SUPPLEMENTARY MATERIALSUPPL. 1 PRISMA checklist

Section # Checklist item Reported on page

TITLE 1 Identify the report as systematic review, meta-analysis or both

1

ABSTRACT 2 Structured summary 2INRODUCTION 3 Rationale 3

4 Objectives 3METHODS 5 Protocol and registration 4

6 Eligibility criteria 47 Information sources 48 Search 59 Study selection 510 Data collection process 511 Data items 712 Risk of bias in individual studies 513 Summary measures 814 Synthesis of results 815 Risk of bias across studies 816 Additional analyses 8

RESULTS 17 Study selection 918 Study characteristics 919 Risk of bias within studies 920 Results of individual studies 921 Synthesis of results 922 Risk of bias across studies 923 Additional analysis 10

DISCUSSION 24 Summary of evidence 10, 1125 Limitations 1126 Conclusions 12

FUNDING 27 Sources of funding 12

SUPPL. 2 The search strategy was performed as previously described for a systematic review on the same topic (Tu et al. 2012). In PubMed we developed a subject-specific search strategy using the following MeSH terms:

- Medline(((((((bone transplantation or bone graft or bone substitutes)) OR (guided tissue regeneration or GTR)) OR (intra bony defect or intra-bony defect or intrabony defect or infra bony defect or infra-bony defect or intrabony defect or intra bony defects or intra-bony defects or intrabony defects or infra bony defects or infra-bony defects or intrabony defects)) OR bone regeneration) OR periodontal regeneration)) AND periodontal diseaseDetails of the search steps:

1. ("bone transplantation"[MeSH Terms] OR ("bone"[All Fields] AND "transplantation"[All Fields]) OR "bone transplantation"[All Fields]) OR ("bone transplantation"[MeSH Terms] OR ("bone"[All Fields] AND "transplantation"[All Fields]) OR "bone transplantation"[All Fields] OR ("bone"[All Fields] AND "graft"[All Fields]) OR "bone graft"[All Fields]) OR ("bone substitutes"[MeSH Terms] OR ("bone"[All Fields] AND "substitutes"[All Fields]) OR "bone substitutes"[All Fields])

2. ("guided tissue regeneration"[MeSH Terms] OR ("guided"[All Fields] AND "tissue"[All Fields] AND "regeneration"[All Fields]) OR "guided tissue regeneration"[All Fields]) OR GTR[All Fields]

3. (intra[All Fields] AND bony[All Fields] AND defect[All Fields]) OR (intra-bony[All Fields] AND defect[All Fields]) OR (intrabony[All Fields] AND defect[All Fields]) OR (infra[All Fields] AND bony[All Fields] AND defect[All Fields]) OR (infra-bony[All Fields] AND defect[All Fields]) OR (intrabony[All Fields] AND defect[All Fields]) OR (intra[All Fields] AND bony[All Fields] AND ("abnormalities"[Subheading] OR "abnormalities"[All Fields] OR "defects"[All Fields])) OR (intra-bony[All Fields] AND ("abnormalities"[Subheading] OR "abnormalities"[All Fields] OR "defects"[All Fields])) OR (intrabony[All Fields] AND ("abnormalities"[Subheading] OR "abnormalities"[All Fields] OR "defects"[All Fields])) OR (infra[All Fields] AND bony[All Fields] AND ("abnormalities"[Subheading] OR "abnormalities"[All Fields] OR "defects"[All Fields])) OR (infra-bony[All Fields] AND ("abnormalities"[Subheading] OR "abnormalities"[All Fields] OR "defects"[All Fields])) OR (intrabony[All Fields] AND ("abnormalities"[Subheading] OR "abnormalities"[All Fields] OR "defects"[All Fields]))

4. "bone regeneration"[MeSH Terms] OR ("bone"[All Fields] AND "regeneration"[All Fields]) OR "bone regeneration"[All Fields]

5. Periodontal[All Fields] AND ("regeneration"[MeSH Terms] OR "regeneration"[All Fields])6. "periodontal diseases"[MeSH Terms] OR ("periodontal"[All Fields] AND "diseases"[All

Fields]) OR "periodontal diseases"[All Fields] OR ("periodontal"[All Fields] AND "disease"[All Fields]) OR "periodontal disease"[All Fields]

7. OR 1/58. 6 AND 79. RCT filter10. Observational study filter11. 9 OR 1012. 11 AND 8

- EMBASEThe PubMed search strategy was adapted for EMBASE as follows:

1. exp bone transplantation/2. (bone and (transplant* or graft* or substitut*)).mp. [mp=title, abstract, subject headings,

heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

3. tissue regeneration/ or bone regeneration/4. (tissue regeneration* or GTR or bone regeneration*).mp. [mp=title, abstract, subject

headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

5. (intra bony defect* or intra-bony defect* or intrabony defect* or infra bony defect* or infra-bony defect* or intrabony defect*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

6. 1 or 2 or 3 or 4 or 57. exp periodontal disease/

8. ((periodontal and disease*) or periodontitis or periodontosis).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

9. 7 or 810. 6 and 911. RCT filter12. Observational study filter13. 11 or 1214. 13 and 10

- Search filters: The following search filters were used to identify RCTs and observational studies: Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity-maximizing version (2008 revision); PubMed format (1); University of Texas School of Public Health. Search filters for cohort studies and clinical trials (PubMed) (2); SIGN Randomised Controlled Trials search filter (EMBASE); SIGN Observational Studies search filter (EMBASE) (3).

SUPPL.3 LIST OF INCLUDED PAPERS:

1. AboElsaad NS, Soory M, Gadalla LM, Ragab LI, Dunne S, Zalata KR, et al. Effect of soft laser and bioactive glass on bone regeneration in the treatment of infra-bony defects (a clinical study). Lasers Med Sci. 2009 May;24(3):387-95.2. Aguirre-Zorzano LA, Estefania-Cundin E, Gil-Lozano J, Martinez-Conde R, Nunez-Anton V, Santamaria-Zuazua J. Periodontal regeneration of intrabony defects using resorbable membranes: determinants of the healing response. An observational clinical study. Int J Periodontics Restorative Dent. 1999 Aug;19(4):363-71.3. Aichelmann-Reidy ME, Heath CD, Reynods MA. Clinical evaluation of calcium sulfate in combination with dimineralized freeze-dried bone allograft for the treatment of human intraosseous defects. J Periodontol. 2004 March;75 (3):340-7.4. Aimetti M, Pigella E, Romano F, Debernardi C. Treatment of mandibular class II furcation defects by the use of amelogenins and autologous bone. Two case reports. Minerva Stomatol. 2005 Oct;54(10):583-91.5. Aspriello SD, Ferrante L, Rubini C, Piemontese M. Comparative study of DFDBA in combination with enamel matrix derivative versus DFDBA alone for treatment of periodontal intrabony defects at 12 months post-surgery. Clin Oral Investig. 2011 Apr;15(2):225-32.6. Batista EL, Jr., Novaes AB, Jr., Simonpietri JJ, Batista FC. Use of bovine-derived anorganic bone associated with guided tissue regeneration in intrabony defects. Six-month evaluation at re-entry. J Periodontol. 1999 Sep;70(9):1000-7.7. 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):1138-44.8. Bender SA, Rogalski JB, Mills MP, Arnold RM, Cochran DL, Mellonig JT. Evaluation of demineralized bone matrix paste and putty in periodontal intraosseous defects. J Periodontol. 2005 May;76(5):768-77.9. Benque E, Zahedi S, Brocard D, Oscaby F, Justumus P, Brunel G. Combined collagen membrane and hydroxyapatite/collagen chondroitin-sulfate spacer placement in the treatment of 2-wall intrabony defects in chronic adult and rapidly progressive periodontitis patients. J Clin Periodontol. 1997 Aug;24(8):550-6.

10. Benque E, Zahedi S, Brocard D, Oscaby F, Justumus P, Brunel G. Guided tissue regeneration using a collagen membrane in chronic adult and rapidly progressive periodontitis patients in the treatment of 3-wall intrabony defects. J Clin Periodontol. 1997 Aug;24(8):544-9.11. Bhongade ML, Tiwari IR. A comparative evaluation of the effectiveness of an anorganic bone matrix/cell binding peptide with an open flap debridement in human infrabony defects: a clinical and radiographic study. J Contemp Dent Pract. 2007;8(6):25-34.12. Bichara J, Greenwell H, Drisko C, Wittwer JW, Vest TM, Yancey J, et al. The effect of postsurgical naproxen and a bioabsorbable membrane on osseous healing in intrabony defects. J Periodontol. 1999 Aug;70(8):869-77.13. Bokan I, Bill JS. Multi-control analysis of 24-month clinical outcomes of guided tissue regeneration of deep periodontal pockets. Croat Med J. 1998 December;39 (4):435-41.14. Bokan I, Bill JS, Schlagenhauf U. Primary flap closure combined with Emdogain alone or Emdogain and Cerasorb in the treatment of intra-bony defects. J Clin Periodontol. 2006 Dec;33(12):885-93.15. Borghetti A, Novakovitch G, Louise F, Simeone D, Fourel J. Cryopreserved cancellous bone allograft in periodontal intraosseous defects. J Periodontol. 1993 Feb;64(2):128-32.16. Bratthall G, Lindberg P, Havemose-Poulsen A, Holmstrup P, Bay L, Soderholm G, et al. Comparison of ready-to-use EMDOGAIN-gel and EMDOGAIN in patients with chronic adult periodontitis. J Clin Periodontol. 2001 Oct;28 (10):923-9.17. Browning ES, Mealey BL, Mellonig JT. Evaluation of a mineralized cancellous bone allograft for the treatment of periodontal osseous defects: 6-month surgical reentry. Int J Periodontics Restorative Dent. 2009 Feb;29(1):41-7.18. Budhiraja S, Bhavsar N, Kumar S, Desai K, Duseja S. Evaluation of calcium sulphate barrier to collagen membrane in intrabony defects. J Periodontal Implant Sci. 2012 Dec;42(6):237-42.19. Camargo PM, Lekovic V, Weinlaender M, Divnic-Resnik T, Pavlovic M, Kenney EB. A surgical reentry study on the influence of platelet-rich plasma in enhancing the regenerative effects of bovine porous bone mineral and guided tissue regeneration in the treatment of intrabony defects in humans. J Periodontol. 2009 Jun;80(6):915-23.20. Camargo PM, Lekovic V, Weinlaender M, Nedic M, Vasilic N, Wolinsky LE, et al. A controlled re-entry study on the effectiveness of bovine porous bone mineral used in combination with a collagen membrane of porcine origin in the treatment of intrabony defects in humans. J Clin Periodontol. 2000 Dec;27(12):889-96.21. Camargo PM, Lekovic V, Weinlaender M, Vasilic N, Kenney EB, Madzarevic M. The effectiveness of enamel matrix proteins used in combination with bovine porous bone mineral in the treatment of intrabony defects in humans. J Clin Periodontol. 2001 Nov;28(11):1016-22.22. Camargo PM, Lekovic V, Weinlaender M, Vasilic N, Madzarevic M, Kenney EB. Platelet-rich plasma and bovine porous bone mineral combined with guided tissue regeneration in the treatment of intrabony defects in humans. J Periodontal Res. 2002 Aug;37(4):300-6.23. Camargo PM, Lekovic V, Weinlaender M, Vasilic N, Madzarevic M, Kenney EB. A reentry study on the use of bovine porous bone mineral, GTR, and platelet-rich plasma in the regenerative treatment of intrabony defects in humans. Int J Periodontics Restorative Dent. 2005 Feb;25(1):49-59.24. Camargo PM, Wolinsky LE, Ducar JP, Lagos R, Pirih FQ, Jeffcoat M, et al. The effect of fibronectin and a bone xenograft on regenerative treatment: a feasibility study. Compend Contin Educ Dent. 2006 Oct;27(10):560-8; quiz 9, 81.25. Cayir Keles G, Ozkan Cetinkaya B, Albayrak D, Koprulu H, Acikgoz G. Comparison of platelet pellet and bioactive glass in periodontal regenerative therapy. Acta Odontol Scand. 2006 01 Nov;64 (6):327-33.

26. Chambrone D, Pasin IM, Chambrone L, Pannuti CM, Conde MC, Lima LA. Treatment of infrabony defects with or without enamel matrix proteins: a 24-month follow-up randomized pilot study. Quintessence Int. 2010 Feb;41(2):125-34.27. Chambrone D, Pasin IM, Conde MC, Panutti C, Carneiro S, de Lima LAPA. Effect of enamel matrix proteins on the treatment of intrabony defects: A split-mouth randomized controlled trial study. Brazilian Oral Research. 2007;21 (3):241-6.28. Chawla K, Lamba AK, Faraz F, Tandon S. Evaluation of beta-tricalcium phosphate in human infrabony periodontal osseous defects: a clinical study. Quintessence Int. 2011 Apr;42(4):291-300.29. Chen CC, Wang HL, Smith F, Glickman GN, Shyr Y, O'Neal RB. Evaluation of a collagen membrane with and without bone grafts in treating periodontal intrabony defects. J Periodontol. 1995 Oct;66(10):838-47.30. Chhabra V, Gill AS, Sikri P, Bhaskar N. Evaluation of the relative efficacy of copolymerized polylactic-polyglycolic acids alone and in conjunction with polyglactin 910 membrane in the treatment of human periodontal infrabony defects: a clinical and radiological study. Indian J Dent Res. 2011 Jan-Feb;22(1):83-9.31. Chitsazi MT, Shirmohammadi A, Faramarzie M, Pourabbas R, Rostamzadeh A. A clinical comparison of nano-crystalline hydroxyapatite (Ostim) and autogenous bone graft in the treatment of periodontal intrabony defects. Med Oral Patol Oral Cir Bucal. 2011 May;16(3):e448-53.32. Christgau M, Bader N, Felden A, Gradl J, Wenzel A, Schmalz G. Guided tissue regeneration in intrabony defects using an experimental bioresorbable polydioxanon (PDS) membrane. A 24-month split-mouth study. J Clin Periodontol. 2002 Aug;29(8):710-23.33. Christgau M, Bader N, Schmalz G, Hiller KA, Wenzel A. GTR therapy of intrabony defects using 2 different bioresorbable membranes: 12-month results. J Clin Periodontol. 1998 Jun;25(6):499-509.34. Christgau M, Manner T, Beuer S, Hiller KA, Schmalz G. Periodontal healing after non-surgical therapy with a modified sonic scaler: a controlled clinical trial. J Clin Periodontol. 2006 Oct;33(10):749-58.35. Christgau M, Moder D, Wagner J, Glassl M, Hiller KA, Wenzel A, et al. Influence of autologous platelet concentrate on healing in intra-bony defects following guided tissue regeneration therapy: a randomized prospective clinical split-mouth study. J Clin Periodontol. 2006 Dec;33(12):908-21.36. Cortellini P, Carnevale G, Sanz M, Tonetti MS. Treatment of deep and shallow intrabony defects. A multicenter randomized controlled clinical trial. J Clin Periodontol. 1998 Dec;25(12):981-7.37. Cortellini P, Nieri M, Pini Prato G, Tonetti MS. Single minimally invasive surgical technique with an enamel matrix derivative to treat multiple adjacent intra-bony defects: Clinical outcomes and patient morbidity. J Clin Periodontol. 2008 July;35 (7):605-13.38. Cortellini P, Paolo G, Prato P, Tonetti MS. Long-term stability of clinical attachment following guided tissue regeneration and conventional therapy. J Clin Periodontol. 1996 Feb;23(2):106-11.39. 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):261-8.40. Cortellini P, Pini Prato G, Tonetti MS. Periodontal regeneration of human intrabony defects with titanium reinforced membranes. A controlled clinical trial. J Periodontol. 1995 Sep;66(9):797-803.41. Cortellini P, Pini Prato G, Tonetti MS. Interproximal free gingival grafts after membrane removal in guided tissue regeneration treatment of intrabony defects. A randomized controlled clinical trial. J Periodontol. 1995 Jun;66(6):488-93.42. Cortellini P, Pini Prato G, Tonetti MS. Periodontal regeneration of human intrabony defects with bioresorbable membranes. A controlled clinical trial. J Periodontol. 1996 Mar;67(3):217-23.

43. Cortellini P, Pini Prato GP, Tonetti MS. No detrimental effect of fibrin glue on the regeneration of intrabony defects. A controlled clinical trial. J Clin Periodontol. 1995 Sep;22(9):697-702.44. Cortellini P, Stalpers G, Mollo A, Tonetti MS. Periodontal regeneration versus extraction and prosthetic replacement of teeth severely compromised by attachment loss to the apex: 5-year results of an ongoing randomized clinical trial. J Clin Periodontol. 2011 Oct;38(10):915-24.45. Cortellini P, Stalpers G, Pini Prato G, Tonetti MS. Long-term clinical outcomes of abutments treated with guided tissue regeneration. J Prosthet Dent. 1999 Mar;81(3):305-11.46. Cortellini P, Tonetti MS. Evaluation of the effect of tooth vitality on regenerative outcomes in infrabony defects. J Clin Periodontol. 2001 Jul;28(7):672-9.47. Cortellini P, Tonetti MS. Microsurgical approach to periodontal regeneration. Initial evaluation in a case cohort. J Periodontol. 2001 Apr;72(4):559-69.48. Cortellini P, Tonetti MS. Clinical performance of a regenerative strategy for intrabony defects: scientific evidence and clinical experience. J Periodontol. 2005 Mar;76(3):341-50.49. Cortellini P, Tonetti MS. Minimally invasive surgical technique and enamel matrix derivative in intra-bony defects. I: Clinical outcomes and morbidity. J Clin Periodontol. 2007 Dec;34(12):1082-8.50. Cortellini P, Tonetti MS. A minimally invasive surgical technique with an enamel matrix derivative in the regenerative treatment of intra-bony defects: a novel approach to limit morbidity. J Clin Periodontol. 2007 Jan;34(1):87-93.51. 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):157-63.52. 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):365-73.53. Cortellini P, Tonetti MS, Lang NP, Suvan JE, Zucchelli G, Vangsted T, et al. The simplified papilla preservation flap in the regenerative treatment of deep intrabony defects: clinical outcomes and postoperative morbidity. J Periodontol. 2001 Dec;72(12):1702-12.54. Cosyn J, Cleymaet R, Hanselaer L, De Bruyn H. Regenerative periodontal therapy of infrabony defects using minimally invasive surgery and a collagen-enriched bovine-derived xenograft: a 1-year prospective study on clinical and aesthetic outcome. J Clin Periodontol. 2012 Oct;39(10):979-86.55. Crea A, Dassatti L, Hoffmann O, Zafiropoulos GG, Deli G. Treatment of intrabony defects using guided tissue regeneration or enamel matrix derivative: a 3-year prospective randomized clinical study. J Periodontol. 2008 Dec;79(12):2281-9.56. Czuryszkiewicz-Cyrana J, Banach J. Autogenous bone and platelet-rich plasma (PRP) in the treatment of intrabony defects. Adv Med Sci. 2006;51 Suppl 1:26-30.57. Da Costa-Noble R, Soustre EC, Cadot S, Lauverjat Y, Lefebvre F, Rabaud M. Evaluation of bioabsorbable elastin-fibrin matrix as a barrier in surgical periodontal treatment. J Periodontol. 1996 Sep;67(9):927-34.58. Danesh-Meyer MJ, Chen ST, Rams TE. Digital subtraction radiographic analysis of GTR in human intrabony defects. Int J Periodontics Restorative Dent. 2002 Oct;22(5):441-9.59. Demir B, Sengun D, Berberoglu A. Clinical evaluation of platelet-rich plasma and bioactive glass in the treatment of intra-bony defects. J Clin Periodontol. 2007 Aug;34(8):709-15.60. Dhawan S, Dhawan R, Gill AS, Sikri P. Comparison of the regenerative potential of an allograft used alone and that in conjunction with an immunosuppressive drug in the treatment of human periodontal infrabony defects: a clinical and radiological study. Indian J Dent Res. 2010 Oct-Dec;21(4):557-63.

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