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Healing Characteristics and Ridge Quantity after Using Enamel Matrix Derivative during Extraction Socket Ridge Preservation

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Title:
Healing Characteristics and Ridge Quantity after Using Enamel Matrix Derivative during Extraction Socket Ridge Preservation
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SCHOENEBECK, ERIC F. ( Author, Primary )
Copyright Date:
2008

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Subjects / Keywords:
Bones ( jstor )
Collagens ( jstor )
Homologous transplantation ( jstor )
Statistical median ( jstor )
Statistical results ( jstor )
Stents ( jstor )
Surgical flaps ( jstor )
Teeth ( jstor )
Tissue grafting ( jstor )
Tooth enamel ( jstor )

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University of Florida
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University of Florida
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Copyright Eric F. Schoenebeck. 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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5/31/2008

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HEALING CHARACTERISTICS AND RIDG E QUANTITY AFTER USING ENAMEL MATRIX DERIVATIVE DURING EXTRAC TION SOCKET RIDGE PRESERVATION By ERIC F. SCHOENEBECK A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2007

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2 Eric F. Schoenebeck

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3 To my parents and brothers, instructors, fell ow residents, my baby boy, and my loving wife. Thank you for all of assistance and support.

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4 ACKNOWLEDGMENTS I would like to thank all of the instructor s who have guided and mentored me, providing me with the necessary f oundation in this wonderful field of de ntistry. I especially thank Arthur Vernino, D.D.S., Ike Aukhil, D.D.S . , and Luciana Machion, D.D.S., PhD.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS...............................................................................................................4 LIST OF TABLES................................................................................................................. ..........7 LIST OF FIGURES................................................................................................................ .........8 LIST OF TERMS...................................................................................................................... .......9 ABSTRACT....................................................................................................................... ............10 CHAPTER 1 INTRODUCTION..................................................................................................................11 2 BACKGROUND....................................................................................................................12 3 AIM OF STUDY................................................................................................................... .16 4 HYPOTHESIS TO BE TESTED IN THIS PROJECT...........................................................17 5 MATERIALS AND METHODS...........................................................................................18 Study Procedure................................................................................................................ ......18 Measurements................................................................................................................... ......19 Surgical Design................................................................................................................ .......20 Post-Surgical Care............................................................................................................. ......22 Re-Entry....................................................................................................................... ...........23 6 RESULTS AND STATIS TICAL ANALYSES.....................................................................32 Results........................................................................................................................ .............32 Statistical Analysis........................................................................................................... .......33 7 DISCUSSION..................................................................................................................... ....44 Limitations.................................................................................................................... ..........51 Conclusion..................................................................................................................... .........52 APPENDIX A STATISTICAL TESTS: RAW DATA................................................................................... 53 B RAW DATA: STENT MEASUREMENTS........................................................................... 60

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6 LIST OF REFERENCES............................................................................................................. ..66 BIOGRAPHICAL SKETCH.........................................................................................................75

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7 LIST OF TABLES Table page 6-1 Ranges in differences for the open groups at 4 months.....................................................35 6-2 Ranges in differences for the closed groups at 4 months...................................................35 6-3 EMD/allograft/membrane (test) mean diffe rences at the five points for open and closed showing average ride di mension reduction at 4 months.........................................35 6-4 Allograft/membrane only (control) mean di fferences at the five points for open and closed showing average ridge di mension reduction at 4 months.......................................36 6-6 Comparison of EMD/allograft/membrane v. Allograft/membrane only at the five measurement points for closed groups show ing mean ridge dimension reduction...........37 B-1 EMD/allograft/membrane (test).........................................................................................60 B-2 Allograft/membrane only (control)....................................................................................63

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8 LIST OF FIGURES Figure page 5-1 Schematic depicting the stent upon a clos ed ridge in crosssection. Probes are inserted into the 5 measurement points in the stent to the soft tissue level.......................24 5-2 Stent fabrication using thermoplastic vacu-form material and a169L bur for measuremen t points...........................................................................................................24 5-3 Shows the thermoplastic stent with th e measurement points at B-5, 0, and L-5. Points for B-10 and L-10 can not be seen in this view......................................................25 5-4 Extraction of non-restorable #29 showing initial incision design.....................................25 5-5 Full thickness flap reflection............................................................................................. .26 5-6 Tooth removal with a periotome........................................................................................26 5-7 Tooth removal complete with intact buccal, lingual, mesial, and distal plates.................27 5-8 Adding 0.7ml of EMD to the allograft for the test group..................................................27 5-9 Allograft with or withou t EMD in the extraction site........................................................28 5-10 Collagen barrier being put into position. Open baseline measurements taken with the thermoplastic stent prior to closure....................................................................................28 5-11 Flap adaptation. Primary closure was not attempted. Closed flap baseline measurements taken at this time with the thermoplastic stent...........................................29 5-12 Closed stent measurement at B5 point during the 4-month re-entry.................................29 5-13 Closed stent measurement at 0 point during the 4-month re-entry....................................30 5-14 Open stent measurement at B5 point during the 4-month re-entry....................................30 5-15 Open stent measurement at L5 point during the 4-month re-entry....................................31 5-16 Implant fixture in place.................................................................................................. ....31 6-1 Comparison of EMD/allograft/membrane v. Allograft/membrane only at the five measurement points for open groups showi ng mean ridge dimension reduction..............36 6-2 Comparison of EMD/allograft/membrane v. Allograft/membrane only at the five measurement points for closed groups show ing mean ridge dimension reduction...........37 6-3 Example case documenting the extraction through the baseline measurement data collection. Complete series...............................................................................................38

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9 LIST OF TERMS Bone Allograft – allogeneic tran splant; refers to a genetically non-identical graft of a similar species; in the case of this st udy, a freeze-dried and fully mineralized preparation in particulate form was used Buccal – pertaining to the cheek side of the ridge Collagen barrier/membrane – a bioresorbable dre ssing generally placed over the surface of a grafted area; primary role is to prevent epitheli um from entering the wound site; will resorb at varying rates depending upon exposur e to the oral environment ant collagen density of the membrane. Due to resorbability, requires no second surgery for retrieval Enamel Matrix Derivative – freeze-dried extract from developing porcine teeth of the enamel matrix proteins, amelogenin (90%), enamelin, tuftelin, and ameloblastin; comes in a propylene glycol alginate carrier; believed to mimic and induce the events that occur during the development of periodontal tissues . May play a role in osteog enesis, angiogenesis, microbial inhibition, and epithelial exclusion Endosseous dental implant – artificial tooth replacement; based upon the discovery by ParIngvar Branemark; most commonly the osse ointegrated type which forms a functional connection with bone Lingual – pertaining to the tongue or palatal side of the ridge Osteoblast – bone forming cell; mononucleate; produce osteoid (mainly TypeI collagen); mineralize the osteoid matrix; has opposite act ivity from osteoclasts that resorb bone Osteoconductive – promotes bone formation by pr oviding a scaffold or matrix from which osteoblastic activity can occur; he lp to bridge existing bony areas Ridge – bony alveolar process in the maxilla a nd the mandible that contains the teeth; will generally atrophy to some degree upon tooth removal Ridge Preservation a surgical ma nipulation in which the extraction socket within the alveolar ridge is treated with a graft, membrane, or sim ilar method with the intent of reducing the amount of atrophy and ridge dimensional loss which generally follows exodontia Thermoplastic stent – plastic gu ide formed from a “suck-down” shell used in a vacu-former; helped standardize measurements in the current study

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10 Abstract of Thesis Presen ted to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science HEALING CHARACTERISTICS AND RIDG E QUANTITY AFTER USING ENAMEL MATRIX DERIVATIVE DURING EXTRAC TION SOCKET RIDGE PRESERVATION By Eric F. Schoenebeck May 2007 Chair: Ikramuddin Aukhil Major: Dental Sciences The purpose of this study was to evaluate the effect of enamel matrix derivative (EMD) in combination with freeze-dried bone allograft (FDBA) and a colla gen barrier on ridge dimension following extraction socket ridge preservation (E SRP). Twenty-four patients requiring tooth extraction and socket preservation for future impl ant placement were selected for the study. Test subjects received FDBA, a collagen barrier and EMD. Control subjects received only the graft and the barrier. Alveolar ridge di mensions were recorded at the initial surgery and at 4 months during re-entry for endosseous implant placement via a thermoplastic sten t to the osseous level and to the soft tissue level. Trephine core samp les were obtained during im plant site preparation for histological analysis. Nonsignificant differences were found between the test treatment and the control treatment in terms of ridge dimensi onal change. This study provides support for the EMD/FDBA/membrane combination and the FDBA /membrane treatment as viable means for ridge preservation. Within the limits of this study, EMD did not seem to add any additional benefit to the use of FDBA and a membrane during extraction socket ridge preservation.

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11 CHAPTER 1 INTRODUCTION Endosseous dental implant plac ement is increasingly becoming the preferred treatment for an edentulous site. Placement of these implant fixtures can often be compromised in ridges that are atrophic in nature. If an implant can not be placed immediately at the time of tooth removal, ridge preservation is a good met hod of developing and preserving an adequate site for future implant placement. Traditionally, autogenous graf ts, allografts, alloplasts, and xenografts have been used for this purpose. A ll grafted sites require appropriate healing time to ensure optimum osseous maturation prior to re-entry. These grafte d sites may continue to show some degree of net bone loss (dimensional reduction) over time due to bone remodeling. In recent years, enamel matrix derivative (EMD) has been used for th e regeneration of periodontal defects, having positive effects on the regeneration of periodontal ligament, bone, and cementum. This study was performed to determine if EMD in combin ation with an allograft would have a more positive effect upon ridge dimensional stability following tooth removal versus an allograft alone.

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12 CHAPTER 2 BACKGROUND A classic study of extraction socket heali ng explains the process by which the osseous defect heals following tooth removal.1 Following the tooth extraction, a blood clot with a dense fibrin network quickly forms. Within 2-3 da ys, there is a preponderance of neutrophils, monocytes, granulocytes, and some fibroblasts and granul ation tissue arises. At approximately 4 days, most of the clot has disappeared and is replaced by granulation tissue while epithelium proliferates at the wound edges. Osteoid tissue appears at th e apex. By one week, increasing amounts of osteoid tissue fills the apex and fo rms along the socket walls and connective tissue increases below the epithelial layer. In three we eks epithelium is covering immature connective tissue and the osteoid woven bone is beginning to mineralize at th e apex. At the 6-week mark, lamellar bone is replacing the w oven bone and the soft tissue has matured covering the socket. Bone fill may take up to 4 months to occur in the socket and seems to never reach the height level of the adjacent teeth. A more recent study by Araujo and Lindhe showed that marked dimensional changes occur up to the first two months following extraction.2 Marked osteoclastic activity resulted in reduction of the crestal region in the buccal and the lingual walls of the socket as bundle bone was replaced by less mineralized woven bone. This vertical loss was significantly greater in the buccal wall than in the lingual wall due to the fact that the buccal plate consists mainly of bundle bone. Secondly, increased horizontal loss seemed to occur as a result of osteoclasts lining the outer surfaces of both plates. Bone loss following tooth removal can result in a site compromised in necessary dimensions for dental implant placement. This loss of bone may affect th e esthetics or prevent placement altogether due to either a close proxim ity to vital structures or insufficient bone

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13 dimensions. Previous studies have shown that tooth removal without concurrent grafting can result in significant loss of he ight and width of the alveolar ridge at the extraction site.3-10 It has been shown that the original height and widt h of the alveolar housi ng is reduced by 40-60% following tooth removal, with the majority of bone loss occurring during the first 2 years.11-14 The rate of atrophy in recently extracted tooth sites occurs at a rate of 0.1mm/year in the maxilla and 0.4mm/year in the mandible.15 The resorption was more ev ident at the facial surface of the ridge due to a thinner buccal plate of alveolar bone.7, 15 There is variability in the amount of ridge resorption among patients following toot h removal. Many factors besides individual patient differences affect the exte nt of resorption. These include the density of the alveolar bone, the number of remaining bony walls following the ex traction (surgica l trauma), the severity of the bone loss associated with peri odontal disease, location of the tooth within the ridge, presence of any infection, and the presence or absence of any adjacent teeth.16 Using one of several types of graft material s, resorption of the alveolar ridge in both horizontal and vertical dimensions can be minimized.5, 6, 9, 17-24 Examples of potential graft materials have included bone aut ografts, allografts, alloplasts, a nd xenografts. These grafts all work via three basic principles in bone fo rmation – osteogenesis, osteoinduction, and osteoconduction.25, 26 Osteogenesis only occurs when vital osteoblasts or pre-osteoblasts are transplanted from an autogenous donor site and directly lead to new bone formation. Osteoinduction occurs when an inductive agent su ch as bone morphogenetic protein (as may be found on demineralized bone allograft) stimulat es undifferentiated stem cells into becoming bone-forming cells. Lastly, osteoconduction occurs when a material such as freeze-dried bone allograft, an alloplast, or a xe nograft act as a scaffold and enable osteoblasts and their precursors to enter the defect, creating hardened matrix.

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14 Background for materials used in this study: Enamel matrix derivative (EMD) is a collection of matrix proteins isolated from deve loping porcine teeth yieldi ng an extract of several enamel matrix proteins, including amelogenin. This freeze-dried extract is dispensed in a propylene glycol alginate carrier. The theory be hind EMD’s mechanism of action is via mimicry of the events that occur during the de velopment of the periodontal tissues.27 Amelogenin and/or other enamel matrix proteins have potentiall y contributed to cement ogenesis, bone formation, and new attachment.28-35 EMD has also provided positive resu lts in the treatment of periodontal defects.36-46 This material has been shown to stimu late new bone, new periodontal ligament, new connective tissue, and new cementum with inserting collagen fibers.47-49 Of particular importance to our study is the role of EMD on bone. Since the present study is aimed at exploring the healing of extracti on sockets, our concern was not w ith the regenerati on of all of the periodontal structures involved with an intrab ony pocket or a recessive defect. A review of the more current literature reveals a great deal of new data pertaining to the re-creation of osseous structure. Recent studies point to apparent role of EM D in osteoblast promotion and upregulation.50-61 Also important to new bone formation is adequate blood flow. It has been reported that EMD may play a ro le in angiogenesis promotion.62, 63 Surprisingly, a search of the current literature reveals that EMD use within ridge preservation has not been studied. Therefore, this study may be the first of its kind. Freeze-dried bone allograft (F DBA) is mineralized human particulate bone ranging from 50-600 microns in particle size which acts as an osteoconductive scaffo ld enabling the body to initiate new bone formation and to vitalize the ex traction site. Upon par tial or full turnover of this allograft 4-6 months later, implants can be placed into a ridge site which has adequate dimensions and bone vitality.19, 64, 65 This procedure provides a predictable opportunity to

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15 maintain bone dimensions at an extraction site for future dental implant placement.66 FDBA placed at the time of extraction preserved the socket and was suitable for implant fixture placement in 4 months.19 Several articles have reported the use of barrier membranes over of the grafted extraction socket. The primary role, according to the princi ples of guided tissue regeneration, has been to prevent an ingrowth of epith elium or connective tissue duri ng the formation of the newly forming bone.67 Where a gingival flap was not elevated and/ or complete flap closure at the wound site was not achieved, the barrier can assist in graft retention. Collagen barriers have proven effective, are biocompatible, and are bior esorbable, thus eliminating the need for a separate surgery for its removal.68-72 I used the extraction socket ridge preservati on (ESRP) technique in my study to preserve the alveolar bone structure following tooth remova l. I used LifeNet freeze-dried bone allograft, with or without Emdogain enamel matrix deri vative (EMD), which was covered by an Ace RCM6 resorbable collagen barrier. My study was designed to evaluate th e effect that EMD had upon the osseous tissue known to f ill the fresh extraction site.

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16 CHAPTER 3 AIM OF STUDY The purpose of this study was to compare the effectiveness of EMD in ESRP when added to bone grafting. There are two specific aims of this study. To compare the clinical eff ects of combining EMD with bone allograft material and a collagen membrane during ESRP by measuri ng the height and width ridge dimensional changes at a soft tissue and a hard tissue level. To provide the histologic evaluation of the qua lity and quantity of bone formation in ESRP when EMD is used in combination with the al lograft and membrane. This will be presented in a subsequent paper. For each comparison, the test sites will have EM D mixed with the graft material, while the control will not include any EMD .

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17 CHAPTER 4 HYPOTHESIS TO BE TESTED IN THIS PROJECT EMD is an effective adjunct to allograft and collagen barriers duri ng ridge preservation. This combination should provide less dimensi onal ridge loss versus a llograft and a collagen barrier alone following tooth remova l and socket preservation.

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18 CHAPTER 5 MATERIALS AND METHODS Study Procedure This was a single-center, parallel, randomized clinical trial conduc ted in the Graduate Periodontics Clinic at the University of Florida, College of Dentistr y. The University of Florida, Health Center Institutional Re view Board (IRB) approved it in May, 2005. Patients included in the study completed an IRB consent form. All pa tients were randomly assigned to a treatment modality prior to the surgery via a coin-flip until near-equal subjects were enrolled in each of the two treatment categories. This study included twenty-four patients, ranging in age from 27 to 79 (mean age 56 years old), requiring extraction of at least one hopeless t ooth in an area that involved restorative implant treatment. A toot h was considered hopeless due to advanced bone loss, gross caries, fracture, malposition, trauma, or endodontic failure. Sites were included in the study that had at least three resi dual bony walls and did not have act ive, purulent infections. Study participants were medically competent to receive routine dental care including local anesthesia and extractions. Exclus ion criteria for the study include d pregnancy, lactating females, uncontrolled diabetes, and subjects with any medical or other contra indications to oral surgery. A complete medical history a nd patient screening to include a blood pressure reading, radiographs and a dental examination was complete d prior to any treatment. Patients completed at least one non-surgical treatment of scaling or scaling and r oot planing prior to extraction. Each patient received a prosthodon tic treatment plan. Our study protocol was consistent with the procedure described by Wang and others in which teeth were extracted with periotomes and elevated with minimal trauma to the socket walls.73 The socket was then completely curetted of any residual soft tissue, active bleeding was

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19 promoted in the extraction site, a bone allograft was placed, and a collagen dressing was applied over the graft. Twenty-four patients (14 males, 10 females) began the current study with eight patients receiving the EMD/allograft/ membrane treatment. Ten patients received the control treatment only with one of these patients providing two separate control sites. Six patients had two separate sites, one receiving the control treat ment and one receiving the test treatment. Therefore, fourteen extraction si tes received the test treatment of EMD plus the allograft and the collagen barrier. Seventeen extraction sites recei ved the control treatment of just the allograft and the collagen barrier. Seventeen were molar sites (8 test, 9 control), nine were premolar site s (5 test, 4 control), and five were sites in the anterior (1 test, and 4 control). Thirt een sites were in the maxilla (5 molars, 5 premolars, and 3 anteriors). The remaining 18 mandibular teeth consisted of 12 molars, 4 premolars, and 2 anteriors. All extr action sites had a tooth present anteriorly and posteriorly to them with the exception of thr ee mandibular molars, one maxillary molar, one mandibular premolar, and one maxillary premolar. Measurements Alginate impressions were taken of all pa tients for the purpose of diagnostic cast and thermoplastic stent fabrication. This stent was used to record accu rate and reproducible measurements of dimensional changes to the ridges following the extraction and grafting procedure. It was meant to repr esent the original width and height dimensions of the ridge prior to tooth extraction. Procedure for stent fabricati on (Figures 5-1, 5-2, and 5-3): An alginate impression was taken of the st udy quadrant and a stone study cast was made. The clinical crown of the tooth to be extracted was removed from the cast.

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20 A stent was made from the study cast usi ng Henry Schein Thermo-Forming Material, Clear – Temporary Splint This stent was trimmed to include one tooth anterior to and one t ooth posterior to the “extraction” site. If a terminal tooth was ex tracted, a longer extensi on that rested upon the ridge was retained. A sufficient flange measuring at least 10mm from the most coronal point of the crest remained facially and lingually to the “extraction” site. A 169L tapered fissure bur was used to place a UNC periodontal probe tip-sized perforation in the stent at the mid-point mesi ally-distally between the teeth on either side of the “extraction” site that in tersected with the facial/lingual midpoint of the crest. This was the crestal point (0-point). Similar perforations were also created 5mm a nd 10mm apical to this crestal point on the facial flange and on the lingual flange as m easured by a piece of dental floss with 5mm increments marked upon it. These were th e mid-buccal (B5), mid-lingual (L5), apicobuccal (B10), and apico-lingual (L10) points. Surgical Design The patients were advised of the risks associ ated with participati on in this study. These included possibilities of pain /discomfort during injection and post-operatively along with infection, bleeding, bruising, swelli ng, local nerve damage (parasth esia), or localized vascular damage. Additional risks as a result of this type of surgery included damage to adjacent structures, allergy to materials, potential perforation of the ma xillary sinus, and alveolar bone fracture. A standard presurgical routine was followed. Pre-operative consents were obtained and a pre-operative health assessment was performed. They rinsed for one minute pre-operatively with 0.12% chlorhexidine gluconate to lower the intraoral bacterial load. Additionally, each patient received an extra-oral facial scrub of 4% chlorhexidine gluconate to reduce external microbial load. Local anesthesia consiste d of application of topical benz ocaine to the injection site followed by usage of 2% lidocaine w/1: 100,000 epinephrine and/or 0.5% bupivicaine w/1:200,000epinephrine.

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21 Following adequate anesthesia , full-thickness lingual and buccal flaps were elevated for access (Figure 5-5). The flaps were elevated to visualize and protect th e cortical bony plate in the event of a subgingival tooth fracture. In most instances, slight verti cal releases were made for the purpose of easier flap manipulation (Fig ure 5-4). These verticals were placed at a position mesial and distal enough from the extr action site to preclude compromising the blood flow to the flaps. The tooth removal was perf ormed as non-traumatically as possible. When possible, periotomes were utilized with extra ca re taken to preserve any remaining buccal plate (Figures 5-6 and 5-7). The amount of remaining alveolar process was recorded and categorized according to the Salama and Salama extracti on socket classification system (Table5-1).74 The authors only included Class I and Class II sockets in this study, a nd specifically only those that left 4 wall and combination 3/4 defects. The Sa lama and Salama classification is listed as follows: Category I -Socket environment with good regenerati ve potential and esthetic prognosis -Less than 5 mm of potential osseous loss on the buccal aspect. Category II -Buccal plate loss of greater th an 5mm to full buccal plate loss -Mostly a defect environment with a potential after-implant placement dehiscence greater than 5 mm. -Defect aspect usually requires attention before implant placement or grafting is needed concurrently Category III -Extraction site severely compromised -Most of the root is in a defective environment -Area must be reconstituted before implantation

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22 All extraction site(s) were filled with the graf t material (FDBA) (Figure 5-9). Test sites received the full carpule (0.7 ml ) of EMD mixed with the FDBA (Figure 5-8) while the control sites received FDBA alone. Collagen barriers were used to cover the graf t material and extended partially under the buccal and lingua l flaps (Figure 5-10). Prior to flap closure, the measurement stent was placed. Baseline bony crest measurements (open) were taken at the crestal point (0point) and then at the mid-bu ccal, mid-lingual, apico-buccal, and apico-lingual points (B5, L5, B10, and L10). These measurements were record ed as the difference from the outer surface of the stent to the bone or the membrane covering the graft. The flaps were returned as close as possible to their original positions and sutured with interrupted bioresorbable Vicryl or chromic gut sutures. In many instances, primary closure of the extraction site was not achieved; therefore a small portion of the membrane remained expos ed (Figure 5-11). This was particularly important in esthetic areas to avoid coronal ad vancement of the mucogingival junction. No periodontal dressing was placed and no patients rece ived any temporary prosthesis that would put any pressure upon the grafted sites. Subseque nt measurements were then repeated following flap closure at the same points on the stent but this time only to so ft tissue. This provided the baseline soft tissue (close d) ridge dimensions. Post-Surgical Care Post –operative care including oral hygiene instructions were pr ovided to the patient verbally and in writing. Patient s also received a 10-day course of post-operat ive antibiotics consisting of amoxicillin 500mg, TID or cli ndamycin 150mg TID for patients allergic to amoxicillin. Two 4oz bottles of chlorhexidine gl uconate were dispensed to all patients to be used BID for 2 weeks with instructions for use. Patients followed a standard post-surgical protocol. They returned to the clinic for 1-week (+/5 days), 2 week, and 1-month (+/1 week) follow-up visits to monitor healing progress.

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23 Re-Entry At 4-months post-ESRP, the sites were evaluated for implant placement. Final soft tissue ridge dimension/stent measurements were taken prior to the surgery (Figures 5-12 and 5-13). These determined the final closed ridge dime nsion. Any preand post-surgical protocols discussed earlier applied for this appointment as well. A gingival flap was reflected on both the buccal and lingual aspect. The measurement stent was once again positioned for final measurements of the bony ridge dimension (Figur es 5-14 and 5-15). This determined the final open ridge dimension. In conjunction with the implant site preparation, an osseous co re was retained. The sample of the grafted area was obtained via a 2mm tre phine bur to 8mm of depth during the osteotomy preparation and was submitted for histological an alysis. This was documented in the future study. The osteotomy was shaped and finished according to standard implant placement protocol, the implant was placed, and the gingiv al tissues were approximated to the implant surface and sutured (Figure 5-16).

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24 Figure 5-1. Schematic depicti ng the stent upon a closed ridge in cross-section. Probes are inserted into the 5 measurement points in the stent to the soft tissue level Figure 5-2. Stent fabrication using thermoplastic vacu-form material and a169L bur for measurement points

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25 Figure 5-3. Shows the thermopl astic stent with the measurem ent points at B-5, 0, and L-5. Points for B-10 and L-10 can not be seen in this view. Figure 5-4. Extraction of non-restorab le #29 showing initial incision design

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26 Figure 5-5. Full thickness flap reflection Figure 5-6. Tooth removal with a periotome

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27 Figure 5-7. Tooth removal complete with int act buccal, lingual, mesial, and distal plates Figure 5-8. Adding 0.7ml of EMD to the allograft for the test group

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28 Figure 5-9. Allograft with or w ithout EMD in the extraction site Figure 5-10. Collagen barrier bei ng put into position. Open base line measurements taken with the thermoplastic stent prior to closure

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29 Figure 5-11. Flap adaptation. Primary closur e was not attempted. Closed flap baseline measurements taken at this time with the thermoplastic stent Figure 5-12. Closed stent measurement at B5 point during the 4-month re-entry

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30 Figure 5-13. Closed stent measurement at 0 point during the 4-month re-entry Figure 5-14. Open stent measurement at B5 point during the 4-month re-entry

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31 Figure 5-15. Open stent measurement at L5 point during the 4-month re-entry Figure 5-16. Implant fixture in place

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32 CHAPTER 6 RESULTS AND STATISTICAL ANALYSES Results Fourteen patients (7 male, 7 female), rangi ng in age from 49 to 77 (mean 62 y.o.), provided a total of seventeen su rgical sites through full treatment in cluding implant placement. Six patients (4 females, 2 males) received the test treatment only, while six patients (5 males, 1 female) received the control treatment only. One of the patients in the control group provided 2 separate control sites. Two patients (both female) received both a test site and a control site. Therefore, eight sites receiving the EMD were completed through the implant stage. Nine control sites completed full trea tment through the study. The contro l sites were composed of 4 anterior sites, 4 molar sites, and 1 premolar site . Six were maxillary s ites and 3 were mandibular sites. The test sites were compos ed of 3 molar sites, 4 premolar si tes, and 1 anterior site. Five were mandibular sites and 3 were maxillary sites. Ten patients did not complete full treatment in the study. Five patients were dropped from the study due to an inability to re-enter the grafted sites within the 4-month period. One patient moved from the area. One patient stopped treatmen t due to a change in health status and three patients had a change in their prosthodontic treatment plans. Data is presented on the seventeen sites fr om the fourteen patients that completed treatment through the dental implant phase. Toot h removal in all instan ces occurred with no adverse events. If the tooth site presented with fully intact buccal and lingual plates, these were maintained throughout the extraction. Thirteen of the sites presen ted as type I sockets according to the Salama and Salama classification system. Four sockets were considered type 2 sockets (2 tests, 2 controls). In each of these, a 6-7 mm portion of the buccal plate was missing prior to

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33 extraction. In two of the occurrences, these bucca l plate defects coincided with vertical root fractures. In the other two instan ces, these defects were a result of endodontic strip perforations. Two patients (1 test, 1 control) experienced post-operative infections with expression of purulence and symptomatic swelli ng. These patients were seen at the first recall and given another week of antibiotics. These infections we re not clinically present by the one-month recall and the grafts did not require removal. Subseque nt implant placement was not affected in these infected sites. In all cases, the measurement stents fit at the 4-month re-entry, i ndicating minimal tooth movement. Core samples and implant fixture placements were also completed uneventfully according to the described protocol. Results of the histological study will be reported in another paper. Raw data collected from the closed (soft tissu e level) sites and the open (osseous level) sites for the test group and the c ontrol group can be seen in tables A-1 and A-2 in Appendix A. Ranges for the open and closed groups are show n in tables 6-1 and 6-2. Stent measurement changes were calculated between th e baseline readings at the tim e teeth were removed and then again at the four-month marks (implant placement) for the closed and open sets. These were completed at the 0, B5, B10, L5, and L10-points (Tables 6-3 and 6-4). Mean changes with standard deviations were tabulated for the test group and al so for the control group at each of these 5 points to the osseous level and then also to the soft tissue level. The EMD/allograft/membrane groups were compared to the Allograft/membrane only groups. These figures are provided in tabl es 6-5 and 6-6 and visually depi cted in graphs 6-1 and 6-2. Statistical Analysis Mann-Whitney tests were performed for each of the comparisons presented. Comparisons were made at the patient level versus the site le vel due to the number of subjects present in the

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34 current study. For the purpose of uniformity, the cont rol site only was used in one of the patients providing a test and a control site . Likewise, only the test site was used in the other subject providing a test site and a cont rol site. These sites were chosen based upon a coin-flip. A comparison of ridge preservation treatm ent with EMD/allograft/membrane with Allograft/membrane resulted in a non-significant difference in ridge dimensional change (pvalue = 0.383) at the open level and also a non-significant difference (p-value = 0.535) was found at the closed level. Next, comparisons were run to determine if any significant ridge dimensional change differences were present between treatment of the buccal side of the ridge and the lingual side of the ridge for the test groupopen and closed, an d for the control groupopen and closed. No significant differences were found between the buccal side or the lingual side at each of these groups (p-values = 0.259, 0.535, 0.128, 0.128, respectively). Comparisons of the differences of the mid-buccal/lingual (B5/L5) and apicalbuccal/lingual (B10/L10) height levels were also made. Once again these potential differences were tested for the test-open and closed, and c ontrolopen and closed groups. Non-significant differences were found in ridge di mensional change for the various treatment levels (p-values = 0.620, 0.805, 0.259, 0.128, respectively). Lastly, all results for both patie nt groups (test and control) were pooled to determine if there were overall differences between the mi d-buccal/lingual and apical-buccal/lingual height levels for the open and closed groups. The test s were also run to de termine if dimensional change differences existed between the buccal an d lingual sides of the ridge for the open and closed groups when the test a nd control results were pooled. N on-significant differences were found at the two ridge hei ghts for the open and closed groups (p-value = 0.250, 0.206

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35 respectively). A significant difference was found between the buccal and th e lingual sides of the ridge for the pooled open group (p-value = 0.048) w ith greater loss occurri ng at the buccal ridge, while a non-significant relationship was seen at the closed group (p-value = 0.270). Table 6-1. Ranges in differences for the open groups at 4 months EMD/Allograft/Membrane v. Control (Open) Open range (mm) Open range (mm) Buccal 10 0 to 4 -1 to 5 Buccal 5 1 to 2 0 to7 0 1 to 5 -1 to 8 Lingual 5 0 to 3 -1 to 5 Lingual 10 -2 to 4 -3 to 3 Table 6-2. Ranges in differences fo r the closed groups at 4 months EMD/Allograft/Membrane v. Control (Closed) Closed range (mm) Closed range (mm) Buccal 10 0 to 5 0 to 2 Buccal 5 -1 to 3 0 to 4 0 0 to 3 -2 to 3 Lingual 5 -1 to 5 -2 to 3 Lingual 10 0 to 5 2 to 2 Table 6-3. EMD/allograft/membrane (test) mean di fferences at the five points for open and closed showing average ride di mension reduction at 4 months Open Avg. Difference Closed Avg. Difference Buccal 10 1.625 1.375 Buccal 5 1.625 1.000 0 2.875 1.125 Lingual 5 1.250 1.250 Lingual 10 0.500 1.125

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36 Table 6-4. Allograft/Membrane On ly (Control) mean differences at the five points for open and closed showing average ridge dimension reduction at 4 months Open Avg. Difference Closed Avg. Difference Buccal 10 1.444 1.000 Buccal 5 2.222 1.556 0 1.889 0.444 Lingual 5 1.000 1.111 Lingual 10 0.111 0.111 Table 6-5. Comparison of EMD/ Allograft/Membrane v. Allograft/B arrier Only at the five measurement points for open groups showi ng mean ridge dimension reduction. EMD/Allograft/Membrane v. Control (Open) Open Avg. Difference Open Avg. Difference Buccal 10 1.625.598 1.444.740 Buccal 5 1.625.518 2.222.986 0 2.875.246 1.889.713 Lingual 5 1.250.165 1.000.000 Lingual 10 0.500.000 0.111.028 Open EMD/Allograft v. Control -3 -2.5 -2 -1.5 -1 -0.5 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Buccal 10 Buccal 5 0 Lingual 5 Lingual 10 Ridge Dimension Changes (mm) Open EMD Open Control Figure 6-1. Comparison of EMD/ Allograft/Membrane v. Allograft/M embrane Only at the five measurement points for open groups show ing mean ridge dimension reduction

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37 Table 6-6. Comparison of EMD/ Allograft/Membrane v. Allograft/Membrane Only at the five measurement points for closed groups show ing mean ridge dimension reduction. EMD/Allograft/Membrane v. Control (Closed) Closed Avg. Difference Closed Avg. Difference Buccal 10 1.375.996 1.000.707 Buccal 5 1.000.195 1.556.509 0 1.125.126 0.444.810 Lingual 5 1.250.832 1.111.453 Lingual 10 1.125.727 0.111.054 Closed EMD/Allograft v. Control -3 -2.5 -2 -1.5 -1 -0.5 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Buccal 10 Buccal 5 0 Lingual 5 Lingual 10 Ridge Dimension Closed EMD Closed Control Figure 6-2. Comparison of EMD/ Allograft/Membrane v. Allograft/M embrane Only at the five measurement points for closed groups show ing mean ridge dimension reduction

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38 (a) (b) Figure 6-3. Example case documenting the extrac tion through the baselin e measurement data collection. Complete series: (a) Non-restor able #19. (b) Extrac tion site with full thickness flaps raised and bony socket walls intact. (c) Allograf t with or without EMD in place. (d) Adaptation of the co llagen barrier. (e) Baseline open B-10 measurement. (f) Baseline open B-5 measur ement. (g) Baseline open 0 measurement. (h) Baseline open L-5 measurement. (i) Ba seline open L-10 measurement. (j) Flap adaptation without primary closure. (k) Baseline closed B-10 measurement. (l) Baseline closed B-5 measurement. (m) Baseline closed 0 measurement. (n) Baseline closed L-5 measurement. (o) Baseline closed L-10 measurement.

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39 (c) (d) (e) Figure 6-1. Continued

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40 (f) (g) (h) Figure 6-1. Continued

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41 (i) (j) (k) Figure 6-1. Continued

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42 (l) (m) (n) Figure 6-1. Continued

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43 (o) Figure 6-1. Continued

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44 CHAPTER 7 DISCUSSION Tooth removal results in the partial resorption and loss of the alveolus at the edentulous site.4, 7, 8, 10, 21, 75 The maxillary anterior alveolar ridge can reduce by 23 % in the first 6 months up to 34% over the first 5 years. 17 Resorption in the posterior ma ndible occurs initially from the buccal, causing the alveolar cr est to displace more lingually.7, 17 When appropriate, an immediate implant fixture may be placed within the fresh extraction socket.76-79 This may help to preserve the alveolar bone height and width and also can eliminate the need for a second surgery. This procedure can also often-time s reduce the overall treatment time to the final restoration. Covani showed a greater amount of dimensional ridge width loss when implants were placed 6-8 weeks post-extractio n versus implants placed immediately.11 In both situations the extraction sites received no graft material. On occasion, a lack of available residual bone, infection at the site, proximity to vital structures , and difficulty in attainin g primary stability that is common in molar sites, prevents placement of an endosseous implant fixture at the time of the tooth removal. Any surgical manipulation to preserve the maximum amount of bone in healing sockets is always desirable when fu ture implant placements are planned. Preservation of the socket at the time of exodontia may also obviate the need for challenging future ridge augmentation procedures in the event of eventual implant fixture placement.5-7, 9, 17-23, 80 A study performed by Lekovic show ed less crestal bone loss, more internal socket fill, and less horizontal ridge re sorption occurred at 6 months in the group that received socket preservati on versus the control group.21 Nevins et al studied the fate of the residual buccal plate following extraction of teeth w ith prominent facial roots. CT scans were performed at the time of graft pl acement, at 30 days, and then again at 90 days to assess the

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45 buccal plate and the healed form of the edentulo us site. A loss of less than 20% of the buccal plate was seen in 79% of the grafted sites wher eas 71% of the ungrafted controls demonstrated greater than 20% loss of the buccal plate.9 In ungrafted controls, Sc hropp showed that alveolar ridge width decreased form 12mm to 5.9mm (50%), height cha nged less than 1mm, a larger percentage of loss occurred in molars than pr emolars, and 66% of loss occurred in the first 3 months.81 This provided a good reason why the authors of this study chose to re-enter the sites at 4 months for the implant placement. The majority of change within the ridge dimensions would be expected to occur in the first few mont hs, therefore waiting longer would seem to be unnecessary. Our results provide further support that applying a graft to the fresh extraction socket will prevent substantial loss of the sock et dimensions. Our width losses averaged 22.5% and 29.6% at the 5mm points for the test and th e control, respectively. The losses at the 10mm points were 17.9% and 7.4% for the test group and the control group, re spectively. This study utilized freeze-dried bone allograf t (FDBA), a material proven eff ective for the purpose of ridge preservation.7, 19 Iasella et al compared extraction sites preserved with FDBA and collagen barriers to non-gr afted controls.7 They mixed tetracycline with the allograft and primary closure was not a requirement. Ridge height and ridge width dimensional changes were measured with digital calipers and an acrylic st ent. Both the test group and th e control group lost some width. The ridge widths decreased 1.6mm more in the non-grafted controls. Mo re of the resorption occurred in the buccal surface and maxillary sites lost more width than the mandibular sites. There was a vertical dimensional difference of 2.2mm between the test and the control group, with the grafted group actually gaining 1.3mm of height. In the current study, average lo sses of width ranged from 2.12 5 mm to 2.875 in the open EMD/allograft/membrane (test) set and 1.555 mm to 3.222mm in the open Allograft/membrane

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46 only (control) set. Verticall y, the average loss in the open te st group was 2.875mm and in the open control group was 1.889mm. For the closed sets, the test group average width loss ranged from 2.250mm to 2.500mm while the control group averages range d from 1.111mm to 2.667mm. Vertical dimensional losses averaged 1.125mm for the test group and 0.444mm for the control group. Generally, the current study ag reed with the fact that the buccal side of the ridge had a greater dimensional loss than the lingual side. The only groups that did not align with this finding were the closed EMD/allograft/membran e B5 and L5 averages. The FDBA/membrane combination with or without the EMD used in th is study provided an adequate ridge dimension to place the dental implants w ithout need for furthe r grafting. Even though there was some loss of ridge dimension, both combinations provide adequa te ridge preservation at the 4 month mark. A great deal of documentation exists for the us e of EMD as a regenerative material. Most studies involve its use in regene rating the periodontal structures destroyed by periodontal disease and generally demonstrate signif icant reduction in probing depth and attachment level gains, with minimal recession.37, 38, 42, 43, 46 EMD/graft/membrane combinations showed improvements in PD decrease and CAL gain in periodontal defects.44, 45, 82-84 There is also support for treatment of class II and class III furcation defects with EMD, showing great er reduction in horizontal and vertical furcation probing depths when co mpared to GTR or surgical debridement.39, 40, 85, 86 EMD and its link to cementum growth have been reported.33, 35 Sculean et al provided a case report showing histology confir ming a new attachment apparatu s in a defect treated with EMD, a bovine graft, and GTR.49 Regenerated bone, PDL, and cementum were described. Animal studies and human studies show that the EMD stays present on root surfaces for approximately 2-4 weeks.31, 87-89 The potential mechanism for action of EMD has been described. Multiple in vitro studies show EMD’ s ability to upregulate and modulate different

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47 cell types in the dental environment. EMD pr omotes the fibroblast-l ike cell repopulation during the first few weeks in monkeys.88 It promotes attachment of PDL by increasing TGF-Beta1 and alkaline phosphatase activity by the PDL and gingival fibroblasts.90 EMD had an ability to induce matrix synthesis in cultured human PDL cells.91 It also demonstrated an increased proliferation and colonizati on of periodontal fibroblasts.92 An increased association between IGF-1 PDL fibroblas ts was reported.93 Increased PDL cell growt h, attachment, and metabolism via an increased intracellular cAMP signaling cascade involving greater amounts of TGF beta-1, IL-6, and PDGF-AB have been described.34 Particularly important to the scope of this study, are the effects that EMD appears to have upon osseous regeneration. In vitro and animal studi es exist that present the role that EMD has in osteoblast differentiation and proliferation. EMD is involved in early osteoblast proliferation and it enhances differentiation as the cell line matures.52, 56, 58 EMD is described as possessing osteoinductive activity with BMP-li ke and TGF-beta-like qualities.56, 61 Galli et al and Ohyama et al showed increased osteoblast differentia tion marked by increased alkaline phosphatase, osteocalcin, and osteoprotegrin while Galli et al also showed enhanced osteoblast cell growth, and reduced osteoclast differentiation marked by decreased RANKL release.50, 60 It was determined that EMD promoted osseous fo rmation by modulating re gulatory biochemicals involved in bone metabolism and it increases leve ls of COX-2 and decreases levels of RANKL by 50%.53 Another study showed that EMD promoted osteoblast proliferati on and differentiation through increased expression of th e markers collagen alpha-1, oste ocalcin, bone sialoprotein, and insulin-like growth factor-1.51 It indirectly had an effect upon osteoclast proliferation and function through expression of the osteoc last decoy receptor, osteoprotegrin.51 Yoneda and

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48 others determined that EMD caused increased osteoblastic activity a nd osteoblast phenotypic expression via increased alkali ne phosphatase, osteopontin, ty pe I collagen, TGF beta-1, osteocalcin, and matrix me talloproteinase production.57 Hagewald and others showed an increased metabolic activity with increas ed alkaline phosphatase, increased calcium accumulation within osteoblasts, and increased mineral deposition in the presence of EMD.54 EMD may mediate the gene transcription of bo ne sialoprotein, finding a 2.8 times increase of this protein implicated in the nucleati on of hydroxyapatite during bone formation.55 Kim and others showed that higher concentrations of EMD in rats yielded an increased foreign body presence and eosinophilic round bod ies containing amelogenins.59 These were believed to have the ability to promote the turnover of mesenchymal ce lls into hard-tissue form ing cells at the site. The role that EMD may have upon osseous modeling and remodeling would be very advantageous to the events of the current study. An upregulation of the processes involved with osteogenesis would possibly lead to quicker form ation of bone, faster turnover of the existing graft material, and perhaps a dens er quality of bone. This may further reduce ridge dimensional loss following extraction and shorten the necessary maturation time until implant fixture placement. Our results do not show a statistical difference when applying EMD to the graft material. Our small population size may ha ve prevented any difference from becoming discernible. It has been reported that EMD may have an interaction with epith elium. Lyngstadaas showed inhibitory effects upon ep ithelium when EMD was present and Kawase demonstrated the possibility that EMD may act to inhibit or sl ow epithelial do wngrowth , thereby altering wound healing, by acting as a cytostatic agen t on cultured human epithelial cells.34, 94 This action of

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49 EMD upon epithelium would act favor ably in the current study, pot entially preven ting epithelial cells from incorporating into the grafted site. Several authors have reported an apparent inhibitory ro le of EMD upon oral microbes. EMD appears to affect bacterial growth.95, 96 Arweiler demonstrated a di rect influence in vivo of EMD on the supragingival plaque. The biofilm vitality was 22% lower.97 An opposing article by Inaba stated that P. gingivalis diminishes th e effects in vitro of EMD in cooperation with gingipains.98 An anti-bacterial effect provided by EMD would be of great benefit to the procedures performed within this study. Two of the grafted sites did become infected during the course of our study, but neither lo st the graft and the implants we re placed as scheduled with no untoward events. Studies exist that show a poten tial for EMD to affect blood -flow and angiogenesis to the wound site and possibly provide a faster mean s of vascularizing the newly grafted site.62, 63, 99 New blood vessel outgrowths as a result of increas ed endothelial cell chem otaxis were seen in mice treated with EMD.63 In a rabbit wound study with cult ured fibroblasts, EMD application increased VEGF levels 5 times greater than in controls and increased MMP-2 more than 3 times from fibroblasts and from endothelial cells.62 Schlueter and others also showed direct stimulation of endothelial cells a nd indirect stimulation of VEGF.99 Generally wound healing was accelerated by the increased release of these gr owth factors and proteinases thereby increasing granulation tissue formation and re modeling. Any potential for EMD to promote angiogenesis would have a direct impact upon the wound healing of the sites within the current study. The quicker the blood supply forms, the fast er the graft site can become nourished. This will allow the necessary conduit system for the full compliment of cells, growth factors, and

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50 nutrients required to remodel the grafted site. Th is may potentially lead to quicker graft turnover into vital osseous structure. There were numerous ways in which a patient could benefit as a result of this study. These included removal of a potentially hopeless/infected tooth, maintena nce of an adequate alveolar ridge, and creation of a suitable site for a future implant that would enab le a definitive fixed restoration. EMD would be a grea t addition to graft materials dur ing socket preservation due to its multifactorial involvement in wound healing a nd tissue regeneration. Roles in osteogenesis, angiogenesis, epithelial exclusi on, and inhibition of b acteria, make EMD a plausible adjunct to the ridge preservation procedure. In contrast, studies also show that EMD may not play much of a role in regeneration and osteogenesis.100-103 Boyan et al and Koike et al found EM D not to be osteoinductive and that it acted more osteoconductive.104, 105 Koike et al further stated that EMD may in fact play an inhibitory role upon hard tissue on the r oot surface.105 EMD may inhibit the maturation of osteoblasts as was noted by a decr ease in collagen synthesis, proteoglycan sulfation, and TGFbeta-1 production.58 In terms of the role that EM D may play upon bone, Okubo et al and Pischon et al found no results that would suppor t an effect upon osteobl ast proliferation or maturation.106, 107 Okubo and others did describe a s timulation of human PDL cells with an increase in IGF-1 and TGF beta 1.106 Pischon determined that EMD was able to stimulate collagen production but not the mineralization pr oducts of osteoblasts despite high levels of calcium intake and alkaline phosphatase activity.107 Our results would seem to compare more with the findings of these authors. No signi ficant differences were found between the grafted sockets in which the EMD was incorporated and in the sockets without the EM D. Clinically at 4

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51 months, it would appear that ad ding the EMD would have no increa sed benefit over simply using the allograft alone. A thorough literature search was performed fo r methods which compare to those in the current study, and to the knowledge of the authors, this is the first articl e that makes mention of mixing EMD with an allograft and using the combination in extraction sockets. Thus, a comparison of our results to other literature is difficult. Further studies are needed to assess the use of this modality in osseous grafting and particularly ridge preservation. Limitations Several limitations occurred during the course of this study. Most deal with the sample size of the study itself. We lost 10 patients fr om the original 24, many of which had multiple sites. Another consideration is the fact that it was difficult to match extraction sites within the mouth and particularly between patients. Matc hing sockets by size, defect, and thinness of bony plates in advance is near impossible for this type of study. A greater number of the test group was made up of mandibular teeth, mainly molar a nd premolars. The control group consisted of a greater proportion of anterior sites and molar sites, mainly in the maxilla. Looking at the literature provided earlier, we would expect to find a greater amount of loss in the mandibular and in the molar areas, potentially stacking the results against the test group. Also, even though healthy subjects were studied, ther e will always be some variabil ity in healing. Every attempt was made to standardize probing, but it was much easier to over-probe when measuring to soft tissue (closed) levels when compared to the hard tissue (open) levels. An attempt was made to standardize the amount of closure that was attained following the initial surgery, but occasionally sites were closed primarily, potentially shortening the vestibule and thus altering the true ridge width dimensions. Two sites did develop infect ions and even though adequate ridge dimension was present for implant placement, the sites ma y have been altered. Opening flaps at the

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52 extraction sites with vertical rel eases could be another potential cause for additional bone loss. The fact that 2 different suture types were used could also play a small role. A larger sample size could possibly reduce the weight of some of these individual problems. Conclusion The current study added more support for the us e of a ridge preservation procedure. It failed to show any enhancement to the healing po tential and bone quantity at the extraction site with the addition of EMD versus simply usi ng the allograft/membrane combination alone. Within the limitations of this study with its sma ll sample size, a clinical difference in prevention of loss of ridge dimension could not be ascertained when compar ed to the control group. An even more critical look at a histological level will be reported in another study.

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53 APPENDIX A STATISTICAL TESTS: RAW DATA Test v. Control (by patient), Open Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Passed (P = 0.797) Group N Missing Median 25% 75% Col 1 7 0 1.800 1.050 1.950 Col 2 7 0 1.200 0.400 1.750 T = 60.000 n(small)= 7 n(big)= 7 P(est.)= 0.371 P(exact)= 0.383 The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.383) Test v. Control (by patient), Closed Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Passed (P = 0.602) Group N Missing Median 25% 75% Col 1 7 0 1.000 0.300 1.650 Col 2 7 0 0.600 0.0500 1.350 T = 57.500 n(small)= 7 n(big)= 7 P(est.)= 0.565 P(exact)= 0.535 The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.535)

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54 Buccal side v. Lingual side, Test (by patient), Open Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Passed (P = 0.857) Group N Missing Median 25% 75% Col 1 7 0 2.000 2.000 5.250 Col 2 7 0 2.000 0.250 4.250 T = 62.000 n(small)= 7 n(big)= 7 P(est.)= 0.249 P(exact)= 0.259 The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.259) Buccal side v. Lingual side, Te st (by patient), Closed Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Passed (P = 0.721) Group N Missing Median 25% 75% Col 1 7 0 0.000 0.000 1.750 Col 2 7 0 1.000 0.250 1.000 T = 47.000 n(small)= 7 n(big)= 7 P(est.)= 0.522 P(exact)= 0.535 The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.535)

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55 Buccal side v. Lingual side, C ontrol (by patient), Open Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Passed (P = 0.515) Group N Missing Median 25% 75% Col 1 7 0 2.000 0.250 4.750 Col 2 7 0 0.000 -0.750 1.750 T = 64.500 n(small)= 7 n(big)= 7 P(est.)= 0.141 P(exact)= 0.128 The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.128) Buccal side v. Lingual side, C ontrol (by patient), Closed Mann-Whitney Rank Sum Test Normality Test: Failed (P = 0.034) Group N Missing Median 25% 75% Col 1 7 0 3.000 0.500 3.875 Col 2 7 0 1.000 -1.250 1.750 T = 65.000 n(small)= 7 n(big)= 7 P(est.)= 0.125 P(exact)= 0.128 The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.128)

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56 Mid (B5 and L5) level v. Apical (B10 and L10), Control (by patient), Open Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Passed (P = 0.551) Group N Missing Median 25% 75% Col 1 7 0 3.000 1.250 4.000 Col 2 7 0 2.000 -1.250 3.125 T = 61.500 n(small)= 7 n(big)= 7 P(est.)= 0.277 P(exact)= 0.259 The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.259) Mid (B5 and L5) level v. Apical (B10 and L10), Control (by patient), Closed Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Passed (P = 0.549) Group N Missing Median 25% 75% Col 1 7 0 2.000 1.250 3.500 Col 2 7 0 1.000 0.250 1.750 T = 65.000 n(small)= 7 n(big)= 7 P(est.)= 0.124 P(exact)= 0.128 The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.128)

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57 Mid (B5 and L5) level v. Apical (B10 and L10), Test (by patient), Open Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Failed (P = 0.015) Group N Missing Median 25% 75% Col 1 7 0 3.000 2.000 3.750 Col 2 7 0 2.000 0.000 4.750 T = 56.500 n(small)= 7 n(big)= 7 P(est.)= 0.654 P(exact)= 0.620 The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.620) Mid (B5 and L5) level v. Apical (B10 and L10), Test (by patient), Closed Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Passed (P = 0.675) Group N Missing Median 25% 75% Col 1 7 0 3.000 1.000 3.750 Col 2 7 0 2.000 0.000 4.250 T = 55.000 n(small)= 7 n(big)= 7 P(est.)= 0.798 P(exact)= 0.805 The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.805)

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58 Mid (B5 and L5) level v. Apical (B10 and L10), All (by patient), Open Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Passed (P = 0.178) Group N Missing Median 25% 75% Col 1 14 0 3.000 2.000 4.000 Col 2 14 0 2.000 0.000 4.000 T = 228.500 n(small)= 14 n(big)= 14 (P = 0.250) The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.250) Mid (B5 and L5) level v. Apical (B10 and L10), All (by patient), Closed Mann-Whitney Rank Sum Test Normality Test: Failed (P = 0.019) Group N Missing Median 25% 75% Col 1 14 0 2.000 1.000 4.000 Col 2 14 0 1.000 0.000 2.000 T = 231.000 n(small)= 14 n(big)= 14 (P = 0.206) The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.206)

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59 Buccal side v. Lingual side, All (by patient), Open Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Passed (P = 0.852) Group N Missing Median 25% 75% Col 1 14 0 2.500 2.000 5.000 Col 2 14 0 1.500 0.000 2.000 T = 246.500 n(small)= 14 n(big)= 14 (P = 0.048) The difference in the median values between the two groups is greater than would be expected by chance; there is a statistically significant difference (P = 0.048) Buccal side v. Lingual side, All (by patient), Closed Mann-Whitney Rank Sum Test Normality Test: Passed (P > 0.050) Equal Variance Test: Passed (P = 0.807) Group N Missing Median 25% 75% Col 1 14 0 2.500 0.000 4.000 Col 2 14 0 1.000 1.000 3.000 T = 227.500 n(small)= 14 n(big)= 14 (P = 0.270) The difference in the median values between th e two groups is not grea t enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P = 0.270)

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60 APPENDIX B RAW DATA: STENT MEASUREMENTS Table B-1 EMD/Allograft/Membrane (Test) Patient #1 Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 59 II 30 Buccal 10 4 8 4 4 8 4 Buccal 5 5 7 2 4 5 1 0 4 7 3 4 5 1 Lingual 5 6 6 0 2 4 2 Lingual 10 3 3 0 2 3 1 Patient #2 Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 64 I 21 Buccal 10 4 4 0 3 3 0 Buccal 5 4 6 2 3 4 1 0 4 6 2 3 5 2 Lingual 5 4 4 0 3 3 0 Lingual 10 4 2 -2 2 2 0 Patient #3 Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 55 I 26 Buccal 10 2 4 2 2 3 1 Buccal 5 5 6 1 4 5 1 0 5 6 1 5 5 0 Lingual 5 4 6 2 3 5 2 Lingual 10 4 4 0 2 3 1

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61 Table B-1 Continued Patient #4 Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 49 30 Buccal 10 3 4 1 2 3 1 Buccal 5 3 5 2 2 3 1 0 3 6 3 3 4 1 Lingual 5 5 5 0 4 4 0 Lingual 10 4 4 0 3 3 0 Patient #5 Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 75 I 29 Buccal 10 2 2 0 1 1 0 Buccal 5 3 5 2 1 4 3 0 1 6 5 1 3 2 Lingual 5 1 3 2 1 2 1 Lingual 10 2 2 0 1 1 0 Patient #6 Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 77 I 4 Buccal 10 3 7 4 2 7 5 Buccal 5 6 8 2 5 7 2 0 5 9 4 5 8 3 Lingual 5 5 8 3 3 8 5 Lingual 10 3 6 3 1 6 5

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62 Table B-1 Continued Patient #7 Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 62 I 3 Buccal 10 4 5 1 3 3 0 Buccal 5 7 8 1 6 5 -1 0 6 9 3 6 6 0 Lingual 5 8 9 1 7 6 -1 Lingual 10 5 9 4 3 5 2 Patient #8 Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 49 I 12 Buccal 10 2 3 1 1 1 0 Buccal 5 3 4 1 1 1 0 0 3 5 2 3 3 0 Lingual 5 3 5 2 1 2 1 Lingual 10 4 3 -1 1 1 0

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63 Table B-2 Allograft/Me mbrane Only (control). Patient #1C Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 65 II 19 Bucca1 10 6 5 -1 5 6 1 Buccal 5 7 7 0 6 9 3 0 7 6 -1 6 8 2 Lingual 5 7 6 -1 7 8 1 Lingual 10 6 5 -1 5 5 0 Patient 2.1C Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 74 I 10 Buccal 10 1 3 2 1 2 1 Buccal 5 3 4 1 3 3 0 0 4 6 2 3 5 2 Lingual 5 6 5 -1 1 3 2 Lingual 10 6 3 -3 1 1 0 Patient 2.2C Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 74 II 11 Buccal 10 1 6 5 1 3 2 Buccal 5 3 10 7 1 5 4 0 4 12 8 3 6 3 Lingual 5 4 9 5 1 4 3 Lingual 10 3 6 3 1 2 1

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64 Table B-2 Continued Patient #3C Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 59 I 3 Buccal 10 4 4 0 3 3 0 Buccal 5 4 6 2 3 3 0 0 3 5 2 3 2 -1 Lingual 5 4 6 2 3 5 2 Lingual 10 3 5 2 3 3 0 Patient #4C Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 52 I 4 Buccal 10 3 3 0 3 3 0 Buccal 5 6 7 1 5 5 0 0 5 7 2 5 4 -1 Lingual 5 6 6 0 4 4 0 Lingual 10 5 3 -2 4 2 -2 Patient #5C Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 77 I 6 Buccal 10 2 4 2 2 3 1 Buccal 5 3 6 3 2 5 3 0 7 6 -1 7 5 -2 Lingual 5 7 6 -1 6 4 -2 Lingual 10 2 4 2 2 2 0

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65 Table B-2 Continued Patient #6C Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 55 I 23 Buccal 10 2 3 1 2 3 1 Buccal 5 5 7 2 4 6 2 0 6 6 0 6 5 -1 Lingual 5 4 6 2 3 5 2 Lingual 10 4 5 1 3 5 2 Patient #7C Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 49 I 31 Buccal 10 4 6 2 3 5 2 Buccal 5 4 6 2 3 4 1 0 3 6 3 3 5 2 Lingual 5 4 6 2 3 4 1 Lingual 10 3 3 0 3 3 0 Patient #8C Open Closed Age Type of Socket Tooth # Baseline 4 month Difference Baseline 4 month Difference 75 I 3 Buccal 10 2 4 2 2 3 1 Buccal 5 3 5 2 2 3 1 0 3 5 2 3 3 0 Lingual 5 4 5 1 2 3 1 Lingual 10 4 3 -1 2 2 0

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66 LIST OF REFERENCES 1. Amler MH. The time sequence of tissue rege neration in human extraction wounds. Oral Surg Oral Med Oral Pathol 1969;27:309-18. 2. Araujo M, Lindhe J. Dimensional ridge alterations following tooth extraction. An experimental study in the dog. J Clin Periodontol 2005;32:212-8. 3. Covani U, Bortolaia C, Barone A, Sbordone L. Bucco-lingual cresta l bone changes after immediate and delayed implant plac ement. J Periodontol 2004;75:1605-12. 4. Devlin H, Ferguson MW. Alveolar ridge re sorption and mandibular atrophy. A review of the role of local and systemic factors. Br Dent J 1991;170:101-4. 5. Guarnieri R, Pecora G, Fini M, Aldini NN, Giardino R, Orsini G, et al. Medical grade calcium sulfate hemihydrate in healing of human extraction sockets: clinical and histological observati ons at 3 months. J Periodontol 2004;75:902-8. 6. Horowitz RA. Extraction environment enhan cement: critical evaluation of early socket healing in long-term barrier-p rotected extraction sockets. Compend Contin Educ Dent 2005;26:703-13. 7. Iasella JM, Greenwell H, Miller RL, Hill M, Drisko C, Bohra AA, et al. Ridge preservation with freeze-dried bone allograf t and a collagen membrane compared to extraction alone for implant site development: a clinical and histologic study in humans. J Periodontol 2003;74:990-9. 8. Lekovic V, Kenney EB, Weinlaender M, Han T, Klokkevold P, Nedic M, et al. A bone regenerative approach to alve olar ridge maintenance following tooth extraction. Report of 10 cases. J Periodontol 1997;68:563-70. 9. Nevins M, Camelo M, De Paoli S, Friedla nd B, Schenk RK, Parma-Benfenati S, et al. A study of the fate of the buccal wall of extracti on sockets of teeth with prominent roots. Int J Periodontics Restorative Dent 2006;26:19-29. 10. Pietrokovski J, Massler M. Alveolar ri dge resorption followi ng tooth extraction. J Prosthet Dent 1967;17:21-7. 11. Grunder U, Polizzi G, Goene R, Hatano N, Henry P, Jackson WJ, et al. A 3-year prospective multicenter follow-up report on the immediate and delayed-immediate placement of implants. Int J Oral Maxillofac Implants 1999;14:210-6. 12. Werbitt MJ, Goldberg PV. Immediate im plantation. Preservation of bone volume and osseous regeneration. J Parodontol 1991;10:157-66. 13. Sevor JJ, Meffert R. Placement of implants in to fresh extraction sites using a resorbable collagen membrane: case reports. Pract Periodontics Aesthe t Dent 1992;4:35-41.

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69 39. Donos N, Glavind L, Karring T, Sculean A. Clinical evaluation of an enamel matrix derivative in the treatment of mandibular degree II fur cation involvement: a 36-month case series. Int J Periodontics Restorative Dent 2003;23:507-12. 40. Donos N, Glavind L, Karring T, Sculean A. Clinical evaluation of an enamel matrix derivative and a bioresorbable membrane in the treatment of degree III mandibular furcation involvement: a series of nine patients. Int J Pe riodontics Restorative Dent 2004;24:362-9. 41. Froum SJ, Weinberg MA, Rosenberg E, Tar now D. A comparative study utilizing open flap debridement with and without enamel matrix derivative in the treatment of periodontal intrabony defects: a 12-month re-entry study. J Periodontol 2001;72:25-34. 42. Harrel SK, Wilson TG, Nunn ME. Prospective assessment of the use of enamel matrix proteins with minimally invasive surgery. J Periodontol 2005;76:380-4. 43. Heden G, Wennstrom JL. Five-year follow-up of regenerative peri odontal therapy with enamel matrix derivative at sites with angular bone de fects. J Periodontol 2006;77:295301. 44. Trombelli L, Annunziata M, Belardo S, Farina R, Scabbia A, Guida L. Autogenous bone graft in conjunction with enamel matrix deri vative in the treatmen t of deep periodontal intra-osseous defects: a repor t of 13 consecutively treated patients. J Clin Periodontol 2006;33:69-75. 45. Sipos PM, Loos BG, Abbas F, Timmerman MF , van der Velden U. The combined use of enamel matrix proteins and a tetracyclin e-coated expanded poly tetrafluoroethylene barrier membrane in the treatment of in tra-osseous defects. J Clin Periodontol 2005;32:765-72. 46. Tsitoura E, Tucker R, Suvan J, Laurell L, Co rtellini P, Tonetti M. Baseline radiographic defect angle of the intrabony defect as a prognostic indicato r in regenerative periodontal surgery with enamel matrix deriva tive. J Clin Periodontol 2004;31:643-7. 47. Mellonig JT. Enamel matrix derivative for periodontal reconstructive surgery: technique and clinical and histologic case report. Int J Periodontic s Restorative Dent 1999;19:8-19. 48. Sculean A, Chiantella GC, Windisch P, Donos N. Clinical and hist ologic evaluation of human intrabony defects treated with an enam el matrix protein derivative (Emdogain). Int J Periodontics Restorative Dent 2000;20:374-81. 49. Sculean A, Windisch P, Chiantella GC. Hu man histologic evalua tion of an intrabony defect treated with enamel matrix deriva tive, xenograft, and GTR. Int J Periodontics Restorative Dent 2004;24:326-33.

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70 50. Galli C, Macaluso GM, Guizzardi S, Vescovini R, Passeri M, Passeri G. Osteoprotegerin and receptor activator of nuclear factor-k appa B ligand modulation by enamel matrix derivative in human alveolar os teoblasts. J Periodontol 2006;77:1223-8. 51. He J, Jiang J, Safavi KE, Spangberg LS, Zhu Q. Emdogain promotes osteoblast proliferation and differentiation and stimulat es osteoprotegerin e xpression. Oral Surg Oral Med Oral Pathol Or al Radiol Endod 2004;97:239-45. 52. Schwartz Z, Carnes DL, Jr., Pulliam R, Lo hmann CH, Sylvia VL, Li u Y, et al. Porcine fetal enamel matrix derivative stimulates proliferation but not differentiation of preosteoblastic 2T9 cells, inhibits proliferation and stimulates differentiation of osteoblastlike MG63 cells, and increases proliferat ion and differentiation of normal human osteoblast NHOst cells. J Periodontol 2000;71:1287-96. 53. Takayanagi K, Osawa G, Nakaya H, Co chran DL, Kamoi K, Oates TW. Effects of enamel matrix derivative on bone-relate d mRNA expression in human periodontal ligament cells in vitro. J Periodontol 2006;77:891-8. 54. Hagewald S, Pischon N, Jawor P, Bernimoulin JP, Zimmermann B. Effects of enamel matrix derivative on proliferation and differe ntiation of primary osteoblasts. Oral Surg Oral Med Oral Pathol Or al Radiol Endod 2004;98:243-9. 55. Shimizu E, Nakajima Y, Kato N, Nakayama Y, Saito R, Samoto H, et al. Regulation of rat bone sialoprotein gene tr anscription by enamel matrix derivative. J Periodontol 2004;75:260-7. 56. Takayama T, Suzuki N, Narukawa M, Tokuna ga T, Otsuka K, Ito K. Enamel matrix derivative stimulates core binding factor alpha1/Runt-related tran scription factor-2 expression via activation of Smad1 in C2C12 cells. J Periodontol 2005;76:244-9. 57. Yoneda S, Itoh D, Kuroda S, Kondo H, Umezawa A, Ohya K, et al. The effects of enamel matrix derivative (EMD) on osteoblastic cells in culture and bone re generation in a rat skull defect. J Periodontal Res 2003;38:333-42. 58. Dean DD, Lohmann CH, Sylvia VL, Cochran DL, Liu Y, Boyan BD, et al. Effect of porcine fetal enamel matrix derivative on chondrocyte proliferati on, differentiation, and local factor production is de pendent on cell maturation stat e. Cells Tissues Organs 2002;171:117-27. 59. Kim NH, Tominaga K, Tanaka A. Analys is of eosinophilic round bodies formed after injection of enamel matrix derivative in to the backs of rats . J Periodontol 2005;76:193441. 60. Ohyama M, Suzuki N, Yamaguchi Y, Maeno M, Otsuka K, Ito K. Effect of enamel matrix derivative on the differentiation of C2C12 cells. J Peri odontol 2002;73:543-50.

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71 61. Suzuki S, Nagano T, Yamakoshi Y, Gomi K, Arai T, Fukae M, et al. Enamel matrix derivative gel stimulates signal transduction of BMP and TGF-{beta}. J Dent Res 2005;84:510-4. 62. Mirastschijski U, Konrad D, Lundberg E, Lyngstadaas SP, Jorgensen LN, Agren MS. Effects of a topical enamel matrix de rivative on skin wound healing. Wound Repair Regen 2004;12:100-8. 63. Yuan K, Chen CL, Lin MT. Enamel matrix de rivative exhibits angioge nic effect in vitro and in a murine model. J Clin Periodontol 2003;30:732-8. 64. Becktor JP, Isaksson S, Sennerby L. Survival analysis of endosseous implants in grafted and nongrafted edentulous maxillae. Int J Oral Maxillofac Implants 2004;19:107-15. 65. Minichetti JC, D'Amore JC, Hong AY. Thr ee-year analysis of Tapered Screw-Vent implants placed into extraction sockets graf ted with mineralized bone allograft. J Oral Implantol 2005;31:283-93. 66. Tischler M, Misch CE. Extraction site bone grafting in general dentistry. Review of applications and principl es. Dent Today 2004;23:108-13. 67. Gottlow J, Nyman S, Karring T, Lindhe J. New attachment formation as the result of controlled tissue regeneration. J Clin Periodontol 1984;11:494-503. 68. Blumenthal NM. The use of collagen me mbranes to guide regeneration of new connective tissue attachment in dogs. J Periodontol 1988;59:830-6. 69. Paul BF, Mellonig JT, Towle HJ, 3rd, Gray JL. Use of a collagen barrier to enhance healing in human periodontal furcation defects. Int J Periodontics Restorative Dent 1992;12:123-31. 70. Pitaru S, Tal H, Soldinger M, Grosskopf A, Noff M. Partial rege neration of periodontal tissues using collagen barriers. Initial obs ervations in the canine. J Periodontol 1988;59:380-6. 71. Tanner MG, Solt CW, Vuddhakanok S. An evaluation of new attachment formation using a microfibrillar collagen barri er. J Periodontol 1988;59:524-30. 72. Wang HL, O'Neal RB, Thomas CL, Shyr Y, MacNeil RL. Evaluation of an absorbable collagen membrane in treating Class II fu rcation defects. J Periodontol 1994;65:1029-36. 73. Wang HL, Kiyonobu K, Neiva RF. Socket au gmentation: rationale and technique. Implant Dent 2004;13:286-96.

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72 74. Salama H, Salama M. The role of orthodont ic extrusive remodeling in the enhancement of soft and hard tissue profiles prior to im plant placement: a systematic approach to the management of extraction site defects. In t J Periodontics Restor ative Dent 1993;13:31233. 75. Mecall RA, Rosenfeld AL. Influence of re sidual ridge resorption patterns on implant fixture placement and tooth position. 1. In t J Periodontics Restorative Dent 1991;11:8-23. 76. Bianchi AE, Sanfilippo F. Single-tooth replacement by immediate implant and connective tissue graft: a 1-9-year clini cal evaluation. Clin Oral Implants Res 2004;15:269-77. 77. Gotfredsen K. A 5-year prospective study of single-tooth replacements supported by the Astra Tech implant: a pilot study. Clin Implant Dent Relat Res 2004;6:1-8. 78. Rosenquist B, Grenthe B. Immediate placemen t of implants into extraction sockets: implant survival. Int J Oral Maxillofac Implants 1996;11:205-9. 79. Wagenberg B, Froum SJ. A retrospective study of 1925 consecutively placed immediate implants from 1988 to 2004. Int J Oral Maxillofac Implants 2006;21:71-80. 80. Irinakis T. Rationale for socket preservati on after extraction of a single-rooted tooth when planning for future implant placement. J Can Dent Assoc 2006;72:917-22. 81. Schropp L, Wenzel A, Kostopoulos L, Karring T. Bone healing and soft tissue contour changes following single-tooth extraction: a clinical and ra diographic 12-month prospective study. Int J Periodontic s Restorative Dent 2003;23:313-23. 82. Dori F, Arweiler N, Gera I, Sculean A. Clin ical evaluation of an enamel matrix protein derivative combined with either a natural bone mineral or beta-tricalcium phosphate. J Periodontol 2005;76:2236-43. 83. Gurinsky BS, Mills MP, Mellonig JT. Clinic al evaluation of demineralized freeze-dried bone allograft and enamel matrix derivative ve rsus enamel matrix derivative alone for the treatment of periodontal o sseous defects in humans. J Periodontol 2004;75:1309-18. 84. Sculean A, Pietruska M, Schwarz F, Willershausen B, Arweiler NB, Auschill TM. Healing of human intrabony defects following regenerative periodonta l therapy with an enamel matrix protein derivativ e alone or combined with a bioactive glass. A controlled clinical study. J Clin Periodontol 2005;32:111-7. 85. Regazzini PF, Novaes AB, Jr., de Oliveira PT , Palioto DB, Taba M, Jr., de Souza SL, et al. Comparative study of enamel matrix deriva tive with or without GTR in the treatment of class II furcation lesions in dogs. Int J Periodontics Restorative Dent 2004;24:476-87.

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73 86. Hovey LR, Jones AA, McGuire M, Mellonig JT, Schoolfield J, Cochran DL. Application of periodontal tissue engineering using enamel matrix derivative and a human fibroblastderived dermal substitute to stimulate pe riodontal wound healing in Class III furcation defects. J Periodontol 2006;77:790-9. 87. Cornelini R, Scarano A, Piattelli M, Andreana S, Covani U, Quaranta A, et al. Effect of enamel matrix derivative (Emdogain) on bone de fects in rabbit tibia s. J Oral Implantol 2004;30:69-73. 88. Gestrelius S, Andersson C, Johansson AC , Persson E, Brodin A, Rydhag L, et al. Formulation of enamel matrix derivative for surface coating. Kinetics and cell colonization. J Clin Periodontol 1997;24:678-84. 89. Yukna RA, Mellonig JT. Histologic eval uation of periodontal healing in humans following regenerative therapy with enamel matrix derivative. A 10-case series. J Periodontol 2000;71:752-9. 90. Van der Pauw MT. Enamel Matrix-Derived Pr otein Stimulates Attachment of Periodontal Ligament Fibroblasts and Enhances Alkalin e Phosphatase Activity and Transforming Growth Factor 1 Release of Periodontal Ligament and Gingival Fibroblasts. J Periodontol 2000;71:31-43. 91. Haase HR, Bartold PM. Enamel matrix deri vative induces matrix synthesis by cultured human periodontal fibroblast cells. J Periodontol 2001;72:341-8. 92. Cattaneo V, Rota C, Silvestri M, Piacentini C, Forlino A, Gallanti A, et al. Effect of enamel matrix derivative on human peri odontal fibroblasts: pr oliferation, morphology and root surface colonization. An in vitro study. J Periodontal Res 2003;38:568-74. 93. Palioto DB, Coletta RD, Graner E, Joly JC, de Lima AF. The influence of enamel matrix derivative associated with insulin-like growth fact or-I on periodontal ligament fibroblasts. J Peri odontol 2004;75:498-504. 94. Kawase T, Okuda K, Yoshie H, Burns DM. Cy tostatic action of enamel matrix derivative (EMDOGAIN) on human oral squamous cell ca rcinoma-derived SCC25 epithelial cells. J Periodontal Res 2000;35:291-300. 95. Spahr A, Lyngstadaas SP, Boeckh C, Anderss on C, Podbielski A, Halle r B. Effect of the enamel matrix derivative Emdogain on the gr owth of periodontal pathogens in vitro. J Clin Periodontol 2002;29:62-72. 96. Sculean A, Auschill TM, Donos N, Brecx M, Arweiler NB. Effect of an enamel matrix protein derivative (Emdogain) on ex vivo de ntal plaque vitalit y. J Clin Periodontol 2001;28:1074-8.

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74 97. Arweiler NB, Auschill TM, Donos N, Sculean A. Antibacterial effect of an enamel matrix protein derivative on in vivo dental biofilm vitality. Clin Oral Investig 2002;6:205-9. 98. Inaba H, Kawai S, Nakayama K, Okahashi N, Amano A. Effect of enamel matrix derivative on periodontal lig ament cells in vitro is diminished by Porphyromonas gingivalis. J Peri odontol 2004;75:858-65. 99. Schlueter SR, Carnes DL, Cochran DL. In v itro effects of enamel matrix derivative on microvascular cells. J Periodontol 2007;78:141-51. 100. Chano L, Tenenbaum HC, Lekic PC, Sodek J, McCulloch CA. Emdogain regulation of cellular differentiation in wounded rat pe riodontium. J Periodontal Res 2003;38:164-74. 101. Donos N, Bosshardt D, Lang N, Graziani F, To netti M, Karring T, et al. Bone formation by enamel matrix proteins and xenografts: an experimental study in the rat ramus. Clin Oral Implants Res 2005;16:140-6. 102. Donos N, Kostopoulos L, Tonetti M, Karring T, Lang NP. The effect of enamel matrix proteins and deproteinized bovi ne bone mineral on heterotopi c bone formation. Clin Oral Implants Res 2006;17:434-8. 103. Gurpinar A, Onur MA, Cehreli ZC, Tasman F. Effect of enamel matrix derivative on mouse fibroblasts and marrow stromal os teoblasts. J Biomater Appl 2003;18:25-33. 104. Boyan BD, Weesner TC, Lohmann CH, Andr eacchio D, Carnes DL, Dean DD, et al. Porcine fetal enamel matrix derivativ e enhances bone formation induced by demineralized freeze dried bone allograft in vivo. J Periodontol 2000;71:1278-86. 105. Koike Y, Murakami S, Matsuzaka K, Inoue T. The effect of Emdogain on ectopic bone formation in tubes of rat demineralized de ntin matrix. J Periodontal Res 2005;40:385-94. 106. Okubo K, Kobayashi M, Takiguchi T, Taka da T, Ohazama A, Okamatsu Y, et al. Participation of endogenous IGF-I and TGF-be ta 1 with enamel matrix derivativestimulated cell growth in human periodont al ligament cells. J Periodontal Res 2003;38:19. 107. Pischon N, Zimmermann B, Bernimoulin JP, Ha gewald S. Effects of an enamel matrix derivative on human osteoblasts and PDL cells grown in organoid cultures. Oral Surg Oral Med Oral Pathol Or al Radiol Endod 2006;102:551-7.

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75 BIOGRAPHICAL SKETCH Eric F. Schoenebeck grew up in Reading, PA and attended the Pennsylvania State University where he studied biol ogy. He graduated from the University of Pennsylvania, School of Dental Medicine, in May 2000. He entered service in the United States Navy, performing an Advanced Education in General De ntistry residency at the Naval Ai r Station in Jacksonville, FL. He has performed as a general dentist at the NAT O Air Station in Keflavik, Iceland and at the U.S. Marine base in Camp Lejeune, N.C. At this time Eric Schoenebeck is completing his postgraduate residency in periodontics at the Univers ity of Florida, College of Dentistry. He is awaiting the next duty station for hi s family to San Diego, CA.