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Synthesis and Properties of Acrylic Copolymers for Ocular Implants

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Title:
Synthesis and Properties of Acrylic Copolymers for Ocular Implants
Copyright Date:
2008

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Subjects / Keywords:
Acrylates ( jstor )
Carbazoles ( jstor )
Cataracts ( jstor )
Copolymers ( jstor )
Heating ( jstor )
Light refraction ( jstor )
Monomers ( jstor )
Optics ( jstor )
Peas ( jstor )
Polymers ( jstor )

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University of Florida
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University of Florida
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Copyright the author. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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6/30/2006

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SYNTHESIS AND PROPERTIES OF ACRYLIC COPOLYMERS FOR OCULAR IMPLANTS By ADAM C. REBOUL 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 Adam C. Reboul

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This document is dedicated to my mo ther, father, and loving wife Julie.

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ACKNOWLEDGMENTS First, I would like to thank my advisor, Professor Eugene Goldberg. If I did not have his encouragement, I would have never been able to complete this work. I would like to thank him for his support throughout my time here at the University of Florida and for giving me the opportunity to work on an interesting project. Other faculty at the University of Florida who I would like to acknowledge for their time and support are Professor Anthony Brennan, Professor Christopher Batich, Professor Elliot Douglas and Professor John Reynolds. I would like to thanks the members of Goldberg research group. I thank Paul Martin, Amin Elachchabi, Jennifer Wrighton, Dr. Daniel Urbaniak, Dr. Margaret Kayo, Dr. Clay Bohn, and Dr. Brian Cuevas for their friendship and assistance in the lab. I would like to thank my family, which has been behind me my entire life. My mother, father, and sister have always supported any life changing decisions I have made. Their love and support have meant more than they can imagine. Lastly, I would like to thank my wife Julie for her love, dedication and sacrifice. Without her love, support and patience, none of this work would have been possible. I will be eternally grateful. iv

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TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................iv LIST OF TABLES .............................................................................................................ix LIST OF FIGURES .............................................................................................................x ABSTRACT .......................................................................................................................xv CHAPTER 1 BACKGROUND..........................................................................................................1 Cataract Treatment Prior to IOLs.................................................................................1 Early IOL Development...............................................................................................2 Generation I: Original Ridley Posterior Chamber Lens..............................................4 Generation II: Early Anterior Chamber Lenses...........................................................5 Generation III: Iris Support Lenses.............................................................................6 Generation IV: Later Model Anterior Chamber IOLs.................................................7 Generation V: Modern PMMA Posterior Chamber IOLs...........................................7 Generation VI: Foldable IOLs.....................................................................................9 2 PHENYLATED ACRYLATE / METHACRYLATE COPOLYMER SYNTHESIS AND CHARACTERIZATION............................................................17 Introduction.................................................................................................................17 AcrySof IOL...............................................................................................................18 PEA/PEMA Materials and Methods...........................................................................19 Synthesis of PEA/PEMA materials.....................................................................19 Differential Scanning Calorimetry (DSC)...........................................................22 Refractometry......................................................................................................22 Monomer/Oligomer extraction............................................................................22 Equilibrium Water Content (EWC).....................................................................22 Unfolding Rate Analysis.....................................................................................23 Results and Discussion...............................................................................................23 Synthesis..............................................................................................................23 PEA and PEMA Homopolymer DSC..................................................................24 Copolymer Synthesis...........................................................................................25 PEA / PEMA Copolymer DSC............................................................................26 v

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Refractive Index..................................................................................................31 Monomer/Oligomer Extraction...........................................................................31 Equilibrium Water Content.................................................................................31 Unfolding Rate Analysis.....................................................................................32 Summary.....................................................................................................................33 Benzyl Acrylate / Benzyl Methacrylate Materials and Methods................................33 Synthesis of BA / BMA Materials.......................................................................33 Differential Scanning Calorimetry......................................................................34 Copolymer Synthesis...........................................................................................36 BA / BMA Copolymer DSC................................................................................36 Refractometry......................................................................................................41 Monomer/Oligomer Extraction...........................................................................41 Equilibrium Water Content.................................................................................42 Unfolding Rate Analysis.....................................................................................42 Summary.....................................................................................................................43 Conclusions.................................................................................................................43 3 N-VINYL CARBAZOLE / PHENYLETHYL ACRYLATE COPOLYMER SYNTHESIS AND CHARACTERIZATION............................................................44 Introduction.................................................................................................................44 NVC/PEA Materials and Methods.............................................................................45 Synthesis of NVC Homopolymer........................................................................45 Poly(N-vinyl carbazole) DSC..............................................................................46 Synthesis of NVC / PEA Copolymers.................................................................46 NVC / PEA Copolymer DSC..............................................................................47 Refractometry......................................................................................................48 Monomer/Oligomer extraction............................................................................48 Equilibrium Water Content (EWC).....................................................................48 Unfolding Rate Analysis.....................................................................................49 Results and Discussion...............................................................................................49 NVC / PEA Copolymer DSC..............................................................................49 Refractive Index..................................................................................................52 N-Vinyl Carbazole Derivatives..................................................................................53 Materials and Methods...............................................................................................53 NVC Derivatives Synthesis.................................................................................53 NVC-1 / NVC-3 NMR........................................................................................55 NVC Derivative Copolymer Synthesis...............................................................56 Differential Scanning Calorimetry (DSC)...........................................................56 Refractometry......................................................................................................57 Equilibrium Water Content (EWC).....................................................................57 Unfolding Rate Analysis.....................................................................................57 Results and Discussion...............................................................................................58 Nuclear Magnetic Resonance (NMR).................................................................58 NVC-1 / PEA Copolymer DSC...........................................................................61 Refractive Index..................................................................................................64 Equilibrium Water Content.................................................................................65 vi

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Unfolding Rate Analysis.....................................................................................65 NVC-3 / PEA Copolymer DSC...........................................................................66 Conclusions.................................................................................................................68 4 ALLYL PHENOTHIAZINE BASED UV ABSORBERS FOR IOL APPLICATIONS........................................................................................................69 Introduction.................................................................................................................69 Blue Light Absorption.........................................................................................71 Blue Light Toxicity.............................................................................................72 Materials and Methods...............................................................................................74 Synthesis..............................................................................................................74 Nuclear Magnetic Resonance Spectroscopy (NMR)...........................................76 UV-Vis Spectroscopy..........................................................................................76 Molar Extinction Coefficients.............................................................................76 Results and Discussion...............................................................................................77 Synthesis..............................................................................................................77 NMR....................................................................................................................77 UV-Vis Spectroscopy..........................................................................................81 Molar Extinction Coefficients.............................................................................83 Conclusions.................................................................................................................83 5 STUDIES CONCERNING VOID (GLISTENING) FORMATION IN LOW TG ACRYLIC POLYMERS USED FOR FOLDABLE IOLS........................................84 Introduction.................................................................................................................84 Materials and Methods...............................................................................................87 Light Microscopy................................................................................................87 Scanning Electron Microscopy (SEM)................................................................87 Thermal Compression.........................................................................................87 Gamma Irradiation ( 60 Co)....................................................................................89 Differential Scanning Calorimetry (DSC)...........................................................91 Equilibrium Water Content (EWC).....................................................................91 Results and Discussion...............................................................................................91 Light Microscopy................................................................................................91 SEM.....................................................................................................................93 Thermal Compression.........................................................................................97 Gamma Irradiation ( 60 Co)....................................................................................98 Differential Scanning Calorimetry (DSC)...........................................................98 Equilibrium Water Content (EWC)...................................................................100 Thermal compressed samples vs. controls.................................................100 Gamma irradiated samples vs. controls......................................................101 Conclusions...............................................................................................................103 6 CONCLUSIONS......................................................................................................104 7 FUTURE WORK......................................................................................................106 vii

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PEA / PEMA Copolymers........................................................................................106 BA / BMA Copolymers............................................................................................106 NVC-1 / PEA Copolymers.......................................................................................106 Phenothiazine UV Absorbers...................................................................................107 Glistenings................................................................................................................107 LIST OF REFERENCES.................................................................................................109 BIOGRAPHICAL SKETCH...........................................................................................115 viii

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LIST OF TABLES Table page 2-1 Phenylethyl acrylate / phenylethyl methacrylate copolymer compositions.............25 2-2 Suitable PEA / PEMA IOL copolymer compositions and properties......................30 2-3 Refractive index measurements for selected copolymer compositions....................31 2-4 Percent weight loss after Soxhlet extraction............................................................31 2-5 Unfolding times for selected copolymer compositions............................................32 2-6 Benzyl acrylate / benzyl methacrylate copolymer compositions.............................35 2-7 Suitable BA / BMA IOL copolymer compositions and properties..........................41 2-8 Refractive index measurements for selected BA/BMA compositions.....................41 2-9 Percent weightt loss after Soxhlet extraction...........................................................41 2-10 Benzyl acrylate / benzyl methacrylate unfolding rate analysis................................42 3-1 Selected NVC / PEA copolymer compositions........................................................46 3-2 Selected NVC / PEA copolymer compositions........................................................52 3-3 Copolymer refractive indicies: NVC / PEA.............................................................52 3-4 Selected NVC-1 / PEA copolymer compositions....................................................64 3-5 Copolymer refractive indicies: NVC-1 / PEA..........................................................64 3-6 Unfolding rate analysis: NVC-1 / PEA...................................................................66 4-1 Transmittance comparison for 20.0D IOLs..............................................................73 4-2 Phenothiazine max values........................................................................................81 4-3 Molar extinction coefficients for phenothiazine UV-absorbers...............................83 ix

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LIST OF FIGURES Figure page 1-1 Structure of PMMA.................................................................................................3 1-2 Sketch of the Ridley posterior chamber lens...........................................................4 1-3 Eye anatomy.............................................................................................................5 1-4 Generation III IOL designs......................................................................................6 1-5 C-Loop and J-Loop posterior chamber PMMA IOLs with blue polypropylene haptics......................................................................................................................8 1-6 Folded J-loop IOL....................................................................................................9 1-7 Structure of PDMS.................................................................................................10 1-8 Structure of HEMA................................................................................................11 1-9 AcrySof foldable acrylic IOL co-monomers.......................................................12 1-10 Sensar IOL monomer structures..........................................................................14 1-11 Optical micrograph of AcrySof one-piece IOL with no glistenings....................15 1-12 Optical micrograph of AcrySof one-piece IOL with glistenings.........................15 2-1 AcrySof polymeric structure................................................................................18 2-2 Free radical copolymer synthesis...........................................................................20 2-3 Bulk polymerization mold.....................................................................................21 2-4 Phenylethyl acrylate (PEA) homopolymer DSC curves........................................24 2-5 Phenylethyl methacrylate (PEMA) homopolymer DSC curves............................24 2-6 Heating DSC scans: 90 PEA / 10 PEMA...............................................................26 2-7 Heating DSC scans: 80 PEA/ 20 PEMA...............................................................26 x

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2-8 Heating DSC scans: 70 PEA/ 30 PEMA...............................................................27 2-9 Heating DSC scans: 60 PEA/ 40 PEMA...............................................................27 2-10 Heating DSC scans: 50 PEA/ 50 PEMA...............................................................28 2-11 Heating DSC scans: 40 PEA / 60 PEMA...............................................................28 2-12 Heating DSC scans: 30 PEA / 70 PEMA..............................................................29 2-13 Heating DSC scans: 20 PEA / 80 PEMA..............................................................29 2-14 Heating DSC scans: 10 PEA / 90 PEMA..............................................................30 2-15 Equilibrium water content of PEA / PEMA copolymers.......................................32 2-16: Structure of benzyl acrylate and benzyl methacrylate.............................................34 2-17 Benzyl acrylate homopolymer DSC curves...........................................................34 2-18 Benzyl methacrylate homopolymer DSC curves...................................................35 2-19 Heating DSC scans: 90 BA / 10 BMA..................................................................36 2-20 Heating DSC scans: 80 BA / 20 BMA..................................................................37 2-21 Heating DSC scans: 70 BA / 30 BMA..................................................................37 2-22 Heating DSC scans: 60 BA / 40 BMA..................................................................38 2-23 Heating DSC scans: 50 BA / 50 BMA..................................................................38 2-24 Heating DSC scans: 40 BA / 60 BMA..................................................................39 2-25 Heating DSC scans: 30 BA / 70 BMA..................................................................39 2-26 Heating DSC scans: 20 BA / 80 BMA..................................................................40 2-27 Heating DSC scans: 10 BA / 90 BMA..................................................................40 2-28 Equilibrium water content of BA / BMA copolymers...........................................42 3-1 N-vinyl carbazole solution polymerization............................................................45 3-2 Poly(N-vinyl carbazole) DSC................................................................................46 3-3 N-vinyl carbazole / phenylethyl acrylate copolymer synthesis.............................47 3-4 Heating DSC scans: 10 NVC / 90 PEA................................................................49 xi

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3-5 Heating DSC scans: 20 NVC / 80 PEA................................................................50 3-6 Heating DSC scans: 30 NVC / 70 PEA................................................................50 3-7 Heating DSC scans: 40 NVC / 60 PEA................................................................51 3-8 Heating DSC scans: 50 NVC / 50 PEA................................................................51 3-9 N-vinyl carbazole derivative synthesis route #1....................................................54 3-10 N-vinyl carbazole derivative synthesis route #2....................................................54 3-11 N-vinyl carbazole derivative/ phenylethyl acrylate copolymer synthesis.............56 3-12 Carbazole impurity signal......................................................................................58 3-13 Allyl carbazole (NVC-1) 1 H NMR spectra............................................................59 3-14 Allyl carbazole (NVC-1) 13 C NMR spectra...........................................................59 3-15 Pentenyl carbazole (NVC-3) 1 H spectra................................................................60 3-16 Pentenyl carbazole (NVC-3) 13 C spectra...............................................................60 3-17 Heating DSC scans: 10 NVC-1 / 90 PEA..............................................................61 3-18 Heating DSC scans: 20 NVC-1 / 80 PEA.............................................................62 3-19 Heating DSC scans: 30 NVC-1 / 70 PEA.............................................................62 3-20 Heating DSC scans: 40 NVC-1 / 60 PEA.............................................................63 3-21 Heating DSC scans: 50 NVC-1 / 50 PEA.............................................................63 3-22 Equilibrium water content of NVC-1 / PEA copolymers......................................65 3-23 Heating DSC scans: 30 NVC-3 / 70 PEA.............................................................66 3-24 Heating DSC scans: 40 NVC-3 / 60 PEA.............................................................67 3-25 Heating DSC scans: 50 NVC-3 / 50 PEA.............................................................67 4-1 Visible radiation spectrum.....................................................................................69 4-2 Transmission spectrum of selected IOLs and natural lenses.................................71 4-3 Photograph of the one-piece AcrySof Natural IOL.............................................72 4-4 Chemical structure of the AcrySof Natural blue light filtering chromophore.....73 xii

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4-5 Synthetic methods for phenothiazine UV-absorbers.............................................75 4-6 Phenothiazine / 2-chlorophenothiazine 1 H NMR proton signals...........................78 4-7 Allyl phenothiazine 1 H NMR spectrum.................................................................79 4-8 Allyl phenothiazine 13 C NMR spectrum................................................................79 4-9 N-allyl-2-chlorophenothiazine 1 H NMR spectrum................................................80 4-10 N-allyl-2-chlorphenothiazine 13 C NMR spectrum.................................................80 4-11 N-allylphenothiazine UV-Vis spectrum................................................................81 4-12 N-allyl-2-chlorophenothiazine UV-Vis spectrum..................................................82 4-13 Phenothiazine UV-absorbers blue absorption at 1.0 wt%.....................................82 5-1 Aluminum mold illustration...................................................................................88 5-2 Thermal compression apparatus with aluminum mold..........................................89 5-3 60 Co Sample carousel.............................................................................................90 5-4 60 Co source with sample carousel inserted............................................................90 5-5 Optical micrograph: X-60 incubated in DI water at 80 o C for 24h (50X).............92 5-6 Optical micrograph: X-60 incubated in BSS at 80 o C for 24h (50X)....................92 5-7 Optical micrograph of a single glistening (200X).................................................93 5-8 Cross Section of X-60 IOL (55X)..........................................................................93 5-9 Cross-section of X-60 IOL with glistenings (37X)................................................94 5-10 Higher magnification X-60 cross-section with glistenings (170X).......................94 5-11 Cross-section of X-60 glistening (300X)...............................................................95 5-12 High magnification of X-60 glistening cross-section (370X)................................95 5-13 Cross-section X-60 glistening with internal defect (450X)...................................96 5-14 Control vs. compressed DSC curves (2 nd scan @ 5 o C/min)..................................99 5-15 Control vs. irradiated DSC curves (2 nd scan @ 5 o C/min)......................................99 5-16 Control vs. treated X-60 EWC in DI water..........................................................100 xiii

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5-17 Control vs. treated X-60 EWC in BSS.................................................................101 5-18 Equilibrium water content of the X-60 control and Gamma irradiated for various doses in DI water.....................................................................................102 5-19 Equilibrium water content of the X-60 lens material control and Gamma irradiated for various doses in BSS......................................................................102 xiv

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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 SYNTHESIS AND PROPERTIES OF ACRYLIC COPOLYMERS FOR OCULAR IMPLANTS By Adam C. Reboul December 2005 Chair: Eugene Goldberg Major Department: Materials Science and Engineering There is a need for flexible polymers with higher refractive index and extended UV absorbing properties for improved intraocular lenses (IOLs). This research was devoted to the synthesis of new acrylic copolymers for foldable IOLs and to studies concerning IOL polymer properties. New polymers were synthesized from phenylated acrylates copolymerized with N-vinyl carbazole derivatives using bulk free radical addition methods. The copolymers had low T g values, high refractive index, and were flexible. The N-vinyl carbazole derivatives were characterized by NMR and copolymers were characterized by DSC, UV-Vis, and refractometry. New phenothiazine based UV absorbers with high extinction coefficients were also synthesized for incorporation into ocular materials. Patent disclosures on UV absorbers and high refractive index polymers were prepared. A so called “glistening” phenomenon that occurs in all foldable intraocular lenses currently in clinical use is poorly understood and was studied. Research on this xv

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microvoid forming behavior included studies and development of methods to inhibit glistening in low T g acrylic based copolymers. Glistenings were characterized using SEM and optical microscopy. A novel technique for inhibiting glistening was found and a patent disclosure was prepared. xvi

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CHAPTER 1 BACKGROUND In the last century, two of the most important advances in the field of ophthalmology have been the development of the intraocular lens (IOL) and the introduction of the operating microscope [1]. The introduction of the operating microscope facilitated the development of microsurgical techniques, sophisticated cataract extraction procedures and intraocular lens implants. Many individuals deserve credit for ideas and important discoveries that have advanced the field of ophthalmology. Dr. Harold Ridley clearly stands alone as the inventor of IOLs and is recognized as the definitive pioneer in this field [1]. In terms of sheer numbers, cataract is the most prevalent ophthalmic disease. More than 50 million people world wide suffer from cataracts resulting in visual impairment [2]. According to the United Nations Population Division, this health problem will become more serious as the median age of the population increases [3]. Surgical removal combined with IOL implantation has become one of the most widespread and highly successful medical procedures with almost 5 million surgeries per year worldwide (Goldberg, personal communication). Cataract Treatment Prior to IOLs Cataract treatment has been practiced for many centuries using a wide variety of techniques. The major complication before the invention of the IOL was attaining high quality postoperative visual rehabilitation because removal of the natural lens resulted in a significant visual disability [4]. 1

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2 Prior to the IOL, spectacles were prescribed for those patients that had their natural lens removed (aphakia). The spectacles proved to be unsatisfactory due to the visual distortions in such high powered lenses [5]. Aphakic spectacles were not pleasant in appearance and were often termed “Coke-bottle bottom” glasses. Aphakic spectacles magnified vision by an additional one-third, thus drastically altering depth perception [5]. In addition, if only one eye needed cataract removal, stereopsis, or three-dimensional vision, was virtually impossible. Other complications of aphakia included jack in the box syndrome, spherical aberration, and image distortion [1]. The invention of the contact lens improved many of the complications associated with aphakia [6]. However, not everyone can wear contact lenses due to environmental factors and/or poor manual dexterity. Poor tolerance of contact lenses may be caused by problems such as dry eyes, a low blink rate, or problems with lens hygiene [7]. The invention of the contact lens was the only significant advancement in aphakic correction in hundreds of years. It was not until the late 1940s that the invention of the IOL would change aphakic visual rehabilitation forever. The tremendous optical advantage an intraocular lens could provide was conceived and acted upon by Dr. Harold Ridley [8]. Early IOL Development In 1949, Dr. Ridley “felt compelled” to develop a synthetic replacement lens after a medical student, Steve Parry, conveyed his disappointment with the treatment of aphakia [9]. Ridley would rely on his World War II experiences to obtain a suitable material for his first artificial lens. During the war, British fighter cockpit canopies made of poly(methyl methacrylate) (PMMA) would fragment due to gunfire. The fragments from some of the canopies would penetrate the eyes of the flight crew. These fragmented

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3 PMMA splinters did not irritate the eyes, and caused very little reaction. Having examined several of these fliers, Ridley made the observation that, “Unless a sharp edge of the plastic material rests in contact with a sensitive and mobile portion of the eye, the tissue reaction is insignificant” [10]. As Ridley considered which material would best be suited for IOL development, he learned that commercial PMMA was not pure enough to be implanted into the human eye [2]. With the help of his friend John Holt at Imperial Chemical Industries, they synthesized Perspex CQ (Clinical Quality) which is still in use today. Perspex CQ had a refractive index of 1.49 and a specific gravity of 1.19 [10]. Figure 1-1 illustrates the chemical structure of PMMA. O O n poly(methyl methacrylate) Figure 1-1: Structure of PMMA The first IOL was made by Rayners of London [2]. The dimensions of the lens were 8.35 mm in diameter, 2.40 mm in thickness and 112 mg in weight. These dimensions were about 1mm less than those of the human lens. The refractive power of the lens was 24 diopters [2]. Ridley implanted his first IOL into the capsular bag of the posterior chamber following extra-capsular cataract extraction (ECCE). The procedure was performed on a 45-year-old woman at St. Thomas Hospital in London on November 29, 1949 [9]. Ridley’s first IOL implantations were a success, but left the patients severely myopic.

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4 Ridley continued to improve his IOLs and procedures. Soon others were improving and implanting IOLs as well. From the first implantation to present day, the evolution of IOLs can be roughly broken down into six generations. Generation I: Original Ridley Posterior Chamber Lens Generation I IOLs were made and implanted from 1949-1954 [11]. These lenses were designed to be similar in size and shape to the human crystalline lens which is anatomically in the posterior chamber of the eye. An adult crystalline lens measures approximately 4 mm in thickness and 9 mm in diameter. Figure 1-2 is a sketch of Ridley’s first posterior chamber lens. Early Ridley IOL Figure 1-2: Sketch of the Ridley posterior chamber lens There were several postoperative complications associated with the first generation IOLs. These included inflammation, pupillary occlusion, thickening of the posterior capsule, loss of anterior chamber, secondary glaucoma, iris atrophy caused by IOL pressure, decentration and dislocation of the lens [1].

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5 Generation II: Early Anterior Chamber Lenses One of the major problems with the original Ridley lens was dislocation. The anterior chamber of the eye was considered for the new implantation site due to its narrow confines [1]. This generation of lenses was developed and implanted from 1952-1962 [11]. PMMA was still the material of choice for IOL optics. Anterior placement of the IOL was also considered an easier technical procedure than posterior placement. Figure 1-3 illustrates the anatomy of the eye with anterior and posterior chambers. Figure 1-3 courtesy of allaboutvision.com. Figure 1-3: Eye anatomy Unlike the original lens developed by Ridley, many anterior chamber lens designs were developed from ideas of many different surgeons who worked with IOLs. Notable during this time were Baron, who implanted the first anterior chamber IOL, Strampelli, Choyce, and Bober-Ans of Denmark [1].

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6 Contact with endothelial cells and corneal decompensation were the two major problems with anterior chamber IOLs. These IOLs had serious long term complications and many surgeons abandoned IOL implantation all together [12]. Generation III: Iris Support Lenses This generation of lenses was developed and implanted during 1953-1973 [11]. Iris support IOLs were designed in an attempt to overcome the problems with Ridley’s posterior chamber lens and the anterior chamber lenses developed in the 1950s. Iris support IOL optics were made of PMMA. In 1953, Epstein introduced the collar stud lens [13]. The central post was 3 mm in diameter and the IOL was placed in the iris plane. Figure 1-4 illustrates Epstein’s collar stud lens and Copeland’s iris support IOL, which evolved from an earlier Epstein Maltese Cross design. The Copeland IOL used two haptics in front of the iris and two haptics behind the iris for support and centralization within the eye. Figure 1-4: Generation III IOL designs. A) Epstein collar stud iris support IOL. B) Copeland’s iris support IOL.

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7 The major complication with the iris support lenses was erosion or chafing of the iris stroma and pigment epithelium at the IOL contact sites [14]. Cornelius Binkhorst of Holland tried improving on the designs of Epstein and Copeland by minimizing the amount of surface area the IOL had in contact with the iris. He hypothesized that contact with the posterior side of the iris would not cause complications; This was later seen to be an incorrect assumption. Generation IV: Later Model Anterior Chamber IOLs This generation of lenses was designed and implanted from about 1963 until the mid 1980s [11]. Iris support IOLs underwent many different design changes from the early 1950s until the early 1980s. During this time, many new anterior chamber fixated IOLs were being introduced. If the anterior IOL design was correctly vaulted and properly sized, long term success could be achieved. PMMA was still the material of choice for these later model anterior chamber IOLs, but many of the IOLs developed during this period had to be removed from the market due to manufacturing defects and design flaws. Generation V: Modern PMMA Posterior Chamber IOLs Modern PMMA posterior chamber IOLs were designed and implanted from about 1975 until the mid -1990’s. During this period, the evolution of extracapsular cataract extraction was marked by four major milestones: Microscopic surgery, phacoemulsification for cataract removal, iridocapsular fixation, and use of flexible haptics [12]. Phacoemulsification was first introduced by Kelman in 1967 [15]. This technique used an ultrasonic vibrating tip to liquefy the natural cataractous crystalline lens. The

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8 lens could then be extracted by aspiration through a much smaller incision than with non-ultrasonic methods. Iridocapsular fixation or in-the-bag fixation, was heavily influenced by Cornelius Binkhorst. He was one of the pioneers in the return to the ECCE procedure [16]. Binkhorst realized that an intact posterior capsule enhanced stability and provided many advantages for IOL implantation. In previous IOL designs, the optics were made of PMMA and remained inflexible. Most IOLs were made as one piece rigid structures that were abrasive and damaging to the tissues of the eye. Flexible haptics made of polypropylene (PP) reduced the surface area and damage to the supporting tissue. The most common designs with flexible haptics were the C-looped and J-looped designs. Figure 1-5 illustrates common flexible haptic IOL designs. Figure 1-5: C-Loop and J-Loop posterior chamber PMMA IOLs with blue polypropylene haptics

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9 A significant modification that took place during the early 1980s was the addition of UVR-absorbing molecules to the IOL optic (PMMA) to prevent retinal damage by solar exposure [17]. The addition of UV-absorbing molecules was done to mimic the UV-absorbing properties of the natural crystalline lens. Ultraviolet radiation below 400nm is absorbed by the eye and passes to the retina after the natural crystalline lens is removed. This UV radiation is thought to cause cystoid macular edema and age-related macular degeneration [18]. UV absorbing molecules are added to all present day IOLs. Generation VI: Foldable IOLs This generation of IOLs began in the mid 1980s and is the most common type of IOL implanted today. The major advantage of foldable IOLs is the ability to insert the lens through a 2.5mm corneal incision. Prior to foldable IOLs, the corneal incision had to be minimally the width of the PMMA optic (usually 6-8 mm). The small incision allows the wound to heal without the need of sutures. Figure 1-6 illustrates a flexible J-loop IOL folded with forceps before insertion into the eye [19]. Figure 1-6: Folded J-loop IOL

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10 Foldable IOL optics have glass transition temperatures that allow the material to be in the rubbery state at room temperature (T g < 25 o C). PMMA has a glass transition temperature of 105 o C. PMMA is a rigid glass at room temperature. The first foldable IOL was a silicone based lens developed by Mazzoco. This lens was termed the “Mazzaco taco” due to its shape when folded. These lenses were of the plate design without loops. This lens was made of the silicone elastomer, poly(dimethyl siloxane) or PDMS. Silicone IOLs have the lowest glass transition temperatures of any IOLs produced (-91 o C to -119 o C) [20]. Figure 1-7 illustrates the structure of PDMS. SiO CH3 CH3 n poly(dimethyl siloxane) Figure 1-7: Structure of PDMS Initially, people were skeptical in predicting that all of the silicone lenses would turn brown and become cataractous with time [21]. This problem was remedied through quality control processes and complete material polymerization. Others reported difficulty in performing YAG laser posterior capsulotomy and a significant increase in capsular opacification and inflammation in the eye with respect to PMMA [22]. Appropriate understanding of new techniques for capsulotomy with the silicone lens has reduced yttrium-aluminum-garnet (YAG) laser pitting to a minimum. Silicone IOLs are hydrophobic in nature and have contact angles ranging from 106 o -119 o [20]. Today, Advanced Medical Optics (AMO) is the leader in the development of the silicone IOL. Another foldable IOL material that is in current use today includes the hydrogel poly(hydroxyl methacrylate) or HEMA. PolyHEMA is hydrophilic in nature with contact

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11 angles ranging from 59 o to 69 o [21]. The monomer in Figure 1-8 can be copolymerized free radically with a variety of different materials such as high refractive index acrylates, cross linkers and UV-absorbers to achieve the final product. O O OH hydroxylethyl methacrylate Figure 1-8: Structure of HEMA PDMS and poly(HEMA) produced suitable foldable IOL materials. The draw back was the low refractive index these materials possessed. Higher refractive index allows for a thinner IOL optic. The desire for thin profile lenses required a higher refractive index material [23, 24]. The most common lens on the market today is the hydrophobic acrylic AcrySof lens developed by Alcon in the early 1990’s. The AcrySof IOL was the first foldable acrylic IOL approved by the FDA. The approach was to build on the success of the PMMA IOLs and specifically design a new, high refractive index, foldable IOL biomaterial. The AcrySof IOL is an acrylic copolymer consisting of phenylethyl acyrlate, phenylethyl methacylate, diacrylate cross-linker and a polymerizable benzotriazole UV absorber. The UV absorbing benzotriazole is covalently bonded to the polymer backbone. The reaction is initiated by the thermal degradation of a peroxide initiator. The IOL optic is formed by reactive extrusion. When polymerization is complete, the material is washed free of any byproducts with an exhaustive solvent

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12 extraction process. Figure 1-9 illustrates the chemical structure of the AcrySof phenylated acrylate comonomers. O O O O phenylethyl acrylate phenylethyl methacrylate Figure 1-9: AcrySof foldable acrylic IOL co-monomers The AcrySof IOL has many favorable properties that are required for a foldable IOL. These properties include high refractive index (D ~ 1.55), chemical stability, absence of leachable monomers, and biocompatibility. Due to the high refractive index, these lenses have the thinnest optic for a given power and optic size. Contact angles for the AcrySof IOLs range from 73 o to 80 o [20]. Continued implantation of the AcrySof IOL revealed a significant reduction in posterior capsule opacification (PCO). Paul Ursell and colleagues reported less PCO with the acrylic lens compared with silicone and PMMA lenses two year postoperatively [25]. The PCO rate for the AcrySof IOL is approximately 11%. PCO for silicone and PMMA range from 36% to 65% [26]. The decrease in PCO was related to two factors. The hydrophobic acrylic adhered to the capsular bag in which it was implanted. This prevented the growth of excess lens epithelial cells (LECs) between the IOL and the capsular bag. Reijo Linnola hypothesized that the adherence of the IOL to the capsular bag allowed only a single layer of LECs to form. With only a single layer of LECs

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13 behind the IOL, the visual axis remains clear [27]. Over time, some of the LECs die, forming a bioactive bond between the capsular bag and the IOL optic. Dr. Linnola and colleagues pursued this theory and determined that fibronectin, an extra-cellular protein, was responsible for this bioactive bond [28, 29]. A second characteristic of the Acrysof IOL that prevented PCO was a sharp, keen, square edge on the optic. Previous silicone and PMMA IOLs had rounded edges. Okihiro Nishi and colleagues investigated the effect of a square edge and PCO reduction [30]. Okihiro concluded that the square edge created a discontinuous bend in the capsular bag. The discontinuous bend combined with the adhesiveness of the acrylic material to the capsular bag were the factors that significantly reduced PCO. The Sensar Ar40 by Allergan Surgical was the second hydrophobic foldable acrylic IOL approved by the FDA. The Sensar IOL is a three-piece foldable acrylic terpolymer with blue core PMMA haptics [31]. The terpolymer optic is composed of ethyl acrylate (EA), ethyl methacrylate (EMA), and 2,2,2-trifluoroethyl methacylate (TFEMA). The material is cross-linked with ethylene glycol dimethacrylate (EGDM). Figure 1-10 illustrates the monomer structures in the Sensar IOL optic. Due to the aliphatic and fluorinated nature of the Sensar acrylics, the refractive index is lower (D~1.47) than the AcrySof IOL (D ~1.55). The fluorinated methacrylate component decreases the surface energy of the IOL and reduces tackiness to itself and surgical instruments. The Sensar lens is lathe cut from polymer sheets. Since the glass transition temperature of the Sensar lens is less than room temperature, the lathe cutting must be done cryogenically. The surface smoothness and round edges of the Sensar IOL are a result of tumble polishing [31].

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14 O O O O O O F F F O O O O ethyl acrylate ethyl methacrylate 2,2,2-trifluoroethyl methacrylate ethylene glycol dimethacrylate (EGDMA) (EA) (EMA) (TFEMA) Figure 1-10: Sensar IOL monomer structures The foldable IOL is the latest chapter in the evolution of the intraocular lens. Low Tg acrylics, silicone, and hydrogels continue to be the materials of choice for IOL manufacturing. Alcon and Advanced Medical Optics (AMO) produce the majority of the foldable IOLs implanted today. One problem that both Alcon and AMO intraocular lenses share is the development of glistenings post-operatively. Glistenings are small voids, or vacuoles that develop within the optic of the IOL. Figure 1-12 illustrates the glistening phenomenon in a 1-piece AcrySof IOL [32]. Early reports of glistenings state that they do not affect visual function, create visual disturbances, induce glare or decrease visual acuity except in the most severe cases [33]. The glistening phenomenon was first deemed a problem related only to the AcrySof IOLs. However, the first report of glistenings was by Ballin in 1984 who described the appearance of vacuoles in a PMMA optic [34]. Glistenings are thought to be related to temperature changes within the IOL optic [35]. To date, there has been no published literature detailing the procedure or

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15 cause of glistening formation. Glistenings continue to be a problem that IOL manufacturers are working to resolve. Figure 1-11: Optical micrograph of AcrySof one-piece IOL with no glistenings [32] Figure 1-12: Optical micrograph of AcrySof one-piece IOL with glistenings [32] It has been more than half a century since Ridley implanted the first IOL. Since then, more than 100 million IOLs have been implanted with remarkable success [31]. The IOL has become one of the most successful long term implants of the twentieth century. Cataract surgery has transformed from a one week procedure with hospitalization to an outpatient procedure with less than ten minutes of surgery time for skilled surgeons. This improvement in ophthalmology has been achieved by continuous advances in surgical technique, instrumentation, and IOL design.

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16 Despite the enormous success of the intraocular lens, opportunities for improved refractive index, blue light absorption, and removal of glistenings from the IOL optic remain. The studies reported here address some of improvements that could be made to low Tg, hydrophobic, acrylic IOL copolymers.

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CHAPTER 2 PHENYLATED ACRYLATE / METHACRYLATE COPOLYMER SYNTHESIS AND CHARACTERIZATION Introduction The goal of these studies was to synthesize hydrophobic, acrylic, foldable copolymers suitable for IOL applications. The desired properties were low glass transition temperature (< 20 o C), high refractive index (1.55+), controlled unfolding rate (5 sec – 60 sec), and low equilibrium water content (< 1wt%). Phenylated acrylics were chosen because they exhibit the material properties desired. The natural crystalline lens is a precisely formed structure consisting of 65% water and 35% organic material (mostly structural proteins) [36]. The proteins are structured in such a manner, that there are negligible local variations in their density, resulting in a transparent material [37]. The natural lens has a refractive index of 1.42. Aging or stress can change the morphology of the proteins, causing the natural lens to lose transparency. This loss in transparency is termed cataract formation. Cataract formation is irreversible and can eventually cause blindness. Intraocular lens (IOL) implantation is performed after cataract removal to replace the optical function of the natural lens. The first material used for IOL implantation was poly(methyl methacrylate) or PMMA. PMMA had good optical properties and was compatible with the tissues of the eye. The glass transition temperature of PMMA is such that it is rigid at room temperature. This made the incision to insert the optic about 6-7 mm in diameter. The invention of phacoemulsification meant the natural lens could 17

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18 be liquefied and removed through a 1.5 mm incision. Using a room temperature foldable material, the incision to implant the IOL could be made 3-4 mm in diameter, requiring no sutures. As a result, various silicone, acrylate and hydrogel lenses have been developed for IOLs. AcrySof IOL The most common IOL implanted in the United States today is the hydrophobic acrylic AcrySof lens. The AcrySof IOL has many favorable properties that make it the industry standard such as high refractive index, adherence to the capsular bag, square edges resulting in low posterior capsule opacification. The AcrySof lens is a polymer prepared from phenylethyl acrylate, phenylethyl methacrylate, 1,4-butanediol diacrylate and 2-(2-hydroxy-3-methallyl-5-methylphenyl) benzotriazole. Figure 2-1 illustrates the chemical structure of the AcrySof lens cross-linked using 1,4-butanediol diacrylate. *CH2 CH2 O O CH2 CH2 CH3 O O CH2 CH2 H CH2 CH3 CH2 OH CH3 N NN * n m o PEA PEMA Benzotriazole UV Absorber Figure 2-1: AcrySof polymeric structure The AcrySof IOL is manufactured using an advanced direct lens forming technology. The reaction is free radical initiated using thermal degradation of a peroxide initiator. High purity monomers are used. The glass transition temperature for the

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19 AcrySof polymer is roughly 15 o C. Unreacted monomer and oligomer are removed by rigorous solvent extraction. The amount of each monomer used during polymerization is proprietary. Because of the low T g , the AcrySof polymer is rubbery at room temperature. This is favorable because flexibility is desired, but rapid unfolding of the IOL is not desired and may rupture the capsular bag once the IOL is inserted. Favorable opening times for a foldable IOL range from five seconds to one minute. The goal of this project was to find new suitable copolymer compositions which may be useful for foldable IOLs. Acrylics were chosen as a starting point due to their demonstrated bioacceptable properties and FDA approval for foldable IOL materials. PEA/PEMA Materials and Methods Phenylethyl acrylate (PEA), phenylethyl methacrylate (PEMA), and ethylene glycol dimethacrylate (EGDMA) were purchased from Polysciences and used as received. All monomers were ophthalmic grade and contained low amounts of inhibitor. 2,2’-Azobisisobutyronitrile (AIBN) was purchased from Aldrich and used as received. Synthesis of PEA/PEMA materials The synthetic method used to synthesize the PEA/PEMA polymers is illustrated in Figure 2-2. The homopolymers of PEA and PEMA were synthesized in bulk using 2 wt% EGDMA cross-linker and 0.5 wt% AIBN initiator. 10 g monomer mixtures were weighed in centrifuge tubes and the appropriate amount of each component was added. The mixture was vortexed for 30 seconds to allow the homogenization. Argon was bubbled through the mixture to remove most of the oxygen present.

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20 O O O O N N CNCN C CN C CN C O O CH2 CNC O O CH2 CN CH O O CH2 CNCH2 C CH3 O O CH2CH CH2 CH3 O O O O n m 65oC 2 + N2 AIBN PEA/PEMA EGDMA Cross-linked Polymer Network Figure 2-2: Free radical copolymer synthesis The mixture was then syringed into a 4”x 4” glass mold. The glass molds were lined with polyethylene terephthalate (PET) to facilitate removal of the polymer. The O

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21 ring spacer was 1 mm in thickness. The glass molds were placed in an oven at 75 o C overnight. Figure 2-3 illustrates the glass mold apparatus used for the bulk polymerizations. The molds were removed from the oven and the glass plates were removed. The polyethylene terephthalate lining containing the polymer was submerged in liquid nitrogen to facilitate removal of the polymer disc. Figure 2-3: Bulk polymerization mold Monomer Solution Injected via Syringe Rubber O Ring Clam p Glass Plates Lined with PET

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22 Differential Scanning Calorimetry (DSC) Differential scanning calorimetry was performed on a Seiko DSC complete with liquid nitrogen controller. All samples were run against an alumina reference in crimped aluminum pans. DSC was performed to determine the glass transition (T g ) temperatures of the homopolymers. A temperature range of -50 o C to 120 o C was used to determine polymer T g . Two scans were performed on each sample at a heating rate of 10 o C/min. Refractometry Refractive index measurements were performed at Key Medical Technologies. Refractive index measurements were performed with an Automatic Refractometer, model CLR 12-70, from Index Instrument and calibrated with a polystyrene standard. Each sample was allowed to equilibrate to 25.5 o C prior to the measurements. The measurements were done in triplicate and the average results recorded. Monomer/Oligomer extraction Unreacted monomer and oligomer were extracted using Soxhlet extraction. Each sample was placed between two cellulose extraction thimbles (33 mm x 80 mm). The samples (usually about 1g) were weighed and the values recorded. The thimbles containing the sample were placed into a Soxhlet extractor and the extractor placed on a 500 mL round bottom containing 250mL of isopropanol. The isopropanol was refluxed and the samples were extracted for 24 hours. Samples were then removed and dried in a vacuum oven at 65 o C for eight hours. The samples were weighed. This process was repeated until no further weight loss was evident; usually 24 hours. Equilibrium Water Content (EWC) A 1g sample was cut from each polymer sheet and weighed dry. Samples were then placed in balanced salt solution (BSS) and allowed to hydrate for 24 hours. They

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23 were removed from the BSS, wiped dry, and the weights measured. The samples were rehydrated and measured again at five days. EWC was measured by the following equation: EWC (wt%) = [(W wet -W dry )/W wet ] x 100 The samples were allowed to hydrate until no further water uptake was observed (usually five days). Unfolding Rate Analysis Three disk shaped samples (8 mm in diameter, 1 mm thick) were cut from each polymer sheet. The sample was folded in half with a pair of forceps and placed on a horizontal surface to unfold. The amount of time for the polymer disc to return to its original shape was recorded. Each measurement was done three times and the average was taken. Tackiness of the polymer samples was also noted. Results and Discussion Synthesis The cross-linked homopolymers of PEA and PEMA were synthesized. The polymer samples were removed from the molds and 8 cm diameter discs were cut. Thickness of the samples was 1 mm. PEA appeared to have a very low T g and was very sticky. This material was very difficult to handle and was not suitable for foldable IOL applications. PEMA was brittle and cracked if bended and also not suitable for foldable IOL applications. DSC was performed to determine the glass transition temperatures of the two homopolymers.

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24 PEA and PEMA Homopolymer DSC 100 PEA (2% EGDM 0.5% AIBN)-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = -5oCTg = -3oC Figure 2-4: Phenylethyl acrylate (PEA) homopolymer DSC curves 100 PEMA (2% EGDM 0.5% AIBN)-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 49oCTg = 46oC Figure 2-5: Phenylethyl methacrylate (PEMA) homopolymer DSC curves

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25 It was found that the T g values for each homopolymers were not suitable for foldable IOL applications. The ideal T g range for a foldable IOL is 10 o C – 15 o C. Many ophthalmologists maintain the operating room temperature several degrees below room temperature for sterility reasons. Polymer T g values higher than 20 o C are not suitable due to the rigid nature of the material at operating room temperatures. The material may be heated to 37 o C before insertion, but this extra step should be avoided if possible. In order to produce a suitable material for foldable IOL applications, copolymers of PEA and PEMA were synthesized. Nine copolymer compositions were prepared. The compositions are summarized in Table 2-1. All percent values in Table 2-1 are recorded as wt%. Table 2-1: Phenylethyl acrylate / phenylethyl methacrylate copolymer compositions 90 PEA / 10 PEMA 2% EGDMA 0.5% AIBN 80 PEA / 20 PEMA 2% EGDMA 0.5% AIBN 70 PEA / 30 PEMA 2% EGDMA 0.5% AIBN 60 PEA / 40 PEMA 2% EGDMA 0.5% AIBN 50 PEA / 50 PEMA 2% EGDMA 0.5% AIBN 40 PEA / 60 PEMA 2% EGDMA 0.5% AIBN 30 PEA / 70 PEMA 2% EGDMA 0.5% AIBN 20 PEA / 80 PEMA 2% EGDMA 0.5% AIBN 10 PEA / 90 PEMA 2% EGDMA 0.5% AIBN Copolymer Synthesis The copolymers were synthesized by the same method mentioned above. The monomer mixtures were weighed in centrifuge tubes and vortexed for 30 seconds or until

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26 the mixture was homogeneous. The mixture was degassed with argon and injected into the PET lined glass molds illustrated above. The samples were polymerized at 75 o C overnight in a temperature controlled oven. The polymer samples were removed and DSC was performed to determine T g values. PEA / PEMA Copolymer DSC 90 PEA / 10 PEMA -40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 2oCTg = 4oC Figure 2-6: Heating DSC scans: 90 PEA / 10 PEMA 80 PEA / 20 PEMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 7oCTg = 8oC Figure 2-7: Heating DSC scans: 80 PEA/ 20 PEMA

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27 70 PEA / 30 PEMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 10oCTg = 11oC Figure 2-8: Heating DSC scans: 70 PEA/ 30 PEMA 60 PEA / 40 PEMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 14oCTg = 15oC Figure 2-9: Heating DSC scans: 60 PEA/ 40 PEMA

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28 50 PEA / 50 PEMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 18oCTg = 16oC Figure 2-10: Heating DSC scans: 50 PEA/ 50 PEMA 40 PEA / 60 PEMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 20oCTg = 21oC Figure 2-11: Heating DSC scans: 40 PEA / 60 PEMA

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29 30 PEA / 70 PEMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 29oCTg = 29oC Figure 2-12: Heating DSC scans: 30 PEA / 70 PEMA 20 PEA / 80 PEMA-5000-4000-3000-2000-10000-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 27oCTg = 28oC Figure 2-13: Heating DSC scans: 20 PEA / 80 PEMA

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30 10 PEA / 90 PEMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 40oCTg = 39oC Figure 2-14: Heating DSC scans: 10 PEA / 90 PEMA The DSC spectra above illustrate which copolymer compositions were suitable for foldable IOL applications. Nine copolymer compositions were synthesized, but only four appear suitable. The copolymers that contained higher amounts of PEA were too tacky and exhibited poor mechanical properties. The copolymers that contained higher amounts of PEMA were too brittle and often would crack during the polymerization process. The four copolymers chosen for further analysis are illustrated in Table 2-2 with T g values and physical properties. Table 2-2: Suitable PEA / PEMA IOL copolymer compositions and properties 80 PEA / 20 PEMA Tg = 8 o C Flexible, Slightly Tacky 70 PEA / 30 PEMA Tg = 11 o C Flexible, Very Little Tackiness 60 PEA / 40 PEMA Tg = 15 o C Flexible, No Tackiness, Good Balance of viscous and elastic properties 50 PEA / 50 PEMA Tg = 17 o C Flexible, No Tackiness, Slightly more viscous character

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31 Refractive Index The four copolymer compositions that were selected above were sent to Key Medical technologies for refractive index measurements. Table 2-3: Refractive index measurements for selected copolymer compositions Copolymer RI 80 PEA / 20 PEMA 1.5555 70 PEA / 30 PEMA 1.5559 60 PEA / 40 PEMA 1.5557 50 PEA / 50 PEMA 1.5551 The refractive index measurements are relatively high compared to many foldable IOLs on the market today (PMMA and PDMS) and were comparable to AcrySof IOL (RI~1.55). Monomer/Oligomer Extraction The extractable content was found to be below the 2 wt% value. Above 2% wt loss, the FDA requires characterization of extractable content and toxicity. Table 2-4: Percent weight loss after Soxhlet extraction Copolymer % wt loss 80 PEA / 20 PEMA 1.0% 70 PEA / 30 PEMA 1.1% 60 PEA / 40 PEMA 1.3% 50 PEA / 50 PEMA 1.2% Equilibrium Water Content The EWC of the selected copolymers ranged from 0.1%-0.2%. These materials are hydrophobic in nature, so low EWC values were expected. The EWC values were measured on days 1 and day 5 after water immersion. No increase in EWC was seen after day 1.

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32 00.050.10.150.20.250.30.350.40.450.580PEA/20PEMA70PEA/30PEMA60PEA/40PEMA50PEA/50PEMACopolymer Composition(wt %)EWC (% ) Figure 2-15: Equilibrium water content of PEA / PEMA copolymers Unfolding Rate Analysis The acceptable values for IOL unfolding times are 5 sec to 60 sec. The main concern is the IOL optic will unfold too rapidly and rupture the posterior capsule, creating unnecessary complications. The entire IOL implantation procedure may take only 10 minutes for a skilled surgeon. For this reason, extremely long unfolding times are not favorable. The times measured were within the acceptable range. The 80 PEA / 20 PEMA composition tended to adhere to itself for a brief moment before unfolding. Table 2-5: Unfolding times for selected copolymer compositions Copolymer T unfold 80 PEA / 20 PEMA 6 sec 70 PEA / 30 PEMA 6 sec 60 PEA / 40 PEMA 10 sec 50 PEA / 50 PEMA 13 sec

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33 Summary Overall, four PEA / PEMA copolymers appear suitable for foldable IOL applications. The 50 PEA / 50 PEMA appeared to be the most favorable monomer ratio to produce foldable IOLs based on tackiness and unfolding times. However, the refractive index measured for this class of materials was only comparable to the AcrySof lens produced by Alcon. For this reason, higher refractive index monomers such as benzyl acrylate and benzyl methacrylate were studied. Benzyl Acrylate / Benzyl Methacrylate Materials and Methods Benzyl Acrylate (BA), Benzyl Methacrylate (BMA), and ethylene glycol dimethacrylate (EGDMA) were purchased from Polysciences and used as received. All monomers were ophthalmic grade and contained low amounts of inhibitor. AIBN was purchased from Aldrich and used as received. Synthesis of BA / BMA Materials The cross-linked homopolymers of BA and BMA were synthesized in bulk using 2 wt% EGDMA (0.02 g) and 0.5 wt% AIBN (0.005 g). Figure 2-15 illustrates the structures of BA and BMA. The monomer mixtures were weighed in centrifuge tubes and the appropriate amount of each component was added. The mixture was vortexed for 30 seconds to allow the homogenization. Argon was bubbled through the mixture to remove most of the oxygen present. The mixture was syringed into the PET lined glass molds shown in Figure 2-3. The molds were placed in a temperature controlled oven at 75 o C overnight. The polymer samples were removed from the glass molds and analyzed.

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34 O O O O Benzyl acrylate Benzyl methacrylate Figure 2-16: Structure of benzyl acrylate and benzyl methacrylate Differential Scanning Calorimetry Homopolymer DSC curves were performed to determine the glass transition temperatures of the benzyl acrylate and benzyl methacrylate homopolymers. Two heating scans per sample were perfomed. 100 BA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 5oCTg = 7oC Figure 2-17: Benzyl acrylate homopolymer DSC curves

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35 100 BMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 62oCTg = 64oC Figure 2-18: Benzyl methacrylate homopolymer DSC curves It was evident that the T g value for BMA was not suitable for foldable IOL applications. BA was flexible but very sticky and difficult to handle. BMA was a rigid glass at room temperature and cracked when flexed at room temperature. In order to produce an improved material for foldable IOL applications, copolymers of BA and BMA were prepared. Nine copolymer compositions were made. The compositions are summarized in Table 2-6. All percent values in Table 2-6 are wt%. Table 2-6: Benzyl acrylate / benzyl methacrylate copolymer compositions 90 BA / 10 BMA 2% EGDMA 0.5% AIBN 80 BA / 20 BMA 2% EGDMA 0.5% AIBN 70 BA / 30 BMA 2% EGDMA 0.5% AIBN 60 BA / 40 BMA 2% EGDMA 0.5% AIBN 50 BA / 50 BMA 2% EGDMA 0.5% AIBN 40 BA / 60 BMA 2% EGDMA 0.5% AIBN 30 BA / 70 BMA 2% EGDMA 0.5% AIBN 20 BA / 80 BMA 2% EGDMA 0.5% AIBN 10 BA / 90 BMA 2% EGDMA 0.5% AIBN

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36 Copolymer Synthesis The copolymers were prepared using the same method used for the PEA / PEMA copolymers. The monomer mixtures were weighed in centrifuge tubes and vortexed for 30 seconds or until the mixture was homogeneous. The mixture was degassed with argon and injected into the PET lined glass molds illustrated above. The samples were polymerized at 75 o C overnight in a temperature controlled oven. The polymer samples were removed and DSC was performed to determine T g values. BA / BMA Copolymer DSC The benzyl acrylate and benzyl methacrylate copolymer DSC was performed in the same manner as the homopolymers. Glass transition temperatures were determined to select suitable foldable IOL compositions. 90 BA / 10 BMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 9oCTg = 11oC Figure 2-19: Heating DSC scans: 90 BA / 10 BMA

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37 80 BA / 20 BMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 16oCTg = 18oC Figure 2-20: Heating DSC scans: 80 BA / 20 BMA 70 BA / 30 BMA-40-30-20-100102030405060708090100Temperture (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 21oCTg = 23oC Figure 2-21: Heating DSC scans: 70 BA / 30 BMA

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38 60 BA / 40 BMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 26oCTg = 28oC Figure 2-22: Heating DSC scans: 60 BA / 40 BMA 50 BA / 50 BMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 32oCTg = 33oC Figure 2-23: Heating DSC scans: 50 BA / 50 BMA

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39 40 BA / 60 BMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 38oCTg = 39oC Figure 2-24: Heating DSC scans: 40 BA / 60 BMA 30 BA / 70 BMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 46oCTg = 44oC Figure 2-25: Heating DSC scans: 30 BA / 70 BMA

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40 20 BA / 80 BMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg =52oCTg = 50oC Figure 2-26: Heating DSC scans: 20 BA / 80 BMA 10 BA / 90 BMA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 57oCTg = 56oC Figure 2-27: Heating DSC scans: 10 BA / 90 BMA

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41 Nine copolymer compositions were prepared and four may be suitable for foldable IOLs. The copolymer that contained 90 wt% BA was tacky and exhibited poor mechanical properties. The copolymers that contained higher amounts of BMA were too brittle and often would crack during the polymerization process. Four copolymers were chosen for further analysis as given in Table 2-7 with T g values and physical properties. Table 2-7: Suitable BA / BMA IOL copolymer compositions and properties 90 BA / 10 BMA Tg = 10 o C Flexible, Slightly Tacky 80 BA / 20 BMA Tg = 17 o C Flexible, No Tackiness, Good balance of viscoelasticity 70 BA / 30 BMA Tg = 22 o C No Tackiness, Slightly flexible 60 BA / 40 BMA Tg = 27 o C No Tackiness, slightly brittle Refractometry The four copolymer compositions that were selected above were sent to Key Medical technologies for refractive index measurements. The results are given in Table 2-8. Table 2-8: Refractive index measurements for selected BA/BMA compositions Copolymer RI 90 BA / 10 BMA 1.5648 80 BA / 20 BMA 1.5627 70 BA / 30 BMA 1.5608 60 BA / 40 BMA 1.5607 The refractive index measurements appear higher than any foldable IOLs on the market today (PMMA and PDMS). There was a slight improvement in RI value over the AcrySof IOL (RI~1.55). Monomer/Oligomer Extraction Table 2-9: Percent weightt loss after Soxhlet extraction Copolymer % wt loss 90 BA / 10 BMA 0.9% 80 BA / 20 BMA 1.1% 70 BA / 30 BMA 1.3% 60 BA / 40 BMA 0.9%

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42 Equilibrium Water Content 00.050.10.150.20.250.30.350.40.450.590BA/10BMA80BA/20BMA70BA/30BMA60BA/40BMACopolymer Composition(wt%)EWC (%) Figure 2-28: Equilibrium water content of BA / BMA copolymers The selected BA/BMA copolymer had EWC values ranging from 0.1% 0.2%. These materials are hydrophobic in nature, so low EWC values were expected. No increase in EWC was seen from day 1 to day 5. Unfolding Rate Analysis Table 2-10: Benzyl acrylate / benzyl methacrylate unfolding rate analysis Copolymer T unfold 90 BA / 10 BMA 7 sec 80 BA / 20 BMA 15 sec 70 BA / 30 BMA 20 sec 60 BA / 40 BMA Did not return to original shape The unfolding times measured for the first three compositions were within the acceptable range. The 90 BA / 10 BMA composition was slightly tacky and would stick to itself for a brief moment before unfolding. The 60 BA / 40 BMA copolymer did not

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43 return to its original shape. This material was too brittle and difficult to fold for foldable IOL applications. The material did not crack, but was very difficult to fold at room temperature. Summary Overall, three BA / BMA copolymers appear suitable for foldable IOL applications. The 80 BA / 20 BMA appeared to be the most favorable monomer ratio for foldable IOLs based on T g , low tackiness and good unfolding time. The refractive index measured for this class of materials was a slight improvement over the AcrySof lens produced by Alcon. Other properties were nearly identical to the PEA / PEMA copolymers that were previously synthesized. Conclusions In total, seven new cross-linked acrylic copolymer compositions were prepared could be suitable for foldable IOL applications. Four PEA / PEMA and three BA / BMA had favorable foldable IOL characteristics. The materials were low T g (< 20 o C), hydrophobic (<1 wt% EWC), high refractive index (>1.55), low extractable content (< 2 wt%) and exhibited controlled unfolding. The BA / BMA compositions showed a slight improvement over the PEA / PEMA materials due to slightly higher refractive index values. In order to produce copolymers with even higher refractive index values (greater than 1.60), different high RI monomers were investigated in this research.

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CHAPTER 3 N-VINYL CARBAZOLE / PHENYLETHYL ACRYLATE COPOLYMER SYNTHESIS AND CHARACTERIZATION Introduction Poly(N-vinyl carbazole) was first synthesized by Reppe and co-workers in 1934 (Reppe and Keyssner DRP 618). The polymerization of N-vinyl carbazole (NVC) and the properties of poly(NVC) are controlled by the electronic and steric influence of the carbazole group [38]. The electronegative nitrogen atom withdraws electrons form the vinyl bond but donates electrons through an inductive effect. This creates an electron rich system that is polymerizable by cationic or free radical methods. NVC cannot be polymerized by anionic means. Radical polymerization was used in manufacturing poly(NVC) marketed as Luvican by BASF AG and as Polectron by General Aniline and Film Corporation [38]. The polymerization of NVC can be performed in bulk, in solution, in suspension, in solid crystalline state, or as a vapour deposition process [39]. Free radical initiators such as AIBN or peroxides readily polymerize NVC. The polymer produced has a refractive index of 1.68 and is colorless [40]. The T g of high molecular weight isotactic poly(NVC) was found to be 227 o C [41]. The glass transition temperature for atactic poly(NVC) has been reported as low as 165 o C. Poly(NVC) has a high glass transition temperature with makes it impractical for foldable IOL applications. NVC copolymerized with a low T g monomer such as 44

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45 phenylethyl acrylate using bulk free radical polymerization, will produce high refractive index copolymers with T g values much lower than that of the NVC homopolymer. NVC/PEA Materials and Methods N-vinyl carbazole (NVC), phenylethyl acrylate (PEA), and ethylene glycol dimethacrylate (EGDMA) were purchased from Polysciences and used as received. All monomers were ophthalmic grade and contained low amounts of hydroquinone inhibitor. AIBN and t-butyl peroxide (Luperox DI) were purchased from Aldrich and used as received. Synthesis of NVC Homopolymer The synthetic method used to prepare the N-vinyl carbazole homopolymer is illustrated in Figure 3-1. At room temperature, NVC is a crystalline solid. The NVC polymerization was done in solution. N N n N-vinyl carbazole (NVC) AIBN Dioxane poly(NVC) Figure 3-1: N-vinyl carbazole solution polymerization 10 g of NVC was placed in a 500 mL round bottom flask. 12.5mg of AIBN was added. 100 mL of 1,4-dioxane was added and the mixture was stirred until the AIBN was dissolved. The solution was purged with argon for 5 minutes. The mixture was heated to reflux and held for 2 hours. The heat was turned off and the flask was allowed to cool. The mixture was precipitated into 700 mL of DI water to reveal a white solid. The solid

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46 was filtered and placed in a vacuum oven to dry. 9.8 grams of the polymer was recovered (98% yield). Poly(N-vinyl carbazole) DSC The T g of the NVC homopolymer was determined to be 175 o C Poly(N-Vinyl Carbazole)0255075100125150175200225250Temperature (oC)Heat Flow (Endo Down) Tg = 175oC Figure 3-2: Poly(N-vinyl carbazole) DSC In order to synthesize materials suitable for foldable IOL applications using NVC, three copolymer compositions, listed in Table 3-1, were selected. PEA was selected as the co-monomer for its high refractive index and low T g (-4 o C). Table 3-1: Selected NVC / PEA copolymer compositions Composition (wt %) 10 NVC / 90 PEA 20 NVC / 80 PEA 30 NVC / 70 PEA Synthesis of NVC / PEA Copolymers The NVC / PEA copolymer synthesis was done in bulk. Figure 3-3 illustrates the synthetic method. The NVC was found to be readily soluble in PEA. The monomers

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47 (10g) were weighed in centrifuge tubes. 2 wt% EGDMA (0.02 g) and 0.5 wt% t-butyl peroxide (0.005 g) were added and the mixture was vortexed for 30 seconds. Argon was bubbled through the solution to remove oxygen. The monomer was injected into PET lined glass molds via syringe. The molds were placed in a 120 o C oven for 12 hours. The molds were removed from the oven and allowed to cool. The polymer (8 cm in diameter and 1 mm thick) was removed and placed on a PET sheet. The samples were cured again at 130 o C for 8 hours to complete polymerization. The sheets were then removed from the oven and allowed to cool. N O O O O N O O n m N-vinyl carbazole Phenylethyl acrylate (NVC) (PEA) + 120oC EGDMA NVC / PEA Copolymer Figure 3-3: N-vinyl carbazole / phenylethyl acrylate copolymer synthesis NVC / PEA Copolymer DSC All differential scanning calorimetry was performed on a Seiko DSC complete with liquid nitrogen controller. All samples were run against an alumina reference in crimped aluminum pans. DSC was performed to determine the glass transition (T g ) temperatures of the NVC homopolymer as well as the NVC / PEA copolymers. A temperature range of -50 o C to 120 o C was used to determine polymer T g . Two scans were performed on each sample. All heating rates were 10 o C/min.

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48 Refractometry All Refractive index measurements were performed at Key Medical Technologies. Refractive index measurements were performed with an Automatic Refractometer, model CLR 12-70, from Index Instrument and calibrated with a polystyrene standard. Each sample was allowed to equilibrate to 25.5 o C prior to the measurements. The measurements were done in triplicate and the average results recorded. Monomer/Oligomer extraction Unreacted monomer and oligomer were extracted using Soxhlet extraction. Each sample (usually 1 g) was placed between two cellulose extraction thimbles (33 mm x 80 mm). The samples were weighed and the values recorded. The thimbles containing the sample were placed into a Soxhlet extractor and the extractor placed on a 500 mL round bottom containing 250 mL of isopropanol. The isopropanol was refluxed. The samples were extracted for 24 hours. The samples were then removed and dried in a vacuum oven at 65 o C for eight hours. The samples were weighed. This process was repeated until no further weight loss was evident, usually 24 hours. Equilibrium Water Content (EWC) A 1g sample was cut from each polymer sheet and weighed dry. Samples were then placed in balanced salt solution (BSS) and allowed to hydrate for 24 hours. They were removed from the BSS, wiped dry, and the weights measured. The samples were rehydrated and measured again at five days. EWC was measured by the following equation: EWC (wt%) = [(W wet -W dry )/W wet ] x 100

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49 The samples were allowed to hydrate until no further water uptake was observed (usually five days). Unfolding Rate Analysis Three disk shaped samples (8 mm in diameter, 1 mm thick) were cut from each polymer sheet. The sample was folded in half with a pair of forceps and placed on a horizontal surface to unfold. The amount of time for the polymer disc to return to its original shape was recorded. Each measurement was done three times and the average was taken. Tackiness of the polymer samples was also noted. Results and Discussion NVC / PEA Copolymer DSC 10 NVC / 90 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 9oCTg = 10oC Figure 3-4: Heating DSC scans: 10 NVC / 90 PEA

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50 20 NVC / 80 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 26oCTg = 27oC Figure 3-5: Heating DSC scans: 20 NVC / 80 PEA 30 NVC / 70 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 30oC Tg = 31oC Figure 3-6: Heating DSC scans: 30 NVC / 70 PEA

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51 40 NVC / 60 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 52oCTg = 54oC Figure 3-7: Heating DSC scans: 40 NVC / 60 PEA 50 NVC / 50 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 50oC Tg = 52oC Figure 3-8: Heating DSC scans: 50 NVC / 50 PEA

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52 The NVC / PEA copolymer DSC curves indicate that above 20% NVC, the T g of the material was too high to be suitable for foldable IOL applications. The copolymers with more than 20 wt% NVC were brittle and cracked if strained. Three of the copolymers were selected for refractive index measurements. The three copolymers chosen for further analysis are illustrated in Table 3-2 with T g values and physical properties. Table 3-2: Selected NVC / PEA copolymer compositions Composition T g Physical Properties 10 NVC / 90 PEA 10 o C No Tackiness, Foldable, Suitable Foldable IOL Material 20 NVC / 80 PEA 26 o C No Tackiness, Slightly Foldable 30 NVC / 70 PEA 30 o C No Tackiness, Cracked when Folded Refractive Index The three copolymer compositions that were selected above were sent to Key Medical technologies for refractive index measurements. The results are given in Table 3-3. Table 3-3: Copolymer refractive indicies: NVC / PEA Copolymer RI 10 NVC / 90 PEA 1.5763 20 NVC / 80 PEA 1.5939 30 NVC / 70 PEA 1.6107 The refractive index values obtained for the NVC / PEA copolymers are higher that any IOL polymer on the current market. The refractive index increase of the copolymer was controlled by the amount of NVC present. Above 10 wt%, the material becomes too brittle for foldable IOL applications. New NVC derivatives were therefore synthesized

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53 with lower T g to increase the amount of carbazole that could be incorporated in the copolymer, and reduce the T g to improve flexibility at room temperature. N-Vinyl Carbazole Derivatives N-vinyl carbazole derivatives, with spacer groups, were synthesized in order to afford more molecular flexibility and to incorporate more wt% carbazole into the copolymer without raising the copolymer T g above 20 o C. This was accomplished by placing methylene spacers between the carbazole unit and the vinyl group. Increasing the aliaphatic content of NVC also decreases the refractive index so the fewest number of methylene spacers for low T g was sought. Synthesis of the NVC derivatives was accomplished using two methods designed for large scale synthesis and simplicity. Materials and Methods Carbazole was purchased from Aldrich and purified by recrystallization in ethanol before use. Allyl bromide, 4-pentenyl bromide, sodium hydride, potassium hydroxide, anhydrous tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethyl sulfoxide-d 6 , ethanol, methanol, diethyl ether, activated carbon and sodium sulfate were purchased from Aldrich and used as received. PEA was purchased from Polysciences and used as received. NVC Derivatives Synthesis Two synthetic routes were used to make the NVC derivatives. The routes are illustrated in figures 3.9 and 3.10. Route #1 was used initially with yields in the range of 60%-65%. Route #2 was chosen because it gave higher yields (80%) and used less hazardous reagents.

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54 N N N H Br Br 9-allyl carbazole 9-(4-pentenyl carbazole) carbazole NaH + (NVC-1) (NVC-3) THF Figure 3-9: N-vinyl carbazole derivative synthesis route #1 N N N H Br Br 9-allyl carbazole 9-(4-pentenyl carbazole) carbazole + (NVC-1) (NVC-3) KOH DMSO Figure 3-10: N-vinyl carbazole derivative synthesis route #2

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55 Method #1: 2.6 g of sodium hydride (108 mmol) and 50 mL of anhydrous THF were placed in a flame dried and argon purged 500 mL three-neck flask equipped with a condenser and addition funnel. 16.7 g of carbazole in 200 mL of dry THF were added drop-wise and the mixture was refluxed for 3 hours. The mixture was allowed to cool and 12 g of allyl bromide in 50 mL of dry THF was added drop-wise. The mixture was refluxed for 3 hours. The mixture was allowed to cool to room temperature and the THF was removed under reduced pressure. The crude product was dissolved in diethyl ether and washed three times with DI water. The ether was removed under reduced pressure to reveal a pale yellow solid. The solid was recrystallized in methanol to remove most of the yellow color. The product was recrystallized once more with activated carbon to yield 11.8 g of white crystals. (57% yield) Method #2: 25 g of carbazole (150 mmol) was added to a three neck flask. The flask was purged with argon. 300 mL of DMSO was added and the mixture was stirred. When all the carbazole was solubilized, 30 g of KOH was added. The mixture was stirred for 3 hours. 24 g of allyl bromide (200 mmol) was added to the flask. The mixture was stirred at room temperature for 4 hours. The mixture was then precipitated into 2 L of DI water. The precipitate was allowed to settle and filtered. The precipitate was collected and recrystallized once to remove most of the pale yellow color. The precipitate was recrystallized again with activated carbon to reveal 25 g of white crystalline 9-allyl carbazole (80% yield). 9-(4-pentenyl carbazole) was synthesized similarly by replacing allyl bromide with 4-pentenyl bromide (76% yield). NVC-1 / NVC-3 NMR Monomer purity and structure confirmation were performed using Nuclear Magnetic Resonance Spectroscopy (NMR). All NMR spectra, 1 H and 13 C were

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56 conducted using a Varian Gemini 300 MHz series superconducting spectrometer system. Sample solutions were made using 75 mg of monomer in d 6 -DMSO. NVC Derivative Copolymer Synthesis NVC-1 and NVC-3 were copolymerized with PEA using the same method as the NVC / PEA copolymers synthesized previously. The NVC derivative was solubilized in PEA and the polymerization was carried out in bulk using free radical initiation (t-butyl peroxide). The polymerization was performed using the PET lined glass molds described previously. N N O O O O O O O O O O N n m O O n m N 9-allyl carbazole 9-(4-pentenyl carbazole) (NVC-1) (NVC-3) phenylethyl acrylate PEA + phenylethyl acrylate PEA + 120oC 120oC NVC-1 / PEA Copolymer NVC-3 / PEA Copolymer Figure 3-11: N-vinyl carbazole derivative/ phenylethyl acrylate copolymer synthesis Differential Scanning Calorimetry (DSC) All differential scanning calorimetry was performed on a Seiko DSC complete with liquid nitrogen controller. All samples were run against an alumina reference in crimped aluminum pans. DSC was performed to determine the glass transition (T g )

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57 temperatures of the homopolymers. A temperature range of -50 o C to 120 o C was used to determine polymer T g . Two scans were performed on each sample. All heating rates were 10 o C/min. Refractometry All Refractive index measurements were performed at Key Medical Technologies. Refractive index measurements were performed with an Automatic Refractometer, model CLR 12-70, from Index Instrument and calibrated with a polystyrene standard. Each sample was allowed to equilibrate to 25.5 o C prior to the measurements. The measurements were done in triplicate and the average results recorded. Equilibrium Water Content (EWC) A 1 g sample was cut from each polymer sheet. The sample was weighed and recorded as dry weight. The sample was placed in balance salt solution (BSS). The sample was allowed to hydrate for 24 hours. The samples were wiped dry and the weights measured. The samples were re-hydrated and measured again at 5 days. The samples were allowed to hydrate until no further water uptake was observed (usually 5 days). Unfolding Rate Analysis Three disk shaped samples (8 mm in diameter, 1 mm thick) were cut from each polymer sheet. The sample was folded in half with a pair of forceps and placed on a horizontal surface to unfold. The amount of time for the polymer disc to return to its original shape was recorded. Each measurement was done three times and the average was taken. Tackiness of the polymer samples was also noted.

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58 Results and Discussion Nuclear Magnetic Resonance (NMR) Product purity and structure confirmation were achieved using NMR. Both NVC-1 and NVC-3 NMR spectra illustrated correct structure and purity. There was no unsubstituted carbazole present in either product. The proton at the N-position of carbazole has a chemical shift of 11.0 ppm. There was no evidence of the carbazole impurity in either 1 H NMR spectrum. The products were completely substituted at the N-position. N H N Singlet at 11.0 ppm Carbazole No Peak N-Allyl Carbazole Figure 3-12: Carbazole impurity signal There were nine different carbons present in the NVC-1 monomer. The 13 C spectrum showed nine peaks. There were eleven different carbons in the NVC-3 monomer. The 13 C spectrum showed eleven peaks. These solutions were made using d 6 -DMSO, so the DMSO impurity should be ignored in all spectra. DMSO is hydroscopic so the water impurity peak should also be ignored.

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59 Figure 3-13: Allyl carbazole (NVC-1) 1 H NMR spectra Figure 3-14: Allyl carbazole (NVC-1) 13 C NMR spectra

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60 Figure 3-15: Pentenyl carbazole (NVC-3) 1 H spectra Figure 3-16: Pentenyl carbazole (NVC-3) 13 C spectra

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61 NVC-1 / PEA Copolymer DSC The addition of one methylene unit between the vinyl bond and the carbazole unit significantly reduced the T g of the copolymers. 50 wt% NVC-1 was incorporated into the copolymer and the T g was 20 o C. The limiting factor was how much NVC-1 would remain soluble in the PEA. The 50 NVC-1 / 50 PEA co-monomer mixture had to be heated repeatedly to sustain a homogeneous mixture. At 50 wt%, the NVC-1 was beginning to crystallize out of solution as the monomer mixture cooled to room temperature. This made the mixture difficult to inject into the mold due to NVC-1 crystals blocking the syringe needle. 10 NVC-1 / 90 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 1oCTg = 2oC Figure 3-17: Heating DSC scans: 10 NVC-1 / 90 PEA

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62 20 NVC-1 / 80 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 5oCTg = 7oC Figure 3-18: Heating DSC scans: 20 NVC-1 / 80 PEA 30 NVC-1 / 70 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 10oCTg = 10oC Figure 3-19: Heating DSC scans: 30 NVC-1 / 70 PEA

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63 40 NVC-1 / 60 PEA-40-30-20-100102030405060708090100Temperature (oC)Het Flow (Endo Down) 1st Scan 2nd Scan Tg = 16oCTg = 18oC Figure 3-20: Heating DSC scans: 40 NVC-1 / 60 PEA 50 NVC-1 / 50 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 20oCTg = 20oC Figure 3-21: Heating DSC scans: 50 NVC-1 / 50 PEA

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64 Based on the DSC results, two compositions were chosen for further analysis. The 40 NVC-1 / 60 PEA and 50 NVC-1 / 50 PEA mixtures were analyzed further due to the high carbazole content these compositions afforded. The 10 wt % and 20 wt% NVC-1 compositions were tacky and difficult to handle. Table 3-4 illustrates the selected copolymer compositions and properties of each. Table 3-4: Selected NVC-1 / PEA copolymer compositions Composition T g Physical Properties 40 NVC-1 / 60 PEA 17 o C No Tackiness, Foldable 50 NVC-1 / 50 PEA 20 o C No Tackiness, Foldable Refractive Index The three copolymer compositions that were selected above were sent to Key Medical technologies for refractive index measurements. The results are given in Table 3-5. Table 3-5: Copolymer refractive indicies: NVC-1 / PEA Copolymer RI 40 NVC-1 / 60 PEA 1.5955 50 NVC-1 / 50 PEA 1.6044 The refractive index values obtained for the NVC-1 / PEA copolymers are higher that any known IOL polymer. The high refractive index was controlled by the amount of carbazole present in the copolymer. At 50 wt% NVC-1, the refractive index of the material was >1.6 and the material remained flexible at room temperature.

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65 Equilibrium Water Content The twoNVC-1 / PEA copolymers had EWC values ranging from 0.06% 0.07%. These materials are hydrophobic; low EWC values were expected. No increase in EWC was seen from day 1 to day 5. NVC-1 / PEA Copolymer EWC00.050.10.150.20.250.30.350.40.450.540 NVC-1 / 60 PEA50 NVC-1 / 50 PEACompositionwt% 0.06 wt%0.07 wt% Figure 3-22: Equilibrium water content of NVC-1 / PEA copolymers Unfolding Rate Analysis The unfolding times measured for the first three compositions were within the acceptable range. These copolymers had significant viscous character. The unfolding was slow and controlled. These materials were found to unfold slower than any copolymer previously synthesized.

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66 Table 3-6: Unfolding rate analysis: NVC-1 / PEA Copolymer T unfold 40 NVC-1 / 60 PEA 18 sec 50 NVC-1 / 50 PEA 30 sec NVC-3 / PEA Copolymer DSC 30 NVC-3 / 70 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 1oCTg = 3oC Figure 3-23: Heating DSC scans: 30 NVC-3 / 70 PEA

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67 40 NVC-3 / 60 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 0oCTg = 1oC Figure 3-24: Heating DSC scans: 40 NVC-3 / 60 PEA 50 NVC-3 / 50 PEA-40-30-20-100102030405060708090100Temperature (oC)Heat Flow (Endo Down) 1st Scan 2nd Scan Tg = 7oCTg = 7oC Figure 3-25: Heating DSC scans: 50 NVC-3 / 50 PEA The NVC-3 / PEA copolymer DSC indicated the 40 wt% NVC-3 copolymer to have a lower T g than the 30 wt% NVC-3 copolymer even after post curing. The NVC-3

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68 copolymer samples were not homogeneous and contained many defects. These defects were most likely due to the poor solubility of NVC-3 in PEA. Concentrations as low as 30 wt% NVC-3 would crystallize out of solution if the monomer mixture was allowed to cool to room temperature. The NVC-3 monomer solutions were difficult to handle and injection into the glass molds was troublesome due to NVC-3 crystals clogging the syringe needle. The NVC-3 also had a lower refractive index value than NVC-1 due to the addition of two added methylene units. Due to the poor sample quality and reduced refractive index, no further analysis was done on the NVC-3 copolymer compositions. Conclusions In summary, several acrylic based copolymers with high refractive index carbazole content were synthesized that exhibited improved properties for foldable IOL applications. The NVC-1 and NVC-3 monomers were successfully synthesized and analyzed. The NVC-3 monomer did not mix favorably with the PEA co-monomer. The NVC / PEA and NVC-1 / PEA copolymers showed excellent mechanical behavior and significant improvements over the PEA / PEMA copolymer used commercially by Alcon. The refractive index for the 50 NVC-1 / 50 PEA copolymer was greater than 1.60, which met the initial goal of this study. The higher refractive index of these materials would allow thinner optics than any foldable IOL on the market today. The polymers are hydrophobic so the added benefit of posterior capsular bag adherence and low PCO rates should be maintained. In the future, to achieve even higher refractive index values of 1.62+, a lower T g , high refractive index co-monomer must be used. This co-monomer should be soluble with at least 50 wt% NVC-1 in order to perform this polymerize in bulk.

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CHAPTER 4 ALLYL PHENOTHIAZINE BASED UV ABSORBERS FOR IOL APPLICATIONS Introduction The human eye is exposed to radiation throughout the life of the patient. This radiation includes wavelengths in the visible region (700 nm – 400 nm) and ultraviolet region (286 nm – 400 nm). Only ultraviolet radiation between 300 nm – 400 nm reaches the inside of the eye due to absorption properties of the cornea [42]. The retinal exposure to UV radiation is minimal due to the additional light attenuation of the crystalline lens [43]. Figure 4-1: Visible radiation spectrum Removal of the natural lens in cataract surgery increases the amount of optical radiation that can reach the retina. The removal of the crystalline lens could allow damaging UV radiation to reach the retina causing photic retinopathy, also known as 69

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70 retinal phototoxicity or foveomacular retinitis [44, 45]. In addition to UV absorption, the ageing crystalline lens blocks potentially phototoxic shorter wavelength blue light [46-48]. Additionally, the natural human lens yellows with age. This color change is likely attributable to oxidation products of tryptophan (n-formyl-kynurenine) and to glycosylation of lens proteins [49]. Absorbing the blue radiation wavelengths (400 nm – 500 nm) would mimic the natural ageing lens. Figure 4-1 illustrates the visible and UV radiation spectrum. Figure 4-1 was courtesy of Paul Ernest M.D. In order to reduce the amount of retinal exposure to UV, IOLs with UV blocking chromophores (benzophenones and benzotriazoles) bonded to the backbone of the polymer were introduced in the early 1980s [43, 50, 51]. IOLs that absorb blue light as well as UV radiation were introduced in the late 1990s based on the assumption that IOLs should mimic the properties of the ageing natural lens [52]. This concept results in a somewhat yellow optic which could also reduce night vision. A comparison of a natural lens from a 4-year-old and a 53-year-old person showed that the older lens has significantly less blue light reaching the retina [43]. Figure 4-2 illustrates the transmission spectrum of various IOLs in clinical use and natural lenses [43]. Figure 4-2 was reproduced with permission from Paul Ernest M.D. The transmission spectrum for a blue absorbing IOL (AcrySof Natural) can be seen to mimic that of the natural lens. The absorption curve fits between the curve for the young and aged lens.

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71 Figure 4-2: Transmission spectrum of selected IOLs and natural lenses Blue Light Absorption There has been some controversy about the removal of blue visible light and scotopic vision or vision in dim light conditions [53]. UV radiation is not useful for human vision, so it makes good sense to use block the UV from reaching the retina. The amount of blue light that should be filtered is a much more difficult decision. It is known that scotopic vision decreases faster than photopic vision (bright light conditions) in ageing adults. Blue light is more important in scotopic than photopic vision [54, 55]. The desired light transmission through an IOL may become a trade off between visual performance and protection against potential blue light retinal phototoxicity. Photopic sensitivity peaks at 555 nm in the green-yellow region of the spectrum [56]. Scotopic sensitivity peaks at 506 nm in the blue-green part of the visible spectrum [56]. Scotopic visual sensitivity decreases twice as fast as photopic sensitivity with increasing age. This loss contributes to difficult night-time vision that occurs independent of retinal disease [57, 58].

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72 Blue Light Toxicity To date, there has been no scientific evidence that proves blue visible light is damaging to the retina. It has been stated that blue light “may be” toxic to the retina, but no scientific study has proven this claim. The push for a blue light absorbing IOL has been mostly the result of marketing strategies and the leading IOL company Alcon, has been very successful in marketing the AcrySof Natural foldable IOL. The AcrySof Natural lens was originally developed to enhance contrast sensitivity but, experimental data showed that there was no contrast sensitivity differences between the yellow IOL and the clear IOLs manufactured previously. The marketing approach was then changed in order to sell the yellow AcrySof IOL based on two main sales arguments: 1. Blue light is toxic to the retina 2. Patients want to be restored to the visual spectrum of the aged lens, not the childhood natural lens Neither of the two points mentioned above have been validated. The major complication to the implementation of the blue absorbing IOL was that the lens was too yellow. Ophthalmologists were hesitant to implant the AcrySof Natural lens due to the bright yellow color and the possibility of scotopic vision loss. Figure 4-3 (courtesy of Paul Ernest M.D.) illustrates the color of the AcrySof Natural foldable IOL Figure 4-3: Photograph of the one-piece AcrySof Natural IOL

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73 The blue light-filtering chromophore found in the AcrySof Natural IOL is a proprietary yellow compound N-2[3-(2-methylphenylazo)-4-hydroxyphenyl] ethyl methacrylamide (Data on File, Alcon Laboratories). This chromophore is covalently bound to the copolymer backbone. The chemical structure of the AcrySof Natural chromophore can be seen in Figure 4-4. N O OH N N H N-2[3-(2-methylphenylazo)-4-hydroxyphenyl] ethyl methacrylamide Figure 4-4: Chemical structure of the AcrySof Natural blue light filtering chromophore The actual weight percentage of blue light filtering chromophore found in the AcrySof Natural IOL is proprietary. This blue light filtering chromophore is used in combination with the UV-absorbing benzotriazole used in previous AcrySof IOLs to mimic the UV and blue light absorption of the natural crystalline lens. Table 4-1 illustrates the transmittance comparison for 20.0 diopter AcrySof IOLs. Table 4-1: Transmittance comparison for 20.0D IOLs [59] IOL Model 400 nm 425 nm 450 nm 475 nm ACRYSOF Single-Piece IOL Model SA60AT 21% 86% 88% 88% ACRYSOF Natural IOL Model SN60AT 6% 31% 47% 69%

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74 The goal of the research reported here was therefore to develop UV-absorbing molecules that absorbed blue visible light with extinction coefficients sufficiently high so that very low concentrations (less yellow) could be used to filter the blue light. The compounds would have to be polymerizable via free radical methods. This would ensure that the material could be covalently bonded to the backbone of the acrylic IOL polymer. This is necessary because these IOL polymers are washed with solvent to remove any unreacted material. Covalently tethering the molecule to the backbone would ensure no UV absorber removal during the extraction process. Emphasis for this study was therefore directed to the synthesis of new allyl functional phenothiazaine compounds. Materials and Methods Phenothiazine, 2-chlorophenothiazine, ally bromide, sodium hydride, potassium hydroxide, THF, benzene, dimethyl sulfoxide (DMSO), dimethyl sulfoxide-d6, methanol, sodium chloride, sodium sulfate and chloroform were purchased from Aldrich and used as received. Synthesis Two different synthetic routes were used to synthesize the phenothiazine UV-absorbing molecules. Method 1 was used for N-allyl phenothiazine because allyl phenothiazine is a liquid at room temperature. The precipitation into DI water created an emulsion that created difficulties when removing product. Method 2 was used for N-allyl-2-chlorophenothiazine. N-allyl-2-chlorophenothiazine was a solid at room temperature. Precipitation into DI water created little difficulty in removing product. The synthetic methods are illustrated in Figure 4-4.

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75 SN SN H Br SN H Cl Br SN Cl NaH THF + Phenothiazine N-allyl phenothiazine 2-chloro-phenothiazine KOH DMSO + N-allyl-2-chloro-phenothiazine Method I Method II Figure 4-5: Synthetic methods for phenothiazine UV-absorbers Method I: 1.8 g (75 mmol) of sodium hydride was added to a flame dried 3-neck flask equipped with a condenser, addition funnel, and magnetic stir bar. 35 mL of anhydrous THF was added to the flask and the mixture was stirred. 10 g (50 mmol) of phenothiazine in 150 mL of anhydrous THF was added drop-wise to the sodium hydride mixture. The mixture was refluxed for three hours. After three hours, the mixture was allowed to cool to room temperature and 9.1 g (75 mmol) of allyl bromide in 35 mL of anhydrous THF was added drop-wise to the mixture. The mixture was again refluxed for three hours. The mixture was cooled and the THF was removed under reduced pressure to yield a yellow oily mixture. The crude yellow oil was dissolved in diethyl ether and washed three times with water. The organic phase was dried with sodium sulfate and the ether was removed under reduced pressure to yield a yellow oil. The oil was dissolved in boiling methanol and precipitated out upon cooling in ice bath to give 7.2 g of product (60% yield).

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76 Method II: 25 g of 2-chlorophenothiazine (107 mmol) was added to a 1L three-neck flask that had been purged with argon. 300 mL of DMSO was added and the mixture was stirred. 30 g (535 mmol) of KOH was added and the mixture was stirred overnight. 18 g of allyl bromide (150 mmol) was added to the mixture. The mixture was allowed to stir for 4 hours. The mixture was poured into 3 L of DI water. Sodium chloride was added to facilitate product precipitation. The brown precipitate was filtered and collected. The precipitate was recrystallized from methanol to yield 22 grams of product (76% Yield). Nuclear Magnetic Resonance Spectroscopy (NMR) Monomer purity and structure confirmation were performed using Nuclear Magnetic Resonance Spectroscopy (NMR). All NMR spectra, 1H and 13C were conducted using a Varian Gemini 300 MHz series superconducting spectrometer system. Sample solutions were made using 75 mg of monomer in d6-DMSO. UV-Vis Spectroscopy UV-Vis spectroscopy was performed using a Shimadzu UV-2401 PC UV-Vis recording spectrophotometer. The material was dissolved in chloroform in 5 different concentrations (1.0 wt%, 0.1 wt%, 0.01 wt%, 0.001wt%, 0.0001 wt%). The solutions were placed in 1 cm path length quartz cuvets and placed in the spectrophotometer. The reference cuvet was filled with chloroform. Molar Extinction Coefficients The molar absorptivity or extinction coefficients were calculated using Beer’s Law. Absorbance at a specific wavelength (A ) depends on the molar concentration (c), light path length in centimeters (L), and molar absorptivity () for the dissolved substance. A = cL

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77 A was determined using the UV-Vis spectra. Molar concentration was known and the path length was measured to be 1 cm. Rearranging Beer’s Law, extinction coefficients were calculated using the following equation: = A c Two wavelengths in the blue visible region (400 nm and 420 nm) were chosen for analysis. These wavelengths were representative of the UV absorbers ability to filter blue light. Results and Discussion Synthesis The synthetic methods that were used to synthesize N-allylphenothiazine and N-allyl-2-chlorphenothiazine were designed to be as simple as possible to readily allow scale-up. Both synthetic methods were one-pot, one-step with minimal purification. N-allylphenothiazine was a yellow oil which made synthetic method II unfavorable. When the N-allylphenothiazine was precipitated into DI water, an emulsion was created. Even with the addition of sodium chloride, the crude material was difficult to recover. Method I gave much better results for N-allylphenothiazine. The only drawback to method I was the use of anhydrous solvents and sodium hydride which can be flammable upon contact with water. N-allyl-2-chlorophenothiazine was a solid at room temperature. Synthetic method II yielded better results. The product precipitated out of solution and was collected with little difficulty. Recrystallization from methanol was the only purification needed. NMR Monomer purity and structure confirmation were achieved using NMR. Both N-allyphenothiazine and N-allyl-2-chlorophenothiazine NMR spectra illustrated correct

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78 structure and purity. There was no unsubstituted phenothiazine present in either product. The protons at the N-positions of phenothiazine and chlorophenothiazine have a chemical shifts of ~8.8 ppm. There was no evidence of this in either 1H NMR spectrum. This would indicate that the products were completely substituted at the N-position. Figure 4-10 illustrates the 1H proton signals for N-allylphenothiazine and N-allyl-2-chlorophenothiazine. SN H SN H Cl SN R SN R Cl Singlet at 8.8 ppm No Signal Figure 4-6: Phenothiazine / 2-chlorophenothiazine 1 H NMR proton signals The ether impurity in the 1 H NMR spectrum of N-allylphenothiazine is due to the incomplete removal of diethyl ether from the product. Ether was added to facilitate transfer from one flask to the next. The material was a viscous oil, so solvent was needed to completely remove the product from the flask. The product was dried in a vacuum oven before analysis, but a small amount of ether remained. The residual ether was later removed with additional drying.

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79 Figure 4-7: Allyl phenothiazine 1 H NMR spectrum Figure 4-8: Allyl phenothiazine 13 C NMR spectrum

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80 Figure 4-9: N-allyl-2-chlorophenothiazine 1 H NMR spectrum Figure 4-10: N-allyl-2-chlorphenothiazine 13 C NMR spectrum

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81 UV-Vis Spectroscopy Figure 4-11 and 4.12 illustrate the strong UV absorption by N-allylphenothiazine and N-allyl-2-chlorophenothiazine. The max values were calculated and are summarized in Table 4-2. Table 4-2: Phenothiazine max values UV Absorber max (nm) N-allylphenothiazine 255 N-allyl-2-chlorophenothiazine 256 N-Allylphenothiazine in CHCl300.511.522.5200250300350400450500550600650700Wavelength (nm)Absorbance 1.0 wt% 0.1 wt% 0.01 wt% 0.001 wt% 0.0001 wt% Figure 4-11: N-allylphenothiazine UV-Vis spectrum

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82 N-Allyl-2-Chlorophenothiazine in CHCl300.511.522.5200250300350400450500550600650700Wavelength (nm)Absorbance 1.0 wt% 0.1 wt% 0.01 wt% 0.001 wt% 0.0001 wt% Figure 4-12: N-allyl-2-chlorophenothiazine UV-Vis spectrum Phenothiazine UV-absorbers at 1.0 wt% in CHCl300.10.20.30.40.50.60.70.80.91350400450500550600650700Wavelength (nm)Absorbance N-allyl-2-chlorophenothiazine N-allylphenothiazine Figure 4-13: Phenothiazine UV-absorbers blue absorption at 1.0 wt%

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83 Molar Extinction Coefficients The extinction coefficients were calculated using the equations described previously. Two wavelengths (400 nm and 420 nm) were chosen for analysis. UV-absorbers are typically used in concentrations of 0.1 wt% 0.4 wt% in current foldable IOL materials (Mentak, K. personal communication). The absorbance curve at 0.1 wt% was chosen for analysis. The wt% values were converted to molar concentration to calculate the extinction coefficients. The results are summarized in Table 4-3. Table 4-3: Molar extinction coefficients for phenothiazine UV-absorbers UV Absorber A 400 A 420 400 (M -1 cm -1 ) 420 (M -1 cm -1 ) N-allylphenothiazine 0.075 0.015 11.97 2.38 N-allyl-2-chlorophenothiazine 0.191 0.061 34.81 11.12 Conclusions New N-allylphenothiazine and N-allyl-2-chlorophenothiazine were successfully synthesized using one pot, one step synthetic routes. Structure and purity were confirmed by 1H and 13C NMR. The UV-Vis spectra show strong absorption in the UV range. The max values were almost identical for both UV absorbers. Both phenothiazines absorb in the visible region. N-allyl-2-chlorphenothaizine absorbs at slightly higher wavelengths than N-allylphenothiazine. The molar extinction coefficients for N-allyl-2-chlorophenothiazine were higher than N-allylphenothiazine at 400 nm and 420 nm. N-allyl-2-chlorophenothizine appears to be a more suitable material than N-allylphenothiazine for designing a blue absorbing foldable IOL. Both UV absorbers were sent to Key Medical Technologies for further analysis. Incorporation into acrylic IOL compositions promise to yield efficient UV absorption with less yellowing than current “blue-blocker” IOLs.

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CHAPTER 5 STUDIES CONCERNING VOID (GLISTENING) FORMATION IN LOW TG ACRYLIC POLYMERS USED FOR FOLDABLE IOLS Introduction The development of small incision cataract surgery has led to an increased number of foldable IOLs implanted each year. Studies on new foldable IOLs of various materials and designs have been the focus of significant research [60-63]. The hydrophobic acrylic AcrySof lens developed by Alcon in the early 1990’s introduced technical innovations such as high refractive index, square edges, and slow controlled unfolding [30, 64-67]. Many studies have reported the appearance of small vacuoles within the optic of the foldable acrylic IOLs. These vacuoles or microvoids have been termed glistenings due to their clinical appearance. Glistenings have been seen as early as the first few weeks after IOL implantation [68-72]. According to several authors, glistenings are caused by water entering vacuoles which are visible to the eye due to refractive index differences between water and the surrounding material [72, 73]. Glistenings do not appear to affect or disturb vision except in the most severe cases [73]. They were first thought to be related to temperature changes within the IOL optic and the AcryPak packaging system of AcrySof IOLs [74]. It was originally thought that the glistening phenomenon was a defect related only to AcrySof IOLs. The packaging system allowed the IOL to be folded without an instrument. Alcon suggested that the sterilization of the IOL in the package could cause 84

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85 changes in the IOL optic, enabling glistening formation. These findings led Alcon to remove the AcryPak system from the market. Later studies showed glistening formation in the Alcon Wagon Wheel packaged AcrySof IOLs as well. This suggested that packaging was not the only factor in glistening formation [74]. Omar and coworkers hypothesized glistening formation was due to temperature changes within the IOL optic [74]. These changes may increase the free volume within the acrylic copolymer which could allow vacuoles to form. When these vacuoles filled with water, the difference in refractive index created the shining appearance seen by the human eye. In an in vitro study, Dick et al. related glistening formation to the lipid and protein concentration in the aqueous humor [70]. The deposition of phospholipids on the IOL optic was thought to decrease the aqueous surface tension, allowing glistenings to form due to the penetration of the hydrophobic polymer. The hydrophobic nature of the material enhances this effect. Glistenings were first reported in 1984 by Ballin, who described their appearance in a poly(methyl methacrylate) (PMMA) optic [75]. In 2000, Ibaraki and Yaguchi reported the first case of glistenings IOL [76]. These findings led to studies of glistening formation in different hydrophilic and hydrophobic foldable IOL materials [63]. Tognetto et al. studied glistening formation in seven different foldable IOLs [63]. Patients were randomized and received one of the following IOLs: CeeOn Edge 911A, (Pharmacia & Upjohn Co.), n = 39; ACR6D (Corneal) n = 36; AcrySof (Alcon) n = 41; SI-40NB (AMO) n = 45; Hydroview H60M (Storz) n = 36; Sensar (AMO) n =

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86 42; Stabibag (Ioltech), n = 34. All operations were performed by the same surgeon and post-operative care was identical for all patients. Statistical analysis was done by comparing their presence and grade of glistenings at 7, 30, 90, 180, 360, and 720 days. Best corrected visual acuity (BCVA) was measured with each patient visit. Glistenings were given a rating of 0-3: 0 = absence, 1 = traces (countable vacuoles), 2 = moderate (low density of unaccountable vacuoles) , 3 = severe (high density of unaccountable vacuoles) [63]. The results showed glistenings present in all the IOLs studied. The percentage of patients with glistenings increased up to 90 days after surgery and then became stable in the 911A, ACR6D, SI-40NB, Hydroview, Sensar, and Stabibag groups [63]. The number of glistenings in the AcrySof IOL increased with time. The mean grade of glistening increased up to 180 days post-op and then became stable in the ACR6D, SI-40NB, Hydroview, Sensar and Stabibag groups. No IOL in the ACR6D, SI-40NB, Hydroview, Sensar, or Stabibag group had glistenings higher than grade 1. In the AcrySof and 911A groups, some IOLs had grade 2 glistenings. No grade 3 glistenings were observed in any of the IOLs studied [63]. To date, there has been no published literature on the exact cause of glistening formation. The only explanation offered was phase separation. The goal of research reported here was to study the glistening phenomenon in a foldable acrylic based copolymer (X-60) supplied by Advanced Vision Sciences (AVS). The X-60 material has been approved by the FDA and is in the process of clinical trials for foldable IOL applications.

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87 The characterization and morphology of the glistening phenomenon were studied to determine the cause and route of formation. Light microscopy, as well as other characterization techniques, were used to study glistenings. Based upon the results, methods for glistening inhibition were developed and are in the process of being patented. Materials and Methods X-60 low T g foldable IOL polymer material was supplied by Advanced Vision Sciences (AVS) in sheet, disc (flying saucer), and lens forms. Samples were used as received and incubated at 80 o C in DI water, balanced salt solution (BSS), and 10% saline to facilitate glistening formation Samples were removed from incubating solutions and analyzed. Light Microscopy Light microscopy was performed using a Zeiss Axioplan 2 light microscope complete with digital capture. The IOL polymer was incubated in DI water, balanced salt solution, or 10% saline and analyzed by light microscopy. Scanning Electron Microscopy (SEM) Scanning Electron Microscopy was performed using a JEOL 6400 microscope. The samples were hydrated in DI water at 80oC for 24 hours. The sample was sectioned and mounted on an aluminum SEM stub, sputter coated with Au/Pd, and SEM was performed (W.D. = 15 @ 5kV). All SEM samples were prepared by Amin Elachchabi and SEMs performed by Paul Martin. Thermal Compression Thermal compression of polymers was performed using a Carver Laboratory Press Model C. The press had two hot plates with digital temperature controllers. An

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88 aluminum mold outer dimensions were 6”x 6” with 5”x 5” inner dimensions. The mold was ” deep. Figure 5-1 illustrates the aluminum mold used for thermal compression. The mold was designed by Dr. Clay Bohn. Figure 5-1: Aluminum mold illustration 3 mm thick X-60 polymer sheets were placed in an 80 o C oven for 1 minute to soften the material. The X-60 samples were then cut to 5”x5” and placed in the aluminum mold. The temperature of the melt press was set at 140 o C. The mold containing the polymer sample was placed in the melt press (Figure 5-1) and allowed to equilibrate to 140 o C (about 10 min). The mold was then pressurized to 20,000lbs of force (800 psi). The pressure was maintained for 24 hours. After 24 hours, the heat controllers were turned off and the mold was allowed to cool to room temperature under pressure (3-4 hrs). The mold was removed and the polymer sample was extracted by removing the back of them mold. The samples were sent to Advanced Vision Sciences for lathe cutting and further analysis. The effect of cooling rate on the polymer sample is currently under investigation.

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89 Figure 5-2: Thermal compression apparatus with aluminum mold Gamma Irradiation ( 60 Co) Samples (3 mm) were cut from the 8”x 16” X-60 polymer sheets supplied by Advanced Vision Sciences. Two 3 mm samples (2” x 5”) for each dose were cut using shears and placed in a rotating carousel at four inches from the 60 Co source (figures 5.3 and 5.4) and irradiated at specific doses (0.5 MRad, 1.0 MRad, 2.0 MRad, 3.0 MRad, 4.0 MRad, 5.0 MRad). The dose rate was calculated to be 507 Rads/min using the known half-life of 60 Co. The rotating carousel was used to average the total dose among the four samples. Hydraulic Press Aluminum Hot Plates Mold Pressure Gauge

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90 Figure 5-3: 60 Co Sample carousel Figure 5-4: 60 Co source with sample carousel inserted

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91 Differential Scanning Calorimetry (DSC) All differential scanning calorimetry was performed on a Seiko DSC complete with liquid nitrogen controller. All samples were run against an alumina reference in sealed aluminum pans. Three scans were performed on each sample. Heating rate were 5 o C/min or 10 o C/min. Equilibrium Water Content (EWC) A sample was cut from each polymer sheet. The sample was weighed and recorded as dry weight. The samples were placed in DI water or balanced salt solution (BSS). The sample was allowed to hydrate for 24 hours. The samples were wiped dry and the weights measured. The samples were placed in the incubating solution and measured again at five and nine days. Results and Discussion Light Microscopy The optical micrographs in figures 5.5 and 5.6 illustrate the differences in size for glistenings in different incubating solutions. Increasing the electrolyte concentration of the surrounding environment produces more but smaller glistenings. The glistenings in Figure 5-5 appear larger in diameter (219mm +/19mm) and smaller in number (9 glistenings/mm 2 ) than those found in Figure 5-6 (88mm +/10mm) (13 glistenings/mm 2 ). The sample in Figure 5-5 was incubated in DI water at 80 o C for 24 hours. The sample in Figure 5-6 was incubated in BSS at 80 o C for 24 hours. 80 o C was chosen as the incubation temperature due to time constraints. At 80 o C, glistenings form overnight. At lower temperatures, the incubation time for glistening formation may be days to months. Figure 5-7 illustrates a single glistening with a defect at the 1 o’clock position. It was hypothesized that this defect was the nano-void inherent in the material before

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92 hydration. This type of defect was observed in many of the glistenings studied with light microscopy and SEM. Figure 5-5: Optical micrograph: X-60 incubated in DI water at 80 o C for 24h (50X) Figure 5-6: Optical micrograph: X-60 incubated in BSS at 80 o C for 24h (50X)

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93 Figure 5-7: Optical micrograph of a single glistening (200X) SEM Figure 5-8: Cross Section of X-60 IOL (55X)

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94 Figure 5-9: Cross-section of X-60 IOL with glistenings (37X) Figure 5-10: Higher magnification X-60 cross-section with glistenings (170X)

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95 Figure 5-11: Cross-section of X-60 glistening (300X) Figure 5-12: High magnification of X-60 glistening cross-section (370X)

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96 Figure 5-13: Cross-section X-60 glistening with internal defect (450X) The images in figures 5.8 5.13 are the first such SEM images reported for IOL polymers exhibiting the glistening phenomenon. The X-60 copolymer was hydrated in balanced salt solution overnight at 80 o C. The lens was sectioned with a razor blade and mounted on aluminum SEM stubs. The samples were sputter coated under vacuum and analyzed using the SEM. If the X-60 material was dehydrated prior to sectioning, no glistenings were seen. Figures 5.8 5.13 illustrate the glistenings that were cross-sectioned with a razor blade. These images confirm that glistenings were in fact micro-vacuoles filled with fluid. The glistening in Figure 5-13 exhibited a small defect structure at the 2 o’clock position. This defect may have been a channel or nanocraze in which the fluid entered the region and expanded the surrounding material based on environment and temperature.

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97 This unique defect structure within the glistening appeared in many of the samples studied. Thermal Compression Glistening formation in low T g IOL materials is a phenomenon that is not fully understood. The current literature discusses glistening morphology, but offers no explanation for their mechanism of formation or solutions to their removal. The images obtained in this research illustrate that glistenings are micro-vacuoles within the material likely filled with fluid. Previous DSC studies showed no evidence of phase separation. The defect structures found in the micrographs above appeared to be a void inherent in the material during polymerization or processing. During hydration, the defects filled with fluid (water) to swell. Both size and number of glistenings could be varied with environment (DI, BSS, 10% saline), time, and temperature. In order to remove these defects that remain in the material after processing, the samples were heated and pressurized for a set time. It was thought that if sufficient heat and pressure were used, the defects might be removed or healed, thus eliminating the potential for glistening formation. The maximum force allowed by the melt press was 20,000 lbs for the mold (5”x5”), a sample pressure of 800 psi. 150 o C was initially used for the thermal treatment, but this temperature was found to discolor the material. 140 o C was used with little discoloration. The material was heated and compressed for 24 hours and was allowed to cool to room temperature while under pressure (3-4 hrs). The sample was then removed and sent to Advanced Vision Sciences for analysis. The treated X-60 samples were lathe cut into lenses and analyzed by Advanced Vision Sciences. It was determined that the thermal compressed samples had a

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98 significantly lower number of glistenings than the untreated materials (controls). The average number of glistenings in the untreated material was 200 glistenings per lens. The treated materials averaged 20 glistenings per lens. The reduced number of glistenings was stable after repeated heating and cooling of the material. These results were supplied by AVS. Gamma Irradiation ( 60 Co) Un-extracted X-60 sheets were gamma irradiated with the thought that voids might be filled by polymerizing the extractables within the material. Samples were irradiated to various doses (0.5 MRad, 1.0 MRad, 2.0 MRad, 3.0 MRad, 4.0 MRad, 5.0 MRad) an analyzed. The polymer discolored (yellowing) due to the radiation (even at 0.5 MRad total dose). The irradiated samples were analyzed using DSC and EWC measurements in order to determine if the radiation polymerized any of the extractable material. Differential Scanning Calorimetry (DSC) In order to determine the effects of thermal compression and gamma irradiation, DSC and EWC were used to study the morphology changes that took place during each treatment. If thermal compression changed the free volume of the X-60 material, a T g shift should occur. Additionally, if a free volume change occurred due to pressure, then the T g should move after repeated heating and cooling scans. If free volume change occurred due to the polymerization of extractable material, then the T g shift should remain constant after repeated heating and cooling scans due to the increase in covalent bonds within the material. Any degradation of the material was not known. The material did discolor due to both heat and radiation.

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99 -30-20-100102030405060708090100110Temperature oCHeat Flow (Endo Down) 1008993-1 Control Tg = 7oC1008993-2 Control Tg = 7oC1008993-4 Control Tg = 7oC1008993-1 Compressed Tg = 8oC1008993-2 Compressed Tg = 8oC1008993-4 Compressed Tg = 7oC Figure 5-14: Control vs. compressed DSC curves (2 nd scan @ 5 o C/min) There was no difference observed in the T g values between the treated materials and the controls. After repeated heating and cooling of the material, the number of transitions and T g values for both treated samples and controls remained the same. -30-20-100102030405060708090100110Temperature (oC)Heat Flow (Endo Down) 1009014-8 Control Tg: 14oC1009014-8 0.5MRad Tg: 15oC1009014-8 1.0MRad Tg: 15oC1009014-8 2.0MRadT g : 14oC1009014-8 3.0MRad Tg: 14oC1009014-7 Control Tg: 15oC1009014-7 4.0MRad Tg: 14oC1009014-7 5.0MRadT g : 15oC Figure 5-15: Control vs. irradiated DSC curves (2 nd scan @ 5 o C/min)

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100 There was no difference observed in the T g values between the irradiated materials and the controls. After repeated heating and cooling of the material, the number of transitions and T g values for both irradiated samples and controls remained the same. Equilibrium Water Content (EWC) Equilibrium water content for both treated and control samples was determined to provide information on the morphology changes that occurred during thermal compression and gamma irradiation. The hypothesis was that the removal or healing of the nano-voids would decrease the rate and/or the total water uptake by the treated material with respect to controls. Figures 5.15 and 5.16 illustrate the EWC rate and total uptake values for the thermally compressed and control samples. Figures 5.17 and 5.18 illustrate the EWC rate and total uptake values for the gamma irradiated and control samples. Figures 5.16 and 5.17 were supplied by Amin Elachchabi. Thermal compressed samples vs. controls The EWC values for both the treated and control samples showed no EWC in the X-60 material in DI water (Control Vs Treated)0.0%0.5%1.0%1.5%2.0%2.5%3.0%3.5%4.0%24 HOURS48 HOURSDAY 9TimeEWC control treated Figure 5-16: Control vs. treated X-60 EWC in DI water

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101 EWC in the X-60 Lens material in Saline (Treated Vs Control)0.0%0.5%1.0%1.5%2.0%2.5%3.0%3.5%4.0%24 HOURS48 HOURSDAY 9TimeEWC Control Treated Figure 5-17: Control vs. treated X-60 EWC in BSS Gamma irradiated samples vs. controls Two different control samples were used (1009014-7 and 1009014-8) because one sample did not provide enough material to complete the study. The 4.0 and 5.0 MRad doses were performed using 1009014-8. It appeared that the radiation at the 0.5 MRad, 1.0 MRad, 4.0 MRad, and 5.0 MRad doses resulted in small increases in EWC values. The decrease in EWC at the 2.0 MRad and 3.0 MRad doses is not understood. There was no meaningful trend observed for any of the gamma irradiated samples. It was not yet determined if the gamma irradiation decreased glistening formation with respect to controls.

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102 2.6%2.7%2.8%2.9%3.0%3.1%3.2%3.3%3.4%EWC (%)1009014-85.0 MRad 1009014-7Control 1009014-8Control 1009014-70.5 MRad 1009014-71.0 MRad 1009014-72.0 MRad 1009014-73.0 MRad 1009014-84.0 MRad Figure 5-18: Equilibrium water content of the X-60 control and Gamma irradiated for various doses in DI water 2.6%2.7%2.8%2.9%3.0%3.1%3.2%3.3%3.4%EWC (%)1009014-7Control 1009014-8Control 1009014-85.0 MRad 1009014-70.5 MRad 1009014-71.0 MRad 1009014-72.0 MRad 1009014-73.0 MRad 1009014-84.0 MRad Figure 5-19: Equilibrium water content of the X-60 lens material control and Gamma irradiated for various doses in BSS.

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103 Conclusions Glistening morphology was characterized by light microscopy and SEM. The glistenings appear as vacuoles that are evident in the hydrated state and therefore likely water-filled. The images in figures 5.8 5.13 were the first SEM images reported for a material exhibiting glistening phenomenon. It was hypothesized from the light microscopy and SEM that glistenings develop from nano-voids that are present in the material after polymerization and processing. Based on the nano-void hypothesis, thermal compression techniques were developed which were successful in inhibiting glistening formation. DSC and EWC characterization showed no changes between thermal compressed samples and controls. Techniques sensitive to changes on the nanometer scale (neutron scattering) might be used to determine nano-void changes due to thermal compression.

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CHAPTER 6 CONCLUSIONS The studies presented in this dissertation were aimed at the development of new and improved foldable, acrylic intraocular lens polymers. Novel high refractive index copolymers were synthesized and characterized. Novel UV/ blue light absorbing allyl functional molecules were synthesized and characterized. Glistening defect morphology was characterized and thermal compression techniques were developed to inhibit formation of vacuoles upon hydration. Eleven (PEA / PEMA) and Eleven new (BA / BMA) copolymer compositions were successfully synthesized using bulk free radical polymerization. Seven compositions were suitable for foldable IOL applications. The materials were low T g (< 20 o C), hydrophobic (<1 wt% EWC), high refractive index (>1.55), and exhibited controllable unfolding. Three BA / BMA compositions exhibited a slight improvement in refractive index over PEA / PEMA and AcrySof materials (1.55 vs. 1.56) NVC was copolymerized with PEA using free radical bulk polymerization. Above 10 wt%, the copolymer T g was too high for foldable IOL applications (>20 o C). At 10 wt% NVC, the refractive index was higher (1.57+) than PEA / PEMA and BA / BMA copolymers. Carbazole monomers: Allyl carbazole (NVC-1) and pentenyl carbazole (NVC-3) were synthesized using one-pot, one-step synthetic techniques. NVC-1 was polymerized with PEA using bulk free radical polymerization. NVC-1 / PEA copolymers showed a significant improvement over the PEA / PEMA and BA / BMA copolymers. These materials were low T g (< 20 o C), hydrophobic (<1 wt% EWC), high refractive index (>1.59), and exhibited controllable unfolding. The NVC-3 monomer did not copolymerize favorably with PEA due to poor solubility in the bulk. N-Allylphenothiazine and N-allyl-2-chlorophenothiazine UV absorbers were synthesized using one-pot, one-step synthetic techniques. The UV-Vis absorption 104

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105 of the phenothiazines was favorable for yellow “blue blocker” IOL use. N-ally-2-chlorophenothiazine absorbed at slightly higher wavelengths than N-allyphenothiazine. Glistenings were characterized using light microscopy and SEM. The SEM images were the first reported for any material exhibiting the glistening phenomenon. Glistenings appeared to originate from nano-voids present in the low T g IOL polymers prior to processing. Thermal compression techniques were developed to significantly inhibit glistening formation presumably by removing or healing nano-voids. The results of this research demonstrated important technological advancements aimed at the development of improved hydrophobic, acrylic, foldable IOLs. Further synthesis, characterization, and process optimization may be necessary for industrial scale applications.

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CHAPTER 7 FUTURE WORK During the course of this research, many opportunities for further experimentation became evident. The following suggestions for future research highlight some of these potential directions. PEA / PEMA Copolymers Synthesize different copolymer compositions by varying the cross-linker concentration. Incorportate UV-absorbing molecules into the copolymer backbone to complete the foldable IOL composition. Send final material to Key Medical Technologies for lenses to be lathe cut from the polymer samples. Determine UV-Vis and refractive index characteristics of the final lens formulation. BA / BMA Copolymers Synthesize different copolymer compositions by varying the cross-linker concentration. Incorportate UV-absorbing molecules into the copolymer backbone to complete the foldable IOL composition. Perform in vitro studies to asses the biocompatibility of the copolymer compositions. Send final material to Key Medical Technologies for lenses to be lathe cut from the polymer samples. Determine UV-Vis and refractive index characteristics of the final lens formulation. NVC-1 / PEA Copolymers Optimize the polymerization conditions. Determine a curing profile that does not discolor the material. 106

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107 Utilize lower temperature peroxide initiators to reduce defects and discoloration. Perform Soxhlet extraction of the copolymers to determine how much monomer / oligomer is extracted. Synthesize different copolymer compositions by varying the cross-linker concentration. Incorportate UV-absorbing molecules into the copolymer backbone to complete the foldable IOL composition. Send final material to Key Medical Technologies for lenses to be lathe cut from the polymer samples. Determine UV-Vis and refractive index characteristics of the final lens formulation. Phenothiazine UV Absorbers Co-polymerize N-allylphenothiazine and N-allyl-2-chlorophenothiazine with the foldable IOL compositions described above. Perform Soxhlet extraction to determine how much phenothiazine is covalently bonded to the polymer backbone. Send final material to Key Medical Technologies for lenses to be lathe cut from the polymer samples. Determine UV-Vis and refractive index characteristics of the final lens formulation. Glistenings Perform next phase of the thermal compression. Pressure will be increased from 800 psi to 5000 psi using a smaller dimension aluminum mold. The temperature should remain at 140 o C. Send the second phase thermal compression samples to AVS so lenses can be lathe cut and analyzed. Determine effect of quenching after the thermal compression treatment. Continue characterization of the inherent voids in the material after polymerization and processing using neutron scattering techniques. Neutron scattering will allow the characterization of nano-sized domains without the need for lens sectioning. Write a research proposal and submit before the deadline to be allotted small angle neutron scattering beam time at Oak Ridge National Laboratories.

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108 Perform transmission electron microscopy (TEM) on the X-60 material to investigate the inherent voids present before glistening formation. Determine the effect that gamma radiation has on the un-extracted samples using Soxhlet extraction. A comparison of irradiated and control samples should be performed. Perform incubation studies to determine why 10% saline increases the potential for glistening formation with respect to balanced salt solution (BSS). Investigate why the high vacuum solvent removal after the extraction process reduces the formation of glistenings. Produce glistening free foldable IOL for the current market.

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LIST OF REFERENCES 1. D. J. Apple, N.M., R. J. Olson, M. C. Kincaid, Intraocular Lenses: Evolution, Designs, Complications, and Pathology, ed. C.-L. Brown. 1989, Baltimore, Maryland: Williams & Wilkins. 2. Azar, D.T., Intraocular Lenses in Cataract and Refractive Surgery, ed. N.F.A. W.J. Stark, R. Peneda, S.H. Yoo. 2001, Philadelphia, Pennsylvania: W.B. Saunders Company. 3. Vision Research: A national plan: 1983-1987, U. S. Department of Health and Human Services, Public Health Service, National Institutes of Health. 4. S. Duke -Elder, D.A., System of Ophthalmology Ophthalmic Optics and Refraction. Vol. 5. 1970, St. Louis, Missouri: CV Mosby. 5. Gernet, H., The binocular confusion in unilateral aphakia. Annual Ophthalmology, 1979. 11: p. 617-621. 6. P. Bernth-Peterson, T.S., Intraocular lenses versus extended-wear contact lenses in aphakic rehabilitation: a controlled clinical study. Acta Ophthalmology, 1983. 61: p. 382-391. 7. Gruber, E., Contact Lens KKversusKK intraocular lens in the correction of aphakia. Transactions of the Ophthalmology Society UK, 1980. 100: p. 231-233. 8. Apple D.J., G.S.C., Evolution of Intraocular Lenses. 1985, Salt Lake City, Utah: University of Utah Printing Service. 9. N.S. Jaffe, M.S.J., G.F Jaffe, Cataract Surgery and Its Complications. 5th ed. 1990, Philadelphia, Pennsylvania: C.V. Mosby. 10. Ridley, H., Intra-ocular acrylic lenses. Transactions of the Ophthalmology Society UK, 1951. 71: p. 617-621. 11. Apple, Complications of intraocular lenses: A historical and histopathological review. Survey of Ophthalmology, 1984. 29: p. 1-54. 12. Shearing, S.P., Evolution of the posterior chamber intraocular lens. Journal of the American Intraocular Implant Society, 1984. 10: p. 343-346. 109

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110 13. Epstein, E., Modified Ridley lenses. British Journal of Ophthalmology, 1959. 43: p. 29-33. 14. Hirschman, H., Intraocular lenses. Advantages and disadvantages of the types of intraocular lens available. Transactions of the American Academy of Ophthalmology and Otolaryngoogyl, 1976. 81: p. 89-92. 15. Kelman, C.D., Phaco-emulsification and aspiration; a new technique of cataract removal; a preliminary report. American Journal of Ophthalmology, 1967. 64: p. 23-25. 16. Binkhorst, C.D., Corneal and retinal complications after cataract extraction: the mechanical aspect of endophthalmodonesis. Ophthalmology, 1980. 87: p. 609-617. 17. Lerman, S., Ultraviolet radiation protection. CLAO J., 1985. 11: p. 39-45. 18. Jampol, L.M., Aphakic cystoid macular edema: a hypothesis. Archives of Ophthalmology, 1985. 14: p. 1134-1135. 19. Nichamin, L.D., Update on IOL Insertion Techniques. 2005: Ophthalmic Hyperguide. p. 1-6. 20. Tehrani, M., Burkhard, D., Beate, W., Tadeusz, P., Wolf, E., Material Properties of Various Intraocular Lenses in an Experimental Study. Ophthalmologica, 2004. 218: p. 57-63. 21. Milauskas, A.T., Silicone intraocular lens implant discoloration in humans. Archives of Ophthalmology, 1991. 109: p. 913-915. 22. P.E. Bath, C.F.B., Y. Dang, Pathology and physics of YAG-laser intraocular lens damage. Journal of Cataract and Refractive Surgery, 1987. 13: p. 47-49. 23. T. Oshika, Y.S., Effect of folding on the optical quality of soft acrylic intraocular lenses. Journal of Cataract and Refractive Surgery, 1996. 22: p. 1360-1364. 24. S. Milazzo, P.T., H. Blin, Alterations to the AcrySof intraocular lens during folding. Journal of Cataract and Refractive Surgery, 1996. 22: p. 1351-1354. 25. Ursell, P.G., Spalton, D.J., Pande, M.V., Hollick, E.J., Barman, S., Boyce, J., Tilling, K., Relationship between intraocular lens biomaterials and posterior capsule opacification. Journal of Cataract and Refractive Surgery, 1998. 22: p. 352-360. 26. Hollick, E.J., Spalton, D.J., Ursell, P.G., Pande, M.V., Lens epithelial cell regression on the posterior capsule with different intraocular lens materials. British Journal of Ophthalmology, 1998. 82: p. 1182-1188.

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111 27. Linnola, R.J., Sandwich theory: Bioactivity-based explanation for posterior capsule opacification. Journal of Cataract and Refractive Surgery, 1997. 23: p. 1539-1542. 28. Linnola, R.J., J.I. Salonen, and R.P. Happonen, Intraocular lens bioactivity tested using rabbit corneal tissue cultures. Journal of Cataract and Refractive Surgery, 1999. 25: p. 1480-1485. 29. Linnola, R.J., Salonen, J.I., Happonen, R.P., Adhesion of soluble fibronectin, laminin, and collagen type IV to intraocular lens materials. Journal of Cataract and Refractive Surgery, 1999. 25: p. 1486-1491. 30. Nishi, O., K. Nishi, and K. Sakanishi, Inhibition of migrating lens epithelial cells at the capsular bend created by the rectangular optic edge of a posterior chamber intraocular lens. Ophthalmic Surgery and Lasers, 1998. 29: p. 587-594. 31. Lane, S., Foldable Hydrophobic Acrylic Intraocular Lenses. 2005: Ophthalmic Hyperguide. p. 1-8. 32. Gregori, N.Z., In vitro comparison of glistening formation among hydrophobic acrylic intraocular lenses. Journal of Cataract and Refractive Surgery, 2002. 28(7): p. 1262-1268. 33. Tognetto, D., Toto, L., Sanguinetti, G., Ravalico, G., Glistenings in Foldable Intraocular Lenses. Journal of Cataract and Refractive Surgery, 2002. 28: p. 1211-1216. 34. Ballin, N., Glistenings in Injection Molded Lenses. American Intra-Ocular Implant Society Journal, 1984. 10: p. 473. 35. Miyata, A. and S. Yaguchi, Equilibrium water content and glistening in acrylic intraocular lenses. Journal of Cataract and Refractive Surgery, 2004. 30: p. 1768-1772. 36. De Groot, J.H., van Beijma, F.J., Haitjema, H.J., Dillingham, K.A., Hodd, K.A., Koopmans, S.A., Norrby, S., Injectable Intraocular Lens Materials Based upon Hydrogels. Biomacromolecules, 2001. 2: p. 628-634. 37. Lerman, S., Radiant Energy in the Eye, ed. S. Lerman. 1980, New York, New York: Macmillan. 73-93. 38. Grazulevicius, J.V., Carbazole-containing polymers: synthesis, properties and applications. Progress in Polymer Science, 2003. 28: p. 1297-1353. 39. Tamada, M., H. Omichi, and N. Okui, Thin Solid Films, 1995. 268: p. 18. 40. Ellinger, L.P., J. Applied Polymer Science Part A, 1965. 9: p. 3939.

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112 41. Pearson, J.M. and M. Stolka, Poly(N-vinylcarbazole). Polymer Monographs. Vol. 61. 1981, New York, New York: Gordon and Breach. 42. Lindstrom, R.L. and N. Doodi, Ultraviolet light absorption in intraocular lenses. Journal of Cataract and Refractive Surgery, 1986. 12: p. 285-289. 43. Ernest, P.H., Light-transmission-spectrum comparison of foldable intraocular lenses. Journal of Cataract and Refractive Surgery, 2004. 30(8): p. 1755-1758. 44. Noell, W.K., V.S. Walker, and B.S. Kang, Retinal damage by light in rats. Invest Ophthalmology, 1966. 5: p. 450-473. 45. Mainster, M.A. and P.L. Turner, Photic retinal injury and safety, in Retina, A.P. Schachat, Editor. 2001, Mosby: St. Louis, Missouri. p. 1797-1809. 46. Boettner, E.A. and J.R. Walter, Transmission of the ocular media. Invest Ophthalmology, 1962. 1: p. 776-783. 47. Mellerio, J., Yellowing of the human lens: nuclear and cortical contributions. Vision Research, 1987. 27: p. 1581-1587. 48. Bron, A.J., Vrensen G.F., and J. Koretz, The ageing lens. Ophthalmologica, 2000. 214: p. 86-104. 49. Sparrow, J.R., A.S. Miller, and J. Zhou, Blue light-absorbing introcular lens and retinal pigment peithelium protectin in vitro. J. Cataract Refract. Surg, 2004. 30: p. 873-878. 50. Lindstrom, R.L. and N. Doddi, Ultraviolet light absorption in intraocular lenses. Journal of Cataract and Refractive Surgery, 1986. 12: p. 285-289. 51. Lin, K., Y. Lin, and J. Lee, Spectral transmission characteristics of spectacle, contact, and intraocular lenses. Annual Ophthalmology, 2002. 34: p. 206-215. 52. Niwa, K., Effects of tinted introcular lens on contrast sensitivity. Ophthalmic Physiol. Opt., 1996. 16: p. 297-302. 53. Mainster, M.A. and J.R. Sparrow, How much blue light should an IOL transmit? Br. J. Ophthalmol, 2003. 87: p. 1523-1529. 54. Jackson, G.R., C. Owsley, and E.P. Cordle, Aging and scotopic sensitivity. Vision Research, 1998. 38: p. 3655-3562. 55. Mainster, M.A. and G. Timberlake, Why HID headlights bother older drivers. British Journal of Ophthalmology, 2003(87): p. 113-117. 56. Wyszecki, G. and W.S. Stiles, Color Science. 1967, New York, New York: John Wiley & Sons.

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113 57. Jackson, G.R., C. Owsley, and G.M. Jr., Aging and dark adamptatoin. Vision Research, 1999. 39: p. 3975-3982. 58. Jackson, G.R. and C. Owsley, Scotopic sensitivity during adulthood. Vision Research, 2000. 40: p. 2467-2473. 59. Alcon, AcrySof Natural single-piece IOL product monograph, Data on File, Alcon Laboratories, Inc. 60. Anderson, C., Foldable Intraocular Lenses. Alcon AcrySof acrylic intraocular lens, ed. D.R. Sanders. 1993, New Jersey: Slack Inc. 161-177. 61. Leaming, D.V., Practice styles and preferences of ASCRS members-1995 Survey. J. Cataract Refract. Surg, 1996. 22: p. 931-939. 62. Oshika, T., Masuda, K., Hayashi, F., Majima, Y., Leaming, D.V., Current trends in cataract and refractive surgery in Japan-1995 Survey. Japanese Journal of Ophthalmology, 1996. 40: p. 419-433. 63. Tognetto, D., Glistenings in foldable intraocular lenses. Journal of Cataract and Refractive Surgery, 2002. 28: p. 1211-1216. 64. Peng, Q., Sugical prevention of posterior capsule opacification. Part 3: intraocular lens optic barrier effect as a second line of defense. Journal of Cataract and Refractive Surgery, 2000. 26: p. 198-213. 65. Nishi, O., Nishi, K., Effect of round-edged acrylic intraocular lenses on preventing posterior capsule opacification. Journal of Cataract and Refractive Surgery, 2001. 27: p. 608-613. 66. Nishi, O., Nishi, K., and K. Wichstrom, Preventing lens epithelial cell migration using introcular lenses with sharp rectangular edges. Journal of Cataract and Refractive Surgery, 2000. 26: p. 1543-1549. 67. Kruger, A.J., Schauersberer, J., Abela, C., Schild, G., Amon, M., Two year results: sharp versus rounded optic edges on silicone edges. Journal of Cataract and Refractive Surgery, 2000. 26: p. 566-570. 68. Kato, K., Nishida, M., Yamane, H., Nakamae, K., Tagami, Y., Tetsumoto, K., Glistening formation in the AcrySof lens initiated by spinodal decomposition of the polymer network by temperature changes. Journal of Cataract and Refractive Surgery 2001. 27: p. 1493-1498. 69. Christiansen, G., Durcan, F.J., Olson, R.J., Christiansen, K., Glistenings in the AcrySof intraocular lens: pilot study. Journal of Cataract and Refractive Surgery, 2001. 27: p. 728-733.

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114 70. Dick, H.B., Olson, R.J., Augustin, A.J., Schwenn, O., Magdowski, G., Pfeiffer, N., Vacuoles in the AcrySof intraocular lens as factor of the presence of serum in aqueous humor. Ophthalmic Research, 2001. 33: p. 61-61. 71. Dogru, M., Tetsumoto, K., Tagami, Y., Kato, K., Nakamae, K., Optical and atomic force microscopy of an explanted AcrySof intraocular lens with glistenings. Journal of Cataract and Refractive Surgery, 2000. 26: p. 571-575. 72. Oshika, T., Shiokawa, Y., Amano, S., Mitomo, K., Influence of glistenings on the optical quality of acrylic foldable intraocular lens. British Journal of Ophthalmology, 2001. 85: p. 1034-1037. 73. Dhaliwal, D.K., Mamalis, N., Olson, R.J., Crandall, A.S., Zimmerman, P., Alldredge, O.C., Durcan, F.J., Omar, O., Visual significance of glistenings seen in the AcrySof intraocular lens. Journal of Cataract and Refractive Surgery, 1996. 22: p. 452-457. 74. Omar, O., Pirayesh, A., Mamalis, N., Olson, R.J., In vitro analysis of AcrySof introcular lens glistenings in AcryPak and Wagon Wheel packaging. Journal of Cataract and Refractive Surgery, 1998. 24: p. 107-113. 75. Ballin, N., Glistenings in injection-molded lens. American Intra-Ocular Implant Society Journal, 1984. 10: p. 473. 76. Ibaraki, N. and C. Yaguchi. Glistenings in Silicone IOLs. in Symposium on Cataract, IOL and Refractive Surgery. 2000. Boston, Massachusetts.

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BIOGRAPHICAL SKETCH Adam Charles Reboul was born on November 23, 1977 in New Iberia, Louisiana, and lived there until the age of three. At the age of three, he moved to Slidell, Louisiana, where he spent his entire childhood. He attended Northshore High School from 1991 until 1995. He began his undergraduate studies in the fall of 1995 at the University of Southern Mississippi in Hattiesburg. He graduated in the summer of 1999 with a B.S. in polymer science. During this time, he worked under Dr. Robert Moore on ion containing polymers. In the fall of 1999, he came to the University of Florida to begin graduate studies under the advisement of Professor John Reynolds in the area of conducting polymers. In the spring of 2002, he received his master’s degree in chemistry and joined the Materials Science and Engineering Department at the University of Florida to continue his graduate career in the field of biomaterials under Professor Eugene Goldberg. 115