Enamel matrix derivative 2011 3 15 KHU R

Enamel matrix derivative 2011년 3월 15 일 KHU 희 치주과 R 1 문 복 PERIO

Contents 1. Introduction 2. Treatment Rationale of EMD 3. Enamel matrix derivative (EMD) 4. Cellular effects of EMD 5. EmdogainⓇ 6. Clinical effects of EMD 7. Conclusions KHU PERIO

Introduction 1, 3, 7 The ideal treatment would be to recover the periodontal tissues that have been lost periodontal tissue regeneration. Following this concept, periodontal regeneration is defined as the reproduction or reconstruction of lost or injured tissue so that the form and function of the lost structures are restored. KHU PERIO

Regenerative surgery 3, 7 Several surgical techniques have been developed in an attempt to regenerate periodontal tissues including guided tissue Both GTR and grafting are based onof the concept regeneration (GTR), boneprocedures grafting (BG) and the use enamel of selective exclusion of epithelial cells from colonizing the matrix derivative(EMD). wound space maintaining for thetechniques blood clotand to Clearly, and current available regenerative regenerate the periodontal tissues. are crude and have poor regeneration-promoting biomaterials clinical predictability. 4 Prevent epithelial down-growth and fibroblast trans-growth Guided tissue regeneration KHU Osteoinductive, osteoconductiv e properties Structural framework Grafting techniques PERIO

Regenerative surgery 3, 7 Periodontal regeneration mediated by EMD is based on a different concept. It is believed that EMD used in periodontal lesions mimics the development of the tooth supporting apparatus during tooth formation. KHU PERIO

Contents 1. Introduction 2. Treatment Rationale of EMD 3. Enamel matrix derivative (EMD) 4. Cellular effects of EMD 5. EmdogainⓇ 6. Clinical effects of EMD 7. Conclusions KHU PERIO

Treatment Rationale of EMD 6, 8 • The initiation of acellular cementum is regulated by the inner enamel epithelium of Herwig's epithelial root sheath(HERS). • The proteins found in acellular cementum have been shown to resemble enamel matrix proteins. • Based on the presence of enamel matrix proteins in acellular cementum, it was thought that these proteins may play a role in the regeneration of periodontal tissues destroyed by periodontal disease. 4 KHU PERIO

Contents 1. Introduction 2. Treatment Rationale of EMD 3. Enamel matrix derivative (EMD) 4. Cellular effects of EMD 5. EmdogainⓇ 6. Clinical effects of EMD 7. Conclusions KHU PERIO

Enamel matrix derivative(EMD)8 -12, 20 10% 90% EMD Amelogenin 90% Amelogenin Proline-rich non-amelgenin Tuftelin Tuft protein Enamelin Serum protein Rapidly degraded • The concentration of amelogenin has been shown to rise sharply during acellular cementum development. • Leucine-rich amelogenin peptides have been shown to have a direct effect on component of, amelogenin may cementoblast activity. As the major contribute significantly to the biologic effects of EMD. KHU PERIO

Mechanism of EMD 23 The mechanism by which EMD promotes PDL regeneration is still largely unknown. (1) Migration & Attachment 2 (2) Proliferation & Growth (3) Differnciation 4 (4) Alveolar bone Alveolar formation KHU PERIO

Contents 1. Introduction 2. Treatment Rationale of EMD 3. Enamel matrix derivative (EMD) 4. Cellular effects of EMD 5. EmdogainⓇ 6. Clinical effects of EMD 7. Conclusions KHU PERIO

Cellular effects of EMD 4, 23 1. Cell attachment, spreading, and chemotaxis • EMD caused an increase in cell attachment of gingival fibroblasts and PDL fibroblasts. • EMD also has a chemotactic effect on endothelial cells. Cell attachment onto EMD is selective for PDL cells in particular and mesenchymal cells in general. 4 KHU PERIO

Cellular effects of EMD 4, 23 2. cell proliferation and survival • EMDs favore cell proliferation of PDL fibroblasts over gingival fibroblasts and over epithelial cells. . PDL fibroblast > gingival fibroblast >> epithelial cell • EMDs stimulate the overgrowth of new blood vessels and increase the number of endothelial cells. Increase of DNA synthesis -> Increase of growth rate -> Up-regulation of cell proliferation KHU PERIO

Cellular effects of EMD 4, 23 3. Expression of transcription factors • EMPs increase the expression of transcription factors : Osx, Cbfa 1 / Runx 2, Sox 9, Zfp 60, AJ 18 related to osteoblast/cementoblast differentiation. 4. Increased intracellular level of c. AMP • The attachment of PDL cells to EMD seems to generate associated with increased cell proliferation, general metabolism and secretion of various autocrine growth factors. 4 KHU secretion PERIO

Cellular effects of EMD 4 5. Expression of growth factors, cytokines, extracellular matrix constituents, and other macromolecules. • The up-regulated molecules are TGF-β 1, BMP-2, BMP-7, PDFG-AB, VEGF, CTGF, FGF-2, IGF-1, TNF-α, IL-6, IL-8, PGE 2, OPN, collagen type Ⅱ and X, MMP-2 and ALP. • EMDs cause a stimulation of total protein synthesis and synthesis of specific extracellular matrix molecules (glycoproteins, proteoglycans) • RANKL / RANK / OPG regulatory axis Bone remododeling EMDs directly up-regulate OPG and down-regulate RANKL production. Thus, EMDs appear to be indirectly involved in the regulation of bone remodelling. KHU PERIO

Cellular effects of EMD 4, 23 PDL cell attachment Intracellular levels of c. AMP Expression of growth factors, cytokines, , EM D PDL cell proliferation Expression of transcription factors KHU Osteoblast/Cementoblast differenciation PERIO

Histologic evidence of EMD 5 Alevolar bone Acellular cementum Periodontal ligament Histologically, EMD applied to root surfaces in monkeys has been shown to produce regeneration through the formation of bone, periodontal ligament, and acellular cementum. KHU PERIO

Contents 1. Introduction 2. Treatment Rationale of EMD 2 3. Enamel matrix derivative (EMD) 4. Cellular effects of EMD 5. EmdogainⓇ 6. Clinical effects of EMD 7. Conclusions KHU PERIO

EmdogainⓇ3, 8 • Freeze-dried enamel matrix protein extract or gel derived from developing tooth buds of 6 -month-old piglets • The only commercially available product using EMD produced by B (Malmo, Sweden) • Originally, vehicle solution (propylene glycol alginate) that had to be mixed before use. • In order to save time and simplify the procedures a ready-to-use Emdogain gel (0. 3 cc/0. 7 cc) was developed. KHU PERIO

EmdogainⓇ protocol 5 Sulcular incision Mechanical debrdement Pappilar preservation flap design 4 KHU PERIO

EmdogainⓇ protocol 5, 18 Application of Pref. Gel The manufacturer of EMD produces root conditioner called Pref. Gel composed of 24% EDTA at neutral p. H. Traditionally root conditioners were used to chemically modify the root surface in order to stimulate periodontal regeneration. There is no evidence that this procedure is effective! KHU PERIO

EmdogainⓇ protocol 5 Irrigation Application of Emdogain Ⓡ Suture 2 Wound is sutured with #5 -0 monofilament using a vertical mattress technique. KHU PERIO

Persistence of the EMD 15 • Test: access flap surgery and additional application of emdogain Control: access flap surgery alone • Immunohistochemical staining using a rabbit-anti-EMD • Immunohistochemical evaluation TEST 1 w 2 w 3 w 4 w CONTROL The results demonstrate for the first time in humans that EMD is present on treated root surface for up to 4 weeks following periodontal surgery. KHU PERIO

Advantages of EMD 1, 3 Simple to use Appliable to multiple teeth No necessity for 2 nd surgical intervention Less postoperative complications 2 KHU PERIO

Contents 1. Introduction 2. Treatment Rationale of EMD 3. Enamel matrix derivative (EMD) 4. Cellular effects of EMD 5. EmdogainⓇ 6. Clinical effects of EMD 7. Conclusions KHU PERIO

Clinical effects of EMD 1 Improvement of periodontal attachment levels(PAL) and decrease of probing pocket depth(ppd) only EMD Flap Operation This meta-analysis showed that EMD achieved better treatment outcomes than flap operation. 4 KHU PERIO

Clinical effects of EMD 1 only EMD GTR With the exception of significantly more postoperative complications in the GTR group, there was no evidence of clinically important differences between GTR and EMD. 4 KHU PERIO

Clinical effects of EMD 2 • Meta-analyses of randomized-controlled trials PPD Bio-guide reduction EMD+GTR only EMD+bone grafts mm e. PTFE Resolut Tissue guide 0. 07 mm Bio-Oss TCP 0. 24 mm DFDBA HA perioglass CAL gain 0. 15 mm 0. 46 When different types of bone grafts and barrier membranes were This meta-analysis not findbovine substantially additional benefits treated separately, did EMD with bone grafts showed greater for EMD ineffects. conjunction with GTR or bone grafts in the treatments The use of bovine bone grafts may provide an additional 1 mm PPD reduction, CAL gain and defect fill that was similar to that shown by direct comparisons. of intra-bony defects. KHU PERIO

Clinical effects of EMD 26 Increased root Coverage & keratinized tissue Cheng (2007) reported that the coronally positioned flap procedure was improved by the modification of adding EMD. Mean Difference CPF+EMD CAL 1. 69± 0. 15 mm 3. 69± 0. 50 mm PPD 0. 31± 0. 02 mm 0. 16± 0. 29 mm Keratin thickness 0. 10± 0. 41 mm 0. 61± 0. 14 mm Gingival recession depth 1. 82± 0. 53 mm 3. 16± 0. 41 mm Root coverage percentage 54. 16 % 84. 42 % KHU PERIO

Clinical effects of EMD 19, 21, 22 Impovement of periodontal wound healing • Wennstrom & Lindhe (2002) mentioned that emdogainⓇ topically applied in instrumented pockets enhance the early healing of periodontal soft tissue wounds. • Parker & Tonetti (2004) demostrated that in human PDL cells EMD down-regulates the expression of genes involved in early inflammatory events of wound healing, whereas genes encoding growth and repair-promoting molecules were up-regulated. KHU PERIO

Clinical effects of EMD 1, 17 Antimicrobial effects • It is of interest to note that the vehicle solution (propylene glycol alginate ) of the EMD has significant antimicrobial effects on periodontal pathogens • Nicole et. al. (2002) reported that EMD has a direct influence on the vitality of supragingival dental plaque. CONTROL TEST <vital fluorescene technique> The antimaicrobial effect of EMD is strongly influenced by the PGA vehicle, which posesses a low p. H and may perturb bacterial cell metabolism. KHU PERIO

Contents 1. Introduction 2. Treatment Rationale of EMD 3. Enamel matrix derivative (EMD) 4. Cellular effects of EMD 5. EmdogainⓇ 6. Clinical effects of EMD 7. Conclusions KHU PERIO

Conclusions 1, 2 1. The clinical efficacy and safety of EMD has been demonstrated. In addition, histologic evidence suggests a potential for true periodontal regeneration. 2. EMD achieved better treatment outcomes than flap operation in the treatment of infrabony defects. 3. There wss no evidence of clinically important differences between GTR and EMD. 4. There was little evidence to support the additional benefits of EMD in conjunction with GTR or bone grafts. 5. EMD in conjuction with bovine bone grafts and Bio-GuideⓇ membrane might provide additional treatment effects. KHU PERIO

References 1. Esposito M et al. Enamel matrix derivative (Emdogain) for periodontal tissue regeneration in intrabony defects. Cochrane Database of Systemic Reviews, Issue 1, 2009 2. Yu-Kang Tu et al. Do bone grafts or barrier membranes provide additional treatment effects for infrabony lesions treated with enamel matrix derivatives? A network meta-analysis of randomized-controlled trials. J Clin Periodontol 2010; 37: 59 -79 3. Fa-Ming Chen et al. A review on endogenous regenerative technology in periodontal regenerative medicine. Biomaterials 2010; 31: 7892 -7927 4. Dieter D. Bosshardt. Biological mediators and periodontal regeneration: a review of enamel matrix proteins at the cellular and molecular levels. J Clin Periodontol 2008; 35: 87 -105 5. James T. Mellonig. Enamel matrix derivative for periodontal reconstructive surgery: technique and clinical and histologic case report. The International Journal of Periodontics & Restorative Dentistry 1999; 19: 9 -19 6. Margarita Zeichner-David. Regeneration of periodontal tissue: cementogenesis revisited. Periodontology 2000 2006; 41: 196 -217 4 7. Position Paper Periodontal Regeneration. J Periodontol 2005; 76 8. Chong et al. Human periodontal fibroblast response to enamel matrix derivative, amelogenin, and platelet derived growth factor-BB, . J Periodontol 2006; 77: 1242 -1252 KHU PERIO

References 9. Alan G. Fincham et. al. Amelogenin proteins of developing dental enamel. Ciba Foundation Symposium 1997; 205: 118 -134 10. J. P. Simmer et. al. Isolation and characterization of a mouse amelogenin expressed in Eschrichia coli. Calcif Tissue Int 1994; 54: 312 -319 11. J. Maycock et al. Characterization of a porcine amelogenin preparation, EMDOGAIN, a biological treatment for periodontal disease. Connective Tissue Research 2002; 43: 472 -476 12. Carolyn W. Gibson. The amelogenin “enamel proteins” and cells in the periodontium. Critical reviews in Eukaryotic Gene Expression 2008; 18: 345360 13. Hammarstrom L. Periodontal regeneration in a buccal dehiscence model in monkeys after application of enamel matrix proteins. J Clin Periodontol 1997; 24: 669 -677 14. 4 Heijl L. Periodontal regeneration with enamel matrix derivative in one human experimental defect. A case report. J Clin Periodontol 1997; 24: 693696 15. Anton Sculean et al. Presense of an enamel matrix protein derivative on human teeth following periodontal surgery. Clin Oral Invest 2002; 6: 183 -187 16. Nicole Birgit Arweiler et al. Antibacterial effect of an enamel matrix protein KHU PERIO derivative on in vivo dental biofilm vitality. Clin Oral Invest 2002; 6: 205 -209

References 17. Seth A. Newman et. al. Effects of enamel matrix derivative on Porphyromonas gingivalis. J Periodontol 2003; 74: 1191 -1195 18. Angelo Mariotti. Efficacy of chemical root surface modifiers in the treatment of periodontal disease. A systematic review. Ann Periodontol 2003; 8: 205 -226 19. Mohamed H. Parker et. al. Gene expression profiles of periodontal ligament cells treated with enamel matrix proteins in vitro: analysis using c. DNA arrays. J Periodontol 2004; 75: 1539 -1546 20. Fernanda Boabaid et al. Leucine-rich amelogenin peptide: a candidate signaling molecule during cementogenesis. J Periodontol 2004; 75: 1126 -1136 21. Wennstrom JL. Et al. Some effects of enamel matrix proteins on wound healing in the dento-gingival region. J Periodontol 2002; 29: 9 -14 22. Nokhbehsaim M. et al. Effects of enamel matrix derivative on periodontal 4 wound healing in an inflammatory enviroment in vitro. J Clin Periodontol 2011; 10: 1 -12 23. Lyngstadaas SP et al. Autocrine growth factors in human periodontal ligament cells cultured on enamel matrix derivative. J Clin Periodontol 2001; 28: 181 -188 24. Fujishiro N. et al. The role of marcrophages in the periodontal regeneration KHU PERIO using Emdogain gel. J Periodont Res 2008; 43: 143 -155

References 25. Vincenzo lorio Siciliano et al. Clinical outcomes after treatment of noncontained intrabony defects with enamel matrix derivative or guided tissue regeneration: a 12 -month randomized controlled clinical trial. J Periodontol 2011; 82: 62 -71 26. Cheng Y-F et. al. Is coronally positioned flap procedure adjunct with enamel matrix derivative or root conditioning a relevant predictor for achieving root coverage? A systematic review. J Periodont Res 2007; 42: 474 -485 27. Andrea Pilloni et al. Root coverage with a coronally positioned flap used in combination with enamel matrix derivative: 18 -month clinical evaluation. J Periodontol 2006; 77: 2031 -2039 4 KHU PERIO

Thank you for Attention. KHU PERIO