Gel OPG-chitosane

L’ostéoprotégérine (OPG) est une protéine appartenant à la superfamille des récepteurs du facteur de nécrose tumorale (TNF) ; il a un rôle majeur dans la régulation de la résorption osseuse en tant qu’inhibiteur de la maturation et de l’activité des ostéoclastes. Il est notamment utilisé en oncologie dans le traitement du carcinome du sein ou le myélome multiple et l’ostéosarcome. Les polymères naturels tels que le chitosane ont des propriétés idéales pour des applications biomédicales, en effet le chitosane et ses dérivés ont des propriétés bénéfiques dans la cicatrisation des plaies. (118)

Une étude (119) vise à formuler un gel d'OPG-chitosane pour la régénération du tissu osseux.

L’étude porte sur des lapins sur lesquels ont été créés des défauts osseux au niveau de l’os pariétal. Les résultats de l’étude montre que le nouveau gel d'OPG-chitosane a la capacité de présenter un profil de libération protéique étendu, de favoriser la croissance des cellules et de subir une dégradation spécifique par le lysozyme, ce qui le rend efficace dans la cicatrisation osseuse. On peut conclure que le gel d'OPG-chitosane présente de nombreuses caractéristiques bénéfiques aux applications d'ingénierie tissulaire.

Le gel OPG-chitosane pourrait être un produit prometteur pour l’ingénierie tissulaire, et ainsi avoir des indications dans le traitement des défauts parodontaux.

CONCLUSION

La mise en œuvre d’une régénération tissulaire parodontale implique une connaissance des données acquises de la science et des indications de chaque technique afin de choisir la meilleure option thérapeutique.

Le choix de la technique entre la régénération tissulaire guidée, les dérivés de la matrice amélaire, les comblements osseux et la combinaison des méthodes découle essentiellement d’une réflexion sur la morphologie des lésions osseuses (nombre de parois résiduelles, profondeur et largeur du défaut).

A l’heure actuelle, les limites de la régénération parodontale sont nombreuses (défauts supra-osseux, lésions inter-radiculaires de classe III, défaut intra-osseux à 1 paroi). C’est dans ce cadre-là que les technologies émergentes trouvent une réelle indication. En effet, les résultats histologiques et cliniques des études menées montrent qu’il est primordial d’accorder une attention particulière à ces innovations.

Les découvertes récentes sur les cellules souches et les avancées médicales en termes d’ingénierie tissulaire constituent un progrès considérable. Il ne fait aucun doute que les cellules souches sont l’avenir en termes de thérapie régénératrice, au même titre que les facteurs de croissance font consensus.

De même, les nouveaux agents thérapeutiques régénératifs (RGTA®_{) ont prouvé}

leur efficacité dans de nombreuses disciplines médicales, leur utilisation future en parodontologie est prometteuse.

Le praticien doit continuellement mettre à jour ses connaissances grâce à la littérature scientifique et les formations continues afin de connaître les dernières avancées.

BIBLIOGRAPHIE

(1) Bouchard P. Parodontologie et dentisterie implantaire. Tome 1, Médecine parodontale. Lavoisier, Paris ; 2015

(2) Borghetti A, Monnet-Corti V. Chirurgie plastique parodontale et péri-implantaire. 3ème _{édition. JPIO, éditions CDP, Paris ; 2017.}

(3) Alimohamad H, Habijanac T, Larjava H, Häkinnen L. Colocalization of the collagen-binding protéoglycans decorin, biglycan, fibromodulin and lumican with different cells in human gingiva. J Periodontal Res 2005, 40 : 73-86.

(4) Melcher AH. Role of the periosteum in repair of wounds of the parietal bone of the rat. Arch Oral Biol. 1969 Sep;14(9):1101-9.

(5) Isidor F, Karring T, Nyman S, Lindhe J. New attachment-reattachment following reconstructive periodontal surgery. J Clin Periodontol. 1985 Oct;12(9):728-35. (6) Hammarström L, Alatli I, Fong CD. Origins of cementum. Oral Dis. 1996

Mar;2(1):63-9.

(7) Isaka J, Ohazama A, Kobayashi M, Nagashima C, Takiguchi T, Kawasaki H, Tachikawa T, Hasegawa K. Participation of periodontal ligament cells with regeneration of alveolar bone. J Periodontol. 2001 Mar;72(3):314-23.

(8) Melcher AH. On the repair potential of periodontal tissues. J Periodontol. 1976 May;47(5):256-60.

(9) Garrett JS. Root planing : a perspective. J Periodontol. 1977 ; 48(9) : 553-7. (10) Steffensen B, Webert HP. Relationship between the radiographic periodontal

defect angle and healing after treatment. J Periodontol. 1989 May;60(5):248-54. (11) Nilvéus RE, Selvig KA. Significance of early healing events on periodontal repair :

a review. J Periodontol. 1992 ; 63(3) : 158-65.

(12) Klein F, Kim TS, Hassfeld S, Staehle HJ, Reitmeir P, Holle R, Eickholz P. Radiographic defect depth and width for prognosis and description of periodontal healing of infrabony defects. J Periodontol. 2001 Dec;72(12):1639- 46.

(13) Tsitoura E, Tucker R, Suvan J, Laurell L, Cortellini P, Tonetti M. Baseline radiographic defect angle of the intrabony defect as a prognostic indicator in regenerative periodontal surgery with enamel matrix derivative. J Clin Periodontol. 2004 Aug;31(8):643-7.

(14) Cortellini P, Bowers GM. Periodontal regeneration of intrabony defects: an evidence-based treatment approach. Int J Periodontics Restorative Dent. 1995 Apr;15(2):128-45.

(15) Jayakumar A, Rohini S, Naveen A, Haritha A, Reddy K. Horizontal alveolar bone loss: A periodontal orphan. J Indian Soc Periodontol. 2010 Jul;14(3):181-5. (16) Melcher AH. Role of periosteum in repair of wounds of the parietal bone of the

rat. Archives of Oral Biology. 1969, 14 : 1101-1109.

(17) Karring T, Nyman S, Gottlow J, Laurell L. Development of the biological concept of guided tissue regeneration – animal and human studies. Periodontal 2000 1993 ; 1 : 26-35.

(18) Karring T, Nyman S, Lindhe J. Healing following implantation of periodontitis affected roots into bone tissue. J Clin Periodontol 1980 ; 7(2) :96-105.

(19) Nyman S, Karring T, Lindhe J, Planten S. Healing following implantation of periodontitis affected roots into gingival connective tissue. J Clin Periodontol 1980: 7: 394-401.

(20) Nyman S, Gottlow J, Karring T, Lindhe J. The regenerative potential of the periodontal ligament. An experimental study in the monkey. J Clin Periodontol 1982: 9: 257-265.

(21) Karring T, Isidor F, Nyman S, Lindhe J. New attachment formation on teeth with a reduced but healthy periodontal ligament. J Clin Periodontol 1985: 12: 51-60. 
 (22) Caton J, Nyman S, Zander H. Histometric evaluation of periodontal surgery. II.

Connective tissue attachment levels after four regenerative procedures. J Clin Periodontol. 1980 Jun;7(3):224-31.

(23) 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

(24) Nyman S, Lindhe J, Karring T, Rylander H. New attachment following surgical treatment of human periodontal disease. J Clin Periodontol 1982: 9: 280-296. (25) Bouchard P. Parodontologie et dentisterie implantaire. Tome 2, Techniques

chirurgicales. Lavoisier, Paris ; 2015.

(26) Cortellini P, Pini Prato G, Tonetti MS. Periodontal regeneration of human infrabony defects. II. Re-entry procedures and bone measures. J Periodontol. 1993 Apr;64(4):261-8.

(27) Ratka-Krüger P, Neukranz E, Raetzke P. Guided tissue regeneration procedure with bioresorbable membranes versus conventional flap surgery in the treatment of infrabony periodontal defects. Journal of Clinical Periodontology 2000, 27 (2): 120-7

(28) Pontoriero R, Lindhe J, Nyman S, Karring T, Rosenberg E, Sanavi F. Guided tissue regeneration in degree II furcation-involved mandibular molars. A clinical study. J Clin Periodontol. 1988 Apr;15(4):247-54.

(29) Becker W, Becker BE, Berg L, Prichard J, Caffesse R, Rosenberg E. New attachment after treatment with root isolation procedures: report for treated Class III and Class II furcations and vertical osseous defects. Int J Periodontics Restorative Dent. 1988;8(3):8-23.

(30) Becker W, Becker BE. Treatment of mandibular 3-wall intrabony defects by flap debridement and expanded polytetrafluoroethylene barrier membranes. Long- term evaluation of 32 treated patients. J Periodontol. 1993 Nov;64(11 Suppl):1138-44.

(31) Flores-de-Jacoby, L. (1991) Parodontaltherapie nach der gesteuerten parodontalen Geweberegeneration. Deutsche Zahn-arztliche Zeitschrift 46, 390– 393.

(32) Brunsvold MA, Mellonig JT. Bone grafts and periodontal regeneration. Periodontol 2000. 1993 Feb; 1:80-91.

(33) Urist MR, DeLange RJ, Finerman GA. Bone cell differentiation and growth factors. Science. 1983 May 13;220(4598):680-6.

(34) Urist MR. Bone: formation by autoinduction. 1965. Clin Orthop Relat Res. 2002 Feb;(395):4-10.

(35) Trombelli L. Wich reconstructive procedures are effective for treating the periodontal intraosseous defect ? Periodontol 2000, 2005. 37 : 88-105.

(36) Nabers Cl, O’Leary TJ. Autogenous bone transplants in the treatment of osseous defects. J Periodontol. 1965 Jan-Feb;36:5-14.

(37) Reynolds MA, Aichelmann-Reidy ME, Branch-Mays GL, Gunsoley JC. The efficacy of bone replacement grafts in the treatment of periodontal osseous defects. A systematic review. Ann Periodontol, 2003, 8 : 227-265.

(38) Baldini N, De Sanctis M, Ferrari M. Deproteinized bovine bone in periodontal and implant surgery. Dent Mater, 2011, 27 : 61-70.

(39) Darby I. Periodontal materials. Aust DentJ, 2011, 56 Suppl I : 107-118.

(40) Hayashi C, Kinoshita A, Oda S, Mizutani K, Shirakata Y, Ishikawa I. Injectable calcium phosphate bone cement provides favorable space and a scaffold for periodontal regeneration in dogs. J Periodontol. 2006 Jun;77(6):940-6.

(41) Yu L1, Li Y, Zhao K, Tang Y, Cheng Z, Chen J, Zang Y, Wu J, Kong L, Liu S, Lei W, Wu Z.A novel injectable calcium phosphate cement-bioactive glass composite for bone regeneration. PLoS One. 2013 Apr 25;8(4):e62570.

(42) Miron RJ, Zhang Q, Sculean A, Buser D, Pippenger BE, Dard M, Shirakata Y10, Chandad F11, Zhang Y12.Osteoinductive potential of 4 commonly employed bone grafts. Clin Oral Investig. 2016 Nov;20(8):2259-2265.

(43) Van der Pauw MT., Van der Bos T., Everts V., Beertsen W. Enamel matrix- derivated protein stimulates attachment of periodontal ligament fibroblasts and enhances alkaline phosphatase activity and transforming growth factor b-1 release periodontal ligament and gingival fibroblasts. J. Periodontol.2000; 71:31- 43.

(44) Kawase T, Okuda K, Yoshie H, Burns DM. Anti-TGF-beta antibody blocks enamel matrix derivative-induced upregulation of p21WAF1/cip1 and prevents its inhibition of human oral epithelial cell proliferation. J Periodontal Res. 2002 Aug;37(4):255-62.

(45) Queiroz LA, Casarin RCV, Dabdoub SM, Tatakis DN, Sallum EA, Kumar PS. Furcation Therapy With Enamel Matrix Derivative: Effects on the Subgingival Microbiome. J Periodontol. 2017 Jul;88(7):617-625.

(46) Hammarstrom L. Enamel matrix, cementum development and regeneration. J Clin Periodontol, 1997, 24 : 658-666.

(47) Tonetti MS., Lang NP., Cortellini P., Suvan JE., Adriaens P., Dubravec D. Enamel matrix proteins in the regenerative therapy of deep infrabony defects. A multicentre randomized controlled clinical trial.J. Clin. Periodontol. 2002;29:317- 325.

(48) Venezia E, Goldstein M, Boyan BD, Schwartz Z. The use of enamel matrix derivative in the treatment of periodontal defects: a literature review and meta- analysis. Crit Rev Oral Biol Med. 2004 Nov 1; 15(6):382-402.

(49) Casarin RC, Ribeiro Edel P, Ribeiro FV, Nociti FH Jr, Sallum AW, Sallum EA, Casati MZ. Influence of anatomic features on the effectiveness of enamel matrix derivative proteins in the treatment of proximal Class II furcation involvements. Quintessence Int. 2009 Oct;40(9):753-61.

(50) Casarin RC, Ribeiro Edel P, Nociti FH Jr, Sallum AW, Ambrosano GM, Sallum EA, Casati MZ. Enamel matrix derivative proteins for the treatment of proximal class II furcation involvements: a prospective 24-month randomized clinical trial. J Clin Periodontol. 2010 Dec;37(12):1100-9.

(51) Casarin RC, Del Peloso Ribeiro E, Nociti FH Jr, Sallum AW, Sallum EA, Ambrosano GM, Casati MZ. A double-blind randomized clinical evaluation of enamel matrix derivative proteins for the treatment of proximal class-II furcation involvements. J Clin Periodontol. 2008 May;35(5):429-37.

(52) Keskiner I, Alkan A, Acikgoz G, Arpak N, Kaplan S, Arslan H. Platelet-rich plasma and autogenous bone graft combined with guided tissue regeneration in periodontal fenestration defects in dogs. Int J Periodontics Restorative Dent. 2014 Nov-Dec;34(6):e112-20.

(53) Sculean A, Nikolidakis D, Schwarz F. Regeneration of periodontal tissues: combinations of barrier membranes and grafting materials - biological foundation and preclinical evidence: a systematic review. J Clin Periodontol. 2008 Sep;35(8 Suppl):106-16.

(54) Sculean A, Windisch P, Chiantella GC, Donos N, Brecx M, Reich E. Treatment of intrabony defects with enamel matrix proteins and guided tissue regeneration. A prospective controlled clinical study. J Clin Periodontol. 2001 May;28(5):397- 403.

(55) Tu YK, Needleman I, Chambrone L, et al. A Bayesian network meta-analysis on comparisons of enamel matrix derivatives, guided tissue regeneration and their combination therapies. J Clin Periodontol, 2012, 39 : 303-314.

(56) Matarasso M, Iorio-Siciliano V, Blasi A, Ramaglia L, Salvi GE, Sculean A. Enamel matrix derivative and bone grafts for periodontal regeneration of intrabony defects. A systematic review and meta-analysis. Clin Oral Investig. 2015 Sep;19(7):1581-93.

(57) Miron RJ, Bosshardt DD, Zhang Y, Buser D, Sculean A. Gene array of primary human osteoblasts exposed to enamel matrix derivative in combination with a natural bone mineral. Clin Oral Investig. 2013 Mar;17(2):405-10.

(58) Trombelli L, Annunziata M, Belardo S, Farina R, Scabbia A, Guida L. Autogenous bone graft in conjunction with enamel matrix derivative in the treatment of deep periodontal intra-osseous defects: a report of 13 consecutively treated patients. J Clin Periodontol. 2006 Jan;33(1):69-75.

(59) Yilmaz S, Cakar G, Yildirim B, Sculean A. Healing of two and three wall intrabony periodontal defects following treatment with an enamel matrix derivative combined with autogenous bone. J Clin Periodontol. 2010 Jun;37(6):544-50. (60) Miron RJ, Guillemette V, Zhang Y, Chandad F, Sculean A. Enamel matrix derivative

in combination with bone grafts: A review of the literature. Quintessence Int. 2014 Jun;45(6):475-87.

(62) Harris RJ, Harris LE, Harris CR, Harris AJ. Clinical evaluation of a combined regenerative technique with enamel matrix derivative, bone grafts, and guided tissue regeneration. Int J Periodontics Restorative Dent. 2007 Apr;27(2):171-9. (63) Jaiswal R, Deo V. Evaluation of the effectiveness of enamel matrix derivative, bone

grafts, and membrane in the treatment of mandibular Class II furcation defects. Int J Periodontics Restorative Dent. 2013 Mar-Apr;33(2):e58-64.

(64) Avila-Ortiz G, De Buitrago JG, Reddy MS. Periodontal regeneration - furcation defects: a systematic review from the AAP Regeneration Workshop. J Periodontol. 2015 Feb;86(2 Suppl):S108-30.

(65) Reddy MS, Aichelmann-Reidy ME, Avila-Ortiz G, Klokkevold PR, Murphy KG, Rosen PS, Schallhorn RG, Sculean A, Wang HL. Periodontal regeneration -

furcation defects: a consensus report from the AAP Regeneration Workshop. J Periodontol. 2015 Feb;86(2 Suppl):S131-3.

(66) Cortellini P, Tonetti MS. Microsurgical approach to periodontal regeneration. Initial evaluation in a case cohort. J Periodontol. 2001 Apr;72(4):559-69.

(67) Cortellini P, Tonetti MS. Improved wound stability with a modified minimally invasive surgical technique in the regenerative treatment of isolated interdental intrabony defects. J Clin Periodontol. 2009 Feb;36(2):157-63.

(68) Mishra A, Avula H, Pathakota KR, Avula J. Efficacy of modified minimally invasive surgical technique in the treatment of human intrabony defects with or without use of rhPDGF-BB gel: a randomized controlled trial. J Clin Periodontol. 2013 Feb;40(2):172-9.

(69) Cortellini P, Tonetti MS. Clinical and radiographic outcomes of the modified minimally invasive surgical technique with and without regenerative materials: a randomized-controlled trial in intra-bony defects. J Clin Periodontol. 2011 Apr;38(4):365-73.

(70) Lallam C. La thérapie matricielle par les RGTA : une innovation appliquée à la parodontite, JPIO 2013; vol.33 n°3; 207-224.

(71) Escartin Q, Lallam-Laroye C, Baroukh B, Morvan FO, Caruelle JP, Godeau G, Barritault D, Saffar JL. A new approach to treat tissue destruction in periodontitis with chemically modified dextran polymers. FASEB J. 2003 Apr;17(6):644-51. (72) Lallam-Laroye C, Escartin Q, Zlowodzki AS, Barritault D, Caruelle JP, Baroukh B,

Saffar JL, Colombier ML. Periodontitis destructions are restored by synthetic glycosaminoglycan mimetic. J Biomed Mater Res A. 2006 Dec 1;79(3):675-83. (73) Lallam-Laroye C, Baroukh B, Doucet P, Barritault D, Saffar JL, Colombier ML.

ReGeneraTing agents matrix therapy regenerates a functional root attachment in hamsters with periodontitis. Tissue Eng Part A. 2011 Sep;17(17-18):2359-67. (74) Spiegelberg L, Djasim UM, van Neck JW, Wolvius EB, van der Wal KG. The effects

of heparan sulphate mimetic RGTA-OTR4120 on irradiated murine salivary glands. J Oral Pathol Med. 2012 Jul;41(6):477-83.

(75) Colombier ML, Lafont J, Blanquaert F, Caruelle JP, Barritault D, Saffar JL. A single low dose of RGTA, a new healing agent, hastens wound maturation and enhances bone deposition in rat craniotomy defects. Cells Tissues Organs. 1999;164(3):131-40.

(76) Tong M, Zbinden MM, Hekking IJ, Vermeij M, Barritault D, van Neck JW. RGTA OTR 4120, a heparan sulfate proteoglycan mimetic, increases wound breaking strength and vasodilatory capability in healing rat full-thickness excisional wounds. Wound Repair Regen. 2008 Mar-Apr;16(2):294-9.

(77) Tong M, Tuk B, Shang P, Hekking IM, Fijneman E, Guijt M, Hovius S, Van Neck JW. Diabetes-Impaired Wound Healing Is Improved by Matrix Therapy With Heparan Sulfate Glycosaminoglycan Mimetic OTR4120 in Rats. Diabetes 2012 Oct; 61(10): 2633-2641.

(78) Malaq AA, Barritault D. A Rapid Response to Matrix Therapy With RGTA in Severe Epidermolysis Bullosa. Eplasty. 2012;12:ic15. Epub 2012 Oct 17.

(79) Yamauchi H, Desgranges P, Lecerf L, Papy-Garcia D, Tournaire MC, Moczar M, Loisance D, Barritault D. New agents for the treatment of infarcted myocardium. FASEB J. 2000 Nov;14(14):2133-4.

(80) Cejkova J, Olmiere C, Cejka C, Trosan P, Holan V. The healing of alkali-injured cornea is stimulated by a novel matrix regenerating agent (RGTA, CACICOL20): a biopolymer mimicking heparan sulfates reducing proteolytic, oxidative and nitrosative damage. Histol Histopathol. 2014 Apr;29(4):457-78.

(81) Brignole-Baudouin F, Warnet JM, Barritault D, Baudouin C. RGTA-based matrix therapy in severe experimental corneal lesions: safety and efficacy studies. J Fr Ophtalmol. 2013 Nov;36(9):740-7.

(82) Chebbi CK, Kichenin K, Amar N, Nourry H, Warnet JM, Barritault D, Baudouin C. Pilot study of a new matrix therapy agent (RGTA OTR4120) in treatment- resistant corneal ulcers and corneal dystrophy. J Fr Ophtalmol. 2008 May;31(5):465-71.

(83) Ramseier CA, Rasperini G, Batia S, Giannobile WV.. Advanced reconstructive technologies for periodontal tissue repair. Periodontol 2000. 2012 Jun;59(1):185-202.

(84) Rosenkranz S, Kazlauskas A. Evidence for distinct signaling properties and biological responses induced by the PDGF receptor alpha and beta subtypes. Growth Factors. 1999;16(3):201-16.

(85) Oates TW, Rouse CA, Cochran DL. Mitogenic effects of growth factors on human periodontal ligament cells in vitro. J Periodontol. 1993 Feb;64(2):142-8.

(86) Ojima Y, Mizuno M, Kuboki Y, Komori T. In vitro effect of platelet-derived growth factor-BB on collagen synthesis and proliferation of human periodontal ligament cells. Oral Dis. 2003;9:144–151.

(87) Marcopoulou CE, Vavouraki HN, Dereka XE, Vrotsos IA. Proliferative effect of growth factors TGF-beta1, PDGF-BB and rhBMP-2 on human gingival fibroblasts and periodontal ligament cells. J Int Acad Periodontol. 2003;5:63–70.

(88) Matsuda N, Lin WL, Kumar NM, Cho MI, Genco RJ. Mitogenic, chemotactic, and synthetic responses of rat periodontal ligament fibroblastic cells to polypeptide growth factors in vitro. J Periodontol. 1992;63:515–525.

(89) Sykaras N, Opperman LA. Bone morphogenetic proteins (BMPs): how do they function and what can they offer the clinician? J Oral Sci. 2003 Jun;45(2):57-73. (90) Khoshkam V, Chan HL, Lin GH, Mailoa J, Giannobile WV, Wang HL, Oh TJ.

Outcomes of regenerative treatment with rhPDGF-BB and rhFGF-2 for periodontal intra-bony defects: a systematic review and meta-analysis. J Clin Periodontol. 2015 Mar;42(3):272-80.

(91) Li F, Yu F, Xu X, Li C, Huang D, Zhou X, Ye L, Zheng L. Evaluation of Recombinant Human FGF-2 and PDGF-BB in Periodontal Regeneration: A Systematic Review and Meta-Analysis. Sci Rep. 2017 Mar 6;7(1):65.

(92) Richardson TP, Peters MC, Ennett AB, Mooney DJ. Polymeric system for dual growth factor delivery. Nat Biotechnol. 2001 Nov;19(11):1029-34.

(93) Nevins M, Camelo M, Nevins ML, Schenk RK, Lynch SE. Periodontal regeneration in humans using recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and allogenic bone. J Periodontol. 2003 Sep;74(9):1282-92.

(94) Oortgiesen DA, Walboomers XF, Bronckers AL, Meijer GJ, Jansen JA. Periodontal regeneration using an injectable bone cement combined with BMP-2 or FGF-2. J Tissue Eng Regen Med. 2014 Mar;8(3):202-9.

(95) Langer R, Vacanti JP. Tissue engineering. Science. 1993 May 14 ; 260(5110) : 920- 6.

(96) Hynes K, Menicanin D, Gronthos S, Bartold PM.Clinical utility of stem cells for periodontal regeneration. Periodontol 2000. 2012 Jun;59(1):203-27.

(97) Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Développement des organismes multicellulaire et Histologie : Vie et mort des cellules dans les tissus. In : Biologie moléculaire de la cellule. Paris : Flammarion Médecine-Science ; 4ème éd. ; 2004.p1225-63.

(98) Duan X, Tu Q, Zhang J, Ye J, Sommer C, Mostoslavsky G, Kaplan D, Yang P, Chen J. Application of induced pluripotent stem (iPS) cells in periodontal tissue regeneration. J Cell Physiol. 2011 Jan;226(1):150-7.

(99) Hynes K, Menicanin D, Gronthos S, Bartold PM. Clinical utility of stem cells for periodontal regeneration. Periodontol 2000. 2012 Jun;59(1):203-27.

(100) Inanç B1, Elçin YM. Stem cells in tooth tissue regeneration--challenges and limitations. Stem Cell Rev. 2011 Sep;7(3):683-92.

(101) Akizuki T, Oda S, Komaki M, Tsuchioka H, Kawakatsu N, Kikuchi A et al. Application of periodontal ligament cell sheet for periodontal regeneration : a pilot study in beagle dogs. J Periodontal Res. 2005 ; 40(3) : 245-51.

(102) Yi L, Ying Z, Gang D, Dianji F, Chunmei Z, Mark P et al. Periodontal Ligament Stem Cell-Mediated Treatment for Periodontitis in Miniature Swine Stem Cells. 2008 ; 26; 1065–1073.

(103) Iwasaki K, Komaki M, Yokoyama N, Tanaka Y, Taki A, Honda I et al. Periodontal regeneration using periodontal ligament stem cell-transferred amnion. Tissue Eng Part A. 2013 : 15.

(104) Bright R, Hynes K, Gronthos S, Bartold PM. Periodontal ligament-derived cells for periodontal regeneration in animal models: a systematic review. J Periodontal Res. 2015 Apr;50(2):160-72.

(105) Kl V, Ryana H, Dalvi PJ. Autologous periodontal stem cell assistance in periodontal regeneration technique (SAI-PRT) in the treatment of periodontal intrabony defects: A case report with one-year follow-up. J Dent Res Dent Clin Dent Prospects. 2017 Spring;11(2):123-126.

(106) Shang F, Liu S, Ming L, Tian R, Jin F, Ding Y, Zhang Y, Zhang H, Deng Z, Jin Y. Human Umbilical Cord MSCs as New Cell Sources for Promoting Periodontal Regeneration in Inflammatory Periodontal Defect. Theranostics. 2017 Sep 26 (107) Carmagnola D, Tarce M, Dellavia C, Rimondini L, Varoni EM. Engineered scaffolds

and cell-based therapy for periodontal regeneration. J Appl Biomater Funct Mater. 2017 Nov 10;15(4):e303-e312.

(108) Miron RJ, Fujioka-Kobayashi M, Buser D, Zhang Y, Bosshardt DD, Sculean A. Combination of Collagen Barrier Membrane with Enamel Matrix Derivative- Liquid Improves Osteoblast Adhesion and Differentiation. Int J Oral Maxillofac Implants. 2017 Jan/Feb;32(1):196-203.

(109) Miron RJ, Shuang Y, Sculean A, Buser D, Chandad F, Zhang Y. Gene array of PDL cells exposed to Osteogain in combination with a bone grafting material. Clin Oral Investig. 2016 Nov;20(8):2037-2043. Epub 2016 Jan 8.

(110) Shirakata Y, Miron RJ, Nakamura T, Sena K, Shinohara Y, Horai N, Bosshardt DD, Noguchi K, Sculean A. Effects of EMD liquid (Osteogain) on periodontal healing in class III furcation defects in monkeys. J Clin Periodontol. 2017 Mar;44(3):298- 307.

(111) Shirakata Y, Miron RJ, Shinohara Y, Nakamura T, Sena K, Horai N, Bosshardt DD, Noguchi K, Sculean A. Healing of two-wall intra-bony defects treated with a novel EMD-liquid-A pre-clinical study in monkeys. J Clin Periodontol. 2017 Dec;44(12):1264-1273.

(112) Gómez-Florit M, Monjo M, Ramis JM. Identification of quercitrin as a potential therapeutic agent for periodontal applications. J Periodontol. 2014 Jul;85(7):966- 74.

(113) Gómez-Florit M, Monjo M, Ramis JM. Quercitrin for periodontal regeneration: effects on human gingival fibroblasts and mesenchymal stem cells. Sci Rep. 2015 Nov 12;5:16593.

(114) Gomez-Florit M, Pacha-Olivenza MA, Fernández-Calderón MC, Córdoba A, González-Martín ML, Monjo M, Ramis JM. Quercitrin-nanocoated titanium surfaces favour gingival cells against oral bacteria. Sci Rep. 2016 Mar 1;6:22444. (115) Rios HF, Bashutski JD, McAllister BS, Murakami S, Cobb CM, Chun YP, Lin Z, Mandelaris GA, Cochran DL. Emerging Regenerative Approaches for Periodontal Reconstruction: Practical Applications From the AAP Regeneration Workshop. Clin Adv Periodontics. 2015 Feb;5(1):40-46.

(116) Hata K. Clinical and preclinical application of PTH and BMP to dental treatment. Clin Calcium. 2016 Mar;26(3):466-74.

(117) Khan AA, Morrison A, Kendler DL, Rizzoli R, Hanley DA, Felsenberg D, McCauley LK, O'Ryan F, Reid IR, Ruggiero SL, Taguchi A, Tetradis S, Watts NB, Brandi ML,