Bone, Periodontal and Dental Pulp Regeneration in Dentistry: A Systematic Scoping Review

Chisini, Luiz Alexandre; Conde, Marcus Cristian Muniz; Grazioli, Guillermo; Martin, Alissa Schmidt San; Carvalho, Rodrigo Varella de; Sartori, Letícia Regina Morello; Demarco, Flávio Fernando

doi:10.1590/0103-6440201902053

Luiz Alexandre Chisini

Graduate Program in Dentistry, School of Dentistry, UFPel - Universidade Federal de Pelotas, RS, Brazil

Graduate Program in Dentistry, School of Dentistry, UNIVATES - Universidade do Vale do Taquari, Lajeado, RS, Brazil

https://orcid.org/0000-0002-3695-0361

Marcus Cristian Muniz Conde

Graduate Program in Dentistry, School of Dentistry, UNIVATES - Universidade do Vale do Taquari, Lajeado, RS, Brazil

https://orcid.org/0000-0003-2662-3305

Guillermo Grazioli

Graduate Program in Dentistry, School of Dentistry, UNIVATES - Universidade do Vale do Taquari, Lajeado, RS, Brazil

Alissa Schmidt San Martin

Graduate Program in Dentistry, School of Dentistry, UNIVATES - Universidade do Vale do Taquari, Lajeado, RS, Brazil

https://orcid.org/0000-0002-2094-774X

Rodrigo Varella de Carvalho

School of Dentistry, IMED - Faculdade Meridional, Passo Fundo, RS, Brazil

https://orcid.org/0000-0002-2644-5820

Letícia Regina Morello Sartori

Graduate Program in Dentistry, School of Dentistry, UFPel - Universidade Federal de Pelotas, RS, Brazil

Flávio Fernando Demarco

Graduate Program in Dentistry, School of Dentistry, UFPel - Universidade Federal de Pelotas, RS, Brazil

Correspondence: Flávio Fernando Demarco, Rua Gonçalves Chaves, 457, 96015-560 Pelotas, RS, Brasil. Tel: +55-53-98111-2528. e-mail: ffdemarco@gmail.com

Studies	Reason
Iwaia 2001³⁰30 Iwaya SI, Ikawa M, Kubota M, et al . Revascularization of an immature permanent tooth with apical periodontitis and sinus tract. Dent Traumatol2001;17:185-187.; Iwaia 2011³¹31 Iwaya S, Ikawa M, Kubota M, et al. Revascularization of an immature permanent tooth with periradicular abscess after luxation. Dent Traumatol 2011;27:55-58.; Bose 2009 ³²32 Bose R, Nummikoski P, Hargreaves K, et al. A Retrospective evaluation of radiographic outcomes in immature teeth with necrotic root canal systems treated with regenerative endodontic procedures. J Endod2009;35:1343-1349.;	Not realized bleeding in the root canal
Okuda 2013 ³³33 Okuda K, Kawase T, Nagata M, Yamamiya K, Nakata K, Wolff LF, et al. Tissue-engineered cultured periosteum sheet application to treat infrabony defects: case series and 5-year results. Int J Periodontics Restorative Dent 2013;33:281-287.	Not SC-BT
Yang 2010 ³⁴34 Yang L, Zhang Y, Dong R, Peng L, Liu X, Wang Y, et al. Effects of adenoviral-mediated coexpression of bone morphogenetic protein-7 and insulin-like growth factor-1 on human periodontal ligament cells. J Periodontal Res 2010;45:532-540.	Not Human
Peck 2012 ³⁵35 Peck MT, Marnewick J, Stephen LX, Singh A, Patel N, Majeed A, et al. The use of leukocyte- and platelet-rich fibrin (L-PRF) to facilitate implant placement in bone-deficient sites: a report of two cases. SADJ2012;67:54-59.	Not growth-factor applying

Year	Author	Cell	Scaffold	Growth Factor	Patients	Follow-up	Parameters	Outcome
2003	Schmelzeisen et al. ⁶⁵65 Schmelzeisen R, Schimming R, Sittinger M, et al. Making bone: implant insertion into tissue-engineered bone for maxillary sinus floor augmentation-a preliminary report. J Craniomaxillofac Surg 2003;31:34-39.	Periosteal	Polymer fleece		2	4 months	Histologic and clinical	Mineralized tissue formed
2004	Warnke et al. ⁷⁷77 Warnke PH, Springer IN, Wiltfang J, Acil Y, Eufinger H, Wehmoller M, et al . Growth and transplantation of a custom vascularised bone graft in a man. Lancet2004;364:766-770.	BMAC	BioOss	rhBMP7	1		Clinical and radiographic	Mineralized tissue formed
2005	Ueda et al. ³⁹39 Ueda M, Yamada Y, Ozawa R, et al. Clinical case reports of injectable tissue-engineered bone for alveolar augmentation with simultaneous implant placement. Int J Periodontics Restorative Dent 2005;25:129-137.	BMMSC	PRP-b-TCP injectable		6	12 months	Radiographic	Mineralized tissue formed (7.3 ± 4.6 mm)
2007	Cerruti et al. ⁷⁵75 Filho-Cerruti H, Kerkis I, Kerkis A, Tatsui NH, da Costa Neves A, Bueno DF, et al . Allogenous bone grafts improved by bone marrow stem cells and platelet growth factors: clinical case reports. Artif Organs2007;31:268-273.	MNC	PRP and Bone scaffod		32	8 months	CT, histologic and clinical	Mineralized tissue formed
2007	Soltan et al. ⁷⁸78 Soltan M, Smiler D, Prasad HS, Rohrer MD, et al. Bone block allograft impregnated with bone marrow aspirate. Implant Dent 2007;16:329-339.	BMAC	Allograft bone block		5	8 months	Histologic and histomorphometry	Mineralized tissue formed (54%)
2007	Smiler et al. ⁷⁹79 Smiler D, Soltan M, Lee JW, et al . A histomorphogenic analysis of bone grafts augmented with adult stem cells. Implant Dent 2007;16:42-53.	BMAC	PepGen Putty or C-Graft		5	7 months	Clinical and histologic	Mineralized tissue formed; (45%)
2007	Zizelmann et al. ⁷¹71 Zizelmann C, Schoen R, Metzger MC, Schmelzeisen R, Schramm A, Dott B, et al . Bone formation after sinus augmentation with engineered bone. Clin Oral Implants Res 2007;18:69-73.	Osteoblast	PLGA		10	3 months	CT	Mineralized tissue formed; High resorption of scaffolds
2008	Pradel et al. ⁷²72 Pradel W, Mai R, Hagedorn GM, Lauer G, Allegrini S, et al . The biomaterial influences the ossification after sinus floor elevation using tissue-engineered bone grafts. Biomedizinische Technik 2008;53:224-228.	Osteoblast	Demineralized bovine bone matrix or from solvent-dehydrated mineralized bovine bone; and graft		6	1 year	Histologic	Mineralized tissue formed. Inflammation and some scaffold resorption was found in 5 months
2008	Shayesteh et al. ⁴⁰40 Shayesteh YS, Khojasteh A, Soleimani M, Alikhasi M, Khoshzaban A, Ahmadbeigi N, et al. Sinus augmentation using human mesenchymal stem cells loaded into a beta-tricalcium phosphate/hydroxyapatite scaffold. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:203-209.	BMMSC	b-TCP/hydroxyapatite		6	12 months	Clinical, radiographic and histologic	Mineralized tissue formed (41.3%)
2008	Yamada et al. ⁴¹41 Yamada Y, Nakamura S, Ito K, Kohgo T, Hibi H, Nagasaka T, et al . Injectable tissue-engineered bone using autogenous bone marrow-derived stromal cells for maxillary sinus augmentation: clinical application report from a 2-6-year follow-up. Tissue Eng Part A 2008;14:1699-1707.	BMMSC	PRP Injectable		12	2-6.3 years: 6.3/ 6.3/ 5.3/ 4.9/ 4.3/ 4.3/ 3.3/ 3.5/ 3.0/ 3.3/ 2.1/ 2.1/ 3.8/ 2.5/ 2.5/ 2.0	Orthopantomograms, histologic, CT	Mineralized tissue formed; increases of 8.8 ± 1.6 mm
2009	Behnia et al. ⁶²62 Behnia H, Khojasteh A, Soleimani M, Tehranchi A, Khoshzaban A, Keshel SH, et al . Secondary repair of alveolar clefts using human mesenchymal stem cells. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:e1-6.	MSC	Demineralized bone mineral and calcium sulfate (Osteoset)		2	4 months	CT	Mineralized tissue formed (34.5%)
2009	D’Aquino et al. ⁵⁸58 d’Aquino R, De Rosa A, Lanza V, Tirino V, Laino L, Graziano A, et al. Human mandible bone defect repair by the grafting of dental pulp stem/progenitor cells and collagen sponge biocomplexes. Eur Cell Mater 2009;18:75-83.	DPSC	Collagen sponge		7	3 months	Histologic and radiographic	Mineralized tissue formed
2009	Mangano et al. ⁷³73 Mangano C , Piattelli A , Mangano A , Mangano F , Mangano A , Iezzi G, et al Combining scaffolds and osteogenic cells in regenerative bone surgery: a preliminary histological report in human maxillary sinus augmentation. Clin Implant Dent Relat Res 2009:11;e92-1e02.	Osteoblasts	PLGA		5	6 months	Clinical, histologic and CT	Mineralized tissue formed; fast resorption of scaffold
2009	McAllister et al. ⁷⁰70 McAllister BS, Haghighat K, Gonshor A, et al. Histologic Evaluation of a Stem Cell-Based Sinus-Augmentation Procedure. J Periodontol 2009;80:679-686.	MSC and osteoprogenitor cells	Bone graft		5	4.1 months	Clinical, radiographic and histologic	Mineralized tissue formed; (vital bone content of 33% - 22% to 40%-)
2010	Lee et al. ⁴²42 Lee J, Sung HM, Jang JD, Park YW, Min SK, Kim EC, et al. Successful reconstruction of 15-cm segmental defects by bone marrow stem cells and resected autogenous bone graft in central hemangioma. J Oral Maxillofac Surg 2010;68:188-194.	BMMSC	Freeze-dried autobone tray and fibrin glue		1	7 months	Histological, clinical and radiographic	Mineralized tissue formed
2010	Sauerbier et al. ⁴³43 Sauerbier S, Stricker A, Kuschnierz J, Buhler F, Oshima T, Xavier SP, et al. In vivo comparison of hard tissue regeneration with human mesenchymal stem cells processed with either the FICOLL method or the BMAC method. Tissue Eng Part C Methods 2010;16:215-223.	BMMSC	FICOLL		4	4,1 months; clinical 2 years	Histologic and clinical	Mineralized tissue formed (19.9% Confidence interval 945% 10.9 to 29%)
2010	Soltan et al. ⁸⁰80 Soltan M, Smiler D, Soltan C, Prasad HS, Rohrer MD, et al. Bone grafting by means of a tunnel dissection: predictable results using stem cells and matrix. Implant Dent 2010;19:280-287.	BMMAC	Resorbable hydroxylapatite OR Allograft		2	4-6 months	Histologic and radiographic	Mineralized tissue formed (34% to 45%)
2010	Mangano et al. ⁶⁹69 Mangano C, Piattelli A, Tettamanti L, Mangano F, Mangano A, Borges F, et al . Engineered bone by autologous osteoblasts on polymeric scaffolds in maxillary sinus augmentation: histologic report. J Oral Implantol2010;36:491-496.	Osteoblasts	PLGA		1	6 months	Histologic and CT	Mineralized tissue formed (28.89% bone and 71.11% medullary spaces)
2011	Brunelli et al. ⁵⁹59 Brunelli G, Motroni A, Carinci F, Graziano A, D’aquino R, Zollino I, et al. Sinus lift augmentation using autologous pulp stem cells: Case report of bone density evaluation. J Inflamm (Lond) 2011;9:31-35.	DPSC	Collagen sponge		1	4 months	Clinical, radiographic and histologic	Mineralized tissue formed
2011	Graziano et al. ³⁶36 Graziano A, D’aquino R, Brunelli G, Fanali S, Carinci F, et al. Sinus lift augmentation using pulp stem cells: A case report and histological evaluation. J Inflamm (Lond) 2011;9.	DPSC	Collagen sponge		1	6 months	Clinical and radiographic	Mineralized tissue formed
2011	Montesani et al. ⁶⁸68 Montesani L, Schulze-Spate U, Dibart S, et al. Sinus augmentation in two patients with severe posterior maxillary height atrophy using tissue-engineered bone derived from autologous bone cells: a case report. Int J Periodontics Restorative Dent 2011;31:391-399.	osteoblast and periosteal cells	nonwoven polyglactin-910 fibers connected by poly-p-dioxanon bonding		2	12 months	Clinical and radiographic	Mineralized tissue formed
2011	Rickert et al. ⁴⁹49 Rickert D, Sauerbier S, Nagursky H, Menne D, Vissink A, Raghoebar GM, et al. Maxillary sinus floor elevation with bovine bone mineral combined with either autogenous bone or autogenous stem cells: a prospective randomized clinical trial. Clin Oral Implants Res 2011;22:251-258.	BMMSC	BioOsss and autogenous stem cells (Test); BioOsss mixed with autogenous bone (Control)		12	14.8 weeks 3-4 months	Histologic	Mineralized tissue formed; test group presented more bone formation than control
2011	Sauerbier et al. ⁸¹81 Sauerbier S, Rickert D, Gutwald R, Nagursky H, Oshima T, Xavier SP, et al . Bone marrow concentrate and bovine bone mineral for sinus floor augmentation: a controlled, randomized, single-blinded clinical and histological trial-per-protocol analysis. Tissue Eng Part A 2011;17:2187-2197.	BMAS	Autogenous bone combination with a bovine bone mineral		26	biopsies 3-4 month	Histologic	Mineralized tissue formed (12.6% ± 1.7%)
2011	Schmelzeisen et al. ⁸²82 Schmelzeisen R, Gutwald R, Oshima T, Nagursky H, Vogeler M, Sauerbier S, et al Making bone II: maxillary sinus augmentation with mononuclear cells-case report with a new clinical method. British Journal of Oral & Maxillofacial Surgery 2011;49:480-482.	BMAC	FICOLL		1	3 months	Histologic	Mineralized tissue formed (26.9%); no signs of inflammation
2012	Behnia et al. ⁶³63 Behnia H, Khojasteh A, Soleimani M, Tehranchi A, Atashi A, et al . Repair of alveolar cleft defect with mesenchymal stem cells and platelet derived growth factors: a preliminary report. J Craniomaxillofac Surg 2012;40:2-7.	MSC	Synthetic biphasic bone substitute	PDGF	3	3 months	CT	Mineralized tissue formed (51.3%)
2012	Hernández-Alfaro et al. ⁸³83 Hernandez-Alfaro F, Ruiz-Magaz V, Chatakun P, Guijarro-Martinez R, et al. Mandibular reconstruction with tissue engineering in multiple recurrent ameloblastoma. Int J Periodontics Restorative Dent 2012;32:e82-e86.	BMAC	Bovine HA	rhBMP-7	1	1 year	Histologic, clinical and radiographic	Mineralized tissue formed
2012	Soltan et al. ⁷⁴74 Soltan M, Rohrer MD, Prasad HS. Monocytes: super cells for bone regeneration. Implant Dent 2012;21:13-20.	Concentrated of monocytes	Demineralized allograft material		2	1 year	Radiographic and histologic	Mineralized tissue formed
2012	Nagata et al. ⁶⁷67 Nagata M, Hoshina H, Li M, Arasawa M, Uematsu K, Ogawa S, et al. A clinical study of alveolar bone tissue engineering with cultured autogenous periosteal cells: coordinated activation of bone formation and resorption. Bone2012;50:1123-1129.	Periosteal	Autogenous bone and PRP		25	1 year	CT	Mineralized tissue formed
2013	Giuliani et al. ⁶6 Giuliani A, Manescu A, Langer M, Rustichelli F, Desiderio V, Paino F, et al. Three years after transplants in human mandibles, histological and in-line holotomography revealed that stem cells regenerated a compact rather than a spongy bone: biological and clinical implications. Stem Cells Transl Med 2013;2:316-324.	DPSC	Collagen sponge		7	3 years	Histologic and radiographic	Mineralized tissue formed
2013	Kaigler et al. ⁴⁴44 Kaigler D, Pagni G, Park CH, Braun TM, Holman LA, Yi E, et al. Stem cell therapy for craniofacial bone regeneration: a randomized, controlled feasibility trial. Cell transplantat 2013;22:767-777.	BMMSC	Absorbable gelatin sponge		N=12 Control=12	1 year	Clinical, radiographic, CT and histologic	Mineralized tissue formed; therapy accelerated alveolar bone regeneration
2013	Sandor et al. ⁵⁷57 Sandor GK, Tuovinen VJ, Wolff J, Patrikoski M, Jokinen J, Nieminen E, et al. Adipose stem cell tissue-engineered construct used to treat large anterior mandibular defect: a case report and review of the clinical application of good manufacturing practice-level adipose stem cells for bone regeneration. J Oral Maxillofac Surg2013;71:938-950.	ASC	b-TCP	rhBMP-2	1	10 months	Histological	Mineralized tissue formed
2013	Yamada et al. ⁴⁶46 Yamada Y, Hara K, Nakamura S, Ueda M, Ito K, Nagasaka T, et al. Minimally invasive approach with tissue engineering for severe alveolar bone atrophy case. Int J Oral Maxillofac Surg 2013;42:260-263.	BMMSC	Membran + PRP Injetável		1	24 months	Histological, CT and radiographic	Mineralized tissue formed
2013	Yamada et al. ⁴⁵45 Yamada Y, Nakamura S, Ito K, Umemura E, Hara K, Nagasaka T, et al. . Injectable bone tissue engineering using expanded mesenchymal stem cells. Stem Cells 2013;31:572-580.	BMMSC	PRP Injectable			3 months	Clinical	Mineralized tissue formed.; all patients improved bone tissue
2013	Zamiri et al. ⁴⁷47 Zamiri B, Shahidi S, Eslaminejad MB, Khoshzaban A, Gholami M, Bahramnejad E, et al . Reconstruction of human mandibular continuity defects with allogenic scaffold and autologous marrow mesenchymal stem cells. J Craniofac Surg2013;24:1292-1297.	BMMSC	Bone Human cadavers (allograft)		3	6 months	CT	Mineralized tissue formed
2014	Marx et al. ⁸⁴84 Marx RE, Harrell DB, et al . Translational research: The CD34+ cell is crucial for large-volume bone regeneration from the milieu of bone marrow progenitor cells in craniomandibular reconstruction. Int J Oral Maxillofac Implants 2014;29:e201-e209.	BMAC	Collagen sponge	rhBMP-2	40	6 months	Clinical, CT, radiographic and histologic	Mineralized tissue formed; Patients that received cells presented more bone formation
2014	Rajan et al. ⁴⁸48 Rajan A, Eubanks E, Edwards S, Aronovich S, Travan S, Rudek I, et al. Optimized cell survival and seeding efficiency for craniofacial tissue engineering using clinical stem cell therapy. Stem Cells Transl Med 2014;3:1495-1503.	BMMSC	b-TCP		1	biopsy 4 months; and 6 months follow-up	CT and histologic	Mineralized tissue formed; 80% of the original jawbone
2014	Rickert et al. ⁵⁰50 Rickert D, Vissink A, Slot WJ, Sauerbier S, Meijer HJ, Raghoebar GM, et al. Maxillary sinus floor elevation surgery with BioOss(R) mixed with a bone marrow concentrate or autogenous bone: test of principle on implant survival and clinical performance. Int J Oral Maxillofac Surg 2014;43:243-247.	BMMSC	BioOss + MSCs and BioOss + autogenous bone		12	1 year	Clinical and radiographic	Mineralized tissue formed; 3 implant (91%) failed in osteointegration
2014	Wildburger et al. ⁵¹51 Wildburger A, Payer M, Jakse N, Strunk D, Etchard-Liechtenstein N, Sauerbier S, et al . Impact of autogenous concentrated bone marrow aspirate on bone regeneration after sinus floor augmentation with a bovine bone substitute - a split-mouth pilot study. Clin Oral Implants Res 2014;25:1175-1181.	BMMSC	Bio-Oss		7	3 and 6 months	Histological and CT	Mineralized tissue formed (13.5%)
2015	Bertolai et al. ⁵²52 Bertolai R, Catelani C, Aversa A, Rossi A, Giannini D, Bani D, et al. Bone graft and mesenchimal stem cells: clinical observations and histological analysis. Clin Cases Miner Bone Metab 2015;12:183-187.	BMMSC	PRP and corticocancellous freeze-dried bone chips		20	3 months	Histological and clinical	Mineralized tissue formed
2015	Park et al. ⁵³53 Park JS, Kim BC, Kim BH, Lee JI, Lee J, et al. Up-and-coming mandibular reconstruction technique with autologous human bone marrow stem cells and iliac bone graft in patients with large bony defect. J Craniofac Surg 2015;26:e718-e720.	BMMSC	Bone from the iliac crest; collagenous membrane		1	1 year	Clinical and radiographic	Mineralized tissue formed
2015	Kaigler et al. ⁵⁴54 Kaigler D, Avila-Ortiz G, Travan S, Taut AD, Padial-Molina M, Rudek I, et al . Bone Engineering of Maxillary Sinus Bone Deficiencies Using Enriched CD90+ Stem Cell Therapy: A Randomized Clinical Trial. J Bone Miner Res 2015;30:1206-1216.	BMMSC	b-TCP		Test=13; Control=13	1 year	Clinical, radiographic, and histologic	Mineralized tissue formed (12.2% ±3.3)
2015	Pasquali et al. ⁸⁵85 Pasquali PJ, Teixeira ML, de Oliveira TA, de Macedo LGS, Aloise AC, Pelegrine AA, et al . Maxillary Sinus Augmentation Combining Bio-Oss with the Bone Marrow Aspirate Concentrate: A Histomorphometric Study in Humans. Int J Biomater 2015: 121286.	BMAC	Bio-Oss		8	6 months	Histologic	Mineralized tissue formed (55.15 ± 20.91)

Year	Author	Cells	Scaffold	Growth factor	Patients	Follow-up	Parameters	Outcome
2006	Yamada et al. ⁵⁵55 Yamada Y, Ueda M, Hibi H, Baba S, et al A novel approach to periodontal tissue regeneration with mesenchymal stem cells and platelet-rich plasma using tissue engineering technology: A clinical case report. Int J Periodontics Restorative Dent 2006;26:363-369.	BMMSC	PRP Injectable	-	1	1 year	Clinical and Radiographic	Bone defects reduced; Reduction on probing depths and gain on clinical attachment
2009	Okuda et al. ⁶⁶66 Okuda K, Yamamiya K, Kawase T, Mizuno H, Ueda M, Yoshie H, et al. Treatment of human infrabony periodontal defects by grafting human cultured periosteum sheets combined with platelet-rich plasma and porous hydroxyapatite granules: case series. J Int Acad Periodontol 2009;11:206-213.	Periosteal	PRP with HA granules	-	3	6 months	Clinical and Radiographic	Radiographic deposition of bone, clinical attachment gain
2010	Feng et al. ⁶⁰60 Feng F, Akiyama K, Liu Y, Yamaza T, Wang TM, Chen JH, et al. Utility of PDL progenitors for in vivo tissue regeneration: a report of 3 cases. Oral Diseases2010;16:20-28.	PDLP	Bone Grafting material Calcitite	-	3	32-72 month	Clinical	Decrease in tooth movement and probing depth and attachment gain
2011	McAllister et al. ⁵⁶56 McAllister BS, et al. Stem cell-containing allograft matrix enhances periodontal regeneration: case presentations. Int J Periodontics Restorative Dent 2011;31:149-155.	MMSC and osteoblast	Allograft bone matrix from cadavers	-	2	6 months	Clinical and radiographic	Radiographic bone deposition and decrease of probing depth
2013	Sankaranar et al. ⁷⁶76 Sankaranarayanan S, Jetty N, Gadagi JS, Preethy S, Abraham SJ, et al . Periodontal regeneration by autologous bone marrow mononuclear cells embedded in a novel thermo reversible gelation polymer. J Stem Cells 2013;8:99-103.	MNC	Thermo-reversible gelation polymer	-	1	36 months	Clinical and Radiographic	Bone height was observed radiographically. Reduction of probing pocket depth, improve of clinical attachment
2014	Aimetti et al. ¹²12 Aimetti M, Ferrarotti F, Cricenti L, Mariani GM, Romano F, et al. Autologous dental pulp stem cells in periodontal regeneration: a case report. Int J Periodontics Restorative Dent 2014;34:s27-33.	DPSC	Collagen sponge	-	1	1 year	Clinical and radiographic	Bone increase was observed by radiographic
2015	Yamada et al. ⁶⁴64 Yamada Y, Nakamura S, Ueda M, Ito K, et al. Papilla regeneration by injectable stem cell therapy with regenerative medicine: long-term clinical prognosis. J Tissue Eng Regen Med 2015;9:305-309.	MSC	PRP and Hyaluronic Acid	-	1		Clinical	Volume of papilla increase

Year	Author	Scaffold	Growth Factor	Patients	Follow-up	Parameters	Outcome
2003	Nevins et al. ⁸⁶86 Nevins M, Camelo M, Nevins ML, Schenk RK, Lynch SE, et al . Periodontal regeneration in humans using recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and allogenic bone. J Periodontol2003;74:1282-1292.	Demineralized freeze-dried bone allograft	rhPDGF-BB	9	9 mths	Clinical, radiographic and histologic	Probing depth reduction (6.42 mm), clinical attachment level gain 6.17 mm, radiographic fill 2.14 mm; Histological evaluation show periodontal regeneration
2005	Nevins et al. ⁸⁷87 Nevins M, Giannobile WV, McGuire MK, Kao RT, Mellonig JT, Hinrichs JE, et al . Platelet-derived growth factor stimulates bone fill and rate of attachment level gain: results of a large multicenter randomized controlled trial. J Periodontol 2005;76:2205-2215.	b-TCP	rhPDGF-BB	180	6 mths	Clinical and radiographic	Improve bone fill, clinical attachment level and reduce gingival retraction
2006	McGuire et al. ⁹²92 McGuire MK, Scheyer ET, et al. Comparison of recombinant human platelet-derived growth factor-BB plus beta tricalcium phosphate and a collagen membrane to subepithelial connective tissue grafting for the treatment of recession defects: A case series. Int J Periodontics Restorative Dent 2006;26:127-133.	b-TCP and collagen membrane	rhPDGF	7	6 mths	Clinical	Favorable clinical results in all cases
2009	Mcguire et al. ⁹³93 McGuire MK, Scheyer ET, Schupbach P, et al. Growth factor-mediated treatment of recession defects: a randomized controlled trial and histologic and microcomputed tomography examination. J Periodontol2009;80:550-564.	b-TCP with a bioabsorbable collagen	rhPDGF-BB	30	6 mths	Clinical, radiographic and Histologic	Recession depth reduction (-2.9 mm), root coverage (90.8%), recession width reduction. Regeneration of periodontal regeneration, cementum and bone.
2009	Schuckert et al. ⁹⁴94 Schuckert KH, Jopp S, Teoh SH, et al. Mandibular Defect Reconstruction Using Three-Dimensional Polycaprolactone Scaffold in Combination with Platelet-Rich Plasma and Recombinant Human Bone Morphogenetic Protein-2: De Novo Synthesis of Bone in a Single Case. Tissue Eng Part A 2009;15:493-499.	Polycaprolactone and PRP	rhBMP-2	1	6 mths	Radiographic and histologic	Radiographic evidence of bone confirmed by biopsy
2010	Schuckert et al. ⁹⁵95 Schuckert KH, Jopp S, Osadnik M, et al. Modern bone regeneration instead of bone transplantation: a combination of recombinant human bone morphogenetic protein-2 and platelet-rich plasma for the vertical augmentation of the maxillary bone-a single case report. Tissue Eng Part C Methods2010;16:1335-1346.	b-TCP and PRP	rhBMP-2	1	1 yr	CT and histologic
2011	Jayakumar et al. ⁸⁸88 Jayakumar A, Rajababu P, Rohini S, Butchibabu K, Naveen A, Reddy PK, et al . Multi-centre, randomized clinical trial on the efficacy and safety of recombinant human platelet-derived growth factor with -tricalcium phosphate in human intra-osseous periodontal defects. J Clin Periodontol 2011;38:163-172.	b-TCP	rhPDGFBB	54	6 mths	Clinical, radiographic	Bone gain radiographic, clinical attachment gain and reduction on probing depth
2011	Nevins et al. ⁸⁹89 Nevins ML, Reynolds MA, et al . Tissue engineering with recombinant human platelet-derived growth factor BB for implant site development. Compend Contin Educ Dent 2011:32;20-27	b-TCP	rhPDGF-BB	3	5 mths	Clinical, radiographic and histologic	Bone gain radiograph and histologic
2011	Nevins et al. ⁹⁰90 Nevins ML, Camelo M, Schupbach P, Nevins M, Kim SW, Kim DM, et al. Human buccal plate extraction socket regeneration with recombinant human platelet-derived growth factor BB or enamel matrix derivative. Int J Periodontics Restorative Dent 2011;31:481-492.	Mineral collagen bone substitute	rhPDGF-BB	16	5 mths	Clinical, radiographic and Histologic	Histological bone; histomorphometric shown more new bone with growth-factor
2011	Sohn et al. ⁹⁷97 Sohn DS, Heo JU, Kwak DH, Kim DE, Kim JM, Moon JW, et al. Bone regeneration in the maxillary sinus using an autologous fibrin-rich block with concentrated growth factors alone. Implant Dent2011;20:389-395.	Fibrin-rich blocks	PRGF	53	10 mths	Clinical, radiographic and Histologic	Histological evidence of bone regeneration
2012	Anitua et al. ⁹⁸98 Anitua E, Prado R, Orive G, et al. Bilateral sinus elevation evaluating plasma rich in growth factors technology: a report of five cases. Clin Implant Dent Relat Res2012;14:51-60.	Bovine anorganic bone	PRGF	5	5 mths	Clinical, radiographic and histologic	More vital bone was observed in growth factor group (21.4%) than control (8.4%) even less inflammation. Immunohistochemical show blood vessels
2012	Taschieri et al. ⁹⁹99 Taschieri S, Corbella S, Del Fabbro M, et al. Use of plasma rich in growth factor for schneiderian membrane management during maxillary sinus augmentation procedure. J Oral Implantol 2012;38:621-627.	Deproteinized bovine bone matrix	PRGF	8	6 mths	Clinical and radiographic	Less complication were observed in group treated with PRGF
2013	Desai et al. ⁹⁶96 Desai SC, Sclaroff A, Nussenbaum B, et al. Use of recombinant human bone morphogenetic protein 2 for mandible reconstruction. JAMA Facial Plast Surg 2013;15:204-209.	b-TCP	rhBMP-2	6	12/ 39/ 36/ 50/ 51/ 28 mths	Clinical and radiographic	From 6 patient one develop infection requiring new intervention
2013	Jensen et al. ⁹¹91 Jensen OT, Cottam J, et al. Posterior Maxillary Sandwich Osteotomy combined with sinus grafting with bone morphogenetic Protein-2 for alveolar reconstruction for dental implants: report of four cases. Int J Oral Maxillofac Implants 2013;28:e415-423.	Absorbable collagen sponge OR bone autograft/xenograft	rhBMP-2 OR PDGF-bb	4	3 yrs/ 4 mths/ 4 mths/ 6 mths	Clinical and radiographic	Bone gain major than 13 mm in all patients
2013	Marx et al. ¹³13 Marx RE, Armentano L, Olavarria A, Samaniego J, et al. rhBMP-2/ACS grafts versus autogenous cancellous marrow grafts in large vertical defects of the maxilla: an unsponsored randomized open-label clinical trial. Int J Oral Maxillofac Implants 2013;28:e243-251.	Collagen sponge; cancellous freeze-dried allogeneic bone; PRP	rhBMP-2	20	6 mths	Clinical, radiographic and histologic	Bone formation (54%) and histological bone regeneration
2013	Nevins et al. ³⁷37 Nevins M, Kao RT, McGuire MK, McClain PK, Hinrichs JE, McAllister BS, et al . Platelet-derived growth factor promotes periodontal regeneration in localized osseous defects: 36-month extension results from a randomized, controlled, double-masked clinical trial. J Periodontol 2013;84:456-464.	b-TCP	PDGF-BB	83	36 mths	Clinical and radiographic	Long-term stable clinical and radiographic improvements;
2013	Sclar et al. ¹⁴14 Sclar AG, Best SP. The combined use of rhBMP-2/ACS, autogenous bone graft, a bovine bone mineral biomaterial, platelet-rich plasma, and guided bone regeneration at nonsubmerged implant placement for supracrestal bone augmentation. A case report. Int J Oral Maxillofac Implants2013;28:e272-276.	Collagen sponge, autogenous bone graft, bovine bone mineral, PRP, and guided bone regeneration	rhBMP-2	1	1 yr	Clinical, radiographic and CT	Increase in bone deposition
2014	Maroo et al. ¹⁵15 Maroo S, Murthy KR, et al. Clinical and radiographic evaluation of recombinant human platelet derived growth factor with beta tricalcium phosphate in the treatment of a periodontal intrabony defect. J Indian Soc Periodontol 2014;18:789-793.	b-TCP	rhPDGF	1	9 mths	Clinical and radiographic	Pocket defect was totally filled by mineral tissue
2014	Maroo et al. ¹⁶16 Maroo S, Murthy KR, et al. Treatment of periodontal intrabony defects using beta-TCP alone or in combination with rhPDGF-BB: a randomized controlled clinical and radiographic study. Int J Periodontics Restorative Dent 2014;34:841-847.	b-TCP	rhPDGF-BB	15	9 mths	Clinical and radiographic	Pocket depth reduction, clinical attachment gain, alveolar crest gain

Year	Author	PRP/PRF	Regeneration	Scaffold /intervention	Control	Patients	Follow-up	Parameters	Outcome
2004	Hanna et al. ¹⁷⁶176 Hanna R, Trejo PM, Weltman RL, et al. Treatment of intrabony defects with bovine-derived xenograft alone and in combination with platelet-rich plasma: A randomized clinical trial. J Periodontol2004;75:1668-1677.	PRP	Periodontal	Bovine derived xenograft	Bone graft	30	6 mths	Clinical and radiographic	PRP improve the results: CAL and PD
2005	Okuda et al. ¹⁷⁷177 Okuda K, Tai H, Tanabe K, Suzuki H, Sato T, Kawase T, et al. Platelet-rich plasma combined with a porous hydroxyapatite graft for the treatment of intrabony periodontal defects in humans: A comparative controlled clinical study. J Periodontol 2005;76:890-898.	PRP	Periodontal	HA	HA	35	12 mths	Clinical and radiographic	Group with PRP show better results
2008	Keceli et al. ¹⁹⁵195 Keceli HG, Sengun D, Berberolu A, Karabulut E. Use of platelet gel with connective tissue grafts for root coverage: a randomized-controlled trial. J Clin Periodontol2008;35: 255-262.	PRP	Periodontal	Connective tissue graft	Connective tissue graft	40	12 mths	Clinical	No differences with addiction of PRP
2008	Piemontese et al. ¹⁷⁸178 Piemontese M, Aspriello SD, Rubini C, Ferrante L, Procaccini M, et al. Treatment of periodontal intrabony defects with demineralized freeze-dried bone allograft in combination with platelet-rich plasma: A comparative clinical trial. J Periodontol 2008;79:802-810.	PRP	Periodontal	Demineralized freeze-dried bone allograft	Demineralized freeze-dried bone allograft	30	12 mths	Clinical and radiographic	Greater changes in PD reduction and CAL
2009	Harnack et al. ¹⁹⁶196 Harnack L, Boedeker RH, Kurtulus I, Boehm S, Gonzales J, Meyle J, et al. Use of platelet-rich plasma in periodontal surgery-a prospective randomised double blind clinical trial. Clin Oral Investig 2009;13:179-1787.	PRP	Periodontal	b-TCP	b-TCP	22	6 mths	Clinical and radiographic	PRP did not improve the results
2009	Pradeep et al. ¹⁸18 Pradeep AR, Pai S, Garg G, Devi P, Shetty SK, et al. A randomized clinical trial of autologous platelet-rich plasma in the treatment of mandibular degree II furcation defects. J Clin Periodontol2009;36:581-588.	PRP	Periodontal	PRP alone	Open flap debridement	20	6 mths	Clinical and radiographic	PRP improve the results: CAL and PD
2009	Torres et al. ¹⁸⁰180 Torres J, Tamimi F, Martinez PP, Alkhraisat MH, Linares R, Hernandez G, et al. Effect of platelet-rich plasma on sinus lifting: a randomized-controlled clinical trial. J Clin Periodontol 2009;36:677-687.	PRP	Bone	Anorganic bovine bone	Anorganic bovine bone	87	24 mths	Clinical, radiographic and histologic	No differences; graft resorption was similar treatment and control
2009	Markou et al. ¹⁷⁹179 Markou N, Pepelassi E, Vavouraki H, Stamatakis HC, Nikolopoulos G, Vrotsos I, et al. Treatment of Periodontal Endosseous Defects With Platelet-Rich Plasma Alone or in Combination With Demineralized Freeze-Dried Bone Allograft: A Comparative Clinical Trial. J Periodontol 2009;80:1911-1919.	PRP	Periodontal	Demineralized freeze-dried bone allograft	PRP alone	24	6 mths	Clinical and radiographic	PRP not improve significantly the treatment
2010	Alissa et al. ¹⁸¹181 Alissa R, Esposito M, Horner K, Oliver R, et al. The influence of platelet-rich plasma on the healing of extraction sockets: an explorative randomised clinical trial. Eur J Oral Implantol 2010;3:121-134.	PRP	Bone	PRP	-	20	3 mths	Clinical and radiographic	PRP show better bone trabecular pattern
2010	Arenaz-Búa et al. ¹⁸²182 Arenaz-Bua J, Luaces-Rey R, Sironvalle-Soliva S, Otero-Rico A, Charro-Huerga E, Patino-Seijas B, et al. A comparative study of platelet-rich plasma, hydroxyapatite, demineralized bone matrix and autologous bone to promote bone regeneration after mandibular impacted third molar extraction. Med Oral Patol Oral Cir Bucal2010;15:e483-489.	PRP	Bone	Synthetic calcium HA or autologous bone OR PRP alone OR allogeneic demineralized bone matrix	Anny material or PRP alone	82	6 mths	Clinical and radiographic	Greatest bone formation was observed in PRP + autologous bone
2010	Badr et al. ¹⁹⁷197 Badr M, Coulthard P, Alissa R, Oliver R. The efficacy of platelet-rich plasma in grafted maxillae. A randomised clinical trial. Eur J Oral Implantol2010;3:233-244.	PRP	Bone	Bone graft	Bone graft	22	5-6 mths	Clinical	Improve in the results was not observed with use of PRP
2011	Sharma et al. ¹⁸⁴184 Sharma A, Pradeep AR, et al. Treatment of 3-wall intrabony defects in patients with chronic periodontitis with autologous platelet-rich fibrin: a randomized controlled clinical trial. J Periodontol2011;82:1705-1712.	PRF	Periodontal	PRF with conventional open-flap debridement	Conventional open-flap debridement alone	42	9 mths	Clinical and radiographic	Highest percentage of bone fill was found in PRF group
2011	Yilmaz et al. ¹⁸⁵185 Yilmaz S, Kabadayi C, Ipci SD, Cakar G, Kuru B, et al. Treatment of intrabony periodontal defects with platelet-rich plasma versus platelet-poor plasma combined with a bovine-derived xenograft: a controlled clinical trial J Periodontol 2011;82:837-844.	PRP	Periodontal	PRP	PPP with Bovine-derived xenograft	20	12 mths	Clinical and radiographic	PPP demonstrated similar efficacy to PRP
2011	Thorat et al. ¹⁸⁶186 Thorat M, Pradeep AR, Pallavi B, et al. Clinical effect of autologous platelet-rich fibrin in the treatment of intra-bony defects: a controlled clinical trial. J Clin Periodontol2011;38:925-932.	PRF	Periodontal	PRF	Conventional open flap debridement alone	40	9 mths	Clinical and radiographic	PRF was better in all clinical and radiographic parameters
2012	Menezes et al. ¹⁸⁷187 Menezes LM, Rao J, et al. Long-term clinical evaluation of platelet-rich plasma in the treatment of human periodontal intraosseous defects: A comparative clinical trial. Quintessence Int 2012;43:571-582.	PRP	Periodontal	Porous HA and PRP	Porous HA	60	4 yrs	Clinical and radiographic	PRP improve the results
2012	Pradeep et al. ¹⁸⁸188 Pradeep AR, Rao NS, Agarwal E, Bajaj P, Kumari M, Naik SB, et al. Comparative evaluation of autologous platelet-rich fibrin and platelet-rich plasma in the treatment of 3-wall intrabony defects in chronic periodontitis: a randomized controlled clinical trial. J Periodontol2012;83:1499-1507.	PRP and PRF	Periodontal	PRP or PRF with open-flap debridement or autologous	Open-flap debridement alone	54	9 mths	Clinical and Radiographic	PD and CAL were better in PRF followed by PRP. Bone fill was more observed in PRF group
2013	Bajaj et al. ¹⁸⁹189 Bajaj P, Pradeep AR, Agarwal E, Rao NS, Naik SB, Priyanka N, et al. Comparative evaluation of autologous platelet-rich fibrin and platelet-rich plasma in the treatment of mandibular degree II furcation defects: a randomized controlled clinical trial. J Periodontal Res 2013;48:573-581.	PRP and PRF	Periodontal	PRP or PRF with open-flap debridement	Open-flap debridement alone	42	9 mths	Clinical and radiographic	CAL were better in PRF and PRP. No differences were observed among PRP and PRF
2013	Khairy et al. ¹⁹⁸198 Khairy NM, Shandy EE, Askar NA, El-Rouby DH, et al. Effect of platelet rich plasma on bone regeneration in maxillary sinus augmentation (randomized clinical trial). Int J Oral Maxillofac Surg 2013;42:249-255.	PRP	Bone	PRP with autogenous bone	Autogenous bone	15	6 mths	Clinical, radiographic and histologic	PRP group show more bone density
2013	Hauser et al. ¹⁹⁰190 Hauser F, Gaydarov N, Badoud I, Vazquez L, Bernard JP, Ammann P, et al. Clinical and histological evaluation of postextraction platelet-rich fibrin socket filling: a prospective randomized controlled study. Implant Dent 2013;22:295-303.	PRF	Bone	PRF or PRF and socket filling	Extraction alone	23	2 mths	Clinical, radiographic and histologic	PRF group shown better results
2014	Eskan et al. ¹⁹¹191 Eskan MA, Greenwell H, Hill M, Morton D, Vidal R, Shumway B, et al. Platelet-rich plasma-assisted guided bone regeneration for ridge augmentation: a randomized, controlled clinical trial. J Periodontol2014;85:661-668.	PRP	Bone	PRP and resorbable polylactide membrane	Resorbable polylactide without PRP	28	4 mths	Clinical, radiographic and histologic	PRP shown more bone gain
2015	Angelo et al. ¹⁹²192 Angelo T, Marcel W, Andreas K, Izabela S. Biomechanical Stability of Dental Implants in Augmented Maxillary Sites: Results of a Randomized Clinical Study with Four Different Biomaterials and PRF and a Biological View on Guided Bone Regeneration. Biomed Res Int 2015;2015:850340.	PRF	Bone	Biphasic (60% HA/40% b-TCP) or monophasic (100% b-TCP)	Bi or monophasic without PRF	82	8.3 mths	Clinical, radiographic and histologic	PRF shown superior mechanical stability to restored alveolar bone
2015	Narang et al. ¹⁴⁴144 Narang I, Mittal N, Mishra N, et al. A comparative evaluation of the blood clot, platelet-rich plasma, and platelet-rich fibrin in regeneration of necrotic immature permanent teeth: A clinical study. Contemp Clin Dent 2015;6:63-68.	PRP and PRF	Pulp	PRP and PRF revascularization	Blood Clot revascularization	15	18 mths	Clinical and radiographic	PRF was superior that PRP. PRF and PRF were better than control group
2015	Pradeep et al. ¹⁹19 Pradeep AR, Nagpal K, Karvekar S, Patnaik K, Naik SB, Guruprasad CN, et al. Platelet-rich fibrin with 1% metformin for the treatment of intrabony defects in chronic periodontitis: a randomized controlled clinical trial. J Periodontol2015;86:729-737.	PRF	Bone and Periodontal	PRF OR PRF with Metformin 1% OR Open-flap debridement with PRF plus 1% metformin	Open-flap debridement alone	120	9 mths	Clinical and radiographic	PRF + 1% MF group showed greater improvements in clinical parameters
2015	Shah et al. ¹⁹⁴194 Shah M, Patel J, Dave D, Shah S.Comparative evaluation of platelet-rich fibrin with demineralized freeze-dried bone allograft in periodontal infrabony defects: A randomized controlled clinical study. J Indian Soc Periodontol2015;19:56-60.	PRF	Periodontal	Open flap debridement and PRF	Open-flap debridement + Demineralized freeze-dried bone allograft	20	6 mths	Clinical and radiographic	Better result observed in PRF group
2015	Kumar et al. ¹⁹³193 Kumar N, Prasad K, Ramanujam L, K R, Dexith J, Chauhan A Evaluation of treatment outcome after impacted mandibular third molar surgery with the use of autologous platelet-rich fibrin: a randomized controlled clinical study. J Oral Maxillofac Surg 2015;73:1042-1049.	PRF	Bone	PRF		31	3 mths	Clinical and radiographic	Bone density was more in PRF group

[1] Correspondence: Flávio Fernando Demarco, Rua Gonçalves Chaves, 457, 96015-560 Pelotas, RS, Brasil. Tel: +55-53-98111-2528. e-mail: ffdemarco@gmail.com

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Bone, Periodontal and Dental Pulp Regeneration in Dentistry: A Systematic Scoping Review

Abstract