequently, it was found in swine coronary arteries that restenosis as a result of balloon angiop lasty consisted of vessel remodeling and neointimal hyperplasia, while in-stent rest enosis consisted of mostly neointimal hyperplasia.11 Nakatani et al. concluded th at neointimal proliferation of smooth muscle cells poststenting persisted longer than the pr oliferation associated with balloon angioplasty.{Nakatani, 2003 #61} Likewise, Ho fma et al. suggested stenting lead to longer wound healing cascades due to the permanency of st ent placement leading to longterm endothelial dysfunction and in flammation.{Hofma, 2001 #194} These developments have lead to a focus in targe ting cell cycle regulation as treatment against in-stent restenosis.

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8 Figure 2.2 Histological section of restenotic arteries foll owing balloon angioplasty and stenting.10 Indolfi et al. 2003 Today, metallic vascular stents are availabl e in several materials including various grades of stainless steel, cobalt-chromium, tantalum and nickel-titanium compounds.12 However, when implanted without further surf ace treatment, many metallic formulations are thrombogenic and do not inhibit neointimal hyperplasia.13 Several coatings for enhanced biocompatibility of metallic stent materials have been investigated including inorganic/ceramic coatings (gold, carbon, ir idium oxide and silicon carbide), synthetic and biological polymers (polyurethane, pol ylactic acid, phosphorylcholine, chondroitin sulfate, hyaluronic acid, fibri n, elastin and cellulose), and drugs (heparin, sirolimus and paclitaxel).14 Gold, carbon, and silicon carbide (SiC) inor ganic/ceramic coatings on stents have been studied in human clinical trials.13, 14 In the first 30 days after intervention, gold coated stents were discovered to have no antithrombotic effects, and exhibited an increased incidence of neointimal hyperplasia within the first year.13, 14 Carbon coated stents, such as Carbostent (Sorin Biomed ica Cardio), were found to yield low major adverse cardiac event (MACE) (12%) and bina ry restenosis (11%) rates at 6 months

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9 follow-up with 112 intermediate risk patients.13 SiC coatings have been used without reports of biocompatibility issues, however high concentrations of SiC debris can be cytotoxic. 14 SiC coatings did not have a considerab le affect on rate of restenosis when compared with balloon angioplasty alone in a clinical trial.13 Synthetic and biological polymeric coatings have also been inve stigated in human clinical trials. Specificall y, phosphorylcholine coatings ha ve been evaluated in the SOPHOS (Study of Phosphorylcho line on Stents) trial with 42 5 patients. At 6 months, this study showed a MACE of 13.4% for Phosphor ylcholine coated stents versus 15% for uncoated stents.14 The 6 month binary restenosis ra te was 17.7% for the coated group. The researchers in this study concluded ther e was a less severe in flammatory response associated with phosphorylcholine coating as compared with several other polymers for the same application. Immobilized drug coatings have been used in the clinical setting where drugs can be physically adsorbed or chemically tethered to the stent surface. Heparin coated Palmaz-Schatz stents exhibited comparable e ffectiveness in the prevention of restenosis when compared with uncoated stents comb ined with systemic abciximab treatments.14 Heparin coated stents did not demonstrat e any significant differences in MACE and binary restenosis rates. The authors conclude d that heparin coated st ents did not have an effect on in-stent restenosis.13 Sirolimus and paclitaxel have also been examined in a clinical setting. Sirolimus coated stents when compared with unc oated stents (26.6%) had a 0% binary restenosis rate at 6 months post-intervention.13 The authors reported that no late thrombosis occurred with the siroli mus eluting treatment. ASPECT (Asian Paclitaxel-Eluting Stent Clinical Trial) examined a high and low dose condition for

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10 paclitaxel coated stents with no polymer carrier.13 The 6 month binary restenosis rate was 4% versus 27% for the uncoated group. MACE rates are currently unpublished for this study. Inert coatings alone on stents have not reduc ed restenosis rates or thrombosis to an acceptable level. Additionally, drug coatings alone did not yield satisfactory outcomes. Consequently, many vascular device companies ha ve or are in the process of developing drug-eluting stents to combat in-stent restenosis.15 Some of the drugs involved in clinical trials of drug eluting stents include rapa mycin (sirolimus), paclitaxel, tacrolimus, everolimus, 17 -estradiol, and dexamethasone.8, 10, 15 The two most extensively evaluated drugs undergoing drug eluting stent clin ical trials are paclitaxel and rapamycin (sirolimus). However, STRIDE (A St udy of Antirestenosis with the BiodivYsio Dexamethasone-Eluting Stent), clinical tr ial launched in February 2003 and more recently the EASTER trial (Estrogen and Sten ts to Eliminate Restenosis), has yielded promising results in some patients.15 Sirolimus (Rapamycin) Eluting Stents Sirolimus (Rapamycin) is an immunos uppressant antibiot ic derived from streptomyces hygroscopicus from Easter Island soil samples.16 Sirolimus functions by binding to immunophilins inhibiting cell signal transduction thus targeting cell cycle progression.16-18 Sirolimus inhibits VSMC migration in vitro and proliferation in vitro and in vivo The results of several clinical trial investigations on the effects of sirolimus on restenosis rates have been remarkable with 1 year MACE as low as 0% and in-stent restenosis of 2.0%.13, 16 The Cordis CYPHER stent is currently one of two drug eluting coronary stents approved for use in humans in the United States, Figure 2.3. The stent is

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11 loaded with sirolimus to an effective surface concentration of approximately 150-180 g/cm2.14, 16 Despite the clinical be nefits of sirolimus eluting stents, varying degrees of inflammation, delayed endothelializati on and toxicity concerns remain.10, 15, 16, 18 Figure 2.3 Various stents. A) CYPHER sirolimus-eluting coronary stent by Cordis Corporation, B) Stent by Boston Sc ientific Corporation, C) Stent by Medtronic, Inc Paclitaxel Eluting Stents Paclitaxel is an antineoplastic and ch emotherapeutic agent derived from yew trees.16 Similar to sirolimus, paclitaxel interr upts signal transduction and has been shown to inhibit the proliferation and migration of VSMC. As in the ASPECT trial, the ELUTES (Evaluation of Paclitaxel Eluting Stents) also suggests a dose dependency for paclitaxel effectiveness in reducing restenosis and MACE.13 However, paclitaxel in the TAXUS I trial proved to be prom ising at 6 months with 0% binary restenosis for coated stents compared with 11% in the bare stent group. Additionally, no MACE was observed at 12 months. 16

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12 Like the Cordis CYPHER stent, Boston Scientifics NIR poly(lactide-cocaprolactone) copolymer and paclitaxel stent is also approved for use in humans, see Figure 2.3. There are approximately 200 g of paclitaxel loaded per stent.19 Problems associated with paclitaxel eluting stents include incomplete healing due to delayed endothelialization, persistence of macrophages, and deposition of fibrin. Furthermore, it was found that 80% of the loaded drug releas ed within the first 3 days of deployment.10, 15, 16, 19 17 -estradiol Eluting Stents The release of 17 -estradiol has been investigat ed with phosphorylcholine coated stents. In 2002, Biocompatib les Ltd. filed a world pate nt titled Stents with DrugContaining Amphiphilic Polymer Coating.20 The invention disclosed a shape memory alloy stent with a zwitterionic coating cap able of releasing hydrophobic or hydrophilic drugs. On March 17, 2004, an Estrogen And Stents To Eliminate Restenosis (EASTER) clinical trial report was released indicating that the release of 17 -estradiol was safe and may be effective in inhibiting in-stent restenosis in humans.21 17 -estradiol was eluted from phosphorylcholine coatings on 316-L st ainless steel balloon expandable stents during the EASTER clinical trials.21 However, a burst releas e profile was observed and the total release was completed within the first 24 hours of stent deployment. The surface concentration used in this study was determined to be 2.52 g/mm2. 21 Despite the rapid release, no in-stent thro mbosis occurred and late-stent malapposition was not detected. Additionally, no edge rest enosis was found at a 6 month follow-up. At 1-year, revascularization and low ra tes of restenosis were observed.21 In each follow-up, system toxicity was not evident. The EASTER trials indicate that 17 -estradiol is a

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13 viable alternative approach to other restenosis reducing agents. Althoug h it has been reported that complete inhibition of reste nosis was not observed, changing drug release properties, doses, and coating materials may improve efficacy. The release properties of 17 -estradiol chemically incor porated into poly(acrylic acid) coated 316-L stainless steel plates by a hydrolysable covalent bond has been investigated in an in vitro model.22 The initial 17 -estradiol concentrat ion in this study was determined to be ~12.2 g/cm2 and released for two week s, with no initial burst effect. Currently, an in vivo investigation in a porcine cor onary injury model has yielded promising preliminary results demonstrating a significantly lower incidence of restenosis at 8.58% when compared with non-17 -estradiol treated stents (11.62%).22 Dexamethasone Eluting Stents Dexamethasone is a synthetic glucocortico steroid that produces anti-inflammatory responses by interfering with macropha ges and modifies protein synthesis.16, 23, 24 The release of dexamethasone from a biodegrad able poly-L-lactic aci d coating has been studied by Lincoff et al.25 The investigation yielded in tense inflammatory response by 28 days after implantation, which was attribut ed to the degradation mechanisms of the coating. It was also shown in this study th at dexamethasone did not decrease neointimal hyperplasia in the porcine cor onary artery after stent ove rexpansion trauma. Lincoff suggested the inflammatory responses th at should have been suppressed by dexamethasone did not moderate a key pathwa y to restenosis in the porcine coronary model. Dexamethasone release from liposome co atings composed of phosphatidylcholine and cholesterol have been investigated and are ongoing in the STRIDE trials.16, 23, 24 The STRIDE study has demonstrated a significant re duction of in-stent restenosis with a 6

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14 month follow-up binary re stenosis rate of 13.3%.16, 23 From the STRIDE study, dexamethasone release from phosphorylcholine coating was found to be feasible and safe with no increases in thrombosis and low even t rates. However, neointimal thickening was not found to decrease in this study. This observation was attributed to the low concentration of dexamethasone administered in the study. The authors suggested that further studies investigating higher dose treatment with dexamethasone would be necessary.23 The use of dexamethasone impregnated in si licone coated stents was also briefly investigated in a porcine model. The resu lts of these studies s howed evidence of high anti-inflammatory and antifibrotic effects.16 Drug Release from Silicone Hormone delivery from silastic vaginal rings has been widely available and accepted for hormone replacement therapy and contraception.26-33 Silastic vaginal rings have been shown to be effective fo r sustained and steady release of 17 -estradiol (Estring) and several other commerci ally available hormones. Sustained release of these therapeutic agents from silicone has been attributed to the hydrophobicity of the material a nd lipophilic nature of the hormones.27-30, 34, 35 The successes of hormone replacement therapy and contraceptive silastic vaginal rings suggest that it is feasible to achieve steady state release of steroid hormones from silicone coatings. In addition to silastic vaginal ri ngs, polydimethylsiloxane (PDMS), is currently used in several biomedical applications such as intraocular lenses, catheters, and various cosmetic implants.16, 31, 36-39

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15 Keratome Blades Keratome blades are used in phacoem ulsification procedures for cataract surgeries.40 These blades are designed as single use devices, but can greatly affect the level of trauma associated w ith these surgeries. The shar pness, material composition, and geometries of these devices all contribute to this. As with stents, blade su rface properties can greatly affect the degree of inflammati on after tissue contact, which can result in complications such as astigmatism. Infl ammation is also caused by the implant procedure, which requires a small incision wi th a width of ~3 mm, where blades have been reported to cause unpredictable incisi ons due to poor translat ion across the cornea.41 The surgery also includes the extraction of the cataract and na tural vitreous and replacement with either a silicone oil or polysaccharide emulsion. If the implant is a foldable intraocular lens, then the incision can self-seal. Otherw ise, the incision will require enlargement and must be sutured, glued or taped closed to heal.1 Blade surface properties can greatly affect inflammation asso ciated with both the cataract removal and intraocular lens placement procedure. Furthe rmore, infection at th e incision site can prolong inflammation and associated complications. Materials for Coatings and Implantable Medical Devices 316-L stainless steel has been used for several biomedical device applications including drug eluting stents. 316-L stainle ss steel has a composition in the range of <0.03% C, 16-18.5% Cr, 10-14% Ni, 2-3% Mo, <2% Mn, <1% Si, <0.045% P, <0.03% S, and Fe as the remaining constituent. De pth profiling studies of stainless steel films indicate high Cr2O3 surface content, which is a key component in corrosion resistance.12 This Cr3+ rich layer has an approximate thic kness of ~ 2 nm after electropolishing.12 Additionally, trivalent chromium is an e ssential trace mineral, unlike hexavalent

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16 chromium which has been shown to be toxic. Stainless steel has been used in permanent stent devices. It remains an ideal candida te for this application due to exhibiting relatively inert material beha vior in most corrosive e nvironments. However, 316L stainless steels do exhibit some unfavorable susceptibility to potenti al consequences of injury due to acute localized thrombus formation or neointimal hyperplasia.1 Coupling agents are commonly used to enhance the binding of coatings to substrates. For 316-L stainless steel, sila nes such as tetraethoxysilane (TEOS), hexamethyldisilane (HMDS), Bis(3-triethoxy silylpropyl) tetrasul fide, and SID-4612 (a silazane) are typically employe d. Many silane coupling agents require more than a single step procedure for treatment. However, chromium (III) methacrylate and chromium (III) fatty acid coupling agents deve loped around 1942 that require only single step procedures for treatment (Figures 2.4, 2.5).42, 43 As shown in Figure 2.4, Volan is a chlorinated metal alkoxide with two Cltethered to each Cr3+. The chlorine content is controll ed by the percent of solids or salts in the mixture. The Volan has more chlorine content than Volan L making it more stable to hydrolysis. The scientists w ho developed this coupling agent claim the Clremains tethered to the Cr3+ even after bonding. However, th ey have also suggested that the coupling action may be a slightly acidi c reaction creating som e chlorinated salt byproducts.43 Volan L is designed to bind polyesters, epoxies, phenolics, vinyls, and acrylics to inorganic or polar surfaces such as glass, me tals, polymer, silica, boron and some natural surfaces.

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17 O O CH3 CH2 Cr Cl Cl Cr Cl Cl O H Figure 2.4 Volan and Volan L bonding agent, chromium (III) methacrylate QuilonL is also a metal alkoxide coupling ag ent that is chromium (III) fatty acid based, see Figure 2.5. Fatty acid based systems can be useful for formation of carbonaceous surfaces that will undergo furthe r treatments for binding organic coatings onto inorganic surfaces. Cr O O Cl Cl R Cr O Cl Cl Figure 2.5 Quilon L bonding agent, chromium (III) fatty acid where R=C14-18 The Cr3+ of Quilon L, Volan, and Volan L may interact favorably with the Cr2O3 surface protective f ilms on 316L stainless steel. It is feasible to bind various monomers and vinyl addition silicones to th is surface by reacting with the methacrylate and fatty acid groups of these metal alkoxides. Table 2.1 lists the chromium complex constituents of Volan, Volan L and QuilonL as provided by the manufacturer.

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18 Table 2.1 Metal alkoxide chro mium complex constituents Volan Volan L QuilonL Chrome Complex, % (active ingredient) 19-21 17-18 61 % Chromium 6.0 6.0 9.2 % Chloride 8.2 3.2 12.7 % Methacrylic Acid or % Fatty Acid (C14-18) 5.1 5.1 21.2 Several hydrophilic polymers have been investigated for biomedical device applications such as poly(methacr yloyloxyethyl phosphorylcholine), polyvinylpyrrolidone polydimethylacrylam ide, and poly(potassium sulfopropyl acrylate). These polymers have been show n to be biocompatible and have been investigated for ophthalmic a nd cardiovascular applications.13, 44-49 The monomer structures for these material s are illustrated in Figure 2.6.

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19 N O O N O O O P O O O N+ O O S O O O K+ NVP DMA MPC KSPA Figure 2.6 Hydrophilic monomer structures: 2-methacryloyl oxyethyl phosphorylcholine (MPC), N-vinyl pyrrolidone (NVP), N,N-dimethylacrylamide (DMA), and potassium 3-sulfopropyl acrylate (KSPA). Table 2.2 Silicone curing systems Peroxide Si Si Si Si +Peroxide Condensation Si OH O H Si Si O Si +H+ + H2O Metal Salt Si H O H Si Si O Si +Metal Salt + H2 Vinyl Addition Si H Si Si Si +Pt Polydimethylsiloxane (PDMS) is a hydrophobi c polymer that is currently used in biomedical applications.50 As indicated in Table 2.2, ther e are four primary methods for curing silicone. Currently, the vinyl addi tion curing system is used predominantly.51 Many commercial formulations of silicone ar e available as two-component systems that cure through platinum catalyzed hydrosilylation.51 This reaction is il lustrated in Figure 2.7. Part A consists of silicone oligomers with vinyl terminated silanes, resin reinforcing

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20 fillers, and the platinum catalyst.52 Part B consists of hydride functional silicone oligomers and vinyl terminated silanes. To increase PDMS modulus, tensile strength, tear strength, and abrasion resistance, most silicones are reinforced with silica particulates.51 The silicone that will be used in this project is resin rein forced rather than particulate filled. The curing process is initiated when th e components are combined. Heat is added to increase the curing rate and bring the process to completion. Si O O H CH3 CHSi CH3 O CH3 C H2 Si O O CH2 CH3 CH2 Si CH3 O CH3 +Pt Figure 2.7 Silicone vinyl addition curing system Significance Implantable medical devices often cause a cascade of responses due to trauma associated with implantation and material-tissue interfacial incompatibility. Furthermore, it has been demonstrated that drug therapy can reduce or control the host response to implants and possibly encourage wound healing. It is apparent that there is a need for enhancing the surface properties coupled w ith localized drug therapy for implant applications such as endovascular stents and su rgical devices such as keratome blades. It is the goal of this research to develop new coating systems that are coupled by a one step coupling wash of 316L stainless steel to enhance coating stability and delivery of therapeutic agents, thus laying the groundwor k for studies focused on biocompatibility testing of these promising surface modifications.

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21 CHAPTER 3 METAL ALKOXIDE TREATMENTS AND LOW DOSE GAMMA SURFACE MODIFICATION OF STAINLESS STEEL Introduction Stenosis of the coronary arteries is now often treated by percutaneous transluminal coronary angioplasty combin ed with endovascular stent implantation. Endovascular stents coated with hydrophili c polymers have been shown to exhibit reduced platelet reactivity and accumulation in-vivo compared to uncoated metal stents.44, 45 These coatings may decrease the risk of throm bosis and can potentially be loaded with therapeutic agents that reduce the incidence of post-intervention co mplications such as restenosis.53, 54 Ongoing problems with coatings are drug rel ease to inhibit restenosis and adhesion to the substrate metals. Poor coating adhe sion can lead to delamination or otherwise make the coating unstable thus rendering th e surface modification unacceptable. This research was devoted to metal alkoxide surf ace treatments that may enhance the adhesion and stability of coatings on metallic substrates. The two main objectives of this research were to develop new metal alkoxide treatment s using trivalent chro mium metal alkoxides for enhancing stability of subsequently a pplied polymeric coatings produced by gamma irradiation. Metal Alkoxide Treatments Silane coupling agents have been used extensively for applications such as aminosilanes used in the fiberglass indus try, acryloxypropyltrimethoxysilanes used in

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22 optical fiber coatings, and tetraethoxysilane in sol-gel processes for forming ceramic coatings and materials. The treatment process often requires several steps to complete, in addition to the procedures associated with the specific coating technology. Silane coupling systems often include a priming step in which agents such as bis[3(triethoxysilyl)propyl]-tetrasulfide are appl ied metal surfaces. The agent is then hydrolyzed and converted to silanol. The c oupling treatment is completed by condensing a silane coupling agent such as divinyltetramet hyldisilazane to the pr etreated substrate. The functionalized substrate is often heat ed to promote further condensation and formation of stable covalent bonds and driv ing off the organic species. The resulting porous gel can be sintered, or heated, under vacuum to remove the hydrolyzed organic species, promote further condensation and incr ease density. The approach taken here utilizes metal alkoxides with hydrolysable allylic or ganic species. The process used in this research deviates from conventional solgel processes because it does not involve the sintering step. This deviation preserves the porosity of the gel and presence of the allyl organic species within the porous structure. The uns aturated functionality of the hydrolyzates, such as with acrylates and meth acrylates, is utilized to graft or enhance grafting of polymeric coating to inorgani c materials such as stainless steel. Medical grade 316L stainless steel develops a corrosion-inhibiting Cr2O3 coating of approximately 2 nm thick when the material is electropolished. The treatment of the protective layer by a chromium coupling syst em using new trival ent chromium based metal alkoxides binding agents to enhance th e binding and stability of coatings is explored. Newer metal alkoxides such as chromium (III) methacrylates or chromium (III) fatty acids are used to f unctionalize surfaces by a simple solution dipping process.

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23 Research aimed at development of chromium priming as an approach to improving various subsequent surface m odifications is reported here. Materials and Methods Preparation of 316L stainless steel substrates Substrates of 316L stainless steel (1 cm x 1 cm) were cut from a single stock of foil that had a thickness of approximately 0.1 mm Substrate surfaces were cleaned by sequential sonication for 5 minutes at 47 KHz at room temperature in 30 mL each of 1,1,1-trichloroethane, chloroform, acetone, methanol, and Ultrapure water then dried under vacuum at 60C. Fifty substrates were cleaned at a time. Substrates were not electropolished. Treating 316L stainless st eel with metal alkoxides Clean substrates were placed in 25 mL a queous solutions of 2%, 10% or 100% v/v chromium III fatty acid (Quilon L, DuPont) for 1 single dip, 10 minutes rotating or 60 minutes while rotating. Ten substrates were treated for every 25 mL solution. Treated substrates were removed from solutions and allowed to either air dry or rinsed with Ultrapure water, then dried in air at room temperature. S ilver acrylate (Gelest, Inc.) treatments were also explored. Silver ac rylate was purchased in powder form and the chemical structure is given in Figure 3.1. Three silver acryl ate treatment solutions were prepared in volumes of 25 mL with 2% w/v concentrations in isopropanol, acetone or a mixture similar in formulation to Volan L, see Table 3.1. O O Ag+ Figure 3.1 Silver Acrylate (Geles t, Inc., Morrisville, PA).

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24 Table 3.1 Volan L solution and Silver Acrylate mixed solvent solution composition. Ingredient Volan L Silver Acrylate Complex, % (active ingredient) 17-18 17-18 % Isopropanol 56 56 % Acetone 10 10 % Water 16 16 Chromium alkoxide degradation study Chromium complex degradation was studi ed to compare freshly opened stock solutions and solutions that had aged for appr oximately 12 months since their first use. The solutions studied were chromium III fatty acid (Quilon L, DuPont) and chromium III methacrylate (Volan and Volan L, DuPont) at concentra tions of 2% and 10% v/v solutions where 25 mL of each solution was prepared for treating 10 stainless steel substrates each. Cleaned subs trates were placed in the solutions for 10 minutes while rotating, then removed and allowed to air dry. Controls in all cases consisted of untreated 316L stainless steel specimens that were cleaned as previously described. Analysis Treatments were analyzed by x-ray photoelectron spectroscopy (XPS/ESCA) analysis using a Kratos Analytical Su rface Analyzer XSAM 800. Analysis was performed using Mg and Al anodes for excitation. Survey scans were taken in low resolution with a dwell time of 150, 10 sweeps, and step size of 0.5 in FRR mode with both Al and Mg anodes. Elemental scans were taken in medium resolution with a dwell time of 60, 20 sweeps, and step size of 0.05 in FRR mode with only Al anode. Results and Discussion The Quilon L, Volan and Volan L manufacturer, Dupont, suggests the optimal treating solution concen tration for all substrate materi als is 2% v/v with water and

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25 buffered to pH = 7.0, a solution concentration optimization study was done to verify the this. It is important to point out that previ ous work in this laboratory by Dr. D. Urbaniak indicated that it is not n ecessary to buffer the metal alkoxide bonding agent solutions prior to application. This work showed th at surface treatment with buffered solutions often resulted in uneven chrome comple x deposition when examined by scanning electron microscopy (SEM), while buffered solutions yielded even, homogeneous surface treatments that were suitable for subs equent surface modification procedures.55 For chromium alkoxide treatment optimization, XPS was used to examine surface concentrations of C1s, O1s, Fe2p3, Cr2p3, a nd Cl2p peaks on treated 316L stainless steel substrates. The C1s peak was examined for pol y(ethylene terephthalate ), a material used as an internal C1s and O1s reference. The theoretical relative c oncentrations of carbon and oxygen atoms are 71.4% and 28.6%, respectiv ely. The experimental results were 73.1% C1s and 26.9% O1s, see Figure 3.3 for the survey scan. The difference was small and could be attributed to low molecula r weight carbon deposition during the 24 hour vacuum cycle. The primary C1s peak co rresponding to C-C bonding should be around 284.6 eV, but our analysis of PET yielded a primary C1s peak at 281.7 eV. This 3 eV shift to lower binding energy s hould be considered when examining all XPS data in this work. The raw XPS data are reported here without any post-processing such as signal normalization or shifting.

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26 Figure 3.2 XPS survey of PET. It is significant that as the metal al koxides are deposited from the solution the chromium moiety will bind to the chromium oxide on the surface of the substrate causing the methacrylate or fatty acid chains to be oriented away from the substrate. This orientation becomes important when discussi ng relative elemental concentrations since XPS has a surface sensitivity of 2-20 atomic layers.56 For example, if the fatty acid chain is 18 carbons long and even folded on itself, the carbon signal detect ed by XPS would be much more efficient than th e surface chromium, iron, etc. Elemental analysis of Quilon L treated substrates yielded no significant difference in peak location or surface concen trations for the C1s and Cl2p peaks of 2% and 10% v/v treating solutions for single dip, 10 minutes and 60 minutes tumble washing. This was true for air dry and rinse, then air dry conditions. There appeared to be no advantage in rinsing the treated substrates before drying. Additionally, increased Cl2p was observed for 10% v/v treating solutions that were rinsed a nd then air dried.

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27 Substrates treated with 10% v/v solutions appeared to be spotty, while 100% v/v treatments resulted in scaly surfaces that easily peeled away from the substrate. This was not observed for any 2% v/v solution treated substrates. The relative iron content was lowest with the 100% v/v treatments, which wa s an expected outcome since the treatment is much denser. As listed in Table 3.2, the relative surface chromium content increased for all conditions when compared with untreated 316L stainless steel, which corresponded with the binding of chromium base d metal alkoxides to the surface. Lastly, all conditions resulted in an increase in the C1s surface concentration, which corresponds to the fatty acid groups of Quilon L, suggesting that the ch rome complex was deposited during treatment. Table 3.2 XPS analysis for air dried sa mples without rinsing: % Cr2p3 and % C1s relative to % O1s, Fe2p3 and Cl2p. All conditions were examined on 316L stainless steel. Condition % Cr2p3 % C1s Untreated 316L SS, Control 1.8 48.8 2 % Quilon L, Single Dip 2.7 68.5 2 % Quilon L, 10 Min 3.7 64.1 2 % Quilon L, 60 Min 3.1 68.5 10 % Quilon L, Single Dip 2.4 67.3 10 % Quilon L, 10 Min 2.5 67.3 10 % Quilon L, 60 Min 2.6 69.5 100 % Quilon L, Single Dip 1.6 82.1 100 % Quilon L, 10 Min 2.0 75.5 100 % Quilon L, 60 Min 3.3 63.7 The use of silver acrylate was investigated to examine the feasibility of using other allyl metal alkoxide systems and was of pa rticular interest because of potential antimicrobial properties that may arise from th e silver moiety. Sin ce silver acrylate is only available in powder form, attempts were made to develop a treatment solution to functionalize stainless steel. A 50% isopropanol and 50% ace tone solution was used to

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28 dissolve the metal alkoxide. The result was a 2% w/v solution. Next, acetone was used to dissolve the silver acrylate resulting in a 2% w/v solution. Finally, a solution was prepared similar to that of Volan L for the silver acrylate treating soluti on. All three treatment groups were analyzed by XPS and elemental analysis focused on C1s, O1s, Fe2p3, Cr2p3 and Ag3d5. The isopropa nol/acetone/water (like Volan L) solution yielded the highest surface concentration of Ag3d5 at 3.5% compared with 0.9%, which was the same for both the isopropanol/acetone and acetone solutions, see Figure 3.3. The antimicrobial aspect of this treatment will be further analyzed in Chapter 6. AG3D5 1 x 10 3 50 60 70 80 90 100 110CPS 385 380 375 370 365 360 355 350 Binding Energy (eV) Figure 3.3 XPS spectra of Ag3d5 of silver acrylate treatment on 316L stainless steel. Fourier Transform Infrared-Attenuated To tal Reflectance (FTIR-ATR) analysis was attempted, but no signal was achieved due to surface concentrations of the chrome complex being below the detectable limit of the instrument. The same was true for silver acrylate treated substrates. Chromium alkoxide priming solution stabilit y over time was investigated. Dupont suggests that these stock solutions remain highl y stable over time. The stability of stock solutions was investigated by comparing th e C1s and O1s oxidative states of surfaces

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29 treated with freshly opened stock solutions a nd solutions that had aged for approximately 12 months since their first use. Evidence of oxidative degradation was seen as stock solutions of Quilon L aged as shown by the shift to higher binding energies for both the O1s and C1s peaks corresponding to an increas e in concentration of -C=O bonding when there should be an increase d concentration of C-C corres ponding to the complexed long aliphatic chains. The spectra are shown in Figure 3.4. Another interesting observation was a solution color change from dark green to dark blue-teal further supporting chemical changes in the priming solution 12 months afte r first use. For chromium (III) fatty acid coupling agent used in this study exhibite d a change in surface composition of the functionalized stainless steel surfaces compar ed with untreated st ainless steel when analyzed by XPS. The changes in peak location and color were not observed for Volan or Volan L, see Figure 3.5. There was a 4 eV shift to hi gher binding energies seen for the C1s peak for Volan L treatments when compared with Quilon L, suggesting a greater quantity of surface carbon associated with the vinyl functionality of the methacrylate group. However, C1s in 316L stainless steel was obser ved to be at similar binding energies to Volan and Volan L treatment groups, which was highe r than expected. The expected binding energy for C1s on 316L stainless stee l was at a lower energy, closer to the primary C1s peak from the PET reference at 281.7 eV. XPS indicated that Volan L surface functionalized st ainless steel had 0% chlorine content, which was lowest when compared with other treatments used in this study. This is a favorable outcome since chlorine ions have been associat ed with stainless steel corrosion.

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30 A1 A2 B2 B1 C1 C2 A1 A1 A2 A2 B2 B2 B1 B1 C1 C1 C2 C2 Figure 3.4 XPS C1s and O1s spectra of : A) Previously-opened 2% Quilon L treatment on 316 L stainless steel, B) Newly-opened 2% Quilon L treatment on 316 L stainless steel, and C) 316L stainless steel control.

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31 B2 B2 A1 A1 A2 A2 B1 B1 C1 C1 C2 C2 Figure 3.5 XPS C1s and O1s spectra of : A) Previously-opened 2% Volan treatment on 316 L stainless steel, B) Newly-opened 2% Volan treatment on 316 L stainless steel, and C) 316L stainless steel control. Summary The results of the optimization stud y suggests a 2% v/v treating solution concentration is sufficient for priming the su rface and exhibits reduc ed chlorine content at the stainless steel surfa ce compared with 10% and 100% v/v concentrations. Rinsing the treated samples prior to drying in air was di d not seem to effect to treatment outcome. As expected, using the solutions without furthe r dilutions (100%) result ed in surfaces that were discolored and flaky. Although the tr eatments were not flaky, 10% v/v treatments were also discolored and a ppeared spotty. From this study, the best treatment was

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32 determined to be 2% v/v solutions with 10 mi nute tumble washes and dried in air without rinsing, similar to the manufacturers suggestion. Silver acrylate seemed to deposit the most silver complex in mixtures similar in composition to Volan L. These studies will be inves tigated further in later chapters. Based on XPS data, degradation seems to only effect the Quilon L treatment solutions even though solutions were backfille d with argon gas after each use. Volan and Volan L did not exhibit any binding energy shifts when comparing previouslyopened to newly-opened stock solutions. An interesting observation was that Volan L treated substrates had lower chlorine su rface concentrations than other chromium alkoxide treatments. Existing transition metals prevalent on the su rface of a substrate can be used with metal alkoxides of the same transitions meta ls to enhance the binding and stability of coatings. This can easily reduced the numbe r of steps associated with functionalizing 316L stainless steel. Low Dose Gamma Irradiation Grafting of Polymers to Metal Alkoxide Treated Substrates Gamma irradiation has been used to surface modify polymers by initiating polymerizations that result in grafting onto a material.55, 57 Grafting by high energy radiation most often involves radical excitation of substr ates and monomers. Gamma radiation is deeply penetrati ng, unlike other forms of high energy ionizing radiation such as electron beam accelerators. As a conseque nce, the effects of gamma irradiation are less dependent on substrate orientation and resu lt in more uniform treatments to complex geometries.

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33 Gamma radiation generates reactive sites in the monomer solu tion, as well as on the substrate. This is a unique advantage of radiation grafting with gamma irradiation in that fewer steps may be required to functiona lize a substrate and to generate radicals at the surface compared with other techniques. Using this surface modification technique in conjunction with surfaces that have been functionalized by metal alkoxide treatments may enhance the adhesion and stability of me tal surface modifications. Grafting can be achieved by polymer growth from tethered functional groups. Gamma irradiation also lends itself to medical device modification since gamma radiation is often used for st erilization; although usually at significantly higher doses of ~2.5 MRads. No chemical or UV initiator s are necessary, making gamma irradiation a relatively clean procedure without initiator re sidues. In this la boratory, low dose gamma irradiation (< 0.25 MRads total dose) has been shown to be effective for surface modification of a wide variety of substrate materials without inducing radiation damage to substrates. Reported here is the radiat ion grafting of hydrophilic polymers on stainless steel which has been surf ace treated with chromium alkoxide bonding agents. The resulting hydrophilic polymer surfaces were highly adherent and stable, as well as lubricious to the touch. Materials and Methods Preparation and treatment of 316 L stainless steel substrates Substrates of 316L stainless steel (1 cm x 1 cm) were cut from a single stock of foil with thicknesses of approximately 0.1 mm Substrate surfaces were cleaned by sequential sonication for 5 minutes at 47 KHz and room temperature in 30 mL each of 1,1,1-trichloroethane, chloroform, acetone, methanol, and Ultrapure water then dried

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34 under vacuum at 60C. Fifty substrates were cl eaned at a time. Stai nless steel substrates were not electropolished. For chromium alkoxide treatment, clean subs trates were placed in 25 mL aqueous solutions of 2% v/v chromium III fatty acid (Quilon L, DuPont) or chromium III methacrylate (Volan and Volan L, DuPont) for 10 minutes while rotating. 25 mL solutions were used to treat 10 samples at a time. Treated substrates were removed from solutions and allowed to air dry. Controls consisted of untreated 316L st ainless steel that undergoes irradiation treatment in monomer solutions and substr ates that received no treatment and no irradiation with monomer solutions. Preparation of monomer solutions Monomer stock solutions of 10% v/v con centration with Ultrapure water were prepared for all gamma irradiated experime nts. The monomers investigated were 2methacryloyloxyethyl phosphorylcholine (MPC; Dr. Ishihara, University of Tokyo), Nvinyl-2-pyrrolidone (NVP; Polysciences, Inc), n,n-dimethylacrylamide (DMA; Polysciences, Inc.), potassium 3-sulfopropyl acrylate (KSPA; Raschi g GmbH). The comonomer systems consisted of 9.5% monome r and 0.5% DMA with Ultrapure water, where the monomer was MPC, NVP, or KSPA. Gamma irradiation of substrates 316L stainless steel substrat es were transferred to te st tubes containing 3 mL aqueous solutions of either 10% v/v monomers with Ultrapure water or 9.5% monomer and 0.5% DMA with Ultrapure water. Th e solutions were de gassed using vacuum generated by a mechanical pump, and subseque ntly backfilled with argon gas. The specimens were capped, placed in a 60Co gamma irradiator and exposed to total doses of

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35 0.1 or 0.15 Mrads at dose rates in the range of 569 536 rads/min. As shown in Figure 3.6, a rotating sample stage was used to account for uneven doses that may be caused by the asymmetrical shape of the gamma source. After irradiation, samples were placed into new test tubes and tumble washed for one w eek with 5 mL of Ultr apure water, which was decanted and replaced with 5 mL three times. Figure 3.6 60Co gamma irradiator and rotating sample stage. Analysis Surface modified 316L stainless steel subs trates were characterized by captive air bubble contact angle with a Ram-Hart A-100 goniometer, by scanning electron microscopy with a JEOL 6400 SEM, by fourier-tr ansform infrared (FTIR) with a Nicolet Magna 706 (ZnSe crystal, 45) and by x-ra y photoelectron spectroscopy (XPS) analysis with Kratos Analytical Surface Analyzer XSAM 800 under the same conditions as previously described in the first portion of this chapter. SEM analysis was conducted with a working distance of 15 mm, 5 kV and condenser setting was at 10 with units in 6 x 10-6 Amps. The stability of grafted polymer coatings was evaluated by measuring contact

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36 angles after initial hydration following irradi ation and washing with Ultrapure water, dehydration in vacuum, and th en again after rehydration. Results and Discussion Contact angle measurements for untreated substrates that underwent radiation grafting in monomer and co-monomer solutions yielded contact angles in the range of 22 40. With the exception of hydrophobic recovery of the most hydrophilic surfaces, there was little difference in contact angle ch anges when tested for stability. This is illustrated graphically in Figures 3.7 3.13. Af ter irradiation, DMA graft solutions were very viscous and to some extent stretchy. The substrates used in the DMA-only grafts were extremely difficult to remove from the crosslinked DMA surrounding them. For this reason DMA data was not included in all studies. These very hi gh viscosities did not occur for co-monomer solutions with DMA. Contact AngleNVP Untreated 316L SS34 40 43 46 4040 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) NVP-Initial NVP-Dehydrated NVP-Rehydrated 316L SS Control Figure 3.7 Contact angle stability of untreated 316L stainles s steel irradiated to 0.1 and 0.15 Mrads in 10% NVP / Ultrapure water solutions.

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37 Contact AngleMPC Untreated 316L SS27 28 33 28 40 42 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) MPC-Initial MPC-Dehydrated MPC-Rehydrated 316L SS Control Figure 3.8 Contact angle stability of untreated 316L stainles s steel irradiated to 0.1 and 0.15 Mrads in 10% MPC / Ultrapure water solutions. Contact AngleDMA Untreated 316L SS28 32 31 30 33 28 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRad)Contact Angle (Degrees) DMA-Initial DMA-Dehydrated DMA-Rehydrated 316L SS Control Figure 3.9 Contact angle stability of untreated 316L stainles s steel irradiated to 0.1 and 0.15 Mrads in 2.5% DMA / Ultrapure water solutions.

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38 Contact AngleKSPA Untreated 316L SS31 29 32 25 3434 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) KSPA-Initial KSPA-Dehydrated KSPA-Rehydrated 316L SS Control Figure 3.10 Contact angle stabil ity of untreated 316L stainl ess steel irradiated to 0.1 and 0.15 Mrads in 10% KSPA / Ultrapure water solutions. Contact AngleNVP/DMA Untreated 316L SS27 31 25 43 33 36 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) NVP/DMA-Initial NVP/DMA-Dehydrated NVP/DMA-Rehydrated 316L SS Control Figure 3.11 Contact angle stabil ity of untreated 316L stainl ess steel irradiated to 0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DMA / Ultrapure water solutions.

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39 Contact AngleMPC/DMA Untreated 316L SS23 22 36 38 28 33 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) MPC/DMA-Initial MPC/DMA-Dehydrated MPC/DMA-Rehydrated 316L SS Control Figure 3.12 Contact angle stabil ity of untreated 316L stainl ess steel irradiated to 0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DMA / Ultrapure water solutions. Contact AngleKSPA/DMA Untreated 316L SS28 32 43 44 38 31 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) KSPA/DMA-Initial KSPA/DMA-Dehydrated KSPA/DMA-Rehydrated 316L SS Control Figure 3.13 Contact angle stabil ity of untreated 316L stainl ess steel irradiated to 0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DM A / Ultrapure water solutions. Contact angle results varied for NVP, KSPA and respective co-monomer grafting solutions with DMA on metal alkoxide f unctionalized substrates. With Quilon L no significant change in contact angle was found compared with untreated 316L stainless steel irradiated in the same monomer solutions. Volan treatment result in contact angles of ~20 for all NVP and KSPA grafting so lutions with no hydrophobic recovery. This

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40 stability was not observed for co-mon omer systems where there was hydrophobic recovery for some conditions. Volan L consistently reduced th e contact angles to ~20 for NVP and KSPA grafts. Additionally, contac t angles as low as 18 were found for comonomer systems with no hydrophobic recovery. Hydrophilicity of these coatings was stable. This data is shown in Figures 3.14 3.25. Contact AngleNVP QuilonL Treated 316L SS50 41 35 39 39 42 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) NVP-Initial NVP-Dehydrated NVP-Rehydrated 316L SS Control Figure 3.14 Contact angl e stability of Quilon L treated 316L stainl ess steel irradiated to 0.1 and 0.15 Mrads in 10% NVP / Ultrapure water solutions. Contact AngleKSPA QuilonL Treated 316L SS39 48 26 45 51 32 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) KSPA-Initial KSPA-Dehydrated KSPA-Rehydrated 316L SS Control Figure 3.15 Contact angl e stability of Quilon L treated 316L stainl ess steel irradiated to 0.1 and 0.15 Mrads in 10% KSPA / Ultrapure water solutions.

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41 Contact AngleNVP/DMA QuilonL Treated 316L SS36 34 20 34 24 26 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) NVP/DMA-Initial NVP/DMA-Dehydrated NVP/DMA-Rehydrated 316L SS Control Figure 3.16 Contact angle stabil ity of Quilon L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DMA / Ultrapure water solutions. Contact AngleKSPA/DMA QuilonL Treated 316L SS28 49 26 22 30 42 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) KSPA/DMA-Initial KSPA/DMA-Dehydrated KSPA/DMA-Rehydrated 316L SS Control Figure 3.17 Contact angl e stability of Quilon L treated 316L stainl ess steel irradiated to 0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / Ultrapure water solutions.

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42 Contact AngleNVP Volan Treated 316L SS2121 22 32 20 19 0 10 20 30 40 50 60 70 0.10.15 Dose (MRads)Contact Angle (Degrees) NVP-Initial NVP-Dehydrated NVP-Rehydrated Figure 3.18 Contact angl e stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% NVP / U ltrapure water solutions. Contact AngleKSPA Volan Treated 316L SS32 34 36 45 20 17 0 10 20 30 40 50 60 70 0.10.15 Dose (MRads)Contact Angle (Degrees) KSPA-Initial KSPA-Dehydrated KSPA-Rehydrated Figure 3.19 Contact angl e stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% KSPA / Ultrapure water solutions.

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43 Contact AngleNVP/DMA Volan Treated 316L SS20 21 32 37 30 34 0 10 20 30 40 50 60 70 0.10.15 Dose (MRads)Contact Angle (Degrees) NVP/DMA-Initial NVP/DMA-Dehydrated NVP/DMA-Rehydrated Figure 3.20 Contact angl e stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DMA / Ultrapure water solutions. Contact AngleKSPA/DMA Volan Treated 316L SS18 19 31 39 20 29 0 10 20 30 40 50 60 70 0.10.15 Dose (MRads)Contact Angle (Degrees) KSPA/DMA-Initial KSPA/DMA-Dehydrated KSPA/DMA-Rehydrated Figure 3.21 Contact angl e stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / Ultrapure water solutions.

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44 Contact AngleNVP VolanL Treated 316L SS1818 22 23 2222 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) NVP-Initial NVP-Dehydrated NVP-Rehydrated 316L SS Control Figure 3.22 Contact angl e stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% NVP / U ltrapure water solutions. Contact AngleKSPA VolanL Treated 316L SS1717 28 33 20 21 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) KSPA-Initial KSPA-Dehydrated KSPA-Rehydrated 316L SS Control Figure 3.23 Contact angl e stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% KSPA / Ultrapure water solutions.

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45 Contact AngleNVP/DMA VolanL Treated 316L SS1818 2222 20 19 0 10 20 30 40 50 60 70 0.10.15 Dose (MRads)Contact Angle (Degrees) NVP/DMA-Initial NVP/DMA-Dehydrated NVP/DMA-Rehydrated Figure 3.24 Contact angl e stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DMA / Ultrapure water solutions. Contact AngleKSPA/DMA VolanL Treated 316L SS17 18 28 33 24 25 0 10 20 30 40 50 60 70 0.10.15 Dose (MRads)Contact Angle (Degrees) KSPA/DMA-Initial KSPA/DMA-Dehydrated KSPA/DMA-Rehydrated Figure 3.25 Contact angl e stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / Ultrapure water solutions. Contact angle measurements of MPC co atings on metal alkoxide functionalized surfaces were significantly lower than both 316L stainless steel and MPC coated stainless steel with no pre-treatmen t; see Figures 3.26 3.31 and Ta ble 3.3. These results were observed for all MPC and metal alkoxide treatme nt combinations explored in this study. Additionally, MPC and MPC/DMA coated func tionalized substrates were similarly

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46 hydrophilic. After dehydration, MPC and MPC/DMA coatings on functionalized stainless steel exhibited similar hydrophilic ity with no evidence of hydrophobic recovery as well as very little hydration time. Contact AngleMPC QuilonL Treated 316L SS22 20 21 20 1919 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) MPC-Initial MPC-Dehydrated MPC-Rehydrated 316L SS Control Figure 3.26 Contact angl e stability of Quilon L treated 316L stainl ess steel irradiated to 0.1 and 0.15 Mrads in 10% MPC / Ultrapure water solutions. Contact AngleMPC/DMA QuilonL Treated 316L SS21 20 2121 18 17 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) MPC/DMA-Initial MPC/DMA-Dehydrated MPC/DMA-Rehydrated 316L SS Control Figure 3.27 Contact angl e stability of Quilon L treated 316L stainl ess steel irradiated to 0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DMA / Ultrapure water solutions.

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47 Contact AngleMPC Volan Treated 316L SS18 19 18 17 1919 0 10 20 30 40 50 60 70 0.10.15 Dose (MRads)Contact Angle (Degrees) MPC-Initial MPC-Dehydrated MPC-Rehydrated Figure 3.28 Contact angl e stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% MPC / U ltrapure water solutions. Contact AngleMPC/DMA Volan Treated 316L SS19 18 1818 1818 0 10 20 30 40 50 60 70 0.10.15 Dose (MRads)Contact Angle (Degrees) MPC/DMA-Initial MPC/DMA-Dehydrated MPC/DMA-Rehydrated Figure 3.29 Contact angl e stability of Volan treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DMA / Ultrapure water solutions.

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48 Contact AngleMPC VolanL Treated 316L SS17 19 18 19 18 21 50 0 10 20 30 40 50 60 70 00.10.15 Dose (MRads)Contact Angle (Degrees) MPC-Initial MPC-Dehydrated MPC-Rehydrated 316L SS Control Figure 3.30 Contact angl e stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 10% MPC / U ltrapure water solutions. Contact AngleMPC/DMA VolanL Treated 316L SS18 19 1818 1818 0 10 20 30 40 50 60 70 0.10.15 Dose (MRads)Contact Angle (Degrees) MPC/DMA-Initial MPC/DMA-Dehydrated MPC/DMA-Rehydrated Figure 3.31 Contact angl e stability of Volan L treated 316L stainless steel irradiated to 0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DMA / Ultrapure water solutions. As shown by XPS analysis, NVP coatings on Volan L treated stainless steel specimens exhibited the highest N1 s concentrations, where as Quilon L treatments yielded the lowest N1s concentrations as shown in Table 3.4. Additionally, chromium (III) methacrylate pretreatment s resulted in stable hydrophilic surfaces. The P2p and N1s from MPC coated surfaces were analyzed and exhibited a ratio closes t to 1:1 when coated

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49 on Volan L treated stainless steel. These data are summarized in Table 3.3 and Figure 3.32. All MPC coatings on metal alkoxide tr eated substrates resulted in hydrophilic surfaces. Table 3.3 MPC XPS elemental surface com position (%) and rehydrated contact angle of surfaces for dose of 0.1 Mrads. MPC* refers to theoretical concentrations of elemental composition. Treatment C1s O1s N1s P2p Fe2p3 Cr2p3 P2p/N1s Contact Angle () 316L Control 48.2 42.3 < 0.1 0.0 7.9 1.2 0.0 50 None/MPC 42.5 36.6 4.3 1.1 7.5 7.8 0.3 42 QuilonL/MPC 55.0 33.6 3.6 2. 2 2.0 3.6 0.6 19 Volan/MPC 46.0 37.7 4.8 2.8 4.3 4.5 0.6 19 VolanL/MPC 45.6 39.1 4.6 4.0 3.3 3.5 0.9 18 MPC* 57.8 31.6 5.3 5.3 0.0 0.0 1.0 Table 3.4 NVP XPS elemental surface compos ition (%) and rehydrated contact angle of surfaces for dose of 0.1 Mrads. NVP* refe rs to theoretical concentrations of elemental composition. Treatment C1s O1s N1s Fe2p3Cr2p3Cl2p Contact Angle () 316L Control 48.2 42.3 < 0.17.9 1.2 0.0 50 None/NVP 62.5 27.4 3.7 1.9 3.3 1.3 40 QuilonL/NVP 75.6 19.3 2.2 0.3 1.5 1.0 39 Volan/NVP 67.1 23.9 4.0 0.9 2.6 1.6 20 VolanL/NVP 64.6 26.2 5.6 1.5 2.0 0.1 22 NVP* 75 12.5 12.5 0.0 0.0 0.0

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50 C1 C1 C2 C2 B2 B2 B1 B1 A1 A1 A2 A2 Figure 3.32 MPC grafted on trea ted and untreated 316L SS. XPS elemental spectra for N1s and P2p. A) 2% Volan L treated, B) 2% Quilon L treated, and C) untreated. As shown in Table 3.5, XPS analysis of KSPA treatments show ed there was little to no signal from potassium ions. This could be due to dissociation of the potassium salt from sulfopropyl acrylate. This is likely to happen during the irra diation process due to the presence of the electron withdrawing sulfopropyl head which can facilitate dissociation in an irradiated environment. With KSPA, stable hydrophilic surfaces were produced with Volan and Volan L treated substrates.

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51 Table 3.5 KSPA XPS elemen tal surface composition (%) a nd rehydrated contact angle of surfaces for dose of 0.1 Mrads. KSPA* refers to theoretical concentrations of elemental composition. Treatment C1s O1s N1s Fe2p3 Cr2p3K2p3 S2p3 Cl2p Contact Angle () 316L Control 48.2 42.3 < 0.1 7. 9 1.2 0.0 0.0 0.0 50 None/KSPA 56.5 34.4 0.0 2.8 4.4 0.0 3.9 0.0 34 QuilonL/ KSPA 76.7 20.5 0.0 0.4 1.3 0.0 1.1 0.0 32 Volan/KSPA 62.3 31.8 0.0 1.4 3.1 0.0 1.4 0.0 20 VolanL/ KSPA 57.7 33.8 0.0 1.0 5.8 0.0 1.8 0.0 20 KSPA* 46.1 38.5 0.0 0.0 0.0 7.7 7.7 0.0 Figure 3.33 SEM of cleaned 316L stainless steel at 5000x.

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52 Figure 3.34 SEM of 10% v/v MPC gamma irra diation grafted (0.1 MRads) coating on Volan L activated 316L stainless steel at 5000x. From Tables 3.3 3.5, Fe2p3 and Cr2p3 peak s were present even for the most hydrophilic conditions. This sugge sts that coatings are eith er very thin or are not homogeneously coated on the substrate, whic h could be the result of uneven chromium alkoxide binding. SEM micrographs confirme d surface modifications were very thin since much of the 316L topography was dis cernable in all micrographs of gamma irradiation grafted coatings as shown in Fi gures 3.33-34. Based on XPS analysis, surface modifications is likely to be ~2 20 atomic layers in depth. SEM micrographs did not show any evidence of corrosion for gamma irradiated modifications. Summary The results of this study indicate that chromium f unctionalized stainless steel surfaces on which hydrophilic vinyl functional monomers were polymerized results in coatings with improved stability and increase d hydrophilicity in contrast to non-surface functionalized stainless steel.

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53 It should be noted that the stainless steel used in this study had a surface composition somewhat lower in Cr2O3 content than electropolis hed stainless steel which is most often used for endovascular stents. Because the stainless steel used in these and subsequent studies were not electropolis hed, surface elemental compositions will be different from reported values for electropolis hed 316L stainless steel. Also, decreased surface roughness may result from electropolishing. Due to increased surface chromium concentrations as a result of electropolis hing, increase bonding agen t concentrations may result when treating these specimens, which could result in further improved coating stability. Volan L, which resulted in the lowest chlo rine surface content, is an ideal metal alkoxide for functionalizing 316L stainless steel surfaces, since chlorine ions have been associated with pitting corro sion on stainless steels. Evid ence of corrosion was not seen in SEM micrographs for any of the conditions investigated in this study. Due to highly efficient crosslinking, DMA was satisfactory as a co-monomer component. However, no significant advantage was seen for using the co-monomer compared to NVP, MPC and KSPA monomer formulations used here. Stable hydrophilic coatings were prepared by gamma irradiation of monomer solutions on chromium alkoxide functionalized 31 6L stainless steel. MPC coatings on all chromium alkoxide treated substrates resu lted in stable hydr ophilic surfaces. Additionally, Volan and Volan L treatments consistently produced stable hydrophilic surfaces with all monomer and co-monomer systems investigated. Quilon L, which is a trivalent chromium fatty acid, only produced stable hydrophilic coa tings with MPC and MPC/DMA formulations. Overall, stainle ss steel surface modification was enhanced by

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54 the use of the chromium alkoxi de bonding agents and has been shown to be of value to enhance adhesion of polymer coatings to me tallic medical devices such as endovascular stents or keratome blades.

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55 CHAPTER 4 PULSED LASER ABLATION DEPOSI TION (PLAD) AND RF PLASMA POLYMERIZATION DEPOSITION Introduction As discussed is Chapter 3, high energy ioni zing radiation has been used for surface modifying various materials under normal ambient conditions of temperature and pressure with the advantages of substrate geom etry flexibility and absence of chemical or UV initiators for clean modifications. Su rface modifications involving high energy sources and which employ vacuum conditions ca n be used to enhan ce surface binding by ablation etching and deposition. Two examples of such systems are radio frequency glow discharge plasmas (RF plasma), and pulse laser ablation deposition (PLAD). For both, sample orientation can affect coating uniformity as a result of the dir ectional nature of the depositions. This chapter discusses research aimed at exploring the potentially unique effectiveness of trivalent chromium metal al koxide treatments for enhancing the stability of RF plasma and PLAD surface modi fications on 316L stainless steel. Pulsed Laser Ablation Deposition (PLAD) Pulsed laser ablation deposition (PLAD) modification has been reported for many polymers and semiconductor materials. For ex ample, PLAD has been used for modifying fiber surface properties and curing the resin material.58 Of particular, PLAD offers a solvent free method for polymer ization and surface modification.

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56 Coating stainless steel with polymers by pulsed laser ablation/deposition (PLAD) for medical devices is a relatively new concep t. We have pioneered the use of PLAD for the deposition of cross-linked polymer thin films in this laboratory.59 In that research, PLAD was shown to be a feasible technique for coating medical implants.59-61 Following the work of Rau et al, si licone elastomer targets were ablated with a pulsed 248 nm KrF excimer laser to form silicone plasma and deposited onto the substrate. Previous research with silica filled silicone indi cated increasing surface hydrophilicity of PLAD deposits w ith increasing fluence (mJ/cm2, energy density), especially above a fluence of 200 mJ/cm2.60 Furthermore, Rau et al observed that smooth low fluence depositions resulted in hydrophobi c surfaces similar to that of the target material. Whereas, higher fluences deposited somewhat granular surfaces that were hydrophilic. These experiments were conducte d in vacuum environments with higher oxygen contents than the studies presented here. Pulsed laser ablation deposition is carried ou t at vacuum pressures at most of 1 Torr with a target mounted on a rotating base. Th e substrate to be coated is mounted on a stationary fixture. The target absorbs phot ons emitted from a UV laser source at 248 nm. Atoms at the target surface rise to an electr onically excited state. Due to various degrees of excitation, bond rupture and ionization occurs various species from the target material are emitted forming a plume consisting of the excited ionic and radical fragments. This plume of excited species contac ts the substrate, which is positioned as illustrated in Figure 4.1. As the excited plume species cont act the substrate, r ecombination reactions occur with the silicone species and the substr ate. The degree to which the coatings are mechanically and chemically bound to the substrate remain unclear.60

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57 Figure 4.1 Illustration of PLAD system setup.60 In the research reported here, we extende d the initial work of Rau et al and investigated PLAD deposition us ing a biomedical grade poly (dimethylsiloxane), PDMS, containing a nanostructured resin filler (N usil, MED 6820 A, B). Additionally, these investigations were carried out in a vacuum environment that was more oxygen free than the previous studies. The interesting and different results are reported here. Materials and Methods Preparation of silicone targets and substrates PDMS targets were made from a two part resin system (Nusil, MED 6820 A, B and MED 6210 A, B), where MED 6820 silicone is an FDA approved materials for long-term implants beyond 90 days. 5 mL volumes of each resin component (A and B) were measured and placed into separate syringes. Both syringes were concurrently unloaded into a large container, such as a 600 mL Py rex beaker, and hand-mixed with a spatula. The beaker containing the uncured silicone was subsequently degassed by vacuum to allow entrapped air to escape the mixture. The uncured silicone mixture was determined to be sufficiently degassed when no visibl e bubbles were apparent. The mixture was

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58 removed from the vacuum environment and pour ed onto square acetate sheets that were placed on square glass plates (5 x 5) and degassed a second time, after which glass slides of 1mm thickness were placed on each of the four corners of the square acetate sheets. A second acetate sheet was placed on to p of the glass slides followed by another glass plate. The glass slides were slowly pus hed toward the center to remove trapped air and control the casting thickness. Finally, the mixture was cured at 60C for 12 hours resulting in cast silicone sh eets of 1 mm thicknesses. Plaques of 1 cm diameter were punched from the sheets and washed in methanol for 2 hours to clean the target surface. The washed plaques were dried under v acuum for 12 hours and mounted on 1 inch diameter aluminum stubs for use as targets. This procedure was used for the silicone formulations, MED 6820 and MED 6210. Silicon wafers and 316L stainless steel (1 cm x 1 cm x 0.1 mm) were used as substrates for all depositions. Silicon wafe rs were sequentially sonicated in acetone and methanol then dried under vacuum. Stainle ss steel substrates were cleaned by sequential sonication in 1,1,1-trichloroethane, chloro form, acetone, methanol, and Ultrapure water then dried under vacuum at 60C for 12 hours. 316L Stainless was used in two ways, untreated and trea ted with 2% v/v Volan, which is low chlorine chromium (III) methacrylate metal alkoxide. These procedur es are described in detail in Chapter 3. Pulsed laser ablation deposition chamber The PLAD system consisted of a vacuum chamber housing both the target and substrate, see Figure 4.1. To ensure uniform ablation, the target was rotated with a motor for every deposition. A KrF excimer laser (Lambda Physik 301x) operating at 248 nm with a pulse width of 25 ns was used in all experiments. The laser beam was directed into the chamber with a pair of plane mirrors and a collimating lens. A 250 mm lens

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59 focused the laser beam onto the target. With all depositions, a base pressure of at least 5.0 x10-5 mTorr was reached except where noted, after which the chamber was backfilled with helium until a pressure of 100 mTorr was achieved. The energy density (mJ/cm2, fluence) was controlle d by adjusting the energy constant of the laser and the focusing lens to get the desired spot size incident on the target. Fluence is calculated by multiplying the energy constant (mJ) with the measured attenuation error, which is then di vided by the measured spot size (cm2).Th energy constant is a value that is programmed into the operating system. The attenuation error corresponds to the amount of d ecreased laser energy due to th e lens sequence. Finally, the spot size is obtained by vi sually measuring the burned spot the laser leaves on thermal sensitive paper. The fluences used in th is investigation were in the range of 50-400 mJ/cm2. The laser operated at a repetition rate of 5 Hz. The deposition time was 30 minutes, thus the number of laser pulses for each deposition was 9000. Analysis Surfaces were characterized by captive air bubble and sessile drop methods with a Ram-Hart A-100 goniometer, scanning elec tron microscopy with a JEOL 6400 SEM, fourier-transform infrared (FTIR) with a Nicolet Magna 706 (ZnSe crystal, 45) and xray photoelectron spectroscopy (XPS) analysis with Kratos Analytical Surface Analyzer XSAM 800. The analysis conditions used are described in Chapter 3. Results and Discussion Contact angle data are shown in Table 4.1. In contrast to previous PLAD deposition of silica filled PDMS in a chamber containing higher concentrations of oxygen species60, the data here indicate th at higher fluences result in higher contact angles or decreasing hydrophilicity when resin filled silicone was deposited on untreated 316L

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60 stainless steel. Depositions on chromium (III) methacrylate treated 316L stainless steel resulted in contact angles of ~25 for fluences of 125 mJ/cm2. Compared to the hydrophobic depositions on untreat ed 316L stainless steel at fluences of 200 and 400 mJ/cm2, coatings on Volan treated 316L stainless steel swelled with water on contact distorting the topography of the deposition. Thus contact angles were not measurable for these conditions. This is a departure from previous studies conducted in our laboratory, since coating swelling with water has not pr eviously been observed for PLAD treatments. A difference from the earlier work is that in previous studies the chamber was evacuated to a base pressure of 30 mTorr, wh ereas the current studies used base pressures of at least 5.0 x10-5 mTorr, which results in depositions in a more oxygen free environment. In both studies, the chambe r was backfilled with helium to 100 mTorr. Contact angles for MED 6820 and MED 6210, whic h are different from the silica-filled silicones used by Rau et al, depositions on untre ated stainless steel using a base pressure of 30 mTorr was conducted to compare the tw o resin filled materials and verify the hydrophilic results of previously reported studies. The hydrophilicity of MED 6820 and MED 6210 depositions were similar to deposi tions by Rau et al, where contact angles were ~20 at fluences over 200 mJ/cm2. Table 4.1 Contact angle of MED 6820 deposi tions at various fl uences on untreated 316L stainless steel. Fluence (mJ/cm2) 50 75 100 125 200 300 400 Contact Angle 4050 1621 1621 >170>170>170>170 Analysis of nanosurface modified silic on and untreated 316L stainless steel by FTIR-ATR did not yield meas urable peaks for MED 6820 depositions on silicon wafers

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61 at 50-300 mJ/cm2. As illustrated in Figure 4.2, small peaks at 1260, 1215-930, and 900730 cm-1 corresponding to SiMex deformation, SiOSi asymmetric stretching (main chain), and Si(CH2)3 and Si(CH2)2 rocking (chain ends), were evident for depositions at 400 mJ/cm2 fluence on silicon wafer. Spectra for depositions on untreated 316L stainless steel did not result in any detectable peak s. FTIR-ATR of MED 6820 depositions on 2% v/v Volan treated 316L stainless steel yielded spectra for fluences of 125, 200 and 400 mJ/cm2, which were the fluences investigated for the chromium III methacrylate treatment. Although different in magnitude, the spectras shown in Figures 4.3-4.5 reflect similar peaks compared with 400 mJ/cm2 depositions on silicon wafers. While the peak locations are similar to that of MED 6820, the sh apes of the peaks are grossly different as a result of shifts in concentrations of bonding structures. This difference could be due to higher concentrations of specific bonding struct ures deposited such as SiOSi asymmetric stretching as well as sharp increase s in rocking chain ends Si(CH2)3 and Si(CH2)2. This increase can be attributed to scrambling of the molecular structure in the plume that is then recombined. Recombination is not cont rolled resulting in a deviation of PLAD deposited silicone compared with unablated silicone.

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62 Engineering Research Ctr 400 mJ/cm^2 MED 6820 on Silicon Wafer -0.010 -0.005 0.000 0.005 0.010 0.015 0.020 0.025 0.030 0.035 0.040 0.045 0.050Log 1000 2000 3000 4000 cm-1 Engineering Research Ctr 400 mJ/cm^2 MED 6820 on Silicon Wafer -0.010 -0.005 0.000 0.005 0.010 0.015 0.020 0.025 0.030 0.035 0.040 0.045 0.050Log 1000 2000 3000 4000 cm-1 Figure 4.2 FTIR-ATR spectra of MED 6820 deposited at a fluence of 400 mJ/cm2 on silicon wafer. Particle Eng Research Center 400 mJ/cm^2 MED6820 2% Volan 316LSS -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0Log(1/R) 500 1000 1500 2000 2500 3000 3500 4000 Wavenumbers (cm-1) Figure 4.3 FTIR-ATR spectra of MED 6820 deposited at a fluence of 400 mJ/cm2 on 2% Volan treated 316L stainless steel.

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63 Particle Eng Research Center 200 mJ/cm^2 MED6820 2% Volan 316LSS -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0Log(1/R) 500 1000 1500 2000 2500 3000 3500 4000 Wavenumbers (cm-1) Figure 4.4 FTIR-ATR spectra of MED 6820 deposited at a fluence of 200 mJ/cm2 on 2% Volan treated 316L stainless steel. Particle Eng Research Center 125 mJ/cm^2 MED6820 2% Volan 316LSS -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0Log(1/R) 500 1000 1500 2000 2500 3000 3500 4000 Wavenumbers (cm-1) Figure 4.5 FTIR-ATR spectra of MED 6820 deposited at a fluence of 125 mJ/cm2 on 2% Volan treated 316L stainless steel.

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64 Changes in elemental composition of de positions at varying fluences were examined by XPS analysis (Table 4.2 4.3). For MED 6820 coated untreated 316L stainless steel, overall oxygen content decreased with increasing fluence levels, while the silicon content increased. The O:Si ratio at low fluences decreased from approximately 2 to 1 at higher fluences. This may indicate th at a more silica-like film is deposited at lower fluence, while a more PDMS-like film is deposited at higher fluences on untreated 316L stainless steel. Table 4.2 XPS elemental anal ysis (%) of PLAD coated samples on untreated 316L stainless steel. Fluence (mJ/cm2) Fe2p3 O1s C1s Cr2p3 Si2p O:Si Ratio PDMS 0.0 25.0 50.0 0.0 25.0 1.0 400 0.0 27.9 41.1 0.1 25.9 1.1 300 0.1 27.2 46.2 0.2 26.3 1.0 200 0.0 29.1 41.2 0.0 29.8 1.0 125 0.0 32.3 38.8 0.0 28.5 1.1 100 0.3 38.8 33.6 0.1 27.2 1.4 75 0.2 39.7 32.2 0.0 27.8 1.4 50 0.8 35.6 43.8 0.8 18.9 1.9 316L SS Control 5.5 36.1 53.2 1.8 3.5 10.4 At 400 mJ/cm2 fluences, elemental analysis showed that deposited MED 6820 resin-filled silicone coatings on Volan treated 316L stainless steel exhibited similar elemental concentrations as coatings on untre ated stainless steel. However, at lower fluence deposition compositions on Volan treated substrates had higher Si2p and lower O1s concentrations when compared with th e untreated 316L stainless steel group. This difference could be due to several factors. While the chamber is under high vacuum, low molecular weight species still exist. The vacuum pump forces these particles to be pushed against the wall of the chamber decreasing the number of particles freely floating in the system. As the target is ablated, reactive fragments are emitted as a plume and

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65 could react with other particle s in the system. These reactio ns may be the source of the reduced O:Si ratio seen for lower fluence deposition conditions on Volan treated 316L stainless steel. The electron withdrawing vi nyl groups on the 316L stainless steel surface could preferentially bind with the silicone fr agments in the plume, which may be another explanation. It is likely th at a combination of both explan ations is the reason for this reduced O:Si ratio. Table 4.3 XPS elemental analysis ( %) of PLAD coated samples on Volan treated 316L stainless steel. Fluence (mJ/cm2) Fe2p3 O1s C1s Cr2p3 Si2p O:Si Ratio PDMS 0.0 25.0 50.0 0.0 25.0 1.0 400 0.0 25.8 44.6 0.0 29.6 0.9 200 0.0 25.7 35.9 0.0 38.4 0.7 125 0.0 24.0 37.7 0.0 38.2 0.6 316L SS Control 5.5 36.1 53.2 1.8 3.5 10.4 Figure 4.5 SEM of 316L st ainless steel at 500x.

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66 Figure 4.6 SEM of MED6820 PLAD co ated at fluence of 300 mJ/cm2 onto untreated 316L stainless steel at 500x. As shown in Figures 4.5-6, analysis with SEM at 500x showed that coatings on untreated 316L stainless steel exhibited gra nular surface texture at fluences higher than 125 mJ/cm2. For coatings deposited at lower flue nces, surfaces were fairly smooth in comparison. Depositions on Volan treated 316L stainless st eel appeared were very smooth. These observations sugge st that texture may be an important factor in the wettability of PLAD deposited silicone coatings. Summary The results of this investigation indicate a departure from previously published data utilizing the PLAD technique for surface modify ing of 316L stainless steel with PDMS. Biomedical grade poly(dimethylsiloxane), (PDMS), containing a nanostructured resin filler (MED 6820), was used here to form stable, uniform silicone-like coatings on chromium III methacrylate (Volan) treated and untreated 316L stainless steel. The coatings exhibited characteristics that were different from previous results with silica reinforced PDMS in that different elemen tal ratios of O:Si for depositions on Volan

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67 treated and untreated 316L st ainless steel at low fluences were acheived. Differences were seen in contact angles from fluences of 125-400 mJ/cm2, where silicone depositions on chromium alkoxide treated stainless steel were hydrophilic and depositions on untreated stainless steel were hydrophobic. Furthermore, the silicone depositions on untreated stainless steel from previous studies yielded hydr ophilic surface s at higher fluences such as 200-600 mJ/cm2, which was not observed in this study where coatings on untreated stainless steel deposited at high fluences we re hydrophobic indicating that surface bonding characteristics ar e related to laser fluence and chamber oxygen content. This is further supported by FTIR and XPS da ta. These experiments were conducted in a more rigorously controlled oxygen free system than previously published work. From Table 4.2, the %O decrease with increasing fluence may correspond with a more PDMSlike film that is deposited at higher fluen ces for coatings on untreated 316L stainless steel. At 400 mJ/cm2 fluences, depositions on Volan treated 316L stainless steel resulted in PDMS-like thin films. Such PDMS thin films may be useful for drug delivery from surfaces and/or for drug grafting. RF Plasma Surface Modification Radio frequency glow discharge plasma (RF plasma) is a surface modification technique involving high energy and vacuum to achieve surface ablation etching and deposition of RF plasma polymerized monome rs. This technique is commonly used in industry for surface modification. The techno logy involves the RF field excitation of gases such as argon, oxygen, solvents, or m onomer vapors. The RF field excitation causes the gaseous mass to dissociate creating the plasma of excited species, i.e. radicals, ions, ion radicals. The surface binding and recombination of excited species results in

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68 modification of the substrate surfaces. Typicall y, substrates are treate d one side at a time due to the directional nature of this treatment. RF plasma has been used successfully in our laboratory to pretreat polymeric and metallic substrates with hexane plasma for subsequent gamma irra diation polymerization. 57, 62, 63 The hexane plasma deposits a cross linked carbonaceous layer on the substrate surface. The substrate is then submerged in a monomer solution and irradiated immersed in a monomer solution, thus depositing polymer on the RF plasma/hexane coating. Initial contact angles reported were lower than those of samples treated with either RF Plasma or gamma alone. Presented here is an investigation of monomer RF plasma polymerization deposition with monomers, NVP, DMA and co monomer, NVP/DMA. The objective was to evaluate Quilon L (chromium III fatty acid) and Volan L (chromium III methacrylate) treated 316L stai nless steel substrates. Additi onally, a new substrate stage was developed for the purpose of treating both sides of the substrate at the same time by orienting the samples vertically. The resu lts of these studies are reported here. Materials and Methods Preparation of substrate, monomers, and comonomer Substrates of 316L stainless steel (1 cm x 1 cm x 0.1 mm) were cut from a single stock of foil. Stainless steel substrates were cleaned by sequential sonication in 1,1,1trichloroethane, chloroform, acetone, metha nol, and Ultrapure water then dried under vacuum at 60C for 12 hours. 316L Stainle ss was used in three ways, untreated and treated with 2% v/v Volan L or Quilon L, which are low chlorine chromium (III) methacrylate and low chlorine chromium (III) fatty acid metal alkoxide. These procedures are described in Chapter 3.

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69 A quantity of 1 ml of each monomer, NVP and DMA, was poured into separate 25 ml long neck round bottom flasks. For comonomer, NVP/DMA, 500 L of each monomer was poured into one 25 ml long neck round bottom flask. Before each RF plasma treatment, the monomers and comono mer flasks were degassed by vacuum and attached to the RF plasma apparatus. Monomer RF plasma To clean the bell-jar vacuum chamber, it was evacuated to 50 mTorr and purged with argon gas to 1 Torr. This procedure was repeated five times, after which the flow rate of argon gas was reduced and the RF pl asma controller was turn ed on with a power of 50 Watts (incident) and 0 Wa tts (reflected). The RF plasma was allowed to run for 5 minutes thoroughly clean the bell-jar and compon ents. Once this was finished, the flow of argon gas was closed and the bell-jar pre ssure was returned to ambient conditions. Treated substrates were oriented vertica lly on a custom designed sample stage. Three treatment groups were included with each run, untreated, Quilon L, and Volan L treated 316L stainless steel. For each expe rimental run, one flask containing 1 mL of either monomer or comonomer of NVP and DMA were attached to the RF plasma apparatus. The treatment followed the same procedure as describe d above, except after the last evacuation to 50 mTorr, the bell-j ar was backfilled by leaking in volatized monomer or comonomer to 100 mTorr. Afte r this operating pressure was reached, the RF plasma controller was turned on at th e same power as previously described and operated for either 5 or 10 minutes. After the RF plasma was turned off, the chamber was further purged with monome r for 2 minutes to allow for further polymer conversion and reaction with surface radicals. Finall y, the chamber was purged with argon gas to 1 Torr two times before returning the bell-jar pressure to ambient pressure of 760 Torr.

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70 Following treatment, substrates were submerged in UltrapureTM water to wash and await analysis. Analysis RF plasma treated surfaces were char acterized by captive air bubble and sessile drop methods with a Ram-Hart A-100 goniomet er, SEM with a JEOL 6400, FTIR with a Nicolet Magna 706 (ZnSe crystal, 45) and XPS analysis with Kratos Analytical Surface Analyzer XSAM 800 under the same operating conditions as described in Chapter 3. Results and Discussion As shown in Figures 4.74.9, initial contact angles measured prior to drying, were hydrophilic and approximately 20 in all case s. Additionally, both sides of the flat substrates were measured indicating unifo rm modifications substrate surfaces. No differences were seen between 5 and 10 mi nute monomer RF plasma treatments. To determine treatment stability, modified substr ates were dehydrated under vacuum, then rehydrated for 24 hours in UltrapureTM water and rehydrated contact angles were recorded for both sides of each sample. As the data shows in Figures 4.104.12, initial hydrophilicity of monomer RF plasma modifica tions was not reflected in measurements after rehydration. However, some samples onl y lost a fraction of hydrophilicity as shown by the rehydrated DMA RF plasma on Quilon L treated 316L stainless steel of the 10 minute treatment and on Volan L treated 316L stainless steel of the 5 minute treatment. Once again, measurements were consistent for both sides of the sample. The differences seen in initial and rehydrated contact angle data are likely due to condensation of surface species when dehydrated.

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71 Contact AngleUntreated 316L SS, Initial20 18 1919 21 19 0 10 20 30 40 50 60 70 510 Time (Minutes)Contact Angle (Degrees) None-NVP None-DMA None-NVP/DMA Figure 4.7 Initial contact angle measur ements for NVP, DMA and NVP/DMA RF plasma surface modifications on untreated 316L stainless steel. Contact AngleQuilon L Treated 316L SS, Initial20 19 21 18 20 17 0 10 20 30 40 50 60 70 510 Time (Minutes)Contact Angle (Degrees) QL-NVP QL-DMA QL-NVP/DMA Figure 4.8 Initial contact angle measur ements for NVP, DMA and NVP/DMA RF plasma surface modifications on 2% v/v Quilon L treated 316L stainless steel.

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72 Contact AngleVolan L Treated 316L SS, Initial1919 19 18 21 19 0 10 20 30 40 50 60 70 510 Time (Minutes)Contact Angle (Degrees) VL-NVP VL-DMA VL-NVP/DMA Figure 4.9 Initial contact angle measur ements for NVP, DMA and NVP/DMA RF plasma surface modifications on 2% v/v Volan L treated 316L stainless steel. Contact AngleUntreated 316L SS, Rehydrated31 39 36 41 42 44 0 10 20 30 40 50 60 70 510 Time (Minutes)Contact Angle (Degrees) None-NVP None-DMA None-NVP/DMA Figure 4.10 Rehydrated contact angle meas urements for NVP, DMA and NVP/DMA RF plasma surface modifications on untreated 316L stainless steel.

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73 Contact AngleQuilon L Treated 316L SS, Rehydrated30 32 37 25 40 37 0 10 20 30 40 50 60 70 510 Time (Minutes)Contact Angle (Degrees) QL-NVP QL-DMA QL-NVP/DMA Figure 4.11 Rehydrated contact angle meas urements for NVP, DMA and NVP/DMA RF plasma surface modifications on 2% v/v Quilon L treated 316L stainless steel. Contact AngleVolan L Treated 316L SS, Rehydrated32 29 26 36 39 40 0 10 20 30 40 50 60 70 510 Time (Minutes)Contact Angle (Degrees) VL-NVP VL-DMA VL-NVP/DMA Figure 4.12 Rehydrated contact angle meas urements for NVP, DMA and NVP/DMA RF plasma surface modifications on 2% v/v Volan L treated 316L stainless steel. FTIR-ATR analysis did not yield discernable peaks for any conditions examined in this study. This is likely due to low surface concentrations of treatment since RF plasma modifications typically result in thin treatments.

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74 XPS analysis of monomer RF plasma trea ted substrates showed N1s peaks for all conditions in the range of 1.8 to 3.6% when evaluated with C1s, O1s, Fe2p3, Cr2p3 and Cl2p elemental concentrations. The detected N1s peaks correspond to the nitrogen atoms of NVP, DMA, or NVP/DMA depositions. Un modified untreated 316L stainless steel did not exhibit discernable N1s peaks. Increase in C1s was seen for all Quilon L treated 316L stainless steel. This is likely due to polymerization or crosslinking of the fatty acid pendant groups on the chromium alkoxide treat ment. The only difference seen by this analysis between the 5 and 10 minute RF Plasma modifications are reduced Cl2p concentrations for 10 minute treatments. Table 4.4 XPS elemental analys is (%) of 5 minute monomer RF plasma modification of untreated, Volan L and Quilon L treated 316L stainless steel. C1s O1s N1s Fe2p3 Cr2p3 Cl2p Unmodified, Untreated 316L SS 48.2 42.3 < 0.1 7.9 1.2 0.0 NVP Untreated 316L SS 48.9 37.8 3.5 3.5 4.0 2.3 NVP VolanL Treated 316L SS 52.0 36.0 3.4 2.9 3.5 2.2 NVP QuilonL Treated 316L SS 60.9 30.0 3.2 1.2 2.8 1.8 DMA Untreated 316L SS 51.5 37.6 3.3 3.7 1.9 1.9 DMA VolanL Treated 316L SS 50.8 39.1 2.2 2.9 2.4 2.9 DMA QuilonL Treated 316L SS 60.5 32.2 2.3 1.6 0.4 2.7 NVP/DMA Untreated 316L SS 49.1 41.4 1.9 3.9 1.8 1.9 NVP/DMA VolanL Treated 316L SS 53.2 28.4 2.7 2.4 3.9 2.9 NVP/DMA QuilonL Treated 316L SS 63.3 34.9 1.8 0.9 2.5 3.2 Topography changes due to surface modifi cations were not evident in SEM micrographs. Surface modifications may be ~2 20 atomic layers in depth based on elemental analysis depth of penetration limitations. SEM mi crographs did not show any evidence of corrosion thes e surface modifications. Summary In the current studies, elemental analysis showed the presence of nitrogen species that correspond to the monomer species from RF plasma treat ments. Yet, these surface

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75 modifications did not yield st able hydrophilic coatings af ter drying and rehydration. Orienting the samples vertically with a new substrate stage was shown to consistently treat both sides of the substrates. While the use of chromium based metal al koxides did not appear to enhance the stability of monomer RF plasma surf ace modifications, initial contact angle measurements were very hydrophilic and surfaces appeared lubricious prior to drying. This technology may be useful for single us e applications that do not require drying. In our laboratory, hexane RF plasma trea tments on metals have been used as a primer for gamma initiated surface modifi cations by creating a carbonaceous surface layer. Functionalizing 316L stainless steel with metal alkoxide trea tments will prime the surface in a simplified one step process. These functionalized metals can be further modified in a variety of ways including gamma initiated grafting and solution coating.

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76 CHAPTER 5 SOLUTION POLYMERIZATION COATING SURFACE MODIFICATION Introduction A number of common coa ting techniques with poly mer solutions are used extensively for industrial appl ications, i.e. dip coating, sp ray coating, and film casting. These techniques are also used with polymers that are solubilized in a solvent or melt coated above their melting temperature.64 Dip coating, spray co ating and film casting techniques do not ensure bonding at the coati ng-substrate interface and typically result in coatings that are merely adsorbed to the s ubstrate unless coupling ag ents or other priming systems are employed. The focus of this chapter will be polymerizations of monomers in the presence of a solvent and the substrat e surface. This research evaluates the effectiveness of trivalent chromium methacrylate, Volan L, to enhance the binding and stability of hydrophilic and hydrophobic polymer s onto 316L stainless steel by solution polymerization coating. In Chapter 3, substrates were soaked in monomer-solvent solutions that were subsequently treated with high energy ionizi ng radiation to initia te the polymerization and grafting of chains to functionalized surf aces. In the solution polymerization coating studies discussed here, polymerizati on was initiated by the addition of azobisisobutyronitrile (AIBN) initiator and controlling the temperature of the reaction environment. Medical grade silicone was also evaluated with this coating technique. The addition of AIBN to these silicone so lution studies was not necessary, due to the presence of a catalyst for the two component silicone system.

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77 Materials and Methods Preparation and Treatment of 316L Stainless Steel Substrates Stainless steel substrates (1 cm x 1 cm 0.1 mm) were cleaned by sequential sonication with 1,1,1tricholoroethane, chlo roform, acetone, methanol, and UltrapureTM water, after which the substrates. After which, the samples were placed in a vacuum oven at 60oC. Cleaned substrates were washed in a 2 % (v/v) solution of Volan L, which is a chromium (III) methacrylate, with water at room temperature for 10 minutes while agitating. After washing, treated substr ates were removed from the solution and air dried for 2 hours. These procedures are descri bed in detail in Chapter 3. Substrates were coated as described below. Controls consisted of untreated 316L st ainless steel that underwent solution polymerization coating and subs trates that received no chro mium alkoxide treatment or solution polymerization coating. Preparation of Monomer Solutions The monomers used in this study were 2-methacryloyloxyethyl phosphorylcholine (MPC; Dr. Ishihara, University of Tokyo), N-vinyl-2-pyrrolidone (NVP; Polysciences, Inc), and potassium 3-sulfopropyl acrylate (KSPA; Raschig GmbH). MPC, NVP and KSPA monomer stock solutions of 10% v/v concentrations were prepared with 0.125% v/v AIBN initiator and Ultrapure water. A higher MPC and NVP monomer solution concentration of 25% v/v was also evaluated with the same concentration of initiator. A solution volume of 3 ml was used for each substrate. Preparation of Silicone Component Solutions Solutions of 45% v/v Nusil Med 6820 sili cone oligomers components A and B with chloroform were prepared of the same volum e. A 0.75 ml volume of each solution of

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78 components A and B were placed in glass test tubes for each condition and mixed thoroughly resulting in 1.5 ml of both component s A and B with chloroform to treat each substrate. A single cleaned and Volan L treated 316L stainle ss steel substrate was placed into each test tube a nd soaked in the silicone solution for 2 hours while rotating, after which the samples were transferre d to clean test t ubes and cured at 60oC for 12 hours. Solution Polymerization (SP) Coating of Substrates Chromium (III) methacrylate treated 316L stainless steel substrates were transferred to test tubes cont aining aqueous solutions of either 10% v/v, 25% v/v of NVP, MPC, or KSPA monomer with Ultrapure water or 45% MED 6820 oligomers with chloroform. The solutions were then bubbled and backfilled with argon gas. The specimens in monomer solutions were placed in an oven that was heated to a minimum of 70oC and a maximum of 76oC for ~6 hours. After coating, samples were placed in new test tubes and tumble washed for one week with 5 mL of Ultrapure water, which was decanted and replaced three times with 5 mL. Specimens in MED 6820 silicone oligomers solutions were treated as described in the previous section of this chapter. In short, functionalized substrat es were dipped into diluted solutions of uncured silicone components and subsequently heated to cure, which has been shown to be effective for coating silane coupling agent treated stainless steel with silicone.39 Analysis Wettability of coatings was characte rized by sessile drop and captive air bubble contact angle goniometry data using a Ram -Hart A-100 Goniometer. Surface chemistry of modified substrates was characterized w ith Fourier Transform Infrared Attenuated Total Reflectance Spectroscopy (FTIR-ATR)using a Nicolet Magna 706 FTIR, and

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79 elemental composition was analyzed by X-ray photoelectron spectro scopy (XPS) with a Kratos XSAM 800, all under the same conditions as described in Chapter 3. The contact angles for unmodified 316L stainless steel and unmodified resincast MED 6820 silicone are approximately 50 and 90, respectively. Results and Discussion From initial contact angle data show n in Figures 5.1 5.2, differences in wettability were seen for 25% v/v NVP so lution polymerization (SP) coatings when comparing untreated and Volan L treated 316L stainless steel, in that Volan L treated 316L stainless steel exhibited increased wetta bility. This was not observed for the 10% v/v NVP solution concentrations possibly due to kinetics associ ated with the reduction in the amount of reactive species in solution. In contrast, contact angles of ~ 20 were observed for MPC solution coating on untreated and Volan L treated 316L stainless steel for both concentrations, which can be at tributed to the amphoter ic structure of MPC causing increased adsorption onto the substrate. As shown in Figures 5.3 5.4, contact angl e measurements taken immediately after dehydration under vacuum for 24 hours indicated that Volan L treatments maintained the hydrophilicity of coatings with little recovery time. Furthermore, these specimens were lubricious to the touch. Surfaces treated with Volan L and SP coated in NVP and KSPA retained contact angles less than 26 following dehydration. The dehydration process affected coated surfaces that were not treated with Volan L such that contact angles increased beyond 30, which was a similar observation to gamma irradiation grafting studies. While exhibiting increased wettability compared with other solution coatings and unmodified 316L stainless stee l, MPC coatings did not yield measurable differences for the concentrations and substr ate treatment conditions investigated here.

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80 Contact AngleUntreated 316L SS, Initial19 18 26 30 22 0 10 20 30 40 50 60 70 1025 Concentration (%)Contact Angle (Degrees) None-MPC None-NVP None-KSPA Figure 5.1 Initial contact angle measur ements for 10% and 25% v/v monomer SP coated untreated 316L stainless steel. Contact AngleVolan L Treated 316L SS, Initial19 21 25 17 20 0 10 20 30 40 50 60 70 1025 Concentration (%)Contact Angle (Degrees) VL-MPC VL-NVP VL-KSPA Figure 5.2 Initial contact angle measur ements for 10% and 25% v/v monomer SP coated Volan L treated 316L stainless steel.

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81 Contact AngleUntreated 316L SS, Dehydrated1919 32 45 40 0 10 20 30 40 50 60 70 1025 Concentration (%)Contact Angle (Degrees) None-MPC None-NVP None-KSPA Figure 5.3 Contact angle measurements im mediately after dehydration for 10% and 25% v/v monomer SP coated untreated 316L stainless steel. Contact AngleVolan L Treated 316L SS, Dehydrated19 17 26 22 26 0 10 20 30 40 50 60 70 1025 Concentration (%)Contact Angle (Degrees) VL-MPC VL-NVP VL-KSPA Figure 5.4 Contact angle measurements im mediately after dehydration for 10% and 25% v/v monomer SP coated Volan L treated 316L stainless steel. After rehydration, NVP and KSPA SP coati ngs on untreated 316L stainless steel did not recover initial we ttability, see Figures 5.5 5.6. With the Volan L treatment, hydrophilicity was recovered for 25% v/v NVP SP coatings, but not for the 10% v/v concentrations (Figures 5.7 5.8). Once again, this is believed to be associated with with reduced quantity of reactive species for the 10% v/v NVP solution. MPC SP coatings

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82 maintained initial wettability throughout these stability tests for all conditions as presented in Figures 5.9 5.10. As shown in Figures 5.11 5.12, KSPA SP coatings on Volan L treated 316L stainless steel resulted in consistently low c ontact angles, which was not observed for the untre ated stainless steel group. MED 6820 SP coatings on untreated 316L stai nless steel exhibited contact angle measurements of ~ 104. Measurements of these silicone coatings on Volan L treated substrates were ~ 94, which was similar to unmodified MED 6820 substrates of ~ 90. Contact AngleUntreated 316L SS, Rehydrated18 20 29 43 30 50 0 10 20 30 40 50 60 70 01025 Concentration (%)Contact Angle (Degrees) None-MPC None-NVP None-KSPA 316L SS-Control Figure 5.5 Rehydrated contact angle measur ements for 10% and 25% v/v monomer SP coated untreated 316L stainless steel.

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83 Contact AngleVolan L Treated 316L SS, Rehydrated18 17 29 22 24 50 0 10 20 30 40 50 60 70 01025 Concentration (%)Contact Angle (Degrees) VL-MPC VL-NVP VL-KSPA 316L SS-Control Figure 5.6 Rehydrated contact angle meas urements for 10% and 25% v/v monomer solution coated Volan L treated 316L stainless steel. Contact AngleNVP Untreated 316L SS26 30 32 45 29 43 0 10 20 30 40 50 60 70 1025 Concentration (%)Contact Angle (Degrees) NVP-Initial NVP-Dehydrated NVP-Rehydrated Figure 5.7 Contact angle measurements for 10% and 25% v/v NVP SP coated untreated 316L stainless steel.

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84 Contact AngleNVP VolanL Treated 316L SS25 17 26 22 29 22 0 10 20 30 40 50 60 70 1025 Concentration (%)Contact Angle (Degrees) NVP-Initial NVP-Dehydrated NVP-Rehydrated Figure 5.8 Contact angle measurements fo r 10% and 25% v/v NVP SP coated Volan L treated 316L stainless steel. Contact AngleMPC Untreated 316L SS19 18 1919 18 20 0 10 20 30 40 50 60 70 1025 Concentration (%)Contact Angle (Degrees) MPC-Initial MPC-Dehydrated MPC-Rehydrated Figure 5.9 Contact angle measurements for 10% and 25% v/v MPC SP coated untreated 316L stainless steel.

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85 Contact AngleMPC VolanL Treated 316L SS19 21 19 17 18 17 0 10 20 30 40 50 60 70 1025 Concentration (%)Contact Angle (Degrees) MPC-Initial MPC-Dehydrated MPC-Rehydrated Figure 5.10 Contact angle measurements fo r 10% and 25% v/v MPC SP coated Volan L treated 316L stainless steel. Contact AngleKSPA Untreated 316L SS22 40 30 0 10 20 30 40 50 60 70 10 Concentration (%)Contact Angle (Degrees) KSPA-Initial KSPA-Dehydrated KSPA-Rehydrated Figure 5.11 Contact angle measurements for 10% v/v KSPA SP coated untreated 316L stainless steel.

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86 Contact AngleKSPA VolanL Treated 316L SS20 26 24 0 10 20 30 40 50 60 70 10 Concentration (%)Contact Angle (Degrees) KSPA-Initial KSPA-Dehydrated KSPA-Rehydrated Figure 5.12 Contact angle measurements for 10% v/v KSPA SP coated Volan L treated 316L stainless steel. FTIR measurements were carried out on all samples and controls. The polymer coatings did not yield detectable peaks. FT IR-ATR analysis was us eful for evaluation of silicone coatings. The spectra of these SP coated samples compared to spectra of cast silicone slabs may exhibit some spectral di fferences. Siince the MED 6820 silicone has resin reinforced filler; SP coating may change the resin content due to possible dissolution. Compared against unmodified cast silicone substrates, sh ifts were detected in chain end (Si(CH2)3 and Si(CH2)2 rocking) and main chain (SiOSi asymmetric stretching) peaks (1215-930 and 900-730 cm-1, respectively) for both stainless steel coatings. No differences between MED 6820 solution coatings were observed comparing untreated and Volan L treated 316L stainless steel.

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87 Figure 5.13 FTIR-ATR spectra of MED 6820 medical grade silicone. Figure 5.14 FTIR-ATR spectra of MED 6820 SP coated untreated 316L stainless steel. Particle Eng Research Center MED 6820 Dip Coat No Agent 316L SS 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 Log(1/R) 500 1000 1500 2000 2500 3000 3500 4000 Wavenumbers (cm-1) Engineering Research Ctr MED 6820 Unmodified/Unextracted 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Log(1/R) 1000 2000 3000 4000 Wavenumbers (cm-1)

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88 Figure 5.15 FTIR-ATR spectra of MED 6820 SP coating on Volan L treated 316L stainless steel. XPS analysis was used to evaluate the SP coatings for elemental surface concentrations and possible sh ifting of binding energies asso ciated with bonding changes. Substrates treated with Volan L and coated in either 10 or 25% v/v MPC solutions exhibited P2p/N1s peak ratios in the range of ~1.5 for coatings on functionalized stainless steel and ~2.0 on untreated stainless steel. These treatment groups also showed reduced signal from Fe2p3 and Cr2p3, as well as no dete ctable shifting of the C1s peak indicating coverage of the stainless st eel as shown in Table 5.1. NVP solution coatings exhibited N1s peaks, but 10% v/v treatments resulted in noticeable concentrations of Fe2p3 and Cr2p3 signals suggesting either a heterogene ous or very thin coating. SP coating solutions of 25% v/v NVP yielded lower c oncentrations of the surface metals; hence better coverage. Elemental anal ysis did not detect the stainless steel surface metals for the silicone coatings due to the thickness (> 1 m) for these SP coatings. Particle Eng Research Center MED 6820 Dip Coat V-L 316L SS 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 Log(1/R) 500 1000 1500 2000 2500 3000 3500 4000 Wavenumbers (cm-1)

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89 Table 5.1 XPS analysis of SP coated Volan L and untreated 316L stainless steel. C1s O1s N1s Fe2p3 Cr2p3 P2p S2p3 K2p3 Si2p3 10% NVP Untreated SS 50.0 37.8 4.3 3.9 3.9 10% NVP Volan L Treated SS 57.5 31.3 4.3 2.6 4.3 25% NVP Untreated SS 67.0 24.9 3.6 1.9 2.4 25% NVP Volan L Treated SS 70.4 22.2 4.3 1.3 1.8 10% MPC Untreated SS 63.5 23.9 3.9 0.4 0.4 7.7 10% MPC Volan L Treated SS 66.1 22.1 4.7 0.1 0.4 6.6 25% MPC Untreated SS 64.4 22.3 3.0 0.4 0.3 9.7 25% MPC Volan L Treated SS 70.1 20.2 3.1 0.0 0.3 6.3 10% KSPA Untreated SS 49.7 37.8 4.4 5.9 2.2 0.0 10% KSPA Volan L Treated SS 54.4 35.4 2.3 5.5 2.3 0.0 MED6820 Untreated SS 46.3 20.6 0.0 0.6 32.6 MED6820 Volan L Treated SS 46.2 19.5 0.0 0.0 34.4 SEM micrographs indicated that surface modifications were thin and much of the 316L topography was discernable. XPS an alysis suggests that SP coating with hydrophilic monomer resulted in surface modifica tions that are likely to be ~2 20 atomic layers in depth. SEM micrographs di d not show any evidence of corrosion for SP coatings. Summary Stable, hydrophilic coatings were prepared using an in situ solution polymerization coating system. MPC based coatings were ve ry hydrophilic for all conditions. However, 25% v/v NVP SP coatings on Volan L treated 316L stainle ss were more stable and lubricious to the touch than other NVP treatments explor ed in this investigation. Concentration did not appear to affect MPC ba sed coating, but did seem to be a factor for NVP based coatings. Hydrophilic stability of KSPA SP coatings, studied in the 10% v/v concentrations, was enhanced on triv alent chromium methacrylate (Volan L) treated stainless steel. Other th an differences in contact angle measurements, MED 6820 silicone SP coatings yielded similar results when characterized by FTIR-ATR, XPS or SEM. SEM micrographs did not reveal a ny evidence of corrosi on for any treatment group in this study.

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90 In situ solution polymerization coating has been shown to be effective for surface modifying 316L stainless steel with stable and hydrophilic co atings. Such surfaces may be useful for incorporation and controlled release of therapeutic agents from surface modified endovascular sten ts and keratome blades.

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91 CHAPTER 6 LOADING AND RELEASE OF THERAPUETIC AGENTS FROM SURFACE MODIFIED METAL ALKOXIDE TREATED STAINLESS STEEL Introduction Delivering therapeutic concentrations at the specific site that needs treatment is difficult to achieve with conventional syst emic drug administration. Systemic drug delivery carries other problems, including syst emic toxicity and drug residence issues, both of which can lead to further complicati ons. Localized delivery of therapeutic drugs has been evaluated with devices such as endovascular stents where drugs were immobilized onto stents, chemi cally grafted or physically incorporated into coatings.8, 10, 11, 13, 14, 19 The results of these studies have been promising and indicate that targeted localized drug therapy can be achieved at therap eutic levels with low systemic effects. For keratome blades, there is a risk of inf ection due to incision in that any surgical intervention poses a potential ri sk of infection. Release of ofloxacin, an antimicrobial agent, from surface modified stainless steel has not been reported. In this investigation, coating systems estab lished from the previous chapters in this work were loaded with drugs following surface modification. Ofloxacin, a potent flouroquinolone, was investigated as a su rface eluted antimicrobial agent and dexamethasone, a glucocorticoid, was investigat ed as a surface eluted anti-inflammatory agent. The molecular structur es of these drugs are illustrated in Figure 6.1. Drug loading of each coating system was determined by de pletion assay analysis of the drug loading solutions. The depletion analysis was carri ed out assuming that the changes in drug

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92 concentrations of the drug loading soluti ons are equal to the amount taken up by the coatings due to loading. Additionally, lo sses due to drug binding on glassware are not accounted for. N N O N F C O O O H O O H O OH OH F Ofloxacin Dexamethasone Figure 6.1 Molecular structures for ofloxacin and dexamethasone. Materials and Methods Preparation of Substrates and Coatings Stainless steel substrates (1 cm x 1 cm) with thicknesses of ~ 0.1 mm were cleaned by sequential sonication as described in Ch apter 3, and dried in a vacuum oven at 60oC. Substrates were subsequently treated with 2% v/v Volan L according to the procedure also described in Chapter 3. After chromi um III methacrylate treatment, samples were coated as described below. Controls consisted of untreated 316L st ainless steel that underwent radiation grafting or solution coating a nd stainless steel that receiv ed neither chromium alkoxide treatment nor polymer coatings. The monomers used in this study were 2-methacryloyloxyethyl phosphorylcholine (MPC; Dr. Ishihara, University of Tokyo) a nd n-vinyl-2-pyrrolidone (NVP; Polysciences, Inc). Treating volumes of 3 ml were us ed for each substrate with each gamma and solution polymerization (SP) co ating condition. The coatings investigated in this study are summarized in Table 6.1.

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93 For radiation grafted surface modificati ons, stainless steel substrates were deposited in MPC and NVP monomer solutions of 10% v/v concentrations that were prepared in 3 mL volumes in individual te st tubes and degassed by mechanical vacuum pump. The samples were irradiated by a 60Co gamma irradiator and exposed to a total dose of 0.1 Mrads at a dose rate of ~536 rads/min. For solution polymerization (SP) coated surface modifications, cleaned Volan L treated and untreated 316L stai nless steel substrates were tr ansferred to in dividual test tubes containing aqueous solutions of eith er 3 mL of 25% v/v NVP or MPC monomer plus Ultrapure water with 0.125% v/v AI BN initiator or 45% MED 6820 oligomers that consisted of 1.5 mL of component A in chloroform a nd 1.5 mL of component B in chloroform. These solutions were then bubbled and backfilled with argon. Specimens in monomer solutions were placed in an ove n that was heated to a minimum of 70oC for ~6 hours. Specimens contained in the dilute uncur ed silicone coating so lutions were rotated in the solutions for 2 hours at ~25oC, after which the samples were transferred to clean test tubes and cured at 60oC for 12 hours. After coating the surfaces, samples were placed in new test tubes and tumble washed for one week with 5 mL of Ultrapur e water, which was decanted and replaced three times. Post Loading Ofloxacin and Dexamethasone Solutions of 3.0% (w/v) ofloxacin (Sigma -Aldrich) in 2% KOH were prepared. Methanol was used to prepare solutions of 0.5% (w/v) dexamethasone (Sigma-Aldrich). Table 6.1 lists the coatings conditions and drug that was investigated for each. The stainless steel specimens were placed into 3 mL volumes of these solutions and rotated

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94 gently for 24 hrs, after which the samples were removed and dried at room temperature for 24 hrs. Table 6.1 Coating and metal alkoxide treatmen t conditions investigated for drug release where Oflox and Dex refers to ofloxa cin and dexamethasone, respectively. 2% V-L refers to 2 % v/v Volan L. Coat 25% w/v MPC Solution Coated 10% w/v MPC Radiation Grafted 25% v/v NVP Solution Coated 45% v/v MED6820 Solution Coated None Agent 2% V-L None 2% V-L None 2% V-L None 2% V-L None None Oflox Dex Drug Loading Solution Depletion Study Standard curves were established for both ofloxacin and dexamethasone using known drug concentrations from 1ppm to 50ppm in the loading solvents, KOH and methanol, where 1 ppm is equivalent to 1 g/mL. These curves were used to calculate the concentration depletions for this study. The peaks of intere st for ofloxacin and dexamethasone are 288 and 254 nm, respectively. Aliquots of 1 mL were taken from stock solutions before drug loading and from drug soaking solutions after drug uptake, then transferred to UV-Visible Spectroscopy (UV-Vis) cuvettes to be meas ured immediately for depletio n assay analysis. From the UV-Vis absorbance data, the difference in c oncentration of the drug stock solution and that of the solution following the loading pr ocedure was calculated and recorded as the concentration of the drug loaded. These re sults were then normalized for substrate surface area and loading solution concentration. Release of Drugs from Surface Mo dified 316L Stainless Steel Ofloxacin release in vitro was conducted in phosphate buffered saline (PBS). PBS was prepared in our laboratory with a mi xture of 50mM sodium monobasic with 50mM sodium dibasic solutions and adjusted to a pH of 7.4. The PBS stock was filtered through a 0.20 m filter and autoclaved at 120oC. Dexamethasone release in vitro was conducted

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95 in human blood plasma, donated from Shands Hospital Blood Bank, to better emulate the blood tissue environment of endovascular stents. The plasma was kept frozen until use, after which it was thawed and incubated for 5 minutes at 60oC, then centrifuged for 10 minutes. Precipitated proteins were removed and 0.02% of sodium azide was subsequently added to preser ve the plasma, which was used immediately. The release media preparation procedures described here has been reported in previous work conducted by our laboratory.65 Drug release studies were conducted out to 5 days. Drug loaded specimens were placed into 10 mL of respectiv e release media contained in 15 mL capacity centrifuge tubes. Release was carried out at 37oC under continuous rotation. Aliquots of 1 mL were taken each hour for the first five hours and once a day through the fifth day and placed into either UV-Vis cuvettes (PBS) or 1.5 ml capacity centrifuge tubes (plasma). Removed aliquots were replaced with 1 mL of release media at each instance. Dexamethasone in plasma aliquots were sealed and frozen until HPLC analysis. Aliquots of ofloxacin release in PBS were sealed and refrigerated until UV-Vis analysis. Dexamethasone release was quantified by HPLC assays with a system composed of a Perkin Elmer ISS-100 autosampler, a Cons ta Metric LDC Analy tical high pressure pump, 25 L injection loop, an LDC Analytical Spectro Monitor 3200 UV Detector, a Discovery C-18 column (150 x 4.6 mm, 5 ) and HP 3392-A III integrator. A standard curve for the range of 0.25 6 g/mL was prepared from a 100 g/mL solution of dexamethasone in acetonitrile. These st andards were tested with 0.5, 2, and 6 g/mL concentrations of dexamethasone in plasma Due to conducting dexamethasone release studies in plasma, the actual a liquots of released drug were first extracted from the media

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96 by mixing 150 L of the plasma release media with 10 L of triamcinolone acetonide, which was used as an internal standard, and 500 L of ethyl acetate to precipitate the proteins. This combination was mixed for 30 seconds and centrifuged for 10 minutes at 10,000 rpm. The supernatant was then rem oved, vacuum dried, reconstituted in 150 L of acetonitrile, mixed and immediately analy zed by HPLC at a flow rate of 1.2mL/min with an injection volume of 25 L at a temperature of 40C and a set UV detection at 254nm.55, 66 Preparation of Bacterial Cultu res for Zone of Inhibition Bacterial cultures were prepared by spreading 10 L of either s.epidermidis or s.aureus cultures onto plate count agar prepared culture dishes. The concentration of both bacterial cultures were 108 colony forming units/mL. Post loaded ofloxacin in 25% v/v NVP SP coated samples of Volan L and untreated stainless steel were placed into the prepared cultures. Silver acrylate functi onalized stainless steel was also investigated for antimicrobial properties in cultures of both bacterial species. Samples were placed in bacteria seeded dishes and incubated at 37C for 24 hours, after which the zones of inhibition were measured and photographed. The zones are reported as the distance from the sample edge to the edge of the zone that is perpendicular to the sample edge where bacterial growth was inhibited. Analysis Drug depletion assays were used to calc ulate the amount of drug that was loaded into the coatings. The depletion studie s were analyzed by UV-Vis spectroscopy. Aliquots of drug release media from loaded co atings and controls were characterized by examination of sustained release profiles with UV-Vis for ofloxacin release into PBS and HPLC for dexamethasone release into human blood plasma. Reported values for drug

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97 release analysis included three samples for each coating condition. Zones of inhibition were measured metrically using a ruler, where two samples were measured for each condition coating condition. The controls consisted of post loaded and non-loaded samples of unmodified 316L stainless steel and surface modified 316Lstainless steel without Volan L treatment. Results and Discussion The drug solution depletion study was perfor med to determine the concentrations of ofloxacin and dexamethasone uptake by the coating from the drug loading procedure. To calculate the loaded drug concentrati ons, the surface area of the samples were measured and included in the analysis. Table 6.2 and 6.3 list the UV-Vis measured concentrations and sample surface areas as we ll as concentration conversions from ppm to g/mm2 for both the ofloxacin and dexameth asone depletion assays analyses. Table 6.2 Ofloxacin depletion UV-Vis ab sorption measurements in terms of concentration with adjustments for surf ace area and conversions, all values are reported as averages. Total Loaded (ppm) Loading Vol. (mL) Total Loaded ( g) Surface Area (cm2) Uptake ( g/cm2) Uptake ( g/mm2) 25% NVP Volan L 5830 3 17491 3.59 4872 48.7 25% NVP No Agent 3241 3 9723 2.95 3295 33.0 25% MPC Volan L 3648 3 10944 3.94 3132 31.3 25% MPC No Agent 3030 3 9091 3.61 2518 25.2 316L SS Control 4048 3 12142 3.45 3515 35.2

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98 Table 6.3 Dexamethasone depletion UV-Vis absorption measurements in terms of concentration with adjustments for surf ace area and conversions, all values are reported as averages. Total Loaded (ppm) Loading Vol. (mL) Total Loaded ( g) Surface Area (cm2) Uptake ( g/cm2) Uptake ( g/mm2) 25% MPC Volan L 1896 3 5689 3.69 1541 15.4 25% MPC No Agent 1741 3 5222 3.64 1436 14.4 10% MPC Volan L 1896 3 5689 3.33 1710 17.1 10% MPC No Agent 869 3 2607 3.69 774 7.7 45% MED Volan L 1231 3 3694 2.90 1276 12.8 45% MED No Agent 1831 3 5492 3.21 1712 17.1 316L SS Control 1620 3 4888 3.23 1502 15.0 Chromium (III) methacrylate treated 316L st ainless steel substrates that were surface modified generally exhibited increa sed drug uptake values relative to surface specimen surface area as shown in Tables 6.2 and 6.3. The highest ofloxacin uptake value was 48.7 g/mm2, corresponding to 25% v/v NVP SP coatings on Volan L treated 316L stainless steel. 25% v/v NVP SP coatings on untreated stainless steel failed to yield increased ofloxacin lo ading compared with control values. 25% v/v MPC SP coatings on Volan L treated stainless steel resulted in increased uptake (~31.3 g/mm2) compared with MPC SP coated stainless steel that was not treated with Volan L which was ~25.2 g/mm2. However, 25% v/v MPC SP coatings on Volan L treated 316L stainless steel resu lted in similar uptake compared with controls; and MPC SP coatings on untre ated stainless steel had decreased uptake relative to uptake values for controls. Th e polarity of the MPC structure may contribute to these slightly lower drug uptake values. Dexamethasone uptake values were lower than those seen for ofloxacin uptake, which correlates well with the lower loadi ng solution concentrations. MPC SP coatings

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99 on Volan L treated stainless steel had dexamethasone loadings of ~15.4 g/mm2 that were comparable with unmodified stainless steel (control) with uptake values of ~15.0 g/mm2 and coatings on untreated stainl ess steel yielded values of ~14.4 g/mm2. Interestingly, radiation gr afted 10% v/v MPC at 0.1 Mrad s resulted in higher uptake values (~17.1 g/mm2) for the Volan L treated samples and much lower values than controls for coatings on unt reated stainless steel (~7.7 g/mm2). Furthermore, MED 6820 SP coatings on Volan L treated stainless steel yielde d in lower uptake values than MED 6820 SP coatings on untreated stainless steel. This could be attributed to a decrease propensity for swelling when the elastomeric material is bound at the coatingsubstrate interface limiting chain mobility. Sustained release studies we re conducted for the drug loaded specimens described here. Release from all coatings for both drugs was apparent to at least 5 days, which is a significant improvement from studies of the sa me drugs released from radiation grafted hydrophilic coatings in high pH solutions a nd without metal alkoxide surface treatments, where drug release was comple ted in the first two hours. As shown in Figure 6.2, ofloxacin cumulativ e release from NVP SP coatings in the first 48 hours were 0.98 g/mm2 and 0.66 g/mm2 for Volan L and untreated stainless steel, respectively. Cumulative release from controls yielded 0.95 g/mm2, which was similar to released quantities seen for NVP SP coatings on Volan L untreated stainless steel. While controls releas ed a greater fraction of the lo aded drug, this could result in shorter release times overall. Furthermore, as discussed in Chapter 3, the 316L stainless steel used in these studies were not elect ropolished, therefore ha ving characteristically rougher surfaces. The roughness of these surface s can also contribute to increase drug

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100 physical-adsorption onto surfaces. However, extended studies would be necessary to confirm this. Ofloxacin Release from NVP SP Coating0 0.2 0.4 0.6 0.8 1 1.2 0244872 Time (Hrs)Cumulative Release ( g/mm2) 25% NVP Volan L 25% NVP No Agent 316L SS Control Figure 6.2 Ofloxacin release from 25% v/v NVP SP coated Volan L and untreated 316L stainless steel compared with unmodified controls. Ofloxacin Release from MPC SP Coating0 0.2 0.4 0.6 0.8 1 1.2 0244872 Time (Hrs)Cumulative Release ( g/mm2) 25% MPC Volan L 25% MPC No Agent 316L SS Control Figure 6.3 Ofloxacin release from 25% v/v MPC SP coated Volan L and untreated 316L stainless steel compared with unmodified controls.

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101 Ofloxacin cumulative release from MPC SP coated surface modifications (Figure 6.3) were 0.88 g/mm2 and 1.02 g/mm2 for Volan L and untreated stainless steel, respectively, in the first 48 hours. MPC co atings on untreated stai nless steel released greater fractions of the loaded drugs, which could be related to increased release rates and/or the surface roughness. Dexamethasone cumulative release from MPC SP coated, MPC gamma irradiation grafted, and MED6820 SP coated surface m odifications (Figure 6.4-6) were 0.33, 0.33 and 0.31 g/mm2 for Volan L treated stainless steel, respec tively, in the first 120 hours. Cumulative dexamethasone releases from thes e polymer coatings on untreated stainless steel were 0.31, 0.26 and 0.24 g/mm2, respectively. Release from stainless steel controls were also measured, where cumula tive values for these uncoated surfaces were 0.19 g/mm2. All measured release concentrations below the limit of detection of 0.25 g/mL (or approximately 0.01 g/mm2) were not included in these analyses. Dexamethasone Release from MPC SP Coating0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 020406080100120140 Time (Hrs)Cumulative Release ( g/mm2) 25% MPC Volan L 25% MPC No Agent 316L SS Control Figure 6.4 Dexamethasone release from 25% v/v MPC SP coated Volan L and untreated 316L stainless steel co mpared with unmodified controls.

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102 Illustrated graphically in Fi gure 6.4, MPC SP coatings on Volan L treated and untreated stainless steel rel eased similar quantities of loaded dexamethasone, which had longer release times with cumulatively more released drug than c ontrols. In Figure 6.5, MPC gamma irradiation grafted coating on Volan L treated stainless steel yielded increased cumulative release values compared with both untreated stainless steel that was coated and controls. As shown in Figure 6.6, MED6820 SP coatings on Volan L treated stainless steel yielded the greatest cumula tive release values, where the control and MED6820 coated untreated stainl ess steel resulted in similar releases of dexamethasone. Dexamethasone Release from MPC Coating 0.1 MRads0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 020406080100120140 Time (Hrs)Cumulative Release ( g/mm2) 10% MPC Volan L 10% MPC No Agent 316L SS Control Figure 6.5 Dexamethasone release from 10% v/v MPC gamma irradiation graft coated Volan L and untreated 316L stainless st eel compared with unmodified controls.

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103 Dexamethasone Release from MED6820 Coating0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 020406080100120140 Time (Hrs)Cumulative Release ( g/mm2) 45% MED6820 Volan L 45% MED6820 No Agent 316L SS Control Figure 6.6 Dexamethasone release fr om 45% v/v MED6820 SP coated Volan L and untreated 316L stainless steel co mpared with unmodified controls. Zones of inhibition were measur ed for specimens incubated in s.epidermidis and s.aureus cultures. As shown in Table 6.3, very little difference in inhibition zones were seen in s.epidermidis cultures for ofloxacin release from 25% v/v NVP SP coated Volan L and untreated stainless steels, with zone s of 15.5 and 16 mm, respectively. A slightly greater difference in zones was seen for cultures in s.aureous Silver acrylate treatments did not yield a measurable zone in all cultu re plates. However, one specimen in an s.aureus culture resulted in a 2 mm zone. Un modified 316L stainless steel in these bacterial cultures did not yield zones of inhibition. Examples of these zones are shown in Figure 6.7-6.9. These results suggest that ther apeutic doses of ofloxacin were released from the drug loaded coatings.

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104 Figure 6.7 Zone of inhibition of ofloxaci n release from 25% NVP solution coated Volan L treated 316L stainless steel. Le ft-S.Aureus. Right-S.Epidermidis. Figure 6.8 Zone of inhibition of ofloxaci n release from 25% NVP solution coated untreated 316L stainless steel. Le ft-S.Aureus. Right-S.Epidermidis. Figure 6.9 Zone of inhibition of oflox acin release from 2% silver acrylate functionalized 316L stainless steel. Left-S.Aureus. Right-S.Epidermidis.

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105 Summary The stainless steel surface modifications developed here have been shown to be capable of loading with antimicrobial agent, ofloxacin, and anti-inflammatory agent, dexamethasone. Ofloxacin release from surf ace modified stainless steel has not been reported before. Ofloxacin lo ading concentrations of 48.7 g/mm2 were observed for 25% v/v NVP SP coatings on chromium (III) methacrylate activated stainless steel. 25% v/v MPC SP coatings on activated stainless steel exhibited 31.3 g/mm2 of ofloxacin loading. Previous research conducted in this labor atory reported dexamethasone loadings of 4.3 g/mm2 for gamma radiation grafted polymers prepared at high pH.55 Coatings studies hence have higher drug loadings of dexamethasone, where 25% v/v MPC SP solution coatings on chromium (III) methacr ylate activated stainless steel had 15.4 g/mm2 uptake and 10% v/v MPC radiation grafted modifications on chromium (III) methacrylate treated stainless steel yielded 14.4 g/mm2 uptake. These values are approximately three times greater than what was previously reported. Additionally, these new values are much greater than loading va lues reported in the Study of Antirestenosis with the BiodivYsio Dexamethasone-Eluti ng Stent (STRIDE) human multicenter pilot trial, which reported a loading of 0.5 g/mm2 for phosphorylcholine coated stents.23 Non-linear release of these drugs was observe d in a 5 day test. Ofloxacin release in PBS and dexamethasone release in human bl ood plasma was evident past five days. Previously reported in vitro release studies for dexamethas one indicated complete release within 24 hours.23, 55 The highest cumulative release of dexamethasone was seen for 25% MPC SP coated and 10% MPC gamma irradiation grafted Volan L treated stainless

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106 steel. Similar release quantities were also recorded for MPC SP coatings on untreated stainless steel. These results suggest the improved, stable hydrophilic coatings on stainless steel prepared in this study may enhance the loadi ng and prolong the releas e of drugs such as dexamethasone and ofloxacin.

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107 CHAPTER 7 CONCLUSIONS Implanted medical devices often lead to complications associated with tissuematerial interfacial interactions. The overall objective of this rese arch was therefore to study the influence of chromium alkoxide c oupling agents on the adhesion of polymers commonly used in bioactive coatings with the ultimate goal of developing improved methods for surface modification of metallic me dical devices such as endovascular stents and keratome blades to improve biocompatibility. 1. New surface coating methods based on 2% v/v trivalent chromium alkoxide functionalization of 316L stainless steel followed by gamma radiation grafting, pulsed laser ablation deposition, radi o frequency plasma, and solution polymerization coating were developed. 2. Chromium (III) fatty acid and chromium (III) methacrylate treatments were adapted for 316L stainless steel surf ace functionalizations. This surface activation is simpler than most other surface activation methods. 3. Chromium alkoxide treatments were shown to provide corrosion free functionalization of stainless steel surfaces. 4. Chromium alkoxide functionalized stainle ss steel surfaces were coated with hydrophilic vinyl monomers such as MPC a nd NVP to yield greater stability and increased coating hydrophilicity compared to non-surface functionalized stainless steel.

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108 5. MPC and NVP that were radiation grafte d and solution polymerization coated on Volan L metal alkoxide functionalized 316L stainless steel yielded hydrophilic contact angles that were maintained or recovered throughout a drying and rehydrating process. 6. MPC and MPC/DMA surface modifications of stainless steel using chromium alkoxide treated substrates were compared with the untreated stainless steel. Surfaces that were more stable, hydrophili c, and lubricious to the touch were achieved. These coatings maintained excellent hydrophilic properties without measurable recovery time after dehydration. 7. Stable hydrophilic coatings were prepared by gamma irradiation of monomer solutions on chromium alkoxide functiona lized 316L stainless steel. Single monomer formulations of NVP, MPC and KSPA were comparable to copolymers of these monomers with DMA. 8. Crosslinked medical grade re sin-filled silicone was deposited by Pulsed Laser Ablation Deposition (PLAD) to surface modify stainless steel. Parameters such as fluence, oxygen content and base pressu re were varied to deposit PDMS-like or silica-like coatings. 9. PLAD results differ from previous reports in that higher base pr essures such as 30 mTorr yielded hydrophilic coatings at flue nces above 200 mJ/cm2 and lower base pressures such as 5.0 x 10-5 mTorr produced hydrophobic coatings at fluences higher than 125 mJ/cm2.

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109 10. Homogeneous RF-plasma surface modifi cations with NVP, DMA and NVP/DMA at 50 Watts for 5 minute treatment times we re prepared with vertical orientation of samples; a geometry that treat ed both sides of the substrates. 11. RF plasma surface modifications with NVP, DMA, and NVP/DMA resulted in contact angles that were hydrophilic, but not stable. 12. Solution polymerization coating of ch romium (III) methacrylate functionalized 316L stainless steel by NVP, MPC and K SPA was shown to be effective for surface modifying 316L stainless steel to yield stable hydrophilic coatings that were lubricious to the touch. Concentra tions of MPC in the range of 10% v/v and 25% v/v did not appear to affect the lubric ity or stability of these coatings. For NVP based coatings, a higher concentra tion of 25% v/v was preferred. KSPA solution polymerization coatings at 10 % v/v concentration exhibited improved hydrophilic stability on Volan L functionalized stainless steel. 13. The surface modifications prepared in this research were shown to be capable of loading with therapeutic agents for su stained local drug release. Loading concentrations of 48.7 g/mm2 of ofloxacin and 17.1 g/mm2 of dexamethasone were achieved. Some increases in drug loading were seen for surface modified stainless steel with metal alkoxide treatment s. Drug release at therapeutic levels was demonstrated with ofloxacin (ant imicrobial) and dexamethasone (antiinflammatory). Release of these drugs from the surface modifications developed here suggests that such treatments may be tailored for application to a variety of implantable medical devices.

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110 CHAPTER 8 FUTURE WORK Based on this research, several opportuniti es for future studies are suggested: 1. Modifications with Increased Thickne sses on Chromium Alkoxide Functionalized Stainless Steel a. Further modifying initial radiation grafts, solution coatings, with additional radiation gr afting to yield IPNs. b. Add crosslinker, such as ethylene glycol dimethacrylate (EGDMA), in solution coating systems. c. Investigate monomers w ith ionic functionality. d. Use electropolished stainless steel or cobalt-chromium formulation metals to determine if coating a dhesion is thereby affected. 2. Surface Testing a. Study the method of the coupling agent reactions with substrate surfaces and coating solutions. b. Measure adhesive strength of surface modifications using nanoscratch and nanoindentation methods. c. Apply additional methods for su rface thickness measurement. 3. Delivery of Therapeutic Agents a. Study release characteristics as a kine tic process includi ng examination of chemistry relative to time, stress, and strain on the tested system to mimic dynamic in vivo conditions that stents would be subject to.

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111 b. Investigate in situ loading methods and release of ofloxacin, dexamethasone, and other drugs to achieve sustained release beyond 14 days. c. Investigate the use of 17-estradiol, a smooth muscle cell growth modulator, as a restenosis inhibi tor agent released from hydrophilic coatings for stents treated with metal alkoxides. d. Study combination loading and release of drugs such as dexamethasone and 17-estradiol. 4. In vitro Studies a. Examine in vitro cell culture proliferation of endothelial cells on drug loaded and unloaded surface modified materials. b. Examine in vitro cell culture prolifera tion of vascular smooth muscle cells on drug loaded and unloaded surface modified materials. 5. In vivo Studies a. Implant various stent trea tment groups in rabbits

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112 LIST OF REFERENCES 1. Ratner BD, Hoffman AS, Schoen FJ, Lemons JE, Editors. Biomaterials Science: An Introduction to Materials in Medici ne, Academic Press, San Diego, CA 1996:484 pp. 2. Kirchengast M, Munter K. Endothelin and restenosis. Cardiovascular Research 1998; 39:550-555. 3. Sahin NO, Burgess DJ. Competitive inte rfacial adsorption of blood proteins. Farmaco 2003; 58:1017-21. 4. Wang F, Stouffer GA, Waxman S, Uretsky BF. Late coronary stent thrombosis: early vs. late stent thrombos is in the stent era. Cathet er Cardiovasc Interv 2002; 55:142-7. 5. Glanze WDe. The Mosby Medical Encyclopedia. New York: Plume, Penguin Books USA Inc, 1992:926 pp. 6. American Heart Association. www.americanheart.org 2004. 7. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloonexpandable-stent implantation with balloon an gioplasty in patients with coronary artery disease. Benestent Study Group. Ne w England Journal of Medicine 1994; 331:489-95. 8. Dzau VJ, Braun-Dullaeus RC, Seddi ng DG. Vascular proliferation and atherosclerosis: New perspectives and th erapeutic strategies. Nature Medicine 2002; 8:1249-1256. 9. Welt FG, Rogers C. Inflammation and rest enosis in the stent era. Arterioscler Thromb Vasc Biol 2002; 22:1769-76. 10. Indolfi C, Mongiardo A, Curcio A, Torell a D. Molecular mechanisms of in-stent restenosis and approach to therapy with eluting stents. Trends in Cardiovascular Medicine 2003; 13:142-148. 11. Nakatani M, Takeyama Y, Shibata M, et al. Mechanisms of restenosis after coronary intervention: difference betw een plain old balloon angioplasty and stenting. Cardiovascular Pathology 2003; 12:40-48.

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113 12. Schuessler A, Strobel M, Steegmuelle r R, Piper M. Stent materials and manufacturing: requirements and possi bilities/opportunities. ASM Materials & Processes for Medical Devices Conference, Anaheim, CA, 2003. 13. Babapulle MN, Eisenberg MJ. Coated stents for the prevention of restenosis: part II. Circulation 2002; 106:2859-66. 14. Hofma SH, van Beusekom HM, Serr uys PW, van Der Giessen WJ. Recent developments in coated stents. Cu rr Interv Cardiol Rep 2001; 3:28-36. 15. Endovascular Today: Dr ug-Eluting Stent Update. www.evtoday.com 2004. 16. Duda SH, Poerner TC, Wiesinger B, et al. Drug-eluting stents: potential applications for peripheral arterial occl usive disease. Journa l of Vascular and Interventional Radiology 2003; 14:291-301. 17. Sehgal SN. Rapamune (Sirolimus, rapamycin): an overview and mechanism of action. Ther Drug Monit 1995; 17:660-5. 18. Ruygrok PN, Muller DW, Serruys PW. Rapa mycin in cardiovascular medicine. Internal Medicine Journal 2003; 33:103-109. 19. Sousa JE, Serruys PW, Costa MA. New frontiers in cardiology: drug-eluting stents: part II. Circulation 2003; 107:2383-9. 20. Lewis AL, Leppard SW. Stents with drug-containing amphiphilic polymer coating. PCT Int Appl Wo: (Biocompatibles Limited, UK). 2002:51 pp. 21. Abizaid A, Albertal M, Costa Marco A, et al. First human experience with the 17beta-estradiol-eluting sten t: the estrogen and stents to eliminate restenosis (EASTER) trial. Journal of the American College of Cardiology 2004; 43:111821. 22. Joung YK, Kim HI, Kim SS, Chung KH, Jang YS, Park KD. Estrogen release from metallic stent surface fo r the prevention of restenos is. Journal of Controlled Release 2003; 92:83-91. 23. Liu X, Huang Y, Hanet C, et al. Stu dy of antirestenosis with the BiodivYsio dexamethasone-eluting stent (STRIDE): a fi rst-in-human multicenter pilot trial. Catheterization and cardiovascular interven tions : official jour nal of the Society for Cardiac Angiography & Interven tions 2003; 60:172-8; discussion 179. 24. Kallinteri P, Antimisiaris SG, Karnabatidis D, Kalogeropoulou C, Tsota I, Siablis D. Dexamethasone incorporating lipos omes: an in vitro study of their applicability as a slow rel easing delivery system of dexamethasone from covered metallic stents. Biomaterials 2002; 23:4819-26.

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114 25. Lincoff AM, Furst JG, Ellis SG, Tuch RJ Topol EJ. Sustained local delivery of dexamethasone by a novel intravascular eluti ng stent to prevent restenosis in the porcine coronary injury m odel. Journal of the American College of Cardiology 1997; 29:808-816. 26. Wu Z, Bai X. Vertical vi bration method for the measurement of drug release rate of levonorgestrel in contraceptive vagina l rings in vitro. Shengzhi Yu Biyun 1986; 6:18-21. 27. Sarkar NN. Low-dose intravaginal estrad iol delivery using a S ilastic vaginal ring for estrogen replacement therapy in post menopausal women: a review. European Journal of Contraception & Reproductive Health Care: Official Journal of the European Society of C ontraception 2003; 8:217-24. 28. Matlin SA, Belenguer A, Hall PE. Progester one-releasing vaginal rings for use in postpartum contraception. I. in vitro release rates of progesterone from coreloaded rings. Contraception 1992; 45:329-41. 29. Malcolm RK. The intravaginal ring. Dr ugs and the Pharmaceutical Sciences 2003; 126:775-790. 30. Jackanicz T, Croxatto AHB, Drexler LG, Zegers-Hochschild F. Progesterone vaginal ring for treatment of infertilit y. US Patent Application. Us: (The Population Council, USA). 1999:6 pp. 31. Englund DE, Victor A, Johansson ED. Pharmacokinetics and pharmacodynamic effects of vaginal oestradiol administrati on from silastic rings in post-menopausal women. Maturitas 1981; 3:125-33. 32. Holmgren PA, Lindskog M, von Schoultz B. Vaginal rings for continuous lowdose release of oestradiol in the treatment of urogen ital atrophy. Maturitas 1989; 11:55-63. 33. Smith P, Heimer G, Lindskog M, Ulms ten U. Oestradiol-releasing vaginal ring for treatment of postmenopausal urog enital atrophy. Matu ritas 1993; 16:145-54. 34. Zhang C-X, Sheng J, Ma J-T. Drug rel ease system based on silicone rubber and levo-norgestrel. Yingyong Huaxue 2002; 19:597-599. 35. Chauhan PS, Varma KC. In vitro releas e of progestogens from contraceptive implants. Indian Journal of Pharmaceutical Sciences 1986; 48:29-33. 36. Marotta JS, Goldberg EP, Habal MB, et al. Silicone gel breast implant failure: evaluation of properties of shells and ge ls for explanted prostheses and metaanalysis of literature r upture data. Annals of Plas tic Surgery 2002; 49:227-42; discussion 242-7.

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115 37. Schopflin G, Fuchs P, Kolb KH. Pharm aceutical preparations containing silicon rubber. Brit Gb: (Schering A-G, Fed Rep Ger.). 1975:6 pp Addn to Brit 1,412,969. 38. Widenhouse CW, Goldberg EP. Method fo r the surface modification of silicone surfaces for medical goods. PCT Int Appl Wo : (University of Florida, USA; Jabar H; Urbaniak D). 2003:22 pp. 39. Widenhouse CW, Goldberg EP, Seeger JM. Antithrombogenic coatings for biomedical devices. US Pat Appl Publ Us (USA) 2002:11 pp, Cont.-in-part of US Ser No 113,375, abandoned. 40. Akura J, Funakoshi T, Kadonosono K, Sa ito M. Differences in incision shape based on the keratome bevel. J Ca taract Refract Surg 2001; 27:761-5. 41. European Society of Cataract and Refractive Surgeons: www.escrs.org 2005. 42. Kwei JZ-h. Adhesion promoter comprisi ng chromium methacrylate-hydrochloride complexes and poly(vinyl alcohol) for bonding metals and thermoset resins. US Patent Application. Us (E I Du Pont de Nemours & Co, USA). 1999:4 pp, Cont of US Ser No 599,826, abandoned. 43. Keeley C, Kwei JZ-h. Dupont (R) Vola n L (R) Bonding Agent Inquiries: Zaclon, Inc. & Dupont, 2004. 44. Goldberg EP, Yahiaoui A, Mentak K, Erickson TR, Seeger J. Polymer grafting for enhancement of biofunctional propertie s of medical and prosthetic surfaces. US Us (University of Florida, US A). 2002:29 pp, Cont-in-part of US 5,376,400. 45. Seeger JM, Ingegno MD, Bigatan E, et al. Hydrophilic surf ace modification of metallic endoluminal stents. Journal of Vascular Surgery 1995; 22:327-35; discussion 335-6. 46. Ishihara K, Nomura H, Mihara T, Kuri ta K, Iwasaki Y, Nakabayashi N. Why do phospholipid polymers reduce protein ad sorption? Journal of Biomedical Materials Research 1998; 39:323-330. 47. Nakaya T, Li Y. Recent progress of phospholipid polymers. Designed Monomers and Polymers 2003; 6:309-351. 48. New G, Moses Jeffrey W, Roubin Gary S, et al. Estrogen-eluting, phosphorylcholine-coated stent implanta tion is associated with reduced neointimal formation but no delay in vascul ar repair in a porci ne coronary model. Catheterization and Cardiovascul ar Interventions 2002; 57:266-71. 49. Whelan DM, van der Giessen WJ, Krabbendam SC, et al. Biocompatibility of phosphorylcholine coated stents in norm al porcine coronary arteries. Heart (British Cardiac Society) 2000; 83:338-45.

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116 50. Clough RL. High-energy radiation and polymers: A review of commercial processes and emerging applications. Nucl ear Instruments & Methods in Physics Research Section B-Beam Interactions with Materials and Atoms 2001; 185:8-33. 51. Brook MA. Silicon in Organic, Organo metallic, and Polymer Chemistry. New York: John Wiley & Sons, Inc., 2000:680 pp. 52. Arkles B. Gelest: A Survey of Propert ies and Chemistry. Tullytown: Gelest, Inc., 1998:544 pp. 53. Bertrand OF, Sipehia R, M ongrain R, et al. Biocompatib ility aspects of new stent technology. J Am Coll Cardiol 1998; 32:562-71. 54. Wieneke H, Schmermund A, von Birgelen C, Haude M, Erbel R. Therapeutic potential of active stent coating. Expe rt Opin Investig Drugs 2003; 12:771-9. 55. Urbaniak DJ. Surface Modification of Medical Implant Materials with Hydrophilic Polymers for Enhanced Biocompatibility and Delivery of Therapeutic Agents. Gainesville: University of Florida, 2004:176 pp. 56. Campbell D, Pethrick RA, White JR. Polymer Characterization : Physical Techniques. Cheltenham, UK: S Thornes, 2000:viii, 481 pp. 57. Sheets JW. Hydrophilic polymer coatings to prevent tissue adhesion, 1983:xiv, 172 pp. 58. Bityurin N, Muraviov S, Alexandrov A, Malyshev A. UV laser modifications and etching of polymer films (PMMA) below the ablation threshold. Applied Surface Science 1997; 110:270-274. 59. Rau K, Singh R, Goldberg E. Nanoindent ation and nanoscratch measurements on silicone thin films synthesized by pu lsed laser ablation deposition (PLAD). Materials Research Inno vations 2002; 5:151-161. 60. Rau K, Singh R, Goldberg E. Synthesi s and characterization of cross-linked silicone thin films by pulsed laser ablation deposition (PLAD). Materials Research Innovations 2002; 5:162-169. 61. Laude LD, Soudant S, Beauvois S, Renaut D, Jadin A. Laser ablation of charged polymers. Nuclear Instruments & Methods in Physics Research Section B-Beam Interactions with Materi als and Atoms 1997; 131:211-218. 62. Yahiaoui A. Surface modification of intraocular lens polymers by hydrophilic graft polymerization for improved ocular implant biocompatibility, 1990:xvii, 235 pp. 63. Biagtan EC. Effects of gamma radiati on on polymer degradation and surface graft polymerization, 1995:xii, 169 pp.

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117 64. Odian GG. Principles of Polymerization. New York: Wiley, 1991:xxii, 768 pp. 65. Urbaniak DJ, Mauldin J, Goldberg EP. Nanoscratch characterization of polymeric coatings under aqueous conditions. Societ y for Biomaterials 28th Annual Meeting Transactions. Tampa, FL, 2002:569A. 66. Derendorf H, Rohdewald P, Hochhaus G, Mollmann H. Hplc determination of glucocorticoid alcohols, thei r phosphates and hydrocortis one in aqueous-solutions and biological-fluids. Journal of Phar maceutical and Biomed ical Analysis 1986; 4:197-206.

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118 BIOGRAPHICAL SKETCH The author was born in Bronx, NY, lived in Taiwan for two and a half years and in Orlando, FL until she graduated from Lake Brantley High School. She pursued her undergraduate education at University of Florida College of Engineering in the Department of Materials Science and Engineer ing with a focus in Polymers. After a few years in this program, the aut hor also chose to pursue studies in fine arts to further explore her creative talents at the same institution. In August 2001, Margaret was awarded a Bachelors of Science degree, whic h was followed by a Masters of Science in April 2004 both from University of Florida Co llege of Engineering in the Department of Materials Science and Engineering. Finally after numerous evenings in MAE 234D and several bottles of wine, the author de fended her dissertation thesis on June 9th, 2005 and passed. The author was highly involved with extra curricular activit ies. For the University of Florida Benton Engineering Council, sh e served as Society For Biomaterials Representative (2002-03), Assistant Treas urer (2002-03), Finance Committee Member (2002-05), and Treasurer (2003-04). For Societ y For Biomaterials, Ma rgaret served as Secretary (2002-04) of University of Florid a Student Chapter, Secretary (2002-04) of SFB National Student Section, Student Repr esentative (2003-05) of the Long Range Planning Committee, Co-Programs Chair (2003 -05) of Ophthalmologic Biomaterials SIG, Student Representative (2003-05) of Membership Committee, Treasurer (2004-05) of University of Florida Student Chapter, Abstract Reviewer & Moderator (2004-05) for

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119 the 30th Annual Society For Biomaterials Me eting & Expo., Memphis, TN, and Chair (2005-06) of Membership Committee. The authors hobbies include first and fore most wine tasting, college basketball, and dancing to any music that moves her. Additionally, she enjoys oil painting, sculpture, rubber stamping, and jewelry desi gn. Furthermore, she has been known to cook exotic dishes, eat large amounts of salte d pork products, spoil her Abyssinian cats, have success with fix-it-herself projects, a nd she has also been spotted at the driving range from time to time.


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Title: Polymeric Surface Modification of Metallic Medical Implants for Enhanced Stability and Delivery of Therapeutic Agents
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Copyright Date: 2008

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Permanent Link: http://ufdc.ufl.edu/UFE0011321/00001

Material Information

Title: Polymeric Surface Modification of Metallic Medical Implants for Enhanced Stability and Delivery of Therapeutic Agents
Physical Description: Mixed Material
Copyright Date: 2008

Record Information

Source Institution: University of Florida
Holding Location: University of Florida
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POLYMERIC SURFACE MODIFICATION OF METALLIC MEDICAL IMPLANTS
FOR ENHANCED STABILITY AND DELIVERY OF THERAPEUTIC AGENTS
















By

MARGARET W. KAYO


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA


2005

































Copyright 2005

by

Margaret W. Kayo
































This dissertation is dedicated to my family and the close friendships I have made here...















ACKNOWLEDGMENTS

I thank my advisor, Dr. Eugene Goldberg, for his support and leadership, in

addition to his confidence in my abilities. My thanks are also extended to my advisory

committee, Dr. Anthony Brennan, Dr. Chris Batich, Dr. James Seeger and Dr. Kenneth

Wagener. I would also like to acknowledge the expertise of Eric Lambers, Gary

Scheffeile, Paul Martin, Dr. Won-Seok Kim, Dr. Mike Ollinger, Dr. David Norton, Mat

Ivill, Dr. Harmut Derendorff, Dr. Vipul Kumar, Dr. Samuel Farrah and Dr. George

Lukasik.

Thanks are extended to the following people for their technical support and

friendships: Dr. Daniel Urbaniak, Amanda York, Adam Reboul, Adam Feinberg, Dr.

Chris Widenhouse and Jennifer Wrighton.

I thank the following people for their friendship and humor Samesha Barnes, Dr.

Brett Almond, Dr. Clayton Bohn, Iris Enriquez, Jim Schumacher, Anika Odukale, Jompo

Moloye, Tara Wahsington, Amin Elachchabi, Michelle Carman, Leslie Wilson, Thomas

Estes, and Jim Seliga. Finally, I would like to thank my mother, Cecilia Kayo Bressan,

father, David Kayo, stepfather, Ronald Bressan, sister, Rebekah Kao and brother,

Jonathan Kayo for their confidence in my ability to succeed.
















TABLE OF CONTENTS



A C K N O W L E D G M E N T S ................................................................................................. iv

LIST OF TABLES .. ................... ............ ......... .............. viii

LIST OF FIGU RE S .............. .......................... ........................ .. .. .... .x

ABSTRACT ................................................................................ xv

CHAPTER

1 IN T R O D U C T IO N ................................................. .............................................. .

2 BACKGROUND .............................. ............ .............................4

Introduction .................................................................................... . .. ...............4
Endovascular Stents.............................................................. .. 5
Sirolim us (R apam ycin) Eluting Stents ........................................... ............... 10
P aclitax el E luting Stents.................................... ....................... ............... 11......
17p-estradiol E luting Stents ........................................................... ................ 12
D exam ethasone Eluting Stents ....................................................... ................ 13
D rug R release from Silicone............................................................ ............... 14
Keratome Blades............... .................. ............ ............... 15
Materials for Coatings and Implantable Medical Devices ...................................15
S ig n ific a n c e ................................................................................................................ 2 0

3 METAL ALKOXIDE TREATMENTS AND LOW DOSE GAMMA SURFACE
MODIFICATION OF STAINLESS STEEL.........................................................21

In tro d u ctio n ................................................................................................................ 2 1
M etal A lkoxide Treatm ents ................. ................................................................. 21
M materials and M ethods ................................................................... ................ 23
Preparation of 316L stainless steel substrates......................... ................ 23
Treating 316L stainless steel with metal alkoxides.................................23
Chromium alkoxide degradation study .............. .................................... 24
A n a ly sis ........................................................................................................ 2 4
R results and D discussion ..................................... ........................ ................ 24
S u m m ary ............................................................................. . ... ............... 3 1



v









Low Dose Gamma Irradiation Grafting of Polymers to Metal Alkoxide Treated
S u b state s .............................................................................................................. 3 2
M materials and M ethods ................................................................... ................ 33
Preparation and treatment of 316L stainless steel substrates ....................33
Preparation of m onom er solutions .......................................... ................ 34
G am m a irradiation of substrates ............................................. ................ 34
A n aly sis ......................................................................... ... ............... 3 5
R results and D discussion ..................................... ........................ ................ 36
S u m m ary .............................................................................................................. 5 2

4 PULSED LASER ABLATION DEPOSITION (PLAD) AND RF PLASMA
POLYMERIZATION DEPOSITION ...................................................55

Introdu action .................................................................................................. ... ........... 55
Pulsed Laser Ablation Deposition (PLAD) ...........................................................55
M materials and M ethods ............................................... ................. ................ 57
Preparation of silicone targets and substrates ........................................57
Pulsed laser ablation deposition chamber ...............................................58
A n a ly sis ........................................................................................................ 5 9
R results and D discussion ..................................... ........................ ............... 59
S u m m ary .............................................................................................................. 6 6
R F Plasm a Surface M odification................................. ....................... ................ 67
M materials and M ethods .................... .................. .... ................ 68
Preparation of substrate, monomers, and comonomer .................................68
M onom er R F plasm a ................................... ...................... ................ 69
A n a ly sis ........................................................................................................ 7 0
R results and D discussion ..................................... ........................ ................ 70
S u m m ary .............................................................................................................. 7 4

5 SOLUTION POLYMERIZATION COATING SURFACE MODIFICATION........ 76

In tro d u ctio n ................................................................................................................. 7 6
M materials and M ethods .......................................................................... ................ 77
Preparation and Treatment of 316L Stainless Steel Substrates........................77
Preparation of Monomer Solutions ..................................................77
Preparation of Silicone Component Solutions ...............................................77
Solution Polymerization (SP) Coating of Substrates.....................................78
A n a ly sis ............................................................................................................... 7 8
R results and D discussion ................ .............. ............................................ 79
S u m m a ry .................................................................................................................. .. 8 9

6 LOADING AND RELEASE OF THERAPUETIC AGENTS FROM SURFACE
MODIFIED METAL ALKOXIDE TREATED STAINLESS STEEL...................91

In tro d u ctio n ................................................................................................................ 9 1
M materials an d M eth od s ............................................................................. ............... 92
Preparation of Substrates and Coatings ................ ...................................92









Post Loading Ofloxacin and Dexamethasone.................................................93
Drug Loading Solution D epletion Study ........................................ ................ 94
Release of Drugs from Surface Modified 316L Stainless Steel.......................94
Preparation of Bacterial Cultures for Zone of Inhibition ................................. 96
A n a ly sis ............................................................................................................... 9 6
R results and D discussion ................ .............. ............................................ 97
S u m m a ry ................................................................................................................. .. 1 0 5

7 CONCLUSIONS ........................ ............................ ...... .... ............... 107

8 F U T U R E W O R K ...... .. ........ ........ ............................................................. .... 110

LIST O F R EFEREN CE S ... ................................................................... ............... 112

BIO GR APH ICAL SK ETCH .................. .............................................................1...... 18















LIST OF TABLES


Table page

2.1 Metal alkoxide chromium complex constituents.................................................18

2 .2 Silicone curing sy stem s .......................................... .......................... .............. 19

3.1 Volan L solution and Silver Acrylate mixed solvent solution composition .........24

3.2 XPS analysis for air dried samples without rinsing: % Cr2p3 and % C s relative
to % Ols, Fe2p3 and C12p. All conditions were examined on 316L stainless
ste e l ............................................................... 2 7

3.3 MPC XPS elemental surface composition (%) and rehydrated contact angle of
surfaces for dose of 0.1 Mrads. MPC* refers to theoretical concentrations of
elem ental com position ............... .. ............. .............................................. 49

3.4 NVP XPS elemental surface composition (%) and rehydrated contact angle of
surfaces for dose of 0.1 Mrads. NVP* refers to theoretical concentrations of
elem ental com position ............... .. ............. .............................................. 49

3.5 KSPA XPS elemental surface composition (%) and rehydrated contact angle of
surfaces for dose of 0.1 Mrads. KSPA* refers to theoretical concentrations of
elem ental com position ............... .. ............. .............................................. 51

4.1 Contact angle of MED 6820 depositions at various fluences on untreated 316L
sta in le ss ste el ............................................................................................................ 6 0

4.2 XPS elemental analysis (%) of PLAD coated samples on untreated 316L
sta in le ss ste el ............................................................................................................ 6 4

4.3 XPS elemental analysis (%) of PLAD coated samples on Volan treated 316L
sta in le ss ste el ............................................................................................................ 6 5

4.4 XPS elemental analysis (%) of 5 minute monomer RF plasma modification of
untreated, Volan L and Quilon L treated 316L stainless steel ..........................74

5.1 -XPS analysis of SP coated Volan L and untreated 316L stainless steel .............89









6.1 Coating and metal alkoxide treatment conditions investigated for drug release
where Oflox and Dex refers to ofloxacin and dexamethasone, respectively. 2%
V -L refers to 2 % v/v V olan L .......................................................... ............... 94

6.2 Ofloxacin depletion UV-Vis absorption measurements in terms of concentration
with adjustments for surface area and conversions, all values are reported as
a v e ra g e s ................................................................................................................ ... 9 7

6.3 Dexamethasone depletion UV-Vis absorption measurements in terms of
concentration with adjustments for surface area and conversions, all values are
reported as averages. ............. ................ .............................................. 98















LIST OF FIGURES


Figure page

2.1 Illustration of balloon angioplasty and stenting. Adapted from ADAM, Inc............6

2.2 Histological section of restenotic arteries following balloon angioplasty and
stenting .10 Indolfi et al. 2003 ...................................... ....................... .............. .8...

2.3 Various stents. A) CYPHER sirolimus-eluting coronary stent by Cordis
Corporation, B) Stent by Boston Scientific Corporation, C) Stent by Medtronic,
In c ......................................................................................................... . ....... .. 1 1

2.4 Volan and Volan L bonding agent, chromium (III) methacrylate..................... 17

2.5 Quilon L bonding agent, chromium (III) fatty acid where R=C14-18 ......................17

2.6 Hydrophilic monomer structures: 2-methacryloyloxyethyl phosphorylcholine
(MPC), N-vinyl pyrrolidone (NVP), N,N-dimethylacrylamide (DMA), and
potassium 3-sulfopropyl acrylate (K SPA ). ................................... ..................... 19

2.7 Silicone vinyl addition curing system ................................................. ................ 20

3.1 Silver Acrylate (Gelest, Inc., M orrisville, PA). .................................. ................ 23

3.2 XPS survey of PET ...............................26

3.3 XPS spectra of Ag3d5 of silver acrylate treatment on 316L stainless steel. ...........28

3.4 XPS C s and Ols spectra of: A) Previously-opened 2% Quilon L treatment on
316 L stainless steel, B) Newly-opened 2% Quilon L treatment on 316 L
stainless steel, and C) 316L stainless steel control.............................. ................ 30

3.5 XPS C s and Ols spectra of: A) Previously-opened 2% Volan treatment on
316 L stainless steel, B) Newly-opened 2% Volan treatment on 316 L stainless
steel, and C) 316L stainless steel control ........................................... ................ 31

3.6 60Co gamma irradiator and rotating sample stage. ..............................................35

3.7 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and
0.15 Mrads in 10% NVP / UltrapureTM water solutions......................................36









3.8 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and
0.15 Mrads in 10% MPC / UltrapureTM water solutions .....................................37

3.9 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and
0.15 Mrads in 2.5% DMA / UltrapureTM water solutions ...................................37

3.10 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and
0.15 Mrads in 10% KSPA / UltrapureTM water solutions. ..................................38

3.11 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and
0.15 Mrads in 9.5% NVP / 0.5% DMA / UltrapureTM water solutions................. 38

3.12 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and
0.15 Mrads in 9.5% MPC / 0.5% DMA / UltrapureTM water solutions ................39

3.13 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and
0.15 Mrads in 9.5% KSPA / 0.5% DMA / UltrapureTM water solutions...............39

3.14 Contact angle stability of Quilon L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% NVP / UltrapureTM water solutions...........................40

3.15 Contact angle stability of Quilon L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% KSPA / UltrapureTM water solutions.........................40

3.16 Contact angle stability of Quilon L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DMA / UltrapureTM water solutions ......41

3.17 Contact angle stability of Quilon L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / UltrapureTM water solutions.....41

3.18 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1
and 0.15 Mrads in 10% NVP / UltrapureTM water solutions................................42

3.19 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1
and 0.15 Mrads in 10% KSPA / UltrapureTM water solutions...............................42

3.20 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1
and 0.15 Mrads in 9.5% NVP / 0.5% DMA / UltrapureTM water solutions.............43

3.21 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1
and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / UltrapureTM water solutions...........43

3.22 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% NVP / UltrapureTM water solutions...........................44

3.23 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% KSPA / UltrapureTM water solutions.........................44









3.24 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DMA / UltrapureTM water solutions ......45

3.25 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / UltrapureTM water solutions.....45

3.26 Contact angle stability of Quilon L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% MPC / UltrapureTM water solutions ..........................46

3.27 Contact angle stability of Quilon L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DMA / UltrapureTM water solutions.......46

3.28 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1
and 0.15 Mrads in 10% MPC / UltrapureTM water solutions. ..............................47

3.29 Contact angle stability of Volan treated 316L stainless steel irradiated to 0.1
and 0.15 Mrads in 9.5% MPC / 0.5% DMA / UltrapureTM water solutions ..........47

3.30 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% MPC / UltrapureTM water solutions ..........................48

3.31 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DMA / UltrapureTM water solutions.......48

3.32 MPC grafted on treated and untreated 316L SS. XPS elemental spectra for
Nls and P2p. A) 2% Volan L treated, B) 2% Quilon L treated, and C)
u n tre ate d ............................................................................................................. .. 5 0

3.33 SEM of cleaned 316L stainless steel at 5000x..................................... ............... 51

3.34 SEM of 10% v/v MPC gamma irradiation grafted (0.1 MRads) coating on
Volan L activated 316L stainless steel at 5000x .............................. ................ 52

4.1 Illustration of PLA D system setup.60 ......................................................................57

4.2 FTIR-ATR spectra of MED 6820 deposited at a fluence of 400 mJ/cm2 on
silicon w after. .............. ................................................... .................. ....... 62

4.3 FTIR-ATR spectra of MED 6820 deposited at a fluence of 400 mJ/cm2 on 2%
V olan treated 316L stainless steel ...................................................... ................ 62

4.4 FTIR-ATR spectra of MED 6820 deposited at a fluence of 200 mJ/cm2 on 2%
V olan treated 316L stainless steel ...................................................... ................ 63

4.5 FTIR-ATR spectra of MED 6820 deposited at a fluence of 125 mJ/cm2 on 2%
V olan treated 316L stainless steel ...................................................... ................ 63

4.5 SEM of 316L stainless steel at 500x ..................................................... ............... 65









4.6 SEM of MED6820 PLAD coated at fluence of 300 mJ/cm2 onto untreated 316L
stainless steel at 500x. .......... ............ ... ....................................... 66

4.7 Initial contact angle measurements for NVP, DMA and NVP/DMA RF plasma
surface modifications on untreated 316L stainless steel ..................... ................ 71

4.8 Initial contact angle measurements for NVP, DMA and NVP/DMA RF plasma
surface modifications on 2% v/v Quilon L treated 316L stainless steel .............71

4.9 Initial contact angle measurements for NVP, DMA and NVP/DMA RF plasma
surface modifications on 2% v/v Volan L treated 316L stainless steel. ..............72

4.10 Rehydrated contact angle measurements for NVP, DMA and NVP/DMA RF
plasma surface modifications on untreated 316L stainless steel........................... 72

4.11 Rehydrated contact angle measurements for NVP, DMA and NVP/DMA RF
plasma surface modifications on 2% v/v Quilon L treated 316L stainless steel....73

4.12 Rehydrated contact angle measurements for NVP, DMA and NVP/DMA RF
plasma surface modifications on 2% v/v Volan L treated 316L stainless steel.....73

5.1 Initial contact angle measurements for 10% and 25% v/v monomer SP coated
untreated 3 16L stainless steel .............................................................. ................ 80

5.2 Initial contact angle measurements for 10% and 25% v/v monomer SP coated
V olan L treated 316L stainless steel ................................................. ................ 80

5.3 Contact angle measurements immediately after dehydration for 10% and 25%
v/v monomer SP coated untreated 316L stainless steel. ..................... ................ 81

5.4 Contact angle measurements immediately after dehydration for 10% and 25%
v/v monomer SP coated Volan L treated 316L stainless steel..............................81

5.5 Rehydrated contact angle measurements for 10% and 25% v/v monomer SP
coated untreated 316L stainless steel .................................................. ................ 82

5.6 Rehydrated contact angle measurements for 10% and 25% v/v monomer
solution coated Volan L treated 316L stainless steel ....................... ................ 83

5.7 Contact angle measurements for 10% and 25% v/v NVP SP coated untreated
3 16L stainless steel ...................................................................... ............... 83

5.8 Contact angle measurements for 10% and 25% v/v NVP SP coated Volan L
treated 3 16L stainless steel ....................................... ....................... ................ 84

5.9 Contact angle measurements for 10% and 25% v/v MPC SP coated untreated
3 16L stainless steel ...................................................................... ............... 84









5.10 Contact angle measurements for 10% and 25% v/v MPC SP coated Volan L
treated 3 16L stainless steel ....................................... ....................... ................ 85

5.11 Contact angle measurements for 10% v/v KSPA SP coated untreated 316L
sta in le ss ste el ............................................................................................................ 8 5

5.12 Contact angle measurements for 10% v/v KSPA SP coated Volan L treated
3 16L stainless steel ...................................................................... ............... 86

5.13 -FTIR-ATR spectra of MED 6820 medical grade silicone...............................87

5.14 FTIR-ATR spectra of MED 6820 SP coated untreated 316L stainless steel.........87

5.15 FTIR-ATR spectra of MED 6820 SP coating on Volan L treated 316L
sta in le ss ste el ............................................................................................................ 8 8

6.1 Molecular structures for ofloxacin and dexamethasone. ....................................92

6.2 Ofloxacin release from 25% v/v NVP SP coated Volan L and untreated 316L
stainless steel compared with unmodified controls..................... ................... 100

6.3 Ofloxacin release from 25% v/v MPC SP coated Volan L and untreated 316L
stainless steel compared with unmodified controls..................... ................... 100

6.4 Dexamethasone release from 25% v/v MPC SP coated Volan L and untreated
316L stainless steel compared with unmodified controls. ................................101

6.5 Dexamethasone release from 10% v/v MPC gamma irradiation graft coated
Volan L and untreated 316L stainless steel compared with unmodified controls. 102

6.6 Dexamethasone release from 45% v/v MED6820 SP coated Volan L and
untreated 316L stainless steel compared with unmodified controls. ....................103

6.7 Zone of inhibition of ofloxacin release from 25% NVP solution coated Volan
L treated 316L stainless steel. Left-S.Aureus. Right-S.Epidermidis..................104

6.8 Zone of inhibition of ofloxacin release from 25% NVP solution coated untreated
316L stainless steel. Left-S.Aureus. Right-S.Epidermidis ...................................104

6.9 Zone of inhibition of ofloxacin release from 2% silver acrylate functionalized
316L stainless steel. Left-S.Aureus. Right-S.Epidermidis................................ 104















Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

POLYMERIC SURFACE MODIFICATION OF METALLIC MEDICAL IMPLANTS
FOR ENHANCED STABILITY AND DELIVERY OF THERAPEUTIC AGENTS


By

Margaret W. Kayo

August 2005

Chair: Eugene P. Goldberg
Major Department: Materials Science and Engineering

Complications associated with implantable devices have led to research focused on

enhancing surface properties to improve device biocompatibility. Implants such as

endovascular stents and surgical contact devices such as keratome blades are examples of

medical devices that can potentially benefit from enhanced surface properties. Drug

delivery from stent surface modifications has been shown to reduce or control wound

healing response to such implants and enhance wound healing with inhibition of

restenosis. Surface modifications that provide therapeutic effects through the

incorporation and localized action of drugs represent an important area of research for

improved medical devices.

In the study reported here, novel surface modifications of 316L stainless steel have

been prepared with surface functionalized metal alkoxides. The general objective has

been to develop new surface treatments pertinent to metal stents and surgical blades. The

surface modification techniques use in this research included gamma radiation grafting,









solution polymerization coating, thin film deposition by pulsed laser ablation deposition

(PLAD) and radio frequency plasma (RF plasma). The monomers used in these metal

coating systems were designed to produce stable hydrophilic surfaces; N-

vinylpyrrolidone (NVP), 2-methacryloyloxyethyl phosphorylcholine (MPC), N,N-

dimethylacrylamide (DMA), and potassium 3-sulfopropyl acrylate (KSPA). Medical

grade silicones were also studied as coatings on 316L stainless steel using PLAD and

solution polymerization coating methods. Emphasis of the research was on the

evaluation of new metal alkoxide activated stainless steel surfaces with untreated

stainless steel to enhance surface modification stability. Improved hydrophilic surface

modifications of metal alkoxide treated stainless steel were demonstrated to be stable and

lubricious. Surfaces were characterized by contact angle goniometry, FTIR-ATR, XPS

and SEM.

Various conditions were also investigated to develop methods for incorporating

therapeutic agents into modified device surfaces. The drugs studied included ofloxacin,

an antimicrobial agent, and dexamethasone, an anti-inflammatory agent. Loading and

release of these drugs into PBS and human blood plasma were examined by UV-Vis and

HPLC.

In summary, new coating systems and practical process procedures were developed

to enhance the coating stability on 316L stainless steel surfaces and to effectively deliver

therapeutic agents.














CHAPTER 1
INTRODUCTION

The manufacture and sale of implantable devices, such as endoluminal stents and

keratome blades, represent a growing industry in medical treatments that extend and

enhance the quality of life for patients. While manufacturing continues to advance, many

complications remain associated with the biocompatibility of these devices. Material-

tissue interactions play a central role in the bioacceptance of a device. Surface

modification of a medical device is an effective approach to reducing and controlling

post-interventional complications such as inflammation, thrombosis, and restenosis and

to enhance biocompatibility between device materials and local host tissue.

The research presented here was aimed at exploring various new coatings involving

several hydrophilic vinyl monomers and resin reinforced silicone applied in conjunction

with an assortment of metal alkoxide coupling agents through several novel coating

techniques that have been shown to modify surfaces effectively.

316L Stainless steel is widely used in the medical device industry due to its

desirable mechanical properties, low carbon content and high corrosion resistance.

Despite these beneficial characteristics, 316L stainless steel surfaces elicit an

inflammatory and thrombotic cascade when implanted in a blood rich environment in the

human body. For this reason, surface modification is an ideal method to improve the

biocompatibility of 316L stainless steel. Several approaches to modifying metallic

substrates have been investigated and will be presented in this body of work as will the

problems associated with various coating techniques.









A problem inherent to most coatings for medical devices is stability of coatings

over time and when exposed to a variety of storage environments and inadequate

adhesion of the coatings to substrates. The use of a novel coupling system for biomedical

device applications to enhance binding at the polymer and metal interface may resolve

these issues. Metal alkoxides with either methacrylate functionality or fatty acid pendant

groups were investigated in this research.

The research presented here used metal alkoxide coupling systems to enhance the

binding of polymer coatings to metal substrates employing a wide variety of surface

modification techniques. Because these coupling systems have not been used in the

biomedical device industry, their incorporation into medical device surface modification

techniques is a novel approach for developing stable coatings with the potential to release

therapeutic agents from the coatings.

Chapter 2 presents a review of the biological complications associated with medical

implants, examples of device complications from clinical studies and the materials and

technologies that have led to this work. Backgrounds of individual surface modification

techniques will be addressed at the beginning of each respective chapter.

Chapter 3 focuses on the development of metal alkoxide coupling and coating

systems and the use of gamma irradiation for initiating surface reactions in monomer

solutions for modification of metal substrates. The incorporation of metal alkoxide

pretreatments is shown to enhance the stability of the hydrophilic monomers investigated

when grafted by gamma initiation.

Chapter 4 covers the use of Pulsed Laser Ablation Deposition (PLAD) and

monomer RF-plasma. Both techniques require vacuum systems and rely on ionizing the









surfaces with laser and radio frequency generated plasma, respectively. In PLAD, the

influence of chamber oxygen content on coating composition is explored. New coating

conditions are investigated with RF-plasma utilizing individual monomers as well as a

combination. Additionally, the effectiveness of these surface modification techniques are

investigated with metal alkoxide coupling systems.

Chapter 5 describes the effectiveness of metal alkoxide treatments with solution

polymerization coating. In addition to vinyl monomer solutions, dilute reactive resin

reinforced silicone solutions were also investigated in these coating systems.

Chapter 6 highlights sustained release studies demonstrating the potential of metal

alkoxide coupling systems to enhance coating stability for drug delivery applications.

Release of both an antimicrobial and anti-inflammatory drug was investigated with

various gamma irradiated and solution coated systems.

Chapters 7 and 8 review the conclusions drawn from the studies in each chapter

and identify avenues for future studies, respectively.

This body of work is intended to advance the understanding and application of

chromium alkoxide coupling systems to enhance polymer coating stability on stainless

steel surfaces with the potential to release drugs. Biocompatibility is not tested in this

work, while demonstrating biocompatibility is the long-term goal for the coating systems

developed here.














CHAPTER 2
BACKGROUND

Introduction

The manufacturing of implantable medical devices has revolutionized treatment

and quality of life for patients. The strides made in implantable medical device research

have led to a focus on developing surfaces that afford these devices greater

biocompatibility in the human body. For example, surface modifications and

compositional developments of endoluminal stents have reduced restenosis rates.

Additionally, developments in keratome blade sharpness and composition have decreased

trauma after intraocular lens implantation. However, most materials are not readily

accepted by the body and often cause a foreign body response in addition to

inflammatory trauma associated with the process of implantation.1 How well a device is

accepted by a patient's biology is largely governed by chemical or structural surface

interactions between the implanted material and surrounding tissue.1

Immediately after a device has been implanted or is in contact with live biological

tissue, an inflammatory response ensues beginning with the adsorption of a protein

monolayer.1 Monocytes, leukocytes, macrophages, cytokines and other chemical

mediators are signaled to migrate to the injured site and serve to heal or rebuild the tissue.

This initial response can last from minutes to several days depending on the host response

to the implant or type of trauma followed by a chronic response and granulation. When

injured tissue cannot be healed or rebuilt often due to the presence of a foreign body









(implant), local inflammatory cells begin fusing together forming giant cells in an attempt

to wall off the site, which is an end stage healing response.

Thrombosis is a blood compatibility complication associated with most

intravascular implant materials that may otherwise be inert. When these materials are

used for implantable medical devices, platelet activation coupled with inflammation

begins the thrombotic cascade. Thrombosis is initiated by protein adsorption onto a

surface in contact with blood, which causes an irreversible platelet aggregation releasing

a host of factors to essentially coagulate and "plug" an injured site to prevent excessive

blood loss.1-4

Material surfaces that are thrombogenic can be modified to have more compatible

material-tissue interactions for a variety of different surgical instrument and implant

applications. Furthermore, inflammatory response can be controlled without systemic

toxicity through localized release of therapeutic agents. Presented here are two examples

illustrating the clinical needs to enhance material surface properties for increased

biocompatible medical devices for implantation: endovascular stents and keratome

blades. A discussion of materials for coating implantable medical devices will conclude

this background.

Endovascular Stents

Percutaneous transluminal coronary angioplasty (PTCA) is a technique used for the

treatment of coronary atherosclerosis and heart disease, where procedures for

revascularization of coronary arteries involve flattening fatty plaques in the blood vessel

against the vessel walls by a balloon catheter, see Figure 2.1.5 From 1987 to 2001, the

number of PTCA procedures has increased 266% in the United States.6 In 2001,

approximately 571,000 PTCA procedures were performed on 559,000 patients. Also,










475,000 of these procedures included cardiovascular stenting, which has been shown to

significantly reduce restenosis as compared with balloon angioplasty alone.6'7

Before After





A balloon-
tipped tube -
is inserted ir.
coronary artery

Balloon is expanded
several times













OADAlM
Figure 2.1 Illustration of balloon angioplasty and stenting. Adapted from ADAM, Inc.

Restenosis is a phenomenon marked by an occluding lesion occurring after balloon

angioplasty or stenting.5 Restenosis can require repeat surgeries and can lead to death.

For patients undergoing percutaneous balloon angioplasty, 30-40% will develop

restenosis in the first 6 months while stenting decreases the incidence to 20%.7 Although

there have been vast stent technology improvements, the problem of in-stent restenosis

has not been resolved and remains as relevant as the issue of restenosis after PTCA.

Recent studies suggest atherosclerosis, a disorder that causes fatty plaque to deposit

along arterial and vessel walls, involves several factors including inflammation, vascular

smooth muscle cell (VSMC) proliferation/migration, endothelial dysfunction and









extracellular matrix alteration.8 Similar factors are associated with the molecular

mechanisms of restenosis and in-stent restenosis.9-11

Restenosis after balloon angioplasty was found to be distinctively different from in-

stent restenosis from a histological standpoint.10 Indolfi et al. suggests that the

mechanism for restenosis after balloon angioplasty is predominantly due to negative

vessel remodeling, while the proliferation of smooth muscle cells only accounts for 25%

of the phenomenon, as illustrated in Figure 2.2.10 Indolfi et al. noted that there was no

evidence of vessel remodeling with cardiovascular stenting; however, restenosis was still

observed.

The in-stent restenosis mechanism appeared to be due entirely to the proliferation

of smooth muscle cells. Consequently, it was found in swine coronary arteries that

restenosis as a result of balloon angioplasty consisted of vessel remodeling and

neointimal hyperplasia, while in-stent restenosis consisted of mostly neointimal

hyperplasia.11

Nakatani et al. concluded that neointimal proliferation of smooth muscle cells post-

stenting persisted longer than the proliferation associated with balloon

angioplasty. {Nakatani, 2003 #61} Likewise, Hofma et al. suggested stenting lead to

longer wound healing cascades due to the permanency of stent placement leading to long-

term endothelial dysfunction and inflammation. {Hofma, 2001 #194} These

developments have lead to a focus in targeting cell cycle regulation as treatment against

in-stent restenosis.













BALLOON STE
ANGIOPLASTY




00
Figure 2.2 Histological section of restenotic arteries following balloon angioplasty and
stenting.10 Indolfi et al. 2003
Today, metallic vascular stents are available in several materials including various

grades of stainless steel, cobalt-chromium, tantalum and nickel-titanium compounds.12

However, when implanted without further surface treatment, many metallic formulations

are thrombogenic and do not inhibit neointimal hyperplasia.13 Several coatings for

enhanced biocompatibility of metallic stent materials have been investigated including

inorganic/ceramic coatings (gold, carbon, iridium oxide and silicon carbide), synthetic

and biological polymers (polyurethane, polylactic acid, phosphorylcholine, chondroitin

sulfate, hyaluronic acid, fibrin, elastin and cellulose), and drugs (heparin, sirolimus and

paclitaxel).14

Gold, carbon, and silicon carbide (SiC) inorganic/ceramic coatings on stents have

been studied in human clinical trials. 13, 14 In the first 30 days after intervention, gold

coated stents were discovered to have no antithrombotic effects, and exhibited an

increased incidence of neointimal hyperplasia within the first year. 13, 14 Carbon coated

stents, such as Carbostent (Sorin Biomedica Cardio), were found to yield low major

adverse cardiac event (MACE) (12%) and binary restenosis (11%) rates at 6 months









follow-up with 112 intermediate risk patients.13 SiC coatings have been used without

reports of biocompatibility issues, however high concentrations of SiC debris can be

cytotoxic. 14 SiC coatings did not have a considerable affect on rate of restenosis when

compared with balloon angioplasty alone in a clinical trial.13

Synthetic and biological polymeric coatings have also been investigated in human

clinical trials. Specifically, phosphorylcholine coatings have been evaluated in the

SOPHOS (Study of Phosphorylcholine on Stents) trial with 425 patients. At 6 months,

this study showed a MACE of 13.4% for Phosphorylcholine coated stents versus 15% for

uncoated stents.14 The 6 month binary restenosis rate was 17.7% for the coated group.

The researchers in this study concluded there was a less severe inflammatory response

associated with phosphorylcholine coating as compared with several other polymers for

the same application.

Immobilized drug coatings have been used in the clinical setting where drugs can

be physically adsorbed or chemically tethered to the stent surface. Heparin coated

Palmaz-Schatz stents exhibited comparable effectiveness in the prevention of restenosis

when compared with uncoated stents combined with systemic abciximab treatments.14

Heparin coated stents did not demonstrate any significant differences in MACE and

binary restenosis rates. The authors concluded that heparin coated stents did not have an

effect on in-stent restenosis.13 Sirolimus and paclitaxel have also been examined in a

clinical setting. Sirolimus coated stents when compared with uncoated stents (26.6%)

had a 0% binary restenosis rate at 6 months post-intervention.13 The authors reported that

no late thrombosis occurred with the sirolimus eluting treatment. ASPECT (Asian

Paclitaxel-Eluting Stent Clinical Trial) examined a high and low dose condition for









paclitaxel coated stents with no polymer carrier.13 The 6 month binary restenosis rate

was 4% versus 27% for the uncoated group. MACE rates are currently unpublished for

this study.

Inert coatings alone on stents have not reduced restenosis rates or thrombosis to an

acceptable level. Additionally, drug coatings alone did not yield satisfactory outcomes.

Consequently, many vascular device companies have or are in the process of developing

drug-eluting stents to combat in-stent restenosis. 15 Some of the drugs involved in clinical

trials of drug eluting stents include rapamycin (sirolimus), paclitaxel, tacrolimus,

everolimus, 173-estradiol, and dexamethasone.8' 10, 15 The two most extensively

evaluated drugs undergoing drug eluting stent clinical trials are paclitaxel and rapamycin

(sirolimus). However, STRIDE (A Study of Antirestenosis with the BiodivYsio

Dexamethasone-Eluting Stent), clinical trial launched in February 2003 and more

recently the EASTER trial (Estrogen and Stents to Eliminate Restenosis), has yielded

promising results in some patients.15

Sirolimus (Rapamycin) Eluting Stents

Sirolimus (Rapamycin) is an immunosuppressant antibiotic derived from

streptomyces hygroscopicus from Easter Island soil samples.16 Sirolimus functions by

binding to immunophilins inhibiting cell signal transduction thus targeting cell cycle

progression.16-18 Sirolimus inhibits VSMC migration in vitro and proliferation in vitro

and in vivo.

The results of several clinical trial investigations on the effects of sirolimus on

restenosis rates have been remarkable with 1 year MACE as low as 0% and in-stent

restenosis of 2.0%. 13, 16 The Cordis CYPHER stent is currently one of two drug eluting

coronary stents approved for use in humans in the United States, Figure 2.3. The stent is









loaded with sirolimus to an effective surface concentration of approximately 150-180

[pg/cm2.14, 16 Despite the clinical benefits of sirolimus eluting stents, varying degrees of

inflammation, delayed endothelialization and toxicity concerns remain.10, 15, 16, 18





















Figure 2.3 Various stents. A) CYPHER sirolimus-eluting coronary stent by Cordis
Corporation, B) Stent by Boston Scientific Corporation, C) Stent by
Medtronic, Inc

Paclitaxel Eluting Stents

Paclitaxel is an antineoplastic and chemotherapeutic agent derived from yew

trees.16 Similar to sirolimus, paclitaxel interrupts signal transduction and has been shown

to inhibit the proliferation and migration of VSMC. As in the ASPECT trial, the

ELUTES (Evaluation of Paclitaxel Eluting Stents) also suggests a dose dependency for

paclitaxel effectiveness in reducing restenosis and MACE.13 However, paclitaxel in the

TAXUS I trial proved to be promising at 6 months with 0% binary restenosis for coated

stents compared with 11% in the bare stent group. Additionally, no MACE was observed

at 12 months. 16









Like the Cordis CYPHER stent, Boston Scientific's NIR poly(lactide-co-l-

caprolactone) copolymer and paclitaxel stent is also approved for use in humans, see

Figure 2.3. There are approximately 200 [g of paclitaxel loaded per stent.19 Problems

associated with paclitaxel eluting stents include incomplete healing due to delayed

endothelialization, persistence of macrophages, and deposition of fibrin. Furthermore, it

was found that 80% of the loaded drug released within the first 3 days of deployment.10,

15, 16, 19

17p-estradiol Eluting Stents

The release of 17p-estradiol has been investigated with phosphorylcholine coated

stents. In 2002, Biocompatibles Ltd. filed a world patent titled "Stents with Drug-

Containing Amphiphilic Polymer Coating".20 The invention disclosed a shape memory

alloy stent with a zwitterionic coating capable of releasing hydrophobic or hydrophilic

drugs.

On March 17, 2004, an Estrogen And Stents To Eliminate Restenosis (EASTER)

clinical trial report was released indicating that the release of 17p-estradiol was safe and

may be effective in inhibiting in-stent restenosis in humans.21 17p-estradiol was eluted

from phosphorylcholine coatings on 316-L stainless steel balloon expandable stents

during the EASTER clinical trials.21 However, a burst release profile was observed and

the total release was completed within the first 24 hours of stent deployment.

The surface concentration used in this study was determined to be 2.52 ig/mm2. 21

Despite the rapid release, no in-stent thrombosis occurred and late-stent malapposition

was not detected. Additionally, no edge restenosis was found at a 6 month follow-up. At

1-year, revascularization and low rates of restenosis were observed.21 In each follow-up,

system toxicity was not evident. The EASTER trials indicate that 17p-estradiol is a









viable alternative approach to other restenosis reducing agents. Although it has been

reported that complete inhibition of restenosis was not observed, changing drug release

properties, doses, and coating materials may improve efficacy.

The release properties of 17p-estradiol chemically incorporated into poly(acrylic

acid) coated 316-L stainless steel plates by a hydrolysable covalent bond has been

investigated in an in vitro model.22 The initial 17p-estradiol concentration in this study

was determined to be ~12+4.2 ig/cm2 and released for two weeks, with no initial burst

effect. Currently, an in vivo investigation in a porcine coronary injury model has yielded

promising preliminary results demonstrating a significantly lower incidence of restenosis

at 8.58% when compared with non-173-estradiol treated stents (11.62%).22

Dexamethasone Eluting Stents

Dexamethasone is a synthetic glucocorticosteroid that produces anti-inflammatory

responses by interfering with macrophages and modifies protein synthesis.16, '23,24 The

release of dexamethasone from a biodegradable poly-L-lactic acid coating has been

studied by Lincoff et al.25 The investigation yielded intense inflammatory response by 28

days after implantation, which was attributed to the degradation mechanisms of the

coating. It was also shown in this study that dexamethasone did not decrease neointimal

hyperplasia in the porcine coronary artery after stent overexpansion trauma. Lincoff

suggested the inflammatory responses that should have been suppressed by

dexamethasone did not moderate a key pathway to restenosis in the porcine coronary

model.

Dexamethasone release from liposome coatings composed of phosphatidylcholine

and cholesterol have been investigated and are ongoing in the STRIDE trials. 16, 23, 24 The

STRIDE study has demonstrated a significant reduction of in-stent restenosis with a 6









month follow-up binary restenosis rate of 13.3%.16'23 From the STRIDE study,

dexamethasone release from phosphorylcholine coating was found to be feasible and safe

with no increases in thrombosis and low event rates. However, neointimal thickening

was not found to decrease in this study. This observation was attributed to the low

concentration of dexamethasone administered in the study. The authors suggested that

further studies investigating higher dose treatment with dexamethasone would be

23
necessary.

The use of dexamethasone impregnated in silicone coated stents was also briefly

investigated in a porcine model. The results of these studies showed evidence of high

anti-inflammatory and antifibrotic effects.16

Drug Release from Silicone

Hormone delivery from silastic vaginal rings has been widely available and

accepted for hormone replacement therapy and contraception.26-33 Silastic vaginal rings

have been shown to be effective for sustained and steady release of 17p-estradiol

(Estring) and several other commercially available hormones.

Sustained release of these therapeutic agents from silicone has been attributed to

the hydrophobicity of the material and lipophilic nature of the hormones.27-30,34,35 The

successes of hormone replacement therapy and contraceptive silastic vaginal rings

suggest that it is feasible to achieve steady state release of steroid hormones from silicone

coatings. In addition to silastic vaginal rings, polydimethylsiloxane (PDMS), is currently

used in several biomedical applications such as intraocular lenses, catheters, and various

cosmetic implants.16, 31, 36-39









Keratome Blades

Keratome blades are used in phacoemulsification procedures for cataract

surgeries.40 These blades are designed as single use devices, but can greatly affect the

level of trauma associated with these surgeries. The sharpness, material composition, and

geometries of these devices all contribute to this. As with stents, blade surface properties

can greatly affect the degree of inflammation after tissue contact, which can result in

complications such as astigmatism. Inflammation is also caused by the implant

procedure, which requires a small incision with a width of 3 mm, where blades have

been reported to cause unpredictable incisions due to poor translation across the cornea.41

The surgery also includes the extraction of the cataract and natural vitreous and

replacement with either a silicone oil or polysaccharide emulsion. If the implant is a

foldable intraocular lens, then the incision can self-seal. Otherwise, the incision will

require enlargement and must be sutured, glued or taped closed to heal.1 Blade surface

properties can greatly affect inflammation associated with both the cataract removal and

intraocular lens placement procedure. Furthermore, infection at the incision site can

prolong inflammation and associated complications.

Materials for Coatings and Implantable Medical Devices

316-L stainless steel has been used for several biomedical device applications

including drug eluting stents. 316-L stainless steel has a composition in the range of

<0.03% C, 16-18.5% Cr, 10-14% Ni, 2-3% Mo, <2% Mn, <1% Si, <0.045% P, <0.03%

S, and Fe as the remaining constituent. Depth profiling studies of stainless steel films

indicate high Cr203 surface content, which is a key component in corrosion resistance.12

This Cr3+ rich layer has an approximate thickness of- 2 nm after electropolishing.12

Additionally, trivalent chromium is an essential trace mineral, unlike hexavalent









chromium which has been shown to be toxic. Stainless steel has been used in permanent

stent devices. It remains an ideal candidate for this application due to exhibiting

relatively inert material behavior in most corrosive environments. However, 316L

stainless steels do exhibit some unfavorable susceptibility to potential consequences of

injury due to acute localized thrombus formation or neointimal hyperplasia.1

Coupling agents are commonly used to enhance the binding of coatings to

substrates. For 316-L stainless steel, silanes such as tetraethoxysilane (TEOS),

hexamethyldisilane (HMDS), Bis(3-triethoxysilylpropyl) tetrasulfide, and SID-4612 (a

silazane) are typically employed. Many silane coupling agents require more than a single

step procedure for treatment. However, chromium (III) methacrylate and chromium (III)

fatty acid coupling agents developed around 1942 that require only single step procedures

for treatment (Figures 2.4, 2.5).42,43

As shown in Figure 2.4, Volan is a chlorinated metal alkoxide with two Cl-

tethered to each Cr3+. The chlorine content is controlled by the percent of solids or salts

in the mixture. The Volan has more chlorine content than Volan L making it more

stable to hydrolysis. The scientists who developed this coupling agent claim the Cl-

remains tethered to the Cr3+ even after bonding. However, they have also suggested that

the coupling action may be a slightly acidic reaction creating "some" chlorinated salt by-

products.43 Volan L is designed to bind polyesters, epoxies, phenolics, vinyls, and

acrylics to inorganic or polar surfaces such as glass, metals, polymer, silica, boron and

some natural surfaces.










CH3


Figure 2.4 Volan and Volan L bonding agent, chromium (III) methacrylate

QuilonL is also a metal alkoxide coupling agent that is chromium (III) fatty acid

based, see Figure 2.5. Fatty acid based systems can be useful for formation of

carbonaceous surfaces that will undergo further treatments for binding organic coatings

onto inorganic surfaces.

R

0 0


/ O
Cl O'" Cl

Figure 2.5 Quilon L bonding agent, chromium (III) fatty acid where R=C14-18

The Cr3 of Quilon L, Volan, and Volan L may interact favorably with the

Cr203 surface protective films on 316L stainless steel. It is feasible to bind various

monomers and vinyl addition silicones to this surface by reacting with the methacrylate

and fatty acid groups of these metal alkoxides. Table 2.1 lists the chromium complex

constituents of Volan, Volan L and QuilonL as provided by the manufacturer.










Table 2.1 Metal alkoxide chromium complex constituents


Volan


Volan L


QuilonL


Chrome Complex, %
(active ingredient)

% Chromium 6.0 6.0 9.2

% Chloride 8.2 3.2 12.7

% Methacrylic Acid or % 5.1 5.1 21 .
Fatty Acid (C14-18)



Several hydrophilic polymers have been investigated for biomedical device

applications such as poly(methacryloyloxyethyl phosphorylcholine),

polyvinylpyrrolidone, polydimethylacrylamide, and poly(potassium sulfopropyl

acrylate). These polymers have been shown to be biocompatible and have been

investigated for ophthalmic and cardiovascular applications.13, 44-49 The monomer

structures for these materials are illustrated in Figure 2.6.













0




OSfO

0
K


KSPA


MPC
Figure 2.6 -Hydrophilic monomer structures: 2-methacryloyloxyethyl phosphorylcholine
(MPC), N-vinyl pyrrolidone (NVP), N,N-dimethylacrylamide (DMA), and
potassium 3-sulfopropyl acrylate (KSPA).

Table 2.2 Silicone curing systems
Peroxide Per ox


Condensation ,OH H+
S HSi + HoSi i + H20

Metal Salt Si + H S Metal St Si O H

Vinyl Addition SiH Si+ Pt \SSi S




Polydimethylsiloxane (PDMS) is a hydrophobic polymer that is currently used in

biomedical applications.50 As indicated in Table 2.2, there are four primary methods for

curing silicone. Currently, the vinyl addition curing system is used predominantly.51

Many commercial formulations of silicone are available as two-component systems that

cure through platinum catalyzed hydrosilylation.51 This reaction is illustrated in Figure

2.7. Part A consists of silicone oligomers with vinyl terminated silanes, resin reinforcing


NVP




N


DMA









fillers, and the platinum catalyst.52 Part B consists of hydride functional silicone

oligomers and vinyl terminated silanes. To increase PDMS modulus, tensile strength,

tear strength, and abrasion resistance, most silicones are reinforced with silica

particulates.51 The silicone that will be used in this project is resin reinforced rather than

particulate filled. The curing process is initiated when the components are combined.

Heat is added to increase the curing rate and bring the process to completion.

-0 CH3 -0 CH3
1 I Pt I
-O0-Si-H + H2C=CH-Si-O0- _-_ Si-CH2CH-Si-O__
I I I I
OH3 OH3 COH3 H3
Figure 2.7 Silicone vinyl addition curing system

Significance

Implantable medical devices often cause a cascade of responses due to trauma

associated with implantation and material-tissue interfacial incompatibility. Furthermore,

it has been demonstrated that drug therapy can reduce or control the host response to

implants and possibly encourage wound healing. It is apparent that there is a need for

enhancing the surface properties coupled with localized drug therapy for implant

applications such as endovascular stents and surgical devices such as keratome blades. It

is the goal of this research to develop new coating systems that are coupled by a one step

coupling wash of 316L stainless steel to enhance coating stability and delivery of

therapeutic agents, thus laying the groundwork for studies focused on biocompatibility

testing of these promising surface modifications.














CHAPTER 3
METAL ALKOXIDE TREATMENTS AND LOW DOSE GAMMA SURFACE
MODIFICATION OF STAINLESS STEEL

Introduction

Stenosis of the coronary arteries is now often treated by percutaneous transluminal

coronary angioplasty combined with endovascular stent implantation. Endovascular

stents coated with hydrophilic polymers have been shown to exhibit reduced platelet

reactivity and accumulation in-vivo compared to uncoated metal stents.44' 45 These

coatings may decrease the risk of thrombosis and can potentially be loaded with

therapeutic agents that reduce the incidence of post-intervention complications such as

restenosis.53, 54

Ongoing problems with coatings are drug release to inhibit restenosis and adhesion

to the substrate metals. Poor coating adhesion can lead to delamination or otherwise

make the coating unstable thus rendering the surface modification unacceptable. This

research was devoted to metal alkoxide surface treatments that may enhance the adhesion

and stability of coatings on metallic substrates. The two main objectives of this research

were to develop new metal alkoxide treatments using trivalent chromium metal alkoxides

for enhancing stability of subsequently applied polymeric coatings produced by gamma

irradiation.

Metal Alkoxide Treatments

Silane coupling agents have been used extensively for applications such as

aminosilanes used in the fiberglass industry, acryloxypropyltrimethoxysilanes used in









optical fiber coatings, and tetraethoxysilane in sol-gel processes for forming ceramic

coatings and materials. The treatment process often requires several steps to complete, in

addition to the procedures associated with the specific coating technology. Silane

coupling systems often include a priming step in which agents such as bis[3-

(triethoxysilyl)propyl]-tetrasulfide are applied metal surfaces. The agent is then

hydrolyzed and converted to silanol. The coupling treatment is completed by condensing

a silane coupling agent such as divinyltetramethyldisilazane to the pretreated substrate.

The functionalized substrate is often heated to promote further condensation and

formation of stable covalent bonds and driving off the organic species. The resulting

porous gel can be sintered, or heated, under vacuum to remove the hydrolyzed organic

species, promote further condensation and increase density. The approach taken here

utilizes metal alkoxides with hydrolysable allylic organic species. The process used in

this research deviates from conventional sol-gel processes because it does not involve the

sintering step. This deviation preserves the porosity of the gel and presence of the allyl

organic species within the porous structure. The unsaturated functionality of the

hydrolyzates, such as with acrylates and methacrylates, is utilized to graft or enhance

grafting of polymeric coating to inorganic materials such as stainless steel.

Medical grade 316L stainless steel develops a corrosion-inhibiting Cr203 coating of

approximately 2 nm thick when the material is electropolished. The treatment of the

protective layer by a chromium coupling system using new trivalent chromium based

metal alkoxides binding agents to enhance the binding and stability of coatings is

explored. Newer metal alkoxides such as chromium (III) methacrylates or chromium

(III) fatty acids are used to functionalize surfaces by a simple solution dipping process.









Research aimed at development of chromium priming as an approach to improving

various subsequent surface modifications is reported here.

Materials and Methods

Preparation of 316L stainless steel substrates

Substrates of 316L stainless steel (1 cm x 1 cm) were cut from a single stock of foil

that had a thickness of approximately 0.1 mm. Substrate surfaces were cleaned by

sequential sonication for 5 minutes at 47 KHz at room temperature in 30 mL each of

1,1,1-trichloroethane, chloroform, acetone, methanol, and UltrapureTM water then dried

under vacuum at 600C. Fifty substrates were cleaned at a time. Substrates were not

electropolished.

Treating 316L stainless steel with metal alkoxides

Clean substrates were placed in 25 mL aqueous solutions of 2%, 10% or 100% v/v

chromium III fatty acid (Quilon L, DuPont) for 1 single dip, 10 minutes rotating or 60

minutes while rotating. Ten substrates were treated for every 25 mL solution. Treated

substrates were removed from solutions and allowed to either air dry or rinsed with

UltrapureTM water, then dried in air at room temperature. Silver acrylate (Gelest, Inc.)

treatments were also explored. Silver acrylate was purchased in powder form and the

chemical structure is given in Figure 3.1. Three silver acrylate treatment solutions were

prepared in volumes of 25 mL with 2% w/v concentrations in isopropanol, acetone or a

mixture similar in formulation to Volan L, see Table 3.1.



0 Ag
Figure 3.1 Silver Acrylate (Gelest, Inc., Morrisville, PA).









Table 3.1 Volan L solution and Silver Acrylate mixed solvent solution composition.
Ingredient Volan" L Silver Acrylate
Complex, %
17-18 17-18
(active ingredient)
% Isopropanol 56 56
% Acetone 10 10
% Water 16 16

Chromium alkoxide degradation study

Chromium complex degradation was studied to compare freshly opened stock

solutions and solutions that had aged for approximately 12 months since their first use.

The solutions studied were chromium III fatty acid (Quilon L, DuPont) and chromium

III methacrylate (Volan and Volan L, DuPont) at concentrations of 2% and 10% v/v

solutions where 25 mL of each solution was prepared for treating 10 stainless steel

substrates each. Cleaned substrates were placed in the solutions for 10 minutes while

rotating, then removed and allowed to air dry.

Controls in all cases consisted of untreated 316L stainless steel specimens that were

cleaned as previously described.

Analysis

Treatments were analyzed by x-ray photoelectron spectroscopy (XPS/ESCA)

analysis using a Kratos Analytical Surface Analyzer XSAM 800. Analysis was

performed using Mg and Al anodes for excitation. Survey scans were taken in low

resolution with a dwell time of 150, 10 sweeps, and step size of 0.5 in FRR mode with

both Al and Mg anodes. Elemental scans were taken in medium resolution with a dwell

time of 60, 20 sweeps, and step size of 0.05 in FRR mode with only Al anode.

Results and Discussion

The Quilon L, Volan and Volan L manufacturer, Dupont, suggests the optimal

treating solution concentration for all substrate materials is 2% v/v with water and









buffered to pH = 7.0, a solution concentration optimization study was done to verify the

this. It is important to point out that previous work in this laboratory by Dr. D. Urbaniak

indicated that it is not necessary to buffer the metal alkoxide bonding agent solutions

prior to application. This work showed that surface treatment with buffered solutions

often resulted in uneven chrome complex deposition when examined by scanning

electron microscopy (SEM), while buffered solutions yielded even, homogeneous surface

treatments that were suitable for subsequent surface modification procedures.55

For chromium alkoxide treatment optimization, XPS was used to examine surface

concentrations of C Is, Ols, Fe2p3, Cr2p3, and C12p peaks on treated 316L stainless steel

substrates. The C1s peak was examined for poly(ethylene terephthalate), a material used

as an internal C s and Ols reference. The theoretical relative concentrations of carbon

and oxygen atoms are 71.4% and 28.6%, respectively. The experimental results were

73.1% CIs and 26.9% Ols, see Figure 3.3 for the survey scan. The difference was small

and could be attributed to low molecular weight carbon deposition during the 24 hour

vacuum cycle. The primary C1s peak corresponding to C-C bonding should be around

284.6 eV, but our analysis of PET yielded a primary CIs peak at 281.7 eV. This 3 eV

shift to lower binding energy should be considered when examining all XPS data in this

work. The raw XPS data are reported here without any post-processing such as signal

normalization or shifting.










MGSV 1
o104
20_

18.

16

14

12.






4-



1000 900 800 700 600 500 400 300 200 100
Bindmg Er (yeV)
Figure 3.2 XPS survey of PET.

It is significant that as the metal alkoxides are deposited from the solution the

chromium moiety will bind to the chromium oxide on the surface of the substrate causing

the methacrylate or fatty acid chains to be oriented away from the substrate. This

orientation becomes important when discussing relative elemental concentrations since

XPS has a surface sensitivity of 2-20 atomic layers.56 For example, if the fatty acid chain

is 18 carbons long and even folded on itself, the carbon signal detected by XPS would be

much more efficient than the surface chromium, iron, etc.

Elemental analysis of Quilon L treated substrates yielded no significant

difference in peak location or surface concentrations for the C Is and C12p peaks of 2%

and 10% v/v treating solutions for single dip, 10 minutes and 60 minutes tumble washing.

This was true for air dry and rinse, then air dry conditions. There appeared to be no

advantage in rinsing the treated substrates before drying. Additionally, increased C12p

was observed for 10% v/v treating solutions that were rinsed and then air dried.









Substrates treated with 10% v/v solutions appeared to be spotty, while 100% v/v

treatments resulted in scaly surfaces that easily peeled away from the substrate. This was

not observed for any 2% v/v solution treated substrates. The relative iron content was

lowest with the 100% v/v treatments, which was an expected outcome since the treatment

is much denser. As listed in Table 3.2, the relative surface chromium content increased

for all conditions when compared with untreated 316L stainless steel, which

corresponded with the binding of chromium based metal alkoxides to the surface. Lastly,

all conditions resulted in an increase in the C Is surface concentration, which corresponds

to the fatty acid groups of Quilon L, suggesting that the chrome complex was deposited

during treatment.

Table 3.2 XPS analysis for air dried samples without rinsing: % Cr2p3 and % CIs
relative to % Ols, Fe2p3 and C12p. All conditions were examined on 316L
stainless steel.
Condition % Cr2p3 % Cls
Untreated 316L SS, Control 1.8 48.8
2 % Quilon L, Single Dip 2.7 68.5
2 % Quilon L, 10 Min 3.7 64.1
2 % Quilon L, 60 Min 3.1 68.5
10 % Quilon L, Single Dip 2.4 67.3
10 % Quilon L, 10 Min 2.5 67.3
10 % Quilon L, 60 Min 2.6 69.5
100 % Quilon L, Single Dip 1.6 82.1
100 % Quilon L, 10 Min 2.0 75.5
100 % Quilon L, 60 Min 3.3 63.7


The use of silver acrylate was investigated to examine the feasibility of using other

allyl metal alkoxide systems and was of particular interest because of potential

antimicrobial properties that may arise from the silver moiety. Since silver acrylate is

only available in powder form, attempts were made to develop a treatment solution to

functionalize stainless steel. A 50% isopropanol and 50% acetone solution was used to










dissolve the metal alkoxide. The result was a 2% w/v solution. Next, acetone was used

to dissolve the silver acrylate resulting in a 2% w/v solution. Finally, a solution was

prepared similar to that of Volan L for the silver acrylate treating solution. All three

treatment groups were analyzed by XPS and elemental analysis focused on C Is, O 1 s,

Fe2p3, Cr2p3 and Ag3d5. The isopropanol/acetone/water (like Volan L) solution

yielded the highest surface concentration of Ag3d5 at 3.5% compared with 0.9%, which

was the same for both the isopropanol/acetone and acetone solutions, see Figure 3.3. The

antimicrobial aspect of this treatment will be further analyzed in Chapter 6.

AG3D5 1
.103










70






385 380 375 370 365 360 355 350
BindingEngy (-e)
Figure 3.3 XPS spectra of Ag3d5 of silver acrylate treatment on 316L stainless steel.

Fourier Transform Infrared-Attenuated Total Reflectance (FTIR-ATR) analysis

was attempted, but no signal was achieved due to surface concentrations of the chrome

complex being below the detectable limit of the instrument. The same was true for silver

acrylate treated substrates.

Chromium alkoxide priming solution stability over time was investigated. Dupont

suggests that these stock solutions remain highly stable over time. The stability of stock

solutions was investigated by comparing the C Is and Ols oxidative states of surfaces









treated with freshly opened stock solutions and solutions that had aged for approximately

12 months since their first use. Evidence of oxidative degradation was seen as stock

solutions of Quilon L aged as shown by the shift to higher binding energies for both the

Ols and C 1s peaks corresponding to an increase in concentration of -C=O bonding when

there should be an increased concentration of C-C corresponding to the completed long

aliphatic chains. The spectra are shown in Figure 3.4. Another interesting observation

was a solution color change from dark green to dark blue-teal further supporting chemical

changes in the priming solution 12 months after first use. For chromium (III) fatty acid

coupling agent used in this study exhibited a change in surface composition of the

functionalized stainless steel surfaces compared with untreated stainless steel when

analyzed by XPS.

The changes in peak location and color were not observed for Volan or Volan L,

see Figure 3.5. There was a 4 eV shift to higher binding energies seen for the CIs peak

for Volan L treatments when compared with Quilon L, suggesting a greater quantity of

surface carbon associated with the vinyl functionality of the methacrylate group.

However, C s in 316L stainless steel was observed to be at similar binding energies to

Volan and Volan L treatment groups, which was higher than expected. The expected

binding energy for Cls on 316L stainless steel was at a lower energy, closer to the

primary CIs peak from the PET reference at 281.7 eV. XPS indicated that Volan L

surface functionalized stainless steel had 0% chlorine content, which was lowest when

compared with other treatments used in this study. This is a favorable outcome since

chlorine ions have been associated with stainless steel corrosion.










C01 I


CIS I


CIS 1


IL I

/ '1
"6 -. ,





/ I

',j A. ...# ,


Figure 3.4 XPS Cis and Ols spectra of: A) Previously-opened 2% Quilon L treatment
on 316 L stainless steel, B) Newly-opened 2% Quilon L treatment on 316 L
stainless steel, and C) 316L stainless steel control.


II




A


____2





















Cis I


4 4j L


--.

01S 1


Ci I 0 I




d i .',,





Figure 3.5 XPS C s and Ols spectra of: A) Previously-opened 2% Volan treatment on
316 L stainless steel, B) Newly-opened 2% Volan treatment on 316 L
stainless steel, and C) 316L stainless steel control.

Summary

The results of the optimization study suggests a 2% v/v treating solution

concentration is sufficient for priming the surface and exhibits reduced chlorine content

at the stainless steel surface compared with 10% and 100% v/v concentrations. Rinsing

the treated samples prior to drying in air was did not seem to effect to treatment outcome.

As expected, using the solutions without further dilutions (100%) resulted in surfaces that

were discolored and flaky. Although the treatments were not flaky, 10% v/v treatments

were also discolored and appeared spotty. From this study, the best treatment was


BI


-i


:1l









determined to be 2% v/v solutions with 10 minute tumble washes and dried in air without

rinsing, similar to the manufacturer's suggestion.

Silver acrylate seemed to deposit the most silver complex in mixtures similar in

composition to Volan L. These studies will be investigated further in later chapters.

Based on XPS data, degradation seems to only effect the Quilon L treatment

solutions even though solutions were backfilled with argon gas after each use. Volan

and Volan L did not exhibit any binding energy shifts when comparing previously-

opened to newly-opened stock solutions. An interesting observation was that Volan L

treated substrates had lower chlorine surface concentrations than other chromium

alkoxide treatments.

Existing transition metals prevalent on the surface of a substrate can be used with

metal alkoxides of the same transitions metals to enhance the binding and stability of

coatings. This can easily reduced the number of steps associated with functionalizing

316L stainless steel.

Low Dose Gamma Irradiation Grafting of Polymers to Metal Alkoxide Treated
Substrates

Gamma irradiation has been used to surface modify polymers by initiating

polymerizations that result in grafting onto a material.55' 5 Grafting by high energy

radiation most often involves radical excitation of substrates and monomers. Gamma

radiation is deeply penetrating, unlike other forms of high energy ionizing radiation such

as electron beam accelerators. As a consequence, the effects of gamma irradiation are

less dependent on substrate orientation and result in more uniform treatments to complex

geometries.









Gamma radiation generates reactive sites in the monomer solution, as well as on

the substrate. This is a unique advantage of radiation grafting with gamma irradiation in

that fewer steps may be required to functionalize a substrate and to generate radicals at

the surface compared with other techniques. Using this surface modification technique in

conjunction with surfaces that have been functionalized by metal alkoxide treatments

may enhance the adhesion and stability of metal surface modifications. Grafting can be

achieved by polymer growth from tethered functional groups.

Gamma irradiation also lends itself to medical device modification since gamma

radiation is often used for sterilization; although usually at significantly higher doses of

-2.5 MRads. No chemical or UV initiators are necessary, making gamma irradiation a

relatively clean procedure without initiator residues. In this laboratory, low dose gamma

irradiation (< 0.25 MRads total dose) has been shown to be effective for surface

modification of a wide variety of substrate materials without inducing radiation damage

to substrates. Reported here is the radiation grafting of hydrophilic polymers on stainless

steel which has been surface treated with chromium alkoxide bonding agents. The

resulting hydrophilic polymer surfaces were highly adherent and stable, as well as

lubricious to the touch.

Materials and Methods

Preparation and treatment of 316L stainless steel substrates

Substrates of 316L stainless steel (1 cm x 1 cm) were cut from a single stock of foil

with thicknesses of approximately 0.1 mm. Substrate surfaces were cleaned by

sequential sonication for 5 minutes at 47 KHz and room temperature in 30 mL each of

1,1,1-trichloroethane, chloroform, acetone, methanol, and UltrapureTM water then dried









under vacuum at 600C. Fifty substrates were cleaned at a time. Stainless steel substrates

were not electropolished.

For chromium alkoxide treatment, clean substrates were placed in 25 mL aqueous

solutions of 2% v/v chromium III fatty acid (Quilon L, DuPont) or chromium III

methacrylate (Volan and Volan L, DuPont) for 10 minutes while rotating. 25 mL

solutions were used to treat 10 samples at a time. Treated substrates were removed from

solutions and allowed to air dry.

Controls consisted of untreated 316L stainless steel that undergoes irradiation

treatment in monomer solutions and substrates that received no treatment and no

irradiation with monomer solutions.

Preparation of monomer solutions

Monomer stock solutions of 10% v/v concentration with UltrapureTM water were

prepared for all gamma irradiated experiments. The monomers investigated were 2-

methacryloyloxyethyl phosphorylcholine (MPC; Dr. Ishihara, University of Tokyo), N-

vinyl-2-pyrrolidone (NVP; Polysciences, Inc), n,n-dimethylacrylamide (DMA;

Polysciences, Inc.), potassium 3-sulfopropyl acrylate (KSPA; Raschig GmbH). The co-

monomer systems consisted of 9.5% monomer and 0.5% DMA with UltrapureTM water,

where the monomer was MPC, NVP, or KSPA.

Gamma irradiation of substrates

316L stainless steel substrates were transferred to test tubes containing 3 mL

aqueous solutions of either 10% v/v monomers with UltrapureTM water or 9.5% monomer

and 0.5% DMA with UltrapureTM water. The solutions were degassed using vacuum

generated by a mechanical pump, and subsequently backfilled with argon gas. The

specimens were capped, placed in a 60Co gamma irradiator and exposed to total doses of









0.1 or 0.15 Mrads at dose rates in the range of 569 536 rads/min. As shown in Figure

3.6, a rotating sample stage was used to account for uneven doses that may be caused by

the asymmetrical shape of the gamma source. After irradiation, samples were placed into

new test tubes and tumble washed for one week with 5 mL of UltrapureTM water, which

was decanted and replaced with 5 mL three times.



















Figure 3.6 60Co gamma irradiator and rotating sample stage.

Analysis

Surface modified 316L stainless steel substrates were characterized by captive air

bubble contact angle with a Rame-Hart A-100 goniometer, by scanning electron

microscopy with a JEOL 6400 SEM, by fourier-transform infrared (FTIR) with a Nicolet

Magna 706 (ZnSe crystal, 450) and by x-ray photoelectron spectroscopy (XPS) analysis

with Kratos Analytical Surface Analyzer XSAM 800 under the same conditions as

previously described in the first portion of this chapter. SEM analysis was conducted

with a working distance of 15 mm, 5 kV and condenser setting was at 10 with units in 6 x

10-6 Amps. The stability of grafted polymer coatings was evaluated by measuring contact









angles after initial hydration following irradiation and washing with UltrapureTM water,

dehydration in vacuum, and then again after rehydration.

Results and Discussion

Contact angle measurements for untreated substrates that underwent radiation

grafting in monomer and co-monomer solutions yielded contact angles in the range of

220 400. With the exception of hydrophobic recovery of the most hydrophilic surfaces,

there was little difference in contact angle changes when tested for stability. This is

illustrated graphically in Figures 3.7 3.13. After irradiation, DMA graft solutions were

very viscous and to some extent stretchy. The substrates used in the DMA-only grafts

were extremely difficult to remove from the crosslinked DMA surrounding them. For

this reason DMA data was not included in all studies. These very high viscosities did not

occur for co-monomer solutions with DMA.


Contact Angle- NVP Untreated 316L SS

S70
60 50
50
50 4- 40 40 4 40 m NVP-Initial
40 3- NVP-Dehydrated
30 0- o NVP-Rehydrated
20 -- 3 316L SS Control
10
o
00
0 0.1 0.15
Dose (MRads)

Figure 3.7 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and
0.15 Mrads in 10% NVP / UltrapureTM water solutions.









Contact Angle- MPC Untreated 316L SS


* MPC-lnitial
* MPC-Dehydrated
O MPC-Rehydrated
O 316L SS Control


0 0.1 0.15


Dose (MRads)

Figure 3.8 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and
0.15 Mrads in 10% MPC / UltrapureTM water solutions.

Contact Angle- DMA Untreated 316L SS


i28


* DMA-Initial
* DMA-Dehydrated
o DMA-Rehydrated
O 316L SS Control


0.15


Dose (MRad)

Figure 3.9 Contact angle stability of untreated 316L stainless steel irradiated to 0.1 and
0.15 Mrads in 2.5% DMA / UltrapureTM water solutions.










Contact Angle- KSPA Untreated 316L SS


m KSPA-Initial
* KSPA-Dehydrated
O KSPA-Rehydrated
O 316L SS Control


0 0.1 0.15


Dose (MRads)

Figure 3.10 Contact angle stability of untreated 316L stainless steel irradiated to 0.1
and 0.15 Mrads in 10% KSPA / UltrapureTM water solutions.


Contact Angle- NVP/DMA Untreated 316L SS


43
0.15


* NVP/DMA-Initial
m NVP/DMA-Dehydrated
O NVP/DMA-Rehydrated
O 316L SS Control


Dose (MRads)

Figure 3.11 Contact angle stability of untreated 316L stainless steel irradiated to 0.1
and 0.15 Mrads in 9.5% NVP / 0.5% DMA / UltrapureTM water solutions.


i 27
f-











Contact Angle- MPC/DMA Untreated 316L SS

70
6050
4) 50 m MPC/DMA-Initial
40 338
40 33 MPC/DMA-Dehydrated
g 30 o- MPC/DMA-Rehydrated
20 -[ 316L SS Control
0
00
0 0.1 0.15
Dose (MRads)

Figure 3.12 Contact angle stability of untreated 316L stainless steel irradiated to 0.1
and 0.15 Mrads in 9.5% MPC / 0.5% DMA / UltrapureTM water solutions.


Contact Angle- KSPA/DMA Untreated 316L SS

70
60 50
4 50 43 44 KSPA/DMA-Initial
a 1 _38
40 -- KSPA/DMA-Dehydrated
30 -- o KSPA/DMA-Rehydrated
20-- o 316L SS Control
0 10
S0

0 0.1 0.15
Dose (MRads)

Figure 3.13 Contact angle stability of untreated 316L stainless steel irradiated to 0.1
and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / UltrapureTM water solutions.

Contact angle results varied for NVP, KSPA and respective co-monomer grafting

solutions with DMA on metal alkoxide functionalized substrates. With Quilon L no

significant change in contact angle was found compared with untreated 316L stainless

steel irradiated in the same monomer solutions. Volan treatment result in contact angles

of -20 for all NVP and KSPA grafting solutions with no hydrophobic recovery. This








stability was not observed for co-monomer systems where there was hydrophobic

recovery for some conditions. Volan L consistently reduced the contact angles to -200

for NVP and KSPA grafts. Additionally, contact angles as low as 180 were found for co-

monomer systems with no hydrophobic recovery. Hydrophilicity of these coatings was

stable. This data is shown in Figures 3.14 3.25.


Contact Angle- NVP QuilonL Treated 316L SS

70
60 0
W 50 1 m NVP-Initial
F 40 NVP-Dehydrated
30 o NVP-Rehydrated
20 A 316L SS Control
10
00
0 0.1 0.15
Dose (MRads)

Figure 3.14 Contact angle stability of Quilon L treated 316L stainless steel irradiated
to 0.1 and 0.15 Mrads in 10% NVP / UltrapureTM water solutions.

Contact Angle- KSPA QuilonL Treated 316L SS


4 1


0.1
Dose (MRads)


* KSPA-Initial
m KSPA-Dehydrated
o KSPA-Rehydrated
O 316L SS Control


0.15


Figure 3.15 Contact angle stability of Quilon L treated 316L stainless steel irradiated
to 0.1 and 0.15 Mrads in 10% KSPA / UltrapureTM water solutions.


]


32





41


Contact Angle- NVP/DMA QuilonL Treated 316L SS

70
60 50
S50 r m NVP/DMA-Initial
40 264 34 NVP/DMA-Dehydrated
S30 -- NVP/DMA-Rehydrated

00
0 0.1 0.15
Dose (MRads)
Figure 3.16 Contact angle stability of Quilon L treated 316L stainless steel irradiated
to 0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DMA / UltrapureTM water
solutions.

Contact Angle- KSPA/DMA QuilonL Treated 316L SS


II


26 28


LI


0.1
Dose (MRads)


0.15


-I
1


* KSPA/DMA-Initial
* KSPA/DMA-Dehydrated
O KSPA/DMA-Rehydrated
o 316L SS Control


Figure 3.17 Contact angle stability of Quilon L treated 316L stainless steel irradiated
to 0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / UltrapureTM water
solutions.







42



Contact Angle- NVP Volan Treated 316L SS


21 z 20


0.15


19


* NVP-Initial
* NVP-Dehydrated
* NVP-Rehydrated


Dose (MRads)

Figure 3.18 Contact angle stability of Volan treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% NVP / UltrapureTM water solutions.


Contact Angle- KSPA Volan Treated 316L SS

70
60
50 45
0 36 m KSPA-Initial

Figure 3.19 Contact angle stability of Volan treated 316L KS PA-Dehydrated
0.1 and 0.15 Mrads in 10% KSPA / Ultrapure water KSPA-Rehydrated

10 -
0
00
0.1 0.15
Dose (MRads)

Figure 3.19 Contact angle stability of Volan treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% KSPA / UltrapureTM water solutions.











Contact Angle- NVP/DMA Volan Treated 316L SS

70
60
50
O 37 NVP/DMA-Initial
-- a NVP/DMA-Dehydrated
n 320 o NVP/DMA-Rehydrated

20 -
0 -
00
0.1 0.15
Dose (MRads)

Figure 3.20 Contact angle stability of Volan treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DMA / UltrapureTM water solutions.


Contact Angle- KSPA/DMA Volan Treated 316L SS

7 70
60
50
S*m KSPA/DMA-Initial
0 31 m KSPA/DMA-Dehydrated
S18 20 19 o KSPA/DMA-Rehydrated
20

00
0.1 0.15
Dose (MRads)

Figure 3.21 Contact angle stability of Volan treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / UltrapureTM water
solutions.







44



Contact Angle- NVP VolanL Treated 316L SS


m NVP-Initial
* NVP-Dehydrated
o NVP-Rehydrated
O 316L SS Control


0.15


Dose (MRads)

Figure 3.22 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% NVP / UltrapureTM water solutions.


Contact Angle- KSPA VolanL Treated 316L SS

70
60 50
a 50 m KSPA-Initial
40 2- 2 KSPA-Dehydrated
S30 -- 20 0 KSPA-Rehydrated
17 17
20 17 7 316L SS Control
10 --
0
00
0 0.1 0.15
Dose (MRads)

Figure 3.23 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% KSPA / UltrapureTM water solutions.


18 /- //











Contact Angle- NVP/DMA VolanL Treated 316L SS

70
60
50
S*m NVP/DMA-Initial
40
40 NVP/DMA-Dehydrated
30 20 18 19 o NVP/DMA-Rehydrated

10
0
0.1 0.15
Dose (MRads)

Figure 3.24 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% NVP / 0.5% DMA / UltrapureTM water solutions.


Contact Angle- KSPA/DMA VolanL Treated 316L SS

70
60
50
S*m KSPA/DMA-Initial

0 and 0.15 Mrads in KS 9.5% KSPA / 0.5% DMA / UltrPA/DMA-Dehydrated
17Additionally, MPC and MPC/MA coated functionalized KSPA/DMA-Rehydrated
S20 -
10 -

0.1 0.15
Dose (MRads)

Figure 3.25 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% KSPA / 0.5% DMA / UltrapureTM water
solutions.

Contact angle measurements of MPC coatings on metal alkoxide functionalized

surfaces were significantly lower than both 316L stainless steel and MPC coated stainless

steel with no pre-treatment; see Figures 3.26 3.31 and Table 3.3. These results were

observed for all MPC and metal alkoxide treatment combinations explored in this study.

Additionally, MPC and MPC/DMA coated functionalized substrates were similarly







46


hydrophilic. After dehydration, MPC and MPC/DMA coatings on functionalized

stainless steel exhibited similar hydrophilicity with no evidence of hydrophobic recovery

as well as very little hydration time.


Contact Angle- MPC QuilonL Treated 316L SS


- 70
p 60
50
40
S30
20
10
S0


zz 21 19




0.1
Dose (MRads)


20 20 19




0.15


m MPC-Initial
m MPC-Dehydrated
O MPC-Rehydrated
D 316L SS Control


Figure 3.26 Contact angle stability of Quilonw L treated 316L stainless steel irradiated
to 0.1 and 0.15 Mrads in 10% MPC / UltrapureTM water solutions.


Contact Angle- MPC/DMA QuilonL Treated 316L SS


70
60
50
" 40
S30
20
10
S0


a 17



0.1
Dose (MRads)


20 -l 18




0.15


m MPC/DMA-Initial
* MPC/DMA-Dehydrated
O MPC/DMA-Rehydrated
[ 316L SS Control


Figure 3.27 Contact angle stability of Quilon L treated 316L stainless steel irradiated
to 0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DMA / UltrapureTM water
solutions.






47



Contact Angle- MPC Volan Treated 316L SS


18 18 19


19 17 19



0.15


* MPC-Initial
* MPC-Dehydrated
* MPC-Rehydrated


Dose (MRads)

Figure 3.28 Contact angle stability of Volan treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% MPC / UltrapureTM water solutions.


Contact Angle- MPC/DMA Volan Treated 316L SS


19 18 18


18 18 18


m MPC/DMA-Initial
* MPC/DMA-Dehydrated
O MPC/DMA-Rehydrated


0.1 0.15
Dose (MRads)

Figure 3.29 Contact angle stability of Volan treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DMA / UltrapureTM water solutions.






48



Contact Angle- MPC VolanL Treated 316L SS


17 18 18


19 19 21


* MPC-Initial
* MPC-Dehydrated
[ MPC-Rehydrated
o 316L SS Control


0 0.1 0.15
Dose (MRads)

Figure 3.30 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 10% MPC / UltrapureTM water solutions.


Contact Angle- MPC/DMA VolanL Treated 316L SS


18 18 18


19 18 18


MCI


m MPC/DMA-Initial
* MPC/DMA-Dehydrated
O MPC/DMA-Rehydrated


0.1 0.15
Dose (MRads)

Figure 3.31 Contact angle stability of Volan L treated 316L stainless steel irradiated to
0.1 and 0.15 Mrads in 9.5% MPC / 0.5% DMA / UltrapureTM water solutions.

As shown by XPS analysis, NVP coatings on Volan L treated stainless steel

specimens exhibited the highest NIs concentrations, where as Quilon L treatments

yielded the lowest NIs concentrations as shown in Table 3.4. Additionally, chromium

(III) methacrylate pretreatments resulted in stable hydrophilic surfaces. The P2p and NIs

from MPC coated surfaces were analyzed and exhibited a ratio closest to 1:1 when coated


- 70
60 -60
50
40 -
= 30-
20 -
10
0 -










on Volan L treated stainless steel. These data are summarized in Table 3.3 and Figure

3.32. All MPC coatings on metal alkoxide treated substrates resulted in hydrophilic

surfaces.

Table 3.3 MPC XPS elemental surface composition (%) and rehydrated contact angle
of surfaces for dose of 0.1 Mrads. MPC* refers to theoretical concentrations
of elemental composition.
Contact
Treatment Cls 01s Nls P2p Fe2p3 Cr2p3 P2p/N1s Angletact

316L Control 48.2 42.3 < 0.1 0.0 7.9 1.2 0.0 50 4
None/MPC 42.5 36.6 4.3 1.1 7.5 7.8 0.3 42 2
QuilonL/MPC 55.0 33.6 3.6 2.2 2.0 3.6 0.6 19 1
Volan/MPC 46.0 37.7 4.8 2.8 4.3 4.5 0.6 19 1
VolanL/MPC 45.6 39.1 4.6 4.0 3.3 3.5 0.9 18 1
MPC* 57.8 31.6 5.3 5.3 0.0 0.0 1.0 -


Table 3.4


- NVP XPS elemental surface composition (%) and rehydrated contact angle of
surfaces for dose of 0.1 Mrads. NVP* refers to theoretical concentrations of
elemental comDosition.


Contact
Treatment Cls 01s Nls Fe2p3 Cr2p3 CI2p Angle (0)

316L Control 48.2 42.3 < 0.1 7.9 1.2 0.0 50 4
None/NVP 62.5 27.4 3.7 1.9 3.3 1.3 40 3
QuilonL/NVP 75.6 19.3 2.2 0.3 1.5 1.0 39 3
Volan/NVP 67.1 23.9 4.0 0.9 2.6 1.6 20 +2
VolanL/NVP 64.6 26.2 5.6 1.5 2.0 0.1 22 1
NVP* 75 12.5 12.5 0.0 0.0 0.0 -







50













NIS 1 PIP 2

21 ,21



















Figure 3.32 MPC grafted on treated and untreated 316L SS. XPS elemental spectra for
Nls and P2p. A) 2% Volan L treated, B) 2% Quilon L treated, and C)

untreated.

As shown in Table 3.5, XPS analysis of KSPA treatments showed there was little

to no signal from potassium ions. This could be due to dissociation of the potassium salt

from sulfopropyl acrylate. This is likely to happen during the irradiation process due to

the presence of the electron withdrawing sulfopropyl head which can facilitate

dissociation in an irradiated environment. With KSPA, stable hydrophilic surfaces were

produced with Volan and Volan L treated substrates.










Table 3.5 KSPA XPS elemental surface composition (%) and rehydrated contact angle
of surfaces for dose of 0.1 Mrads. KSPA* refers to theoretical concentrations
of elemental comp position.
Contact
Treatment Cls 01s Nls Fe2p3 Cr2p3 K2p3 S2p3 Cl2p Ange (ct

316L Control 48.2 42.3 < 0.1 7.9 1.2 0.0 0.0 0.0 50 4
None/KSPA 56.5 34.4 0.0 2.8 4.4 0.0 3.9 0.0 34 3
QuilonOL/ 76.7 20.5 0.0 0.4 1.3 0.0 1.1 0.0 32 3
KSPA
Volan/KSPA 62.3 31.8 0.0 1.4 3.1 0.0 1.4 0.0 20 2
Voa/ 57.7 33.8 0.0 1.0 5.8 0.0 1.8 0.0 20 2
KSPA
KSPA* 46.1 38.5 0.0 0.0 0.0 7.7 7.7 0.0 -


L stainless steel at 5



























Figure 3.34 SEM of 10% v/v MPC gamma irradiation grafted (0.1 MRads) coating on
Volan L activated 316L stainless steel at 5000x.

From Tables 3.3 3.5, Fe2p3 and Cr2p3 peaks were present even for the most

hydrophilic conditions. This suggests that coatings are either very thin or are not

homogeneously coated on the substrate, which could be the result of uneven chromium

alkoxide binding. SEM micrographs confirmed surface modifications were very thin

since much of the 316L topography was discernable in all micrographs of gamma

irradiation grafted coatings as shown in Figures 3.33-34. Based on XPS analysis, surface

modifications is likely to be ~2 20 atomic layers in depth. SEM micrographs did not

show any evidence of corrosion for gamma irradiated modifications.

Summary

The results of this study indicate that chromium functionalized stainless steel

surfaces on which hydrophilic vinyl functional monomers were polymerized results in

coatings with improved stability and increased hydrophilicity in contrast to non-surface

functionalized stainless steel.









It should be noted that the stainless steel used in this study had a surface

composition somewhat lower in Cr203 content than electropolished stainless steel which

is most often used for endovascular stents. Because the stainless steel used in these and

subsequent studies were not electropolished, surface elemental compositions will be

different from reported values for electropolished 316L stainless steel. Also, decreased

surface roughness may result from electropolishing. Due to increased surface chromium

concentrations as a result of electropolishing, increase bonding agent concentrations may

result when treating these specimens, which could result in further improved coating

stability.

Volan L, which resulted in the lowest chlorine surface content, is an ideal metal

alkoxide for functionalizing 316L stainless steel surfaces, since chlorine ions have been

associated with pitting corrosion on stainless steels. Evidence of corrosion was not seen

in SEM micrographs for any of the conditions investigated in this study. Due to highly

efficient crosslinking, DMA was satisfactory as a co-monomer component. However, no

significant advantage was seen for using the co-monomer compared to NVP, MPC and

KSPA monomer formulations used here.

Stable hydrophilic coatings were prepared by gamma irradiation of monomer

solutions on chromium alkoxide functionalized 316L stainless steel. MPC coatings on all

chromium alkoxide treated substrates resulted in stable hydrophilic surfaces.

Additionally, Volan and Volan L treatments consistently produced stable hydrophilic

surfaces with all monomer and co-monomer systems investigated. Quilon L, which is a

trivalent chromium fatty acid, only produced stable hydrophilic coatings with MPC and

MPC/DMA formulations. Overall, stainless steel surface modification was enhanced by






54


the use of the chromium alkoxide bonding agents and has been shown to be of value to

enhance adhesion of polymer coatings to metallic medical devices such as endovascular

stents or keratome blades.














CHAPTER 4
PULSED LASER ABLATION DEPOSITION (PLAD) AND RF PLASMA
POLYMERIZATION DEPOSITION

Introduction

As discussed is Chapter 3, high energy ionizing radiation has been used for surface

modifying various materials under normal ambient conditions of temperature and

pressure with the advantages of substrate geometry flexibility and absence of chemical or

UV initiators for "clean" modifications. Surface modifications involving high energy

sources and which employ vacuum conditions can be used to enhance surface binding by

ablation etching and deposition. Two examples of such systems are radio frequency glow

discharge plasmas (RF plasma), and pulse laser ablation deposition (PLAD). For both,

sample orientation can affect coating uniformity as a result of the directional nature of the

depositions.

This chapter discusses research aimed at exploring the potentially unique

effectiveness of trivalent chromium metal alkoxide treatments for enhancing the stability

of RF plasma and PLAD surface modifications on 316L stainless steel.

Pulsed Laser Ablation Deposition (PLAD)

Pulsed laser ablation deposition (PLAD) modification has been reported for many

polymers and semiconductor materials. For example, PLAD has been used for modifying

fiber surface properties and curing the resin material.58 Of particular, PLAD offers a

solvent free method for polymerization and surface modification.









Coating stainless steel with polymers by pulsed laser ablation/deposition (PLAD)

for medical devices is a relatively new concept. We have pioneered the use of PLAD for

the deposition of cross-linked polymer thin films in this laboratory.59

In that research, PLAD was shown to be a feasible technique for coating medical

implants.59-61 Following the work of Rau et al, silicone elastomer targets were ablated

with a pulsed 248 nm KrF excimer laser to form silicone plasma and deposited onto the

substrate. Previous research with silica filled silicone indicated increasing surface

hydrophilicity of PLAD deposits with increasing fluence (mJ/cm2, energy density),

especially above a fluence of 200 mJ/cm2.60 Furthermore, Rau et al observed that smooth

low fluence depositions resulted in hydrophobic surfaces similar to that of the target

material. Whereas, higher fluences deposited somewhat granular surfaces that were

hydrophilic. These experiments were conducted in vacuum environments with higher

oxygen contents than the studies presented here.

Pulsed laser ablation deposition is carried out at vacuum pressures at most of 1 Torr

with a target mounted on a rotating base. The substrate to be coated is mounted on a

stationary fixture. The target absorbs photons emitted from a UV laser source at 248 nm.

Atoms at the target surface rise to an electronically excited state. Due to various degrees

of excitation, bond rupture and ionization occurs, various species from the target material

are emitted forming a plume consisting of the excited ionic and radical fragments. This

plume of excited species contacts the substrate, which is positioned as illustrated in

Figure 4.1. As the excited plume species contact the substrate, recombination reactions

occur with the silicone species and the substrate. The degree to which the coatings are

mechanically and chemically bound to the substrate remain unclear.60









Inert Gas


Figure 4.1 Illustration of PLAD system setup.60

In the research reported here, we extended the initial work of Rau et al and

investigated PLAD deposition using a biomedical grade poly (dimethylsiloxane), PDMS,

containing a nanostructured resin filler (Nusil, MED 6820 A, B). Additionally, these

investigations were carried out in a vacuum environment that was more oxygen free than

the previous studies. The interesting and different results are reported here.

Materials and Methods

Preparation of silicone targets and substrates

PDMS targets were made from a two part resin system (Nusil, MED 6820 A, B and

MED 6210 A, B), where MED 6820 silicone is an FDA approved materials for long-term

implants beyond 90 days. 5 mL volumes of each resin component (A and B) were

measured and placed into separate syringes. Both syringes were concurrently unloaded

into a large container, such as a 600 mL Pyrex beaker, and hand-mixed with a spatula.

The beaker containing the uncured silicone was subsequently degassed by vacuum to

allow entrapped air to escape the mixture. The uncured silicone mixture was determined

to be sufficiently degassed when no visible bubbles were apparent. The mixture was









removed from the vacuum environment and poured onto square acetate sheets that were

placed on square glass plates (5" x 5") and degassed a second time, after which glass

slides of 1mm thickness were placed on each of the four corners of the square acetate

sheets. A second acetate sheet was placed on top of the glass slides followed by another

glass plate. The glass slides were slowly pushed toward the center to remove trapped air

and control the casting thickness. Finally, the mixture was cured at 600C for 12 hours

resulting in cast silicone sheets of 1 mm thicknesses. Plaques of 1 cm diameter were

punched from the sheets and washed in methanol for 2 hours to clean the target surface.

The washed plaques were dried under vacuum for 12 hours and mounted on 1 inch

diameter aluminum stubs for use as targets. This procedure was used for the silicone

formulations, MED 6820 and MED 6210.

Silicon wafers and 316L stainless steel (1 cm x 1 cm x 0.1 mm) were used as

substrates for all depositions. Silicon wafers were sequentially sonicated in acetone and

methanol then dried under vacuum. Stainless steel substrates were cleaned by sequential

sonication in 1,1,1-trichloroethane, chloroform, acetone, methanol, and UltrapureTM

water then dried under vacuum at 60C for 12 hours. 316L Stainless was used in two

ways, untreated and treated with 2% v/v Volan, which is low chlorine chromium (III)

methacrylate metal alkoxide. These procedures are described in detail in Chapter 3.

Pulsed laser ablation deposition chamber

The PLAD system consisted of a vacuum chamber housing both the target and

substrate, see Figure 4.1. To ensure uniform ablation, the target was rotated with a motor

for every deposition. A KrF excimer laser (Lambda Physik 301x) operating at 248 nm

with a pulse width of 25 ns was used in all experiments. The laser beam was directed

into the chamber with a pair of plane mirrors and a collimating lens. A 250 mm lens









focused the laser beam onto the target. With all depositions, a base pressure of at least

5.0 x10-5 mTorr was reached except where noted, after which the chamber was backfilled

with helium until a pressure of 100 mTorr was achieved.

The energy density (mJ/cm2, fluence) was controlled by adjusting the energy

constant of the laser and the focusing lens to get the desired spot size incident on the

target. Fluence is calculated by multiplying the energy constant (mJ) with the measured

attenuation error, which is then divided by the measured spot size (cm2).Th energy

constant is a value that is programmed into the operating system. The attenuation error

corresponds to the amount of decreased laser energy due to the lens sequence. Finally,

the spot size is obtained by visually measuring the burned spot the laser leaves on thermal

sensitive paper. The fluences used in this investigation were in the range of 50-400

mJ/cm2. The laser operated at a repetition rate of 5 Hz. The deposition time was 30

minutes, thus the number of laser pulses for each deposition was 9000.

Analysis

Surfaces were characterized by captive air bubble and sessile drop methods with a

Rame-Hart A-100 goniometer, scanning electron microscopy with a JEOL 6400 SEM,

fourier-transform infrared (FTIR) with a Nicolet Magna 706 (ZnSe crystal, 450) and x-

ray photoelectron spectroscopy (XPS) analysis with Kratos Analytical Surface Analyzer

XSAM 800. The analysis conditions used are described in Chapter 3.

Results and Discussion

Contact angle data are shown in Table 4.1. In contrast to previous PLAD

deposition of silica filled PDMS in a chamber containing higher concentrations of oxygen

species60, the data here indicate that higher fluences result in higher contact angles or

decreasing hydrophilicity when resin filled silicone was deposited on untreated 316L









stainless steel. Depositions on chromium (III) methacrylate treated 316L stainless steel

resulted in contact angles of -250 for fluences of 125 mJ/cm2. Compared to the

hydrophobic depositions on untreated 316L stainless steel at fluences of 200 and 400

mJ/cm2, coatings on Volan treated 316L stainless steel swelled with water on contact

distorting the topography of the deposition. Thus, contact angles were not measurable for

these conditions. This is a departure from previous studies conducted in our laboratory,

since coating swelling with water has not previously been observed for PLAD treatments.

A difference from the earlier work is that in previous studies the chamber was

evacuated to a base pressure of 30 mTorr, whereas the current studies used base pressures

of at least 5.0 xl05 mTorr, which results in depositions in a more oxygen free

environment. In both studies, the chamber was backfilled with helium to 100 mTorr.

Contact angles for MED 6820 and MED 6210, which are different from the silica-filled

silicones used by Rau et al, depositions on untreated stainless steel using a base pressure

of 30 mTorr was conducted to compare the two resin filled materials and verify the

hydrophilic results of previously reported studies. The hydrophilicity of MED 6820 and

MED 6210 depositions were similar to depositions by Rau et al, where contact angles

were -200 at fluences over 200 mJ/cm2.

Table 4.1 Contact angle of MED 6820 depositions at various fluences on untreated
316L stainless steel.
Fluence
(mJ/cm2) 50 75 100 125 200 300 400
Contact 40- 16- 16-
onge 40 16 16 >1700 >1700 >1700 >1700
Angle 50 21 210


Analysis of nanosurface modified silicon and untreated 316L stainless steel by

FTIR-ATR did not yield measurable peaks for MED 6820 depositions on silicon wafers









at 50-300 mJ/cm2. As illustrated in Figure 4.2, small peaks at 1260, 1215-930, and 900-

730 cm-1 corresponding to SiMex deformation, SiOSi asymmetric stretching (main chain),

and Si(CH2)3 and Si(CH2)2 rocking (chain ends), were evident for depositions at 400

mJ/cm2 fluence on silicon wafer. Spectra for depositions on untreated 316L stainless

steel did not result in any detectable peaks. FTIR-ATR of VIMED 6820 depositions on 2%

v/v Volan treated 316L stainless steel yielded spectra for fluences of 125, 200 and 400

mJ/cm2, which were the fluences investigated for the chromium III methacrylate

treatment. Although different in magnitude, the spectras shown in Figures 4.3-4.5 reflect

similar peaks compared with 400 mJ/cm2 depositions on silicon wafers. While the peak

locations are similar to that of VIMED 6820, the shapes of the peaks are grossly different as

a result of shifts in concentrations of bonding structures. This difference could be due to

higher concentrations of specific bonding structures deposited such as SiOSi asymmetric

stretching as well as sharp increases in rocking chain ends, Si(CH2)3 and Si(CH2)2. This

increase can be attributed to scrambling of the molecular structure in the plume that is

then recombined. Recombination is not controlled resulting in a deviation of PLAD

deposited silicone compared with unablated silicone.








62



0.050 -
Engineering Research Ctr
0.045 400 mJ/cm^2 MED 6820 on Silicon Wafer

0.040 -

0.035 -

0.030 -

0.025 -

c@.020 -

0.015 -

0.010 -

0.005 -

0.000 -

-0.005 :

-0.010 -
4000 3000 2000 1000
cm-1

Figure 4.2 FTIR-ATR spectra of MED 6820 deposited at a fluence of 400 mJ/cm2 on
silicon wafer.


Particle Eng Research Center
1 8 400 mJ/cmA2 MED6820 2%Volan 316LSS

1 6-

14-



I 0-










02-

o00 o2

o 2- .. .. .
4000 3500 3000 2500 2000 1500 1000 500
Wavenumbers (cm-1)

Figure 4.3 FTIR-ATR spectra of MED 6820 deposited at a fluence of 400 mJ/cm2 on
2% Volan treated 316L stainless steel.













Particle Eng Research Center
1 8- 200 mJ/cm^2 MED6820 2%Volan 316LSS


04-

02-

00-

-0_2
4000 3500 3000 2500 2000 1500 1000 500
Wavenumbers (cm-1)

Figure 4.4 FTIR-ATR spectra of MED 6820 deposited at a fluence of 200 mJ/cm2 on
2% Volan treated 316L stainless steel.


Particle Eng Research Center
125 mJ/cm^2 MED6820 2%Volan 316LSS


4000 3500 3000 2500 2000 1500 1000 5C
Wavenumbers (cm-1)

Figure 4.5 FTIR-ATR spectra of MED 6820 deposited at a fluence of 125 mJ/cm2 on
2% Volan treated 316L stainless steel.










Changes in elemental composition of depositions at varying fluences were

examined by XPS analysis (Table 4.2 4.3). For MED 6820 coated untreated 316L

stainless steel, overall oxygen content decreased with increasing fluence levels, while the

silicon content increased. The O:Si ratio at low fluences decreased from approximately 2

to 1 at higher fluences. This may indicate that a more silica-like film is deposited at

lower fluence, while a more PDMS-like film is deposited at higher fluences on untreated

316L stainless steel.

Table 4.2 XPS elemental analysis (%) of PLAD coated samples on untreated 316L
stainless steel.
Fluence
(mJ/cm2 Fe2p3 Ols CIs Cr2p3 Si2p O:Si Ratio
PDMS 0.0 25.0 50.0 0.0 25.0 1.0
400 0.0 27.9 41.1 0.1 25.9 1.1
300 0.1 27.2 46.2 0.2 26.3 1.0
200 0.0 29.1 41.2 0.0 29.8 1.0
125 0.0 32.3 38.8 0.0 28.5 1.1
100 0.3 38.8 33.6 0.1 27.2 1.4
75 0.2 39.7 32.2 0.0 27.8 1.4
50 0.8 35.6 43.8 0.8 18.9 1.9
316L SS
316L SS 5.5 36.1 53.2 1.8 3.5 10.4
Control


At 400 mJ/cm2 fluences, elemental analysis showed that deposited MED 6820

resin-filled silicone coatings on Volan treated 316L stainless steel exhibited similar

elemental concentrations as coatings on untreated stainless steel. However, at lower

fluence deposition compositions on Volan treated substrates had higher Si2p and lower

Ols concentrations when compared with the untreated 316L stainless steel group. This

difference could be due to several factors. While the chamber is under high vacuum, low

molecular weight species still exist. The vacuum pump forces these particles to be

pushed against the wall of the chamber decreasing the number of particles freely floating

in the system. As the target is ablated, reactive fragments are emitted as a plume and










could react with other particles in the system. These reactions may be the source of the

reduced O:Si ratio seen for lower fluence deposition conditions on Volan treated 316L

stainless steel. The electron withdrawing vinyl groups on the 316L stainless steel surface

could preferentially bind with the silicone fragments in the plume, which may be another

explanation. It is likely that a combination of both explanations is the reason for this

reduced O:Si ratio.

Table 4.3 XPS elemental analysis (%) of PLAD coated samples on Volan treated
316L stainless steel.
Fluence
(mJ/c2) Fe2p3 Ols CIs Cr2p3 Si2p O:Si Ratio
PDMS 0.0 25.0 50.0 0.0 25.0 1.0
400 0.0 25.8 44.6 0.0 29.6 0.9
200 0.0 25.7 35.9 0.0 38.4 0.7
125 0.0 24.0 37.7 0.0 38.2 0.6
316L SS
316L SS 5.5 36.1 53.2 1.8 3.5 10.4
Control


figure 4. SLIVI ot IOL stainless steel at -UUx.



























Figure 4.6 SEM of MED6820 PLAD coated at fluence of 300 mJ/cm2 onto untreated
316L stainless steel at 500x.

As shown in Figures 4.5-6, analysis with SEM at 500x showed that coatings on

untreated 316L stainless steel exhibited granular surface texture at fluences higher than

125 mJ/cm2. For coatings deposited at lower fluences, surfaces were fairly smooth in

comparison. Depositions on Volan treated 316L stainless steel appeared were very

smooth. These observations suggest that texture may be an important factor in the

wettability of PLAD deposited silicone coatings.

Summary

The results of this investigation indicate a departure from previously published data

utilizing the PLAD technique for surface modifying of 316L stainless steel with PDMS.

Biomedical grade poly(dimethylsiloxane), (PDMS), containing a nanostructured resin

filler (MED 6820), was used here to form stable, uniform silicone-like coatings on

chromium III methacrylate (Volan) treated and untreated 316L stainless steel. The

coatings exhibited characteristics that were different from previous results with silica

reinforced PDMS in that different elemental ratios of O:Si for depositions on Volan









treated and untreated 316L stainless steel at low fluences were acheived. Differences

were seen in contact angles from fluences of 125-400 mJ/cm2, where silicone depositions

on chromium alkoxide treated stainless steel were hydrophilic and depositions on

untreated stainless steel were hydrophobic. Furthermore, the silicone depositions on

untreated stainless steel from previous studies yielded hydrophilic surfaces at higher

fluences such as 200-600 mJ/cm2, which was not observed in this study where coatings

on untreated stainless steel deposited at high fluences were hydrophobic indicating that

surface bonding characteristics are related to laser fluence and chamber oxygen content.

This is further supported by FTIR and XPS data. These experiments were conducted in a

more rigorously controlled oxygen free system than previously published work. From

Table 4.2, the %0 decrease with increasing fluence may correspond with a more PDMS-

like film that is deposited at higher fluences for coatings on untreated 316L stainless

steel. At 400 mJ/cm2 fluences, depositions on Volan treated 316L stainless steel

resulted in PDMS-like thin films. Such PDMS thin films may be useful for drug delivery

from surfaces and/or for drug grafting.

RF Plasma Surface Modification

Radio frequency glow discharge plasma (RF plasma) is a surface modification

technique involving high energy and vacuum to achieve surface ablation etching and

deposition of RF plasma polymerized monomers. This technique is commonly used in

industry for surface modification. The technology involves the RF field excitation of

gases such as argon, oxygen, solvents, or monomer vapors. The RF field excitation

causes the gaseous mass to dissociate creating the plasma of excited species, i.e. radicals,

ions, ion radicals. The surface binding and recombination of excited species results in









modification of the substrate surfaces. Typically, substrates are treated one side at a time

due to the directional nature of this treatment.

RF plasma has been used successfully in our laboratory to pretreat polymeric and

metallic substrates with hexane plasma for subsequent gamma irradiation polymerization.
57, 62, 63 The hexane plasma deposits a crosslinked carbonaceous layer on the substrate

surface. The substrate is then submerged in a monomer solution and irradiated immersed

in a monomer solution, thus depositing polymer on the RF plasma/hexane coating. Initial

contact angles reported were lower than those of samples treated with either RF Plasma

or gamma alone.

Presented here is an investigation of monomer RF plasma polymerization

deposition with monomers, NVP, DMA and comonomer, NVP/DMA. The objective was

to evaluate Quilon L (chromium III fatty acid) and Volan L (chromium III

methacrylate) treated 316L stainless steel substrates. Additionally, a new substrate stage

was developed for the purpose of treating both sides of the substrate at the same time by

orienting the samples vertically. The results of these studies are reported here.

Materials and Methods

Preparation of substrate, monomers, and comonomer

Substrates of 316L stainless steel (1 cm x 1 cm x 0.1 mm) were cut from a single

stock of foil. Stainless steel substrates were cleaned by sequential sonication in 1,1,1-

trichloroethane, chloroform, acetone, methanol, and UltrapureTM water then dried under

vacuum at 600C for 12 hours. 316L Stainless was used in three ways, untreated and

treated with 2% v/v Volan L or Quilon L, which are low chlorine chromium (III)

methacrylate and low chlorine chromium (III) fatty acid metal alkoxide. These

procedures are described in Chapter 3.









A quantity of 1 ml of each monomer, NVP and DMA, was poured into separate 25

ml long neck round bottom flasks. For comonomer, NVP/DMA, 500 tL of each

monomer was poured into one 25 ml long neck round bottom flask. Before each RF

plasma treatment, the monomers and comonomer flasks were degassed by vacuum and

attached to the RF plasma apparatus.

Monomer RF plasma

To clean the bell-jar vacuum chamber, it was evacuated to 50 mTorr and purged

with argon gas to 1 Torr. This procedure was repeated five times, after which the flow

rate of argon gas was reduced and the RF plasma controller was turned on with a power

of 50 Watts (incident) and 0 Watts (reflected). The RF plasma was allowed to run for 5

minutes thoroughly clean the bell-jar and components. Once this was finished, the flow

of argon gas was closed and the bell-jar pressure was returned to ambient conditions.

Treated substrates were oriented vertically on a custom designed sample stage.

Three treatment groups were included with each run, untreated, Quilon L, and Volan L

treated 316L stainless steel. For each experimental run, one flask containing 1 mL of

either monomer or comonomer of NVP and DMA were attached to the RF plasma

apparatus. The treatment followed the same procedure as described above, except after

the last evacuation to 50 mTorr, the bell-jar was backfilled by leaking in volatized

monomer or comonomer to 100 mTorr. After this operating pressure was reached, the

RF plasma controller was turned on at the same power as previously described and

operated for either 5 or 10 minutes. After the RF plasma was turned off, the chamber

was further purged with monomer for 2 minutes to allow for further polymer conversion

and reaction with surface radicals. Finally, the chamber was purged with argon gas to 1

Torr two times before returning the bell-jar pressure to ambient pressure of 760 Torr.









Following treatment, substrates were submerged in UltrapureTM water to wash and await

analysis.

Analysis

RF plasma treated surfaces were characterized by captive air bubble and sessile

drop methods with a Rame-Hart A-100 goniometer, SEM with a JEOL 6400, FTIR with a

Nicolet Magna 706 (ZnSe crystal, 450) and XPS analysis with Kratos Analytical Surface

Analyzer XSAM 800 under the same operating conditions as described in Chapter 3.

Results and Discussion

As shown in Figures 4.7- 4.9, initial contact angles measured prior to drying, were

hydrophilic and approximately 200 in all cases. Additionally, both sides of the flat

substrates were measured indicating uniform modifications substrate surfaces. No

differences were seen between 5 and 10 minute monomer RF plasma treatments. To

determine treatment stability, modified substrates were dehydrated under vacuum, then

rehydrated for 24 hours in UltrapureTM water and rehydrated contact angles were

recorded for both sides of each sample. As the data shows in Figures 4.10- 4.12, initial

hydrophilicity of monomer RF plasma modifications was not reflected in measurements

after rehydration. However, some samples only lost a fraction of hydrophilicity as shown

by the rehydrated DMA RF plasma on Quilon L treated 316L stainless steel of the 10

minute treatment and on Volan L treated 316L stainless steel of the 5 minute treatment.

Once again, measurements were consistent for both sides of the sample. The differences

seen in initial and rehydrated contact angle data are likely due to condensation of surface

species when dehydrated.







71



Contact Angle- Untreated 316L SS, Initial


18 19


* None-NVP
O None-DMA
* None-NVP/DMA


10


Time (Minutes)

Figure 4.7 Initial contact angle measurements for NVP, DMA and NVP/DMA RF
plasma surface modifications on untreated 316L stainless steel.


Contact Angle- Quilon L Treated 316L SS, Initial


19 18


* QL-NVP
o QL-DMA
m QL-NVP/DMA


10


Time (Minutes)

Figure 4.8 Initial contact angle measurements for NVP, DMA and NVP/DMA RF
plasma surface modifications on 2% v/v Quilon L treated 316L stainless
steel.


20 19


5


20 Z1'


5







72



Contact Angle- Volan L Treated 316L SS, Initial


19 18


* VL-NVP
O VL-DMA
m VL-NVP/DMA


10


Time (Minutes)

Figure 4.9 Initial contact angle measurements for NVP, DMA and NVP/DMA RF
plasma surface modifications on 2% v/v Volan L treated 316L stainless steel.


Contact Angle- Untreated 316L SS, Rehydrated


36
TYFF


* None-NVP
O None-DMA
* None-NVP/DMA


10


Time (Minutes)

Figure 4.10 Rehydrated contact angle measurements for NVP, DMA and NVP/DMA
RF plasma surface modifications on untreated 316L stainless steel.


19 19


5


QQ 41
.r+







73



Contact Angle- Quilon L Treated 316L SS, Rehydrated

70
S60-
5 50
37 m QL-NVP
430 0 QL-DMA
: 3m QL-NVP/DMA
-20 -
10 -
00
5 10
Time (Minutes)

Figure 4.11 Rehydrated contact angle measurements for NVP, DMA and NVP/DMA
RF plasma surface modifications on 2% v/v Quilon L treated 316L stainless
steel.


Contact Angle- Volan L Treated 316L SS, Rehydrated


29


* VL-NVP
O VL-DMA
* VL-NVP/DMA


Time (Minutes)

Figure 4.12 Rehydrated contact angle measurements for NVP, DMA and NVP/DMA
RF plasma surface modifications on 2% v/v Volan L treated 316L stainless
steel.

FTIR-ATR analysis did not yield discernable peaks for any conditions examined in

this study. This is likely due to low surface concentrations of treatment since RF plasma


modifications typically result in thin treatments.


32









XPS analysis of monomer RF plasma treated substrates showed Nis peaks for all

conditions in the range of 1.8 to 3.6% when evaluated with CIs, Ols, Fe2p3, Cr2p3 and

C12p elemental concentrations. The detected NIs peaks correspond to the nitrogen atoms

ofNVP, DMA, or NVP/DMA depositions. Unmodified untreated 316L stainless steel

did not exhibit discernable NIs peaks. Increase in CIs was seen for all Quilon L treated

316L stainless steel. This is likely due to polymerization or crosslinking of the fatty acid

pendant groups on the chromium alkoxide treatment. The only difference seen by this

analysis between the 5 and 10 minute RF Plasma modifications are reduced C12p

concentrations for 10 minute treatments.

Table 4.4 XPS elemental analysis (%) of 5 minute monomer RF plasma modification of
untreated, Volan L and Quilon L treated 316L stainless steel.
Cls Ols NIs Fe2p3 Cr2p3 C12p
Unmodified, Untreated 316L SS 48.2 42.3 < 0.1 7.9 1.2 0.0
NVP Untreated 316L SS 48.9 37.8 3.5 3.5 4.0 2.3
NVP VolanL Treated 316L SS 52.0 36.0 3.4 2.9 3.5 2.2
NVP QuilonL Treated 316L SS 60.9 30.0 3.2 1.2 2.8 1.8
DMA Untreated 316L SS 51.5 37.6 3.3 3.7 1.9 1.9
DMA VolanL Treated 316L SS 50.8 39.1 2.2 2.9 2.4 2.9
DMA QuilonL Treated 316L SS 60.5 32.2 2.3 1.6 0.4 2.7
NVP/DMA Untreated 316L SS 49.1 41.4 1.9 3.9 1.8 1.9
NVP/DMA VolanL Treated 316L SS 53.2 28.4 2.7 2.4 3.9 2.9
NVP/DMA QuilonL Treated 316L SS 63.3 34.9 1.8 0.9 2.5 3.2


Topography changes due to surface modifications were not evident in SEM

micrographs. Surface modifications may be ~2 20 atomic layers in depth based on

elemental analysis depth of penetration limitations. SEM micrographs did not show any

evidence of corrosion these surface modifications.

Summary

In the current studies, elemental analysis showed the presence of nitrogen species

that correspond to the monomer species from RF plasma treatments. Yet, these surface









modifications did not yield stable hydrophilic coatings after drying and rehydration.

Orienting the samples vertically with a new substrate stage was shown to consistently

treat both sides of the substrates.

While the use of chromium based metal alkoxides did not appear to enhance the

stability of monomer RF plasma surface modifications, initial contact angle

measurements were very hydrophilic and surfaces appeared lubricious prior to drying.

This technology may be useful for single use applications that do not require drying.

In our laboratory, hexane RF plasma treatments on metals have been used as a

primer for gamma initiated surface modifications by creating a carbonaceous surface

layer. Functionalizing 316L stainless steel with metal alkoxide treatments will prime the

surface in a simplified one step process. These functionalized metals can be further

modified in a variety of ways including gamma initiated grafting and solution coating.














CHAPTER 5
SOLUTION POLYMERIZATION COATING SURFACE MODIFICATION

Introduction

A number of common coating techniques with polymer solutions are used

extensively for industrial applications, i.e. dip coating, spray coating, and film casting.

These techniques are also used with polymers that are solubilized in a solvent or melt

coated above their melting temperature.64 Dip coating, spray coating and film casting

techniques do not ensure bonding at the coating-substrate interface and typically result in

coatings that are merely adsorbed to the substrate unless coupling agents or other priming

systems are employed. The focus of this chapter will be polymerizations of monomers in

the presence of a solvent and the substrate surface. This research evaluates the

effectiveness of trivalent chromium methacrylate, Volan L, to enhance the binding and

stability of hydrophilic and hydrophobic polymers onto 316L stainless steel by solution

polymerization coating.

In Chapter 3, substrates were soaked in monomer-solvent solutions that were

subsequently treated with high energy ionizing radiation to initiate the polymerization

and grafting of chains to functionalized surfaces. In the solution polymerization coating

studies discussed here, polymerization was initiated by the addition of

azobisisobutyronitrile (AIBN) initiator and controlling the temperature of the reaction

environment. Medical grade silicone was also evaluated with this coating technique.

The addition of AIBN to these silicone solution studies was not necessary, due to the

presence of a catalyst for the two component silicone system.









Materials and Methods

Preparation and Treatment of 316L Stainless Steel Substrates

Stainless steel substrates (1 cm x 1 cm 0.1 mm) were cleaned by sequential

sonication with 1,1,1-tricholoroethane, chloroform, acetone, methanol, and UltrapureTM

water, after which the substrates. After which, the samples were placed in a vacuum

oven at 60C. Cleaned substrates were washed in a 2 % (v/v) solution of Volan L,

which is a chromium (III) methacrylate, with water at room temperature for 10 minutes

while agitating. After washing, treated substrates were removed from the solution and air

dried for 2 hours. These procedures are described in detail in Chapter 3. Substrates were

coated as described below.

Controls consisted of untreated 316L stainless steel that underwent solution

polymerization coating and substrates that received no chromium alkoxide treatment or

solution polymerization coating.

Preparation of Monomer Solutions

The monomers used in this study were 2-methacryloyloxyethyl phosphorylcholine

(MPC; Dr. Ishihara, University of Tokyo), N-vinyl-2-pyrrolidone (NVP; Polysciences,

Inc), and potassium 3-sulfopropyl acrylate (KSPA; Raschig GmbH). MPC, NVP and

KSPA monomer stock solutions of 10% v/v concentrations were prepared with 0.125%

v/v AIBN initiator and UltrapureTM water. A higher MPC and NVP monomer solution

concentration of 25% v/v was also evaluated with the same concentration of initiator. A

solution volume of 3 ml was used for each substrate.

Preparation of Silicone Component Solutions

Solutions of 45% v/v Nusil Med 6820 silicone oligomers components A and B with

chloroform were prepared of the same volume. A 0.75 ml volume of each solution of









components A and B were placed in glass test tubes for each condition and mixed

thoroughly resulting in 1.5 ml of both components A and B with chloroform to treat each

substrate. A single cleaned and Volan L treated 316L stainless steel substrate was

placed into each test tube and soaked in the silicone solution for 2 hours while rotating,

after which the samples were transferred to clean test tubes and cured at 60C for 12

hours.

Solution Polymerization (SP) Coating of Substrates

Chromium (III) methacrylate treated 316L stainless steel substrates were

transferred to test tubes containing aqueous solutions of either 10% v/v, 25% v/v of NVP,

MPC, or KSPA monomer with UltrapureTM water or 45% MED 6820 oligomers with

chloroform. The solutions were then bubbled and backfilled with argon gas. The

specimens in monomer solutions were placed in an oven that was heated to a minimum of

70C and a maximum of 76C for ~6 hours. After coating, samples were placed in new

test tubes and tumble washed for one week with 5 mL of UltrapureTM water, which was

decanted and replaced three times with 5 mL. Specimens in MED 6820 silicone

oligomers solutions were treated as described in the previous section of this chapter. In

short, functionalized substrates were dipped into diluted solutions of uncured silicone

components and subsequently heated to cure, which has been shown to be effective for

coating silane coupling agent treated stainless steel with silicone.39

Analysis

Wettability of coatings was characterized by sessile drop and captive air bubble

contact angle goniometry data using a Rame-Hart A-100 Goniometer. Surface chemistry

of modified substrates was characterized with Fourier Transform Infrared Attenuated

Total Reflectance Spectroscopy (FTIR-ATR)using a Nicolet MagnaTM 706 FTIR, and









elemental composition was analyzed by X-ray photoelectron spectroscopy (XPS) with a

Kratos XSAM 800, all under the same conditions as described in Chapter 3. The contact

angles for unmodified 316L stainless steel and unmodified resin-cast MED 6820 silicone

are approximately 500 and 900, respectively.

Results and Discussion

From initial contact angle data shown in Figures 5.1 5.2, differences in

wettability were seen for 25% v/v NVP solution polymerization (SP) coatings when

comparing untreated and Volan L treated 316L stainless steel, in that Volan L treated

316L stainless steel exhibited increased wettability. This was not observed for the 10%

v/v NVP solution concentrations possibly due to kinetics associated with the reduction in

the amount of reactive species in solution. In contrast, contact angles of- 200 were

observed for MPC solution coating on untreated and Volan L treated 316L stainless

steel for both concentrations, which can be attributed to the amphoteric structure of MPC

causing increased adsorption onto the substrate.

As shown in Figures 5.3 5.4, contact angle measurements taken immediately after

dehydration under vacuum for 24 hours indicated that Volan L treatments maintained

the hydrophilicity of coatings with little recovery time. Furthermore, these specimens

were lubricious to the touch. Surfaces treated with Volan L and SP coated in NVP and

KSPA retained contact angles less than 260 following dehydration. The dehydration

process affected coated surfaces that were not treated with Volan L such that contact

angles increased beyond 300, which was a similar observation to gamma irradiation

grafting studies. While exhibiting increased wettability compared with other solution

coatings and unmodified 316L stainless steel, MPC coatings did not yield measurable

differences for the concentrations and substrate treatment conditions investigated here.







80



Contact Angle- Untreated 316L SS, Initial


* None-MPC
o None-NVP
m None-KSPA


10 25


Concentration (%)


Figure 5.1 Initial contact angle measurements for 10% and 25% v/v monomer SP
coated untreated 316L stainless steel.


Contact Angle- Volan L Treated 316L SS, Initial


17


-25-
25


10


* VL-MPC
[ VL-NVP
m VL-KSPA


Concentration (%)

Figure 5.2 Initial contact angle measurements for 10% and 25% v/v monomer SP
coated Volan L treated 316L stainless steel.


19 1: 20


I











Contact Angle- Untreated 316L SS, Dehydrated


- 70
60
I-
50
+40
c 30
20
r 10
0
o
0 0


m None-MPC
o None-NVP
m None-KSPA


10 25
10 25


Concentration (%)

Figure 5.3 Contact angle measurements immediately after dehydration for 10% and
25% v/v monomer SP coated untreated 316L stainless steel.


Contact Angle- Volan L Treated 316L SS, Dehydrated

70
60
50 50
9m *VL-MPC
S40
4 30 26 26 O VL-NVP
19 17 VL-KSPA


o
0
10 25
Concentration (%)

Figure 5.4 Contact angle measurements immediately after dehydration for 10% and
25% v/v monomer SP coated Volan L treated 316L stainless steel.

After rehydration, NVP and KSPA SP coatings on untreated 316L stainless steel

did not recover initial wettability, see Figures 5.5 5.6. With the Volan L treatment,

hydrophilicity was recovered for 25% v/v NVP SP coatings, but not for the 10% v/v

concentrations (Figures 5.7 5.8). Once again, this is believed to be associated with with

reduced quantity of reactive species for the 10% v/v NVP solution. MPC SP coatings









maintained initial wettability throughout these stability tests for all conditions as

presented in Figures 5.9 5.10. As shown in Figures 5.11 5.12, KSPA SP coatings on

Volan L treated 316L stainless steel resulted in consistently low contact angles, which

was not observed for the untreated stainless steel group.

MED 6820 SP coatings on untreated 316L stainless steel exhibited contact angle

measurements of- 1040. Measurements of these silicone coatings on Volan L treated

substrates were ~ 940, which was similar to unmodified MED 6820 substrates of 90.


Contact Angle- Untreated 316L SS, Rehydrated

S70
$ 60 50
6) 50 43 m None-MPC
40 29 30 None-NVP
'm 30 None-KSPA
< 20 2-- 316L SS-Control
10

0 10 25
Concentration (%)

Figure 5.5 Rehydrated contact angle measurements for 10% and 25% v/v monomer SP
coated untreated 316L stainless steel.






83



Contact Angle- Volan L Treated 316L SS, Rehydrated

70
60 50
S50 VL-MPC
S40-2- o VL-NVP
S30 22 VL-KSPA
S20 1 o 316L SS-Control
10
00
0 10 25
Concentration (%)

Figure 5.6 Rehydrated contact angle measurements for 10% and 25% v/v monomer
solution coated Volan L treated 316L stainless steel.


Contact Angle- NVP Untreated 316L SS

70
60
50 45 43
S50 45 43
r -I NVP-Initial
40 26 29 30 29 o NVP-Dehydrated

< _^ NVP-Rehydrated


25


Concentration (%)

Figure 5.7 Contact angle measurements for 10% and 25% v/v NVP SP coated untreated
316L stainless steel.






84



Contact Angle- NVP VolanL Treated 316L SS


LL LL
1171 --- E 7


ii


* NVP-Initial
o NVP-Dehydrated
* NVP-Rehydrated


Concentration (%)

Figure 5.8 Contact angle measurements for 10% and 25% v/v NVP SP coated Volan L
treated 316L stainless steel.


Contact Angle- MPC Untreated 316L SS


18 19 20


* MPC-Initial
O MPC-Dehydrated
* MPC-Rehydrated


25


Concentration (%)

Figure 5.9 Contact angle measurements for 10% and 25% v/v MPC SP coated untreated
316L stainless steel.


9s 26


10


19 19


10