Abstract

The aim of presented systematic scoping review was to investigate the actual and future clinical possibilities of regenerative therapies and their ability to regenerate bone, periodontal and pulp with histological confirmation of the nature of formed tissue. Electronic search was conducted using a combination between Keywords and MeSH terms in PubMed, Scopus, ISI-Web of Science and Cochrane library databases up to January 2016. Two reviewers conducted independently the papers judgment. Screened studies were read following the predetermined inclusion criteria. The included studies were evaluated in accordance with Arksey and O’Malley’s modified framework. From 1349 papers, 168 completed inclusion criteria. Several characterized and uncharacterized cells used in Cell Therapy have provided bone regeneration, demonstrating bone gain in quantity and quality, even as accelerators for bone and periodontal regeneration. Synthetic and natural scaffolds presented good cell maintenance, however polyglycolid-polylactid presented faster resorption and consequently poor bone gain. The Growth Factor-Mediated Therapy was able to regenerate bone and all features of a periodontal tissue in bone defects. Teeth submitted to Revascularization presented an increase of length and width of root canal. However, formed tissues not seem able to deposit dentin, characterizing a repaired tissue. Both PRP and PRF presented benefits when applied in regenerative therapies as natural scaffolds. Therefore, most studies that applied regenerative therapies have provided promising results being possible to regenerate bone and periodontal tissue with histological confirmation. However, pulp regeneration was not reported. These results should be interpreted with caution due to the short follow-up periods.

Key Words:
Regenerative therapy; mesenchymal stem cell; tissue engineering; revascularization root canal; scaffolds; cell therapy; platelet-rich fibrin; platelet-rich plasm

Resumo

O objetivo da presente Scoping review foi investigar as possibilidades clínicas atuais e futuras das terapias regenerativas e sua capacidade de regenerar tecido ósseo, periodontal e polpar em humanos com confirmação histológica da natureza do tecido formado. Uma busca eletrônica foi realizada utilizando uma combinação entre as palavras-chave e termos MeSH nos bancos de dados PubMed, Scopus, ISI-web of Science e Cochrane library até janeiro de 2016. Dois revisores realizaram de forma independente o julgamento dos documentos. Os estudos selecionados foram lidos seguindo os critérios de inclusão predeterminados. Os estudos incluídos foram avaliados de acordo com a estrutura modificada de Arksey e O‘Malley. Dos 1349 artigos, 168 preencheram os critérios de inclusão. Várias células caracterizadas e não caracterizadas promoveram regeneração óssea utilizada em terapias celulares, demonstrando ganho ósseo em quantidade e qualidade, de forma rápida para regeneração óssea e periodontal. Os scaffolds sintéticos e naturais apresentaram boa manutenção celular, no entanto o poliglicol-polilácido apresentou uma reabsorção rápida e, consequentemente, pequeno ganho ósseo. A terapia mediada por fatores de crescimento foi capaz de regenerar tecido ósseo e todas as características de um tecido periodontal. Dentes submetidos à revascularização apresentaram aumento do comprimento e largura do canal radicular. No entanto, os tecidos formados não foram capazes de depositar dentina, caracterizando um tecido reparado. Tanto o PRP quanto o PRF parecem apresentar benefícios quando aplicados em terapias regenerativas sendo um bom scaffold natural. Portanto, a maioria dos estudos que aplicaram terapias regenerativas forneceram resultados promissores sendo possível regenerar tecido ósseo e periodontal com confirmação histológica. No entanto, não foi observada regeneração de polpa dental. Estes resultados devem ser interpretados com cautela.

Introduction

Conventional treatments performed on clinical dental practice can restore aesthetic and function after disease or injury, although these treatments do not promote the regeneration of affected structures. In this context, regenerative approaches based on tissue engineering principles aims to restore the natural biological apparatus, which synthetic materials cannot promote ¹1 Langer R, Vacanti JP, et al. Tissue engineering. Science1993;260:920-926.. Since the discovery of mesenchymal stem cells (MSC) in several orals tissues ²2 Gronthos S, Mankani M, Brahim J, Robey PG, Shi S, et al. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A 2000;97:13625-13630.^,33 Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A 2003;100:5807-5812.^,44 Seo BM, Miura M , Gronthos S Bartold PM, Batouli S, Brahim J, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet2004;364:149-155.^,55 Vollner F, Driemel O, Reichert T, Morsczeck C, et al. Isolation and characterization of dental follicle precursor cells (DFPCs). J Stem Cells Regen Med 2007;2:130., regenerative approaches have been investigated aiming to improve the translational potential of regenerative therapies 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.. Dental MSC are easily available and more accessible when compared to bone marrow mesenchymal stem cells (BMMSC) or embryonic stem cells. MSC from the dental pulp (DPSC) of exfoliated deciduous teeth (SHED) rise as an option which could contribute to the development of tooth banks for future clinical applications ⁷7 Demarco FF, Conde MC, Cavalcanti BN, Casagrande L, Sakai VT, Nor JE, et al. Dental pulp tissue engineering. Braz Dent J 2011;22:3-13.^,88 Conde MC, Chisini LA, Grazioli G, Francia A, Carvalho RV, Alcazar JC, et al. Does cryopreservation affect the biological properties of stem cells from dental tissues? a systematic review. Braz Dent J2016;27:633-640.. Such MSC are able to originate mesodermal-derived cell line ⁹9 Liu J, Yu F, Sun Y, Jiang B, Zhang W, Yang J, et al. Concise reviews: Characteristics and potential applications of human dental tissue-derived mesenchymal stem cells. Stem Cells2015;33:627-638. providing, osteoblastic 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., odontoblastic ¹⁰10 Chisini LA, Conde MC, Alcazar JC, Silva AF, Nor JE, Tarquinio SB, et al. Immunohistochemical expression of TGF-beta1 and Osteonectin in engineered and Ca(OH)2-repaired human pulp tissues. Braz Oral Res 2016;30:e93.^,1111 Conde MC, Chisini LA, Demarco FF, Nor JE, Casagrande L, Tarquinio SB, et al. Stem cell-based pulp tissue engineering: variables enrolled in translation from the bench to the bedside, a systematic review of literature. Int Endod J2016;49:543-550. and periodontal cell lineages 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..

Regenerative therapies can be classified in three distinctive approaches that are often used together; the first one relies on the implantation of previously isolated and expanded MSC, which are seeded on scaffolds. This approach is named “stem cell-based therapies” (SC-BT) or just Cell-Based Therapies (C-BT), when differentiated cells are implanted ¹¹11 Conde MC, Chisini LA, Demarco FF, Nor JE, Casagrande L, Tarquinio SB, et al. Stem cell-based pulp tissue engineering: variables enrolled in translation from the bench to the bedside, a systematic review of literature. Int Endod J2016;49:543-550.. The second one, named “Growth Factor-Mediated Therapies” (GF-MT), relies on the ability of scaffolds and implanted growth factors (GF) to attract MSC to the damaged site 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.^,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.^,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.^,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.. The third one, is based in the bioactivity of scaffolds charged (or not) with biomolecules able to provide appropriate adhesion and proliferation of implanted or recruited cells ⁷7 Demarco FF, Conde MC, Cavalcanti BN, Casagrande L, Sakai VT, Nor JE, et al. Dental pulp tissue engineering. Braz Dent J 2011;22:3-13.^,1111 Conde MC, Chisini LA, Demarco FF, Nor JE, Casagrande L, Tarquinio SB, et al. Stem cell-based pulp tissue engineering: variables enrolled in translation from the bench to the bedside, a systematic review of literature. Int Endod J2016;49:543-550..

Venous blood derivatives such as Platelet-Rich Plasma (PRP) and Platelet-Rich Fibrin (PRF), contains high concentrations of transforming growth factor-beta (TGF-b), vascular endothelial growth factor (VEGF), epithelial growth factor (EGF) and insulin-like growth factor I ¹⁷17 Kawase T, et al. Platelet-rich plasma and its derivatives as promising bioactive materials for regenerative medicine: basic principles and concepts underlying recent advances. Odontology2015;103:126-135.. Besides, PRP and PRF application as scaffolds have shown promising clinical results 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.^,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.. PRP comprises the first generation of platelet concentrates; although its inherent biological activity, the need for many centrifugation steps and the addition of xenogeneic thrombin for platelet activation are viewed as hurdles for PRP clinical application ¹⁷17 Kawase T, et al. Platelet-rich plasma and its derivatives as promising bioactive materials for regenerative medicine: basic principles and concepts underlying recent advances. Odontology2015;103:126-135.. Choukroun et al. ²⁰20 Choukroun J, Adda F, Schoeffler C, Vervelle A, et al. Une opportunité en paro-implantologie: le PRF. Implantodontie2001;42. developed the PRF, a second generation of platelet concentrates which requires only one centrifugation step without biochemical blood handling. PRF exhibits a natural support to immunity, guide to angiogenesis and recruitment of MSC ²¹21 Choukroun J, Diss A, Simonpieri A, Girard MO, Schoeffler C, Dohan SL, et al. Platelet-rich fibrin (PRF): a second-generation platelet concentrate. Part IV: clinical effects on tissue healing. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101:e56-60.^,2222 Dohan DM, Choukroun J, Diss A, Dohan SL, Dohan AJ, Mouhyi J, et al. Platelet-rich fibrin (PRF): a second-generation platelet concentrate. Part II: platelet-related biologic features. Oral Surg Oral Med Oral Pathol Oral Radiol Endod2006;101:e45-50.. PRP and PRF have been largely used in both, surgeries for bone repair and root canal revascularization (RCR) in immature permanent teeth with necrotic pulp ²³23 Bezgin T, Yilmaz AD, Celik BN, Kolsuz ME, Sonmez H, et al. Efficacy of Platelet-rich Plasma as a Scaffold in Regenerative Endodontic Treatment. J Endod2015;41:36-44.^,2424 Jadhav GR, Shah D, Raghvendra SS, et al. Autologus Platelet Rich Fibrin aided Revascularization of an immature, non-vital permanent tooth with apical periodontitis: A case report. J Nat Sci Biol Med2015;6:224-225.. RCR is based on blood clot formation into the root canal, previously decontaminated with a triple antibiotic paste ²³23 Bezgin T, Yilmaz AD, Celik BN, Kolsuz ME, Sonmez H, et al. Efficacy of Platelet-rich Plasma as a Scaffold in Regenerative Endodontic Treatment. J Endod2015;41:36-44.^,2525 Conde MC , Chisini LA , Sarkis-Onofre R, Schuch HS, Nor JE , Demarco FF , et al. A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. Int Endod J 2017;50:860-874.. Therefore, stem cells present in the apical papilla can migrate to scaffold formed by blood clot and, thus, restore the pulp or perform the tissue’s maturation ²⁵25 Conde MC , Chisini LA , Sarkis-Onofre R, Schuch HS, Nor JE , Demarco FF , et al. A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. Int Endod J 2017;50:860-874.^,2626 Wigler R, Kaufman AY, Lin S, Steinbock N, Hazan-Molina H, Torneck CD, et al. Revascularization: a treatment for permanent teeth with necrotic pulp and incomplete root development. J Endod2013;39:319-326..

Despite regenerative therapies being a new field in dentistry, this knowledge remains far away from clinical practice. Thus, the aim of this study was to perform a systematic scoping review exploring the actual and future clinical application of regenerative therapies emphasizing bone, periodontal and pulp regeneration with histological confirmation of formed-tissue’s nature.

Material and Methodos

Study Design

The present scoping study was conducted following the modified five-stage framework suggested by Arksey and O’Malley ²⁷27 Arksey H, O’Malley L. Scoping studies: towards a methodological framework, et al . Int J Soc Res Methodol 2005;8:19-32. named Scoping Review. Newly, numerous papers use Scoping Review to state the actual knowledge in a particular area to provide a concise qualitative analysis ²⁵25 Conde MC , Chisini LA , Sarkis-Onofre R, Schuch HS, Nor JE , Demarco FF , et al. A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. Int Endod J 2017;50:860-874.^,2828 Chisini LA , Conde MC M, Grazioli G, Martin ASS, Carvalho RV, Nor JE , et al. Venous blood derivatives as fbs-substitutes for mesenchymal stem cells: a systematic scoping review. Braz Dent J 2017;28:657-668.. About the search strategy, the scoping study is indistinguishable to systematic reviews, directing a systematic and reproducible search. Yet, the main of scoping study is frequently address a wide topic or area and analyze individually the methodological quality in the included papers seeking from different methodologies wide generalizations. Thus, providing an overview of the current knowledge founding conclusions and tendencies from the general data. In addition, other objective of scoping reviews is to identify the literature gaps directing future researches.

Conceptual Definition

According to MeSH database, cell-and tissue-based therapy was defined in 2014 as “Therapies that involve the transplantation of cells or tissues developed for the purpose of restoring the function of diseased or dysfunctional cells or tissues”. Hence, several tissues and cell lineages have been used for this propose being introduced into a patient. Their origin for cell therapy can be autogenic or allogeneic. Although the Growth factor-Mediated therapy is not described in the MeSH terms, this therapy can be described as the therapy that aims to employ growth factors to modulate and control the cells and tissues presents in the patient, being the location and the delivery key points of the therapy ²⁹29 Hajimiri M, Shahverdi S, Kamalinia G, Dinarvand R, et al . Growth factor conjugation: strategies and applications. J Biomed Mater Res A 2015;103:819-838.. Root Canal Revascularization can be defined as regenerative procedure aiming to re-vascularize the pulp tissue and it’s structure with the recruitment of stem cells from apical papilla ²⁵25 Conde MC , Chisini LA , Sarkis-Onofre R, Schuch HS, Nor JE , Demarco FF , et al. A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. Int Endod J 2017;50:860-874.. This procedure is a new treatment option for necrotic immature permanent teeth based on the formation of blood clot into the root canal space. Thus, forming a natural scaffold for anchorage of stem cells, able to promote and contribute to the continuation of root development ²⁵25 Conde MC , Chisini LA , Sarkis-Onofre R, Schuch HS, Nor JE , Demarco FF , et al. A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. Int Endod J 2017;50:860-874..

Search strategy: The structured research was conducted in PubMed, Scopus, Web of Science and Cochrane Library up to January 2016. Mesh terms, commonly used terms, and synonyms were included as part of the search (S1). An extensive combination of keywords was performed to include all the studies of interest (S2). The keywords were selected based on the pre-specified question formulated using the P.I.C.O. principle:

To confirm if the selected studies met the predefined inclusion criteria, full-text papers were read by the same reviewers. Persistent disagreement on inclusion, were resolved by intervention from a third reviewer (FFD). All studies included were assessed and data analysis was performed. After that, MCMC and LAC evaluated manually all references reported in each selected study to identify additional records. Gray literature was evaluated manually in Google Scholar and ResearchGate (researchgate.net).

Results

The initial search yielded 2207 articles (39 papers from gray literature or from references of included studies), being 1349 of them considered unique studies (Fig. 1). After title and abstract evaluation, 173 studies were selected for full-text assessment, from which 168 completed inclusion criteria. Detailed reasons for studies’ exclusion ³⁰30 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.^,3131 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.^,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.^,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.^,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.^,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. are presented in Table 1. Four accompaniments studies were identified (6,36-38). Figure 2 shows the distribution of included studies per years.

Cell and Stem Cell-Based Therapies

Forty-nine studies reported C-BT or SC-BT providing periodontal and bone regeneration (Table 2 and 3). BMMSC were the most applied stem cells for SC-BT (39-56) (Fig. 3). Besides, Adipose Stem Cells (ASC) 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., DPSC 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.^,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.^,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.^,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.^,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. and periodontal ligament stem cell (PDLSC) 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.^,6161 Vandana KL, Desai R, Dalvi PJ, et al. Autologous Stem Cell Application in Periodontal Regeneration Technique (SAI-PRT) Using PDLSCs Directly From an Extracted Tooth...An Insight. Int J Stem Cells 2015;8:235-237. were employed. In addition, some studies did not report the tissue of MSC origin (56,62-64). Periosteal cells (65-68), osteoblastic (56,68-73), concentrate of monocytes ⁷⁴74 Soltan M, Rohrer MD, Prasad HS. Monocytes: super cells for bone regeneration. Implant Dent 2012;21:13-20., Mononuclear Cells (MNC) 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.^,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. and Bone Marrow Aspirate Concentrates (BMAC) (77-85) were used also in Cell-based therapy (Fig. 3).

Bone regeneration based on SC-BT and C-BT provided increase of bone deposition when combined with xenogeneic and alloplastic materials 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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.. Synthetic poly (lactic-co-glycolic acid) (PLGA) presented fast resorption rates in the postoperative first weeks 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.^,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.. Autografts 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.^,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.^,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.^,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.^,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.^,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. and allografts 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.^,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.^,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.^,7474 Soltan M, Rohrer MD, Prasad HS. Monocytes: super cells for bone regeneration. Implant Dent 2012;21:13-20.^,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.^,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.^,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. were successfully applied providing cell maintenance and mineral deposition. The Figure 4 illustrates the main scaffolds used and their classification. De novo bone tissue was histologically described generally as being compact without signs of inflammatory reaction. Bone remodeling, with gradual substitution of scaffolds by new-formed bone matrix, was frequently observed 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.^,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.. Autologous bone without cell implantation also presented bone regeneration, however, the bone quality and vitality trend toward less when compared with SC-BT 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.^,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.. Reported follow-ups ranged from three 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. to 75 months 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..

Five studies evaluated the influence of Bone Morphogenetic Protein (BMP) 2 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.^,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., BMP-7 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.^,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. or Platelet Derived Growth Factor (PDGF) 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. for constructs (MSC+Scaffolds) showing an improved potential of regeneration. Large reconstruction of bone defect - six 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., six to eight 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., seven 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., ten 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.,14 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. and 15 cm 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. - were successful conducted employing BMAC, ASC or BMMSC.

Growth Factor-Mediated Treatment (GF-MT)

Twenty-four studies identified used GF-MT, from which nineteen (Table 4) did not combine them with cellular therapies. The GF applied in the selected studies includes PDGF 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.^,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.^,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.^,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.^,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.^,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.^,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.^,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^,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.^,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.^,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.^,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. BMP-2 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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,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., Plasma Rich in Growth Factors (PRGF) 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.^,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.^,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. and BMP-7 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.^,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.. Such GF were reported as safe and effective in the treatment of periodontal and bone defects 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.^,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.^,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.. Besides, the regeneration provided by these GF seems not to be dose dependent, thus a specific GF concentration must be defined since high GF concentration could be harmful for MSC 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.. Wide bone mandible defects (5 to 12 cm) were regenerated by applying BMP-2 and beta-tricalcium phosphate (b-TCP) scaffolds 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.. Histological analysis showed that density of blood vessels seems to be higher in tissues that utilize GF 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..

Root Canal Revascularization

Increase in length and width of root dentin walls and resolution of periapical lesion in immature permanent teeth with necrotic pulp were reported ²³23 Bezgin T, Yilmaz AD, Celik BN, Kolsuz ME, Sonmez H, et al. Efficacy of Platelet-rich Plasma as a Scaffold in Regenerative Endodontic Treatment. J Endod2015;41:36-44.^,100100 Miltiadous ME, Floratos SG, et al. Regenerative endodontic treatment as a retreatment option for a tooth with open apex - a case report. Braz Dent J 2015;26:552-556.^,101101 Sachdeva GS, Sachdeva LT, Goel M, Bala S, et al. Regenerative endodontic treatment of an immature tooth with a necrotic pulp and apical periodontitis using platelet-rich plasma (PRP) and mineral trioxide aggregate (MTA): a case report. Int Endod J 2015;48:902-910.^,102102 Alobaid AS, Cortes LM, Lo J, Nguyen TT, Albert J, Abu-Melha AS, et al. Radiographic and Clinical Outcomes of the Treatment of Immature Permanent Teeth by Revascularization or Apexification: A Pilot Retrospective Cohort Study. J Endod 2014;40:1063-1070.^,103103 Kaya-Buyukbayram I, Ozalp S, Aytugar E, Aydemir S, et al. Regenerative endodontic treatment of an infected immature dens invaginatus with the aid of cone-beam computed tomography. Case Rep Dent 2014;2014:403045.^,104104 Nagata JY, Figueiredo De Almeida Gomes BP, Rocha Lima TF, Murakami LS, De Faria DE, Campos GR, et al. Traumatized immature teeth treated with 2 protocols of pulp revascularization. J Endod 2014;40:606-612.^,405105 Saoud TMA, Sigurdsson A, Rosenberg PA, Lin LM, Ricucci D, et al. Treatment of a large cystlike inflammatory periapical lesion associated with mature necrotic teeth using regenerative endodontic therapy. J Endod2014;40:2081-2086.^,106106 Saoud TM, Zaazou A, Nabil A, Moussa S, Lin LM, Gibbs JL, et al. Clinical and radiographic outcomes of traumatized immature permanent necrotic teeth after revascularization/revitalization therapy. J Endod 2014;40:1946-1952.^,107107 Nevins AJ, Cymerman JJ, et al. Revitalization of open apex teeth with apical periodontitis using a collagen-hydroxyapatite scaffold. J Endod2015;41:966-973.^,108108 Ray HL, Jr., Marcelino J, Braga R, Horwat R, Lisien M, Khaliq S, et al. Long-term follow up of revascularization using platelet-rich fibrin. Dent Traumatol 2015.^,109109 Abduljabbar F, Bakhsh A, Abed H, et al. Revascularization procedure induced maturogenesis of upper permanent incisor. Oral Health Dent Manag 2014;13:831-834.. Besides, tooth under revascularization could respond positively to thermal and electrical sensibility tests ¹¹⁰110 Ding RY, Cheung GSP, Chen J, Yin XZ, Wang QQ, Zhang CF, et al. Pulp Revascularization of Immature Teeth With Apical Periodontitis: A Clinical Study. J Endod 2009;35:745-749.. Hoshino’s triple antibiotic paste (TAP), containing ciprofloxacin, metronidazole and minocycline, was the most applied intracanal medication ²⁴24 Jadhav GR, Shah D, Raghvendra SS, et al. Autologus Platelet Rich Fibrin aided Revascularization of an immature, non-vital permanent tooth with apical periodontitis: A case report. J Nat Sci Biol Med2015;6:224-225.^,110110 Ding RY, Cheung GSP, Chen J, Yin XZ, Wang QQ, Zhang CF, et al. Pulp Revascularization of Immature Teeth With Apical Periodontitis: A Clinical Study. J Endod 2009;35:745-749.^,111111 Banchs F, Trope M, et al. Revascularization of immature permanent teeth with apical periodontitis: New treatment protocol? J Endod2004;30:196-200.^,112112 Jung IY, Lee SJ, Hargreaves KM, et al. Biologically Based Treatment of Immature Permanent Teeth with Pulpal Necrosis: A Case Series. J Endod2008;34:876-887.^,113113 Reynolds K, Johnson JD, Cohenca N, et al. Pulp revascularization of necrotic bilateral bicuspids using a modified novel technique to eliminate potential coronal discolouration: a case report. Int Endod J 2009;42:84-92.^,114114 Kim JH, Kim Y, Shin SJ, Park JW, Jung IY, et al. Tooth discoloration of immature permanent incisor associated with triple antibiotic therapy: a case report. J Endod 2010;36:1086-1091.^,115115 Petrino JA, Boda KK, Shambarger S, Bowles WR, McClanahan SB, et al. Challenges in regenerative endodontics: a case series. J Endod2010;36:536-541.^,116116 Nosrat A, Seifi A, Asgary S, et al. Regenerative endodontic treatment (revascularization) for necrotic immature permanent molars: A review and report of two cases with a new biomaterial. J Endod 2011;37:562-567.^,117117 Aggarwal V, Miglani S, Singla M, et al. Conventional apexification and revascularization induced maturogenesis of two non-vital, immature teeth in same patient: 24 months follow up of a case. J Conserv Dent 2012;15:68-72.^,118118 Dabbagh B, Alvaro E, Vu DD, Rizkallah J, Schwartz S, et al. Clinical Complications in the Revascularization of Immature Necrotic Permanent Teeth. Pediatr Dent 2012;34:414-417.^,,119119 Gelman R, Park H, et al. Pulp revascularization in an immature necrotic tooth: a case report. Pediatr Dent 2012;34:496-499.^,120120 Jeeruphan T, Jantarat J, Yanpiset K, Suwannapan L, Khewsawai P, Hargreaves KM, et al. Mahidol study 1: comparison of radiographic and survival outcomes of immature teeth treated with either regenerative endodontic or apexification methods: a retrospective study. J Endod2012;38:1330-1336.^,121121 Kottoor J, Velmurugan N, et al. Revascularization for a necrotic immature permanent lateral incisor: a case report and literature review. Int J Paediatr Dent 2012;23:310-316.^,122122 Lenzi R, Trope M, et al. Revitalization procedures in two traumatized incisors with different biological outcomes. J Endod2012;38:411-414.^,123123 Narayana P, Hartwell GR, Wallace R, Nair UP, et al. Endodontic clinical management of a dens invaginatus case by using a unique treatment approach: A case report. J Endod 2012;38:1145-1148.^,124124 Nosrat A, Homayounfar N, Oloomi K, et al. Drawbacks and unfavorable outcomes of regenerative endodontic treatments of necrotic immature teeth: A literature review and report of a case. J Endod2012;38:1428-1434.^,125125 Shivashankar VY, Johns DA, Vidyanath S, Ramesh Kumar M, et al. Platelet Rich Fibrin in the revitalization of tooth with necrotic pulp and open apex. J Conserv Dent 2012;15:395-398.^,126126 Chen X, Bao ZF, Liu Y, Liu M, Fin XQ, Xu XB. Regenerative Endodontic Treatment of an Immature Permanent Tooth at an Early Stage of Root Development: A Case Report. J Endod2013;39:719-722.^,127127 Forghani M, Parisay I, Maghsoudlou A, et al. Apexogenesis and revascularization treatment procedures for two traumatized immature permanent maxillary incisors: a case report. Restor Dent Endod 2013;38:178-181.^,128128 Jadhav G, Shah N, Logani A, et al. Comparative outcome of revascularization in bilateral, non-vital, immature maxillary anterior teeth supplemented with or without platelet rich plasma: A case series. J Conserv Dent 2013;16:568-572.^,129129 Kalaskar RR, Kalaskar AR, et al. Maturogenesis of non-vital immature permanent teeth. Contemp Clin Dent 2013;4:268-270.^,130130 Keswani D, Pandey RK, et al. Revascularization of an immature tooth with a necrotic pulp using platelet-rich fibrin: a case report. Int Endod J2013;46:1096-1104.^,131131 Martin G, Ricucci D, Gibbs JL, Lin LM, et al. Histological findings of revascularized/revitalized immature permanent molar with apical periodontitis using platelet-rich plasma. J Endod2013;39:138-144.^,132132 Mishra N, Narang I, Mittal N, et al. Platelet-rich fibrin-mediated revitalization of immature necrotic tooth. Contemp Clin Dent 2013;4:412-415.^,133133 Sonmez IS, Oba AA, Almaz ME, et al. Revascularization/Regeneration Performed in Immature Molars: Case Reports. J Clin Pediatr Dent 2013;37:231-234.^,134134 Wang HJ, Chen YHM, Chen KL, et al. Conservative treatment of immature teeth with apical periodontitis using triple antibiotic paste disinfection. J Dent Sci2013.^,135135 Yang J, Zhao Y, Qin M, Ge L, et al. Pulp revascularization of immature dens invaginatus with periapical periodontitis. J Endod2013;39:288-292.^,136136 Chandran V, Chacko V, Sivadas G, et al. Management of a nonvital young permanent tooth by pulp revascularization. Int J Clin Pediatr Dent 2014;7:213-216.^,137137 Jadhav GR, Shah N, Logani A, et al. Platelet-rich plasma supplemented revascularization of an immature tooth associated with a periapical lesion in a 40-year-old man. Case Rep Dent2014;2014:479584.^,138138 Nagaveni NB, Poornima P, Joshi JS, Pathak S, Nandini DB, et al. Revascularization of immature, nonvital permanent tooth using platelet-rich fibrin in children. Pediatr Dent 2015;37:1-6.^,139139 Solomon RV, Faizuddin U, Guniganti SS, Waghray S, et al. Analysis of the rate of maturogenesis of a traumatized Cvek's stage 3 anterior tooth treated with platelet-rich fibrin as a regenerative tool using three-dimensional cone-beam computed tomography: An original case report. Indian J Dent Res 2015;26:90-95.^,140140 Wang Y, Zhu XF, Zhang CF, et al. Pulp revascularization on permanent teeth with open apices in a middle-aged patient. J Endod2015;41:1571-1575.^,141141 Farsi N, Abuzeid S, El Ashiry E, et al. Revascularization of dental pulp in human necrotic permanent teeth with immature apex: Three case reports. Life Science Journal2013;10:1516-1521.^,142142 Santiago CN, Pinto SS, Sassone LM, HirataR, Fidel, SR Jr., et al. Revascularization Technique for the Treatment of External Inflammatory Root Resorption: A Report of 3 Cases. J Endod2015;41:1560-1564.^,143143 Torabinejad M, Turman M, et al. Revitalization of tooth with necrotic pulp and open apex by using platelet-rich plasma: A case report. J Endod 2011;37:265-268., providing good infection control 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.. However, TAP possess an inherent potential for tooth discoloration as drawback. Tooth discoloration is unleashed by the contact of minocycline with the root walls during time needed for infection eradication ²⁵25 Conde MC , Chisini LA , Sarkis-Onofre R, Schuch HS, Nor JE , Demarco FF , et al. A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. Int Endod J 2017;50:860-874.. Thus, some studies have been investigating the substitution of minocycline by amoxicillin ¹⁰⁰100 Miltiadous ME, Floratos SG, et al. Regenerative endodontic treatment as a retreatment option for a tooth with open apex - a case report. Braz Dent J 2015;26:552-556.^,145145 Thomson A, Kahler B, et al. Regenerative endodontics - Biologically-based treatment for immature permanent teeth: A case report and review of the literature. Aust Dent J 2010;55:446-452.^,146146 Kahler B, Mistry S, Moule A, Ringsmuth AK, Case P, Thomson A, et al. Revascularization outcomes: A prospective analysis of 16 consecutive cases. J Endod 2014;40:333-338., cefaclor ²³23 Bezgin T, Yilmaz AD, Celik BN, Kolsuz ME, Sonmez H, et al. Efficacy of Platelet-rich Plasma as a Scaffold in Regenerative Endodontic Treatment. J Endod2015;41:36-44.^,147147 Thibodeau B, Trope M, et al. Pulp revascularization of a necrotic infected immature permanent tooth: case report and review of the literature. Pediatr Dent 2007;29:47-50.^,148148 Thibodeau B, et al. Case report: pulp revascularization of a necrotic, infected, immature, permanent tooth. Pediatr Dent 2009;31:145-148.^,149149 Kim DS, Park HJ, Yeom JH, Seo JS, Ryu GJ, Park KH, et al. Long-term follow-ups of revascularized immature necrotic teeth: three case reports. Int J Oral Sci 2012;4:109-113.^,150150 Amit V, Jain A, Nayak UA, Bhat M, et al. Maturogenesis by revascularization in an infected immature permanent tooth. J Indian Soc Pedod Prev Dent 2014;32:172-175.^,151151 Bezgin T, Yilmaz AD, Çelik BN, Sönmez H, et al. Concentrated platelet-rich plasma used in root canal revascularization: 2 case reports. Int Endod J2014;47:41-49.^,152152 Lei LS, Chen YM, Zhou RH, Huang XJ, Cai ZY, et al. Histologic and Immunohistochemical Findings of a Human Immature Permanent Tooth with Apical Periodontitis after Regenerative Endodontic Treatment. J Endod 2015;41:1172-1179., clindamycin ¹⁵³153 McTigue DJ, Subramanian K, Kumar A, et al. Management of immature permanent teeth with pulpal necrosis: A case series. Pediatr Dent 2013;35:55-60., tetracycline ¹⁵⁴154 Guven Polat G, Yildirim C, Akgun OM, Altun C, Dincer D, Ozkan CK, et al. The use of platelet rich plasma in the treatment of immature tooth with periapical lesion: a case report. Restor Dent Endod 2014;39:230-234. and doxycycline ¹⁵⁵155 Jadhav G, Shah N, Logani A, et al. Revascularization with and without platelet-rich plasma in nonvital, immature, anterior teeth: a pilot clinical study. J Endod 2012;38:1581-1587.^,156156 Nagy MM, Tawfik HE, Hashem AAR, Abu-Seida AM, et al. Regenerative potential of immature permanent teeth with necrotic pulps after different regenerative protocols. J Endod2014;40:192-198.^,157157 Raju SM, Singhyadav S, Ramakumar M, et al. Revascularization of immature mandibular premolar with pulpal necrosis - a case report. J Clin Diagn Res2014;8:ZD29-ZD31. or utilization of Ca(OH)₂¹⁵⁸158 Cotti E, Mereu M, Lusso D, et al. Regenerative treatment of an immature, traumatized tooth with apical periodontitis: report of a case. J Endod 2008;34:611-616.^,159159 Cehreli ZC, Isbitiren B, Sara S, Erbas G, et al. Regenerative endodontic treatment (revascularization) of immature necrotic molars medicated with calcium hydroxide: A case series. J Endod2011;37:1327-1330.^,160160 Cehreli ZC, Sara S, Aksoy B, et al. Revascularization of immature permanent incisors after severe extrusive luxation injury. J Can Dent Assoc 2012;78.^,161161 Chen MYH, Chen KL, Chen CA, Tayebaty F, Rosenberg PA, Lin LM, et al. Responses of immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscess to revascularization procedures. Int Endod J 2012;45:294-305.^,162162 Rudagi KB, Rudagi BM, et al. One-step apexification in immature tooth using grey mineral trioxide aggregate as an apical barrier and autologus platelet rich fibrin membrane as an internal matrix. J Conserv Dent 2012;15:196-199.^,163163 Shimizu E, Jong G, Partridge N, Rosenberg PA, Lin LM, et al. Histologic observation of a human immature permanent tooth with irreversible pulpitis after revascularization/regeneration procedure. J Endod2012;38:1293-1297.^,164164 Paryani K, Kim SG, et al. Regenerative endodontic treatment of permanent teeth after completion of root development: A report of 2 cases. J Endod2013;39:929-934.^,165165 Shimizu E, Ricucci D, Albert J, Alobaid AS, Gibbs JL, Huang GTJ, et al. Clinical, radiographic, and histological observation of a human immature permanent tooth with chronic apical abscess after revitalization treatment. J Endod 2013;39:1078-1083.^,166166 Soares AD, Lins FF, Nagata JY, Gomes B, Zaia AA, Ferraz CCR, et al. Pulp Revascularization after Root Canal Decontamination with Calcium Hydroxide and 2% Chlorhexidine Gel. J Endod2013;39:417-420.^,167167 Nagata JY, Rocha-Lima TF, Gomes BP, Ferraz CC, Zaia AA, Souza-Filho FJ, et al. Pulp revascularization for immature replanted teeth: A case report. Aust Dent J 2015;60:416-420.^,168168 Yadav P, Pruthi PJ, Naval RR, Talwar S, Verma M, et al. Novel use of platelet-rich fibrin matrix and MTA as an apical barrier in the management of a failed revascularization case. Dent Traumatol 2015;31:328-31.. Besides, some studies did not use intracanal medication ¹⁶⁹169 Shah N, Logani A, Bbaskar U, Aggarwal V, et al. Efficacy of revascularization to induce apexification/apexogensis in infected, nonvital, immature teeth: A pilot clinical study. J Endod 2008;34:919-925.^,170170 Shin SY, Albert JS, Mortman RE, et al. One step pulp revascularization treatment of an immature permanent tooth with chronic apical abscess: a case report. Int Endod J2009;42:1118-1126.^,171171 McCabe P, et al. Revascularization of an immature tooth with apical periodontitis using a single visit protocol: A case report. Int Endod J2015;48:484-497.^,171). Although revascularization have been indicated for immature permanent teeth, recent studies demonstrated to be possible to perform revascularization in necrotic mature teeth ¹⁰⁵105 Saoud TMA, Sigurdsson A, Rosenberg PA, Lin LM, Ricucci D, et al. Treatment of a large cystlike inflammatory periapical lesion associated with mature necrotic teeth using regenerative endodontic therapy. J Endod2014;40:2081-2086.^,172172 Saoud TMA, Huang GTJ, Gibbs JL, Sigurdsson A, Lin LM, et al. Management of Teeth with Persistent Apical Periodontitis after Root Canal Treatment Using Regenerative Endodontic Therapy. J Endod2015;41:1743-1748.. Few failures have been reported for teeth under revascularization, mainly due to crown fractures ¹³¹131 Martin G, Ricucci D, Gibbs JL, Lin LM, et al. Histological findings of revascularized/revitalized immature permanent molar with apical periodontitis using platelet-rich plasma. J Endod2013;39:138-144.^,165165 Shimizu E, Ricucci D, Albert J, Alobaid AS, Gibbs JL, Huang GTJ, et al. Clinical, radiographic, and histological observation of a human immature permanent tooth with chronic apical abscess after revitalization treatment. J Endod 2013;39:1078-1083., root canal reinfection ¹⁰²102 Alobaid AS, Cortes LM, Lo J, Nguyen TT, Albert J, Abu-Melha AS, et al. Radiographic and Clinical Outcomes of the Treatment of Immature Permanent Teeth by Revascularization or Apexification: A Pilot Retrospective Cohort Study. J Endod 2014;40:1063-1070.^,173173 Lin LM, Shimizu E, Gibbs JL, Loghin S, Ricucci D, et al. Histologic and histobacteriologic observations of failed revascularization/revitalization therapy: a case report. J Endod2014;40:291-295. and impossibility to induce the initial periapical bleeding ¹¹⁰110 Ding RY, Cheung GSP, Chen J, Yin XZ, Wang QQ, Zhang CF, et al. Pulp Revascularization of Immature Teeth With Apical Periodontitis: A Clinical Study. J Endod 2009;35:745-749.. The tissue formed through revascularization presented blood vessels ¹³¹131 Martin G, Ricucci D, Gibbs JL, Lin LM, et al. Histological findings of revascularized/revitalized immature permanent molar with apical periodontitis using platelet-rich plasma. J Endod2013;39:138-144.^,174174 Meschi N, Hilkens P, Lambrichts I, Van den Eynde K, Mavridou A, Strijbos O, et al. Regenerative endodontic procedure of an infected immature permanent human tooth: an immunohistological study. Clin Oral Investig 2016;20:807-814.^,175175 Becerra P, Ricucci D, Loghin S, Gibbs JL, Lin LM, et al. Histologic study of a human immature permanent premolar with chronic apical abscess after revascularization/revitalization. J Endod2014;40:133-139. with fibrous connective tissue ¹⁷⁵175 Becerra P, Ricucci D, Loghin S, Gibbs JL, Lin LM, et al. Histologic study of a human immature permanent premolar with chronic apical abscess after revascularization/revitalization. J Endod2014;40:133-139. and areas with deposition of a cementum/bone-like tissue ¹³¹131 Martin G, Ricucci D, Gibbs JL, Lin LM, et al. Histological findings of revascularized/revitalized immature permanent molar with apical periodontitis using platelet-rich plasma. J Endod2013;39:138-144.^,165165 Shimizu E, Ricucci D, Albert J, Alobaid AS, Gibbs JL, Huang GTJ, et al. Clinical, radiographic, and histological observation of a human immature permanent tooth with chronic apical abscess after revitalization treatment. J Endod 2013;39:1078-1083.^,173173 Lin LM, Shimizu E, Gibbs JL, Loghin S, Ricucci D, et al. Histologic and histobacteriologic observations of failed revascularization/revitalization therapy: a case report. J Endod2014;40:291-295.^,175175 Becerra P, Ricucci D, Loghin S, Gibbs JL, Lin LM, et al. Histologic study of a human immature permanent premolar with chronic apical abscess after revascularization/revitalization. J Endod2014;40:133-139. without presence of dentin ¹⁷⁵175 Becerra P, Ricucci D, Loghin S, Gibbs JL, Lin LM, et al. Histologic study of a human immature permanent premolar with chronic apical abscess after revascularization/revitalization. J Endod2014;40:133-139. or fibrous nerves ¹⁷⁴174 Meschi N, Hilkens P, Lambrichts I, Van den Eynde K, Mavridou A, Strijbos O, et al. Regenerative endodontic procedure of an infected immature permanent human tooth: an immunohistological study. Clin Oral Investig 2016;20:807-814.. This way, the tissue presented more characteristics of a repair than regenerated tissue ¹⁷⁵175 Becerra P, Ricucci D, Loghin S, Gibbs JL, Lin LM, et al. Histologic study of a human immature permanent premolar with chronic apical abscess after revascularization/revitalization. J Endod2014;40:133-139..

PRP and PRF in Tissue Reparation

Venous blood derivatives presented benefits when applied for bone, periodontal and pulp regeneration 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.^,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.^,2424 Jadhav GR, Shah D, Raghvendra SS, et al. Autologus Platelet Rich Fibrin aided Revascularization of an immature, non-vital permanent tooth with apical periodontitis: A case report. J Nat Sci Biol Med2015;6:224-225.^,128128 Jadhav G, Shah N, Logani A, et al. Comparative outcome of revascularization in bilateral, non-vital, immature maxillary anterior teeth supplemented with or without platelet rich plasma: A case series. J Conserv Dent 2013;16:568-572.^,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.^,155155 Jadhav G, Shah N, Logani A, et al. Revascularization with and without platelet-rich plasma in nonvital, immature, anterior teeth: a pilot clinical study. J Endod 2012;38:1581-1587.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,183183 Sharma A, Pradeep AR, et al. Autologous platelet-rich fibrin in the treatment of mandibular degree II furcation defects: a randomized clinical trial. J Periodontol 2011;82:1396-1403.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.. In this way, few studies did not observe improvement of regeneration results after PRP and PRF application 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.^,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.^,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.^,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.. 60% of selected clinical trials (Table 5) evaluated regeneration induced by PRP-based therapies, while 28% evaluated PRF and 12% both.

The higher follow-up reported was 4 years 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.. Benefits of PRP 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. or PRF 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. for bone regeneration seems to provide better results when combined with autologous bone instead of PRP/PRF alone. Although PRF possess higher GF amounts than PRP, studies comparing both venous blood derivatives found similar results for bone and periodontal regeneration 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.^,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.. Thus, PRP and PRF provided significant improvement, clinically and radiographically, in 3-wall periodontal intrabony defects 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.^,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.. On the other hand, one study performing revascularization reported best results for PRF 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..

Regeneration with Histological Confirmation

In Figure 3 is displayed the pooled of regeneration data, which shows that all studies employing cell and SC-BT were able to promote regeneration of bone with histological confirmation of tissue nature. Periodontal regeneration with SC-BT did not performed histological analysis. GF-MT promote bone and periodontal regeneration in all included studies. However, the papers that evaluated histologically the features of revascularization of root canal did not observe regeneration of dental pulp. PRP and PRF improved the regeneration of bone with histological features. Periodontal regeneration using PRP and PRF did not confirm with histological analysis.

Possibilities and Perspectives of Clinical Transition

Injectable scaffolds appear as an interesting option facilitating the clinical application of regenerative therapies 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.^,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.^,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.^,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.^,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. even as the use of PRP, when combined with biomaterials can facilitate the clinical manipulation of the materials for graft 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.^,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.. Other possibility related, the replacement of xenogeneic fetal bovine serum by autologous human serum, has been reported as an option to reduce exogenous agents to ex vivo cell expansion ²⁸28 Chisini LA , Conde MC M, Grazioli G, Martin ASS, Carvalho RV, Nor JE , et al. Venous blood derivatives as fbs-substitutes for mesenchymal stem cells: a systematic scoping review. Braz Dent J 2017;28:657-668.^,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.^,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..

Discussion

The presented systematic scoping review showed that bone and periodontal regeneration can be successfully achieved, presenting histological confirmations of new regenerate tissue. Dental pulp regeneration was not achieved by revascularization; such therapy provided just repaired pulp-like tissue. Clinical, radiographic, histological and immunohistochemical data confirmed the nature of regenerated tissues by SC-BT and GF-MT 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.^,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.. Besides, PRP and PRF were able to improve bone deposition 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..

In fact, SC-BT or GF-MT comprise important strategies to improve bone regeneration. 30 studies employed SC-BT and confirmed regeneration by histological analysis. All included papers showed a new regenerated tissue with better characteristics than control groups without use of cells. A clinical trial regarding bone regeneration by SC-BT reported excellent results for sinus floor elevation after 3-4 months applying MSC with bovine bone mineral 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.. Histological analysis showed 17.7% of bone formation in SC-BT group while in control group, just 12% of new bone was formed. Similarly, bone tissue regenerated by applying an inorganic bone scaffold charged with PRGF, exhibited more blood vessels than those tissues regenerated with scaffolds alone 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.. Autologous bone without cell implantation also provided bone regeneration - due to osteoconductive properties. However, the bone quality is smaller when compared with cell and stem cell-based therapies 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.^,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.. Therefore, the bone regeneration can be achieved without use of SC-BT, although its use increases bone deposition and maturation of bone tissue.

Likewise, GF-MT has been used to induce recruitment and differentiation of stem cells located in the target tissue ⁷7 Demarco FF, Conde MC, Cavalcanti BN, Casagrande L, Sakai VT, Nor JE, et al. Dental pulp tissue engineering. Braz Dent J 2011;22:3-13.. Thus, the use of GF-MT was effective in 100% of studies that confirmed the regeneration through histological analysis, being able to increase the regenerative potential to periodontal tissue. De novo tissue showed new compact bone without signs of inflammatory reaction. Bone remodeling 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. with gradually substitution of scaffolds for bone was frequently observed 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.^,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.. Similarly, complete periodontal regeneration was reported with deposition of new cement, alveolar bone and connective tissue using PDGF-BB in demineralized freeze-dried bone allograft or b-TCP + bioresorbable collagen 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.^,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.. In contrast, no signs of periodontal regeneration were detected in control group 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.. Periodontal ligament and gingival tissue present stem cells able to deposit bone and cement. Such cell population can be recruited by growth factors to induce tissue regeneration ⁴4 Seo BM, Miura M , Gronthos S Bartold PM, Batouli S, Brahim J, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet2004;364:149-155.^,199199 Tang L, Li N, Xie H, Jin Y. Characterization of mesenchymal stem cells from human normal and hyperplastic gingiva. J Cell Physiol2011;226:832-842.. GF-MT is considered easier to apply than SC-BT ⁷7 Demarco FF, Conde MC, Cavalcanti BN, Casagrande L, Sakai VT, Nor JE, et al. Dental pulp tissue engineering. Braz Dent J 2011;22:3-13.. GF-MT reduces costs since there is no need for an additional intervention for cell isolation. Furthermore, GF-MT presents insignificant risk of contamination since does not require the addition of xenogeneic substances as medium culture and its supplementation ²⁸28 Chisini LA , Conde MC M, Grazioli G, Martin ASS, Carvalho RV, Nor JE , et al. Venous blood derivatives as fbs-substitutes for mesenchymal stem cells: a systematic scoping review. Braz Dent J 2017;28:657-668.^,200200 Chisini LA, Karam SA, Noronha TG, Sartori LRM, San Martin AS, Demarco FF, et al. Platelet-Poor Plasma as a Supplement for Fibroblasts Cultured in Platelet-Rich Fibrin. Acta Stomatol Croat 2017;51:133-140..

PRP and PRF have been reported as extracellular matrix mimetics being both able to guide cell behavior showing interesting results combined with SC-BT and C-BT therapy 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.^,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.^,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.^,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.^,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.^,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.^,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.^,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.. In addition, the use of PRP and PRF provided bone regeneration confirmed by histological analysis. In a recent case series, the bone formed as of a combination of MSC and PRP exhibited better histological results, suggesting this combination can significantly improve bone formation 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.. The use of PRP seems to increase the histological features proving good osteoconductive properties 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.^,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.. Bone formation in sinus lifting was more efficient in group treated with PRP than in the control group (with inorganic bovine bone alone) 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.. Combination of autologous BMMSC with PRP and cancellous freeze-dried bone chips also provided good results by exhibiting more cellular components than group BMMSC-PRP free 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.. In the same way, PRF alone presented a propensity to regenerate higher bone volume and quality, even as PRF combined with socket filling 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.. Thus, the application of both generations of blood concentrated can be used for periodontal defects treatment, alone or combined with conventional open flap debridement providing goods results 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.^,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.^,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..

Regarding scaffolds, the major part of studies report good properties in relationship to the ability of maintenance the cell adherence and maintenance the structure to promote the regeneration process, however, some points have been highlighted regarding the PLGA 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.^,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.. Two studies evaluated the potential of osteoblastic cells seeded on PLGA scaffolds for bone regeneration, reported unfavorable results 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.^,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.. This was due to fast bone resorption observed after 3 months in sinus augmentation, which was significantly higher in PLGA (90%) than that observed for autologous iliac crest bone implants (29%) 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.. Polymeric scaffolds should be incorporated in metabolic routes to be replaced by cell-secreted extracellular matrix. However, this process should not be so fast ⁷7 Demarco FF, Conde MC, Cavalcanti BN, Casagrande L, Sakai VT, Nor JE, et al. Dental pulp tissue engineering. Braz Dent J 2011;22:3-13.. After adhesion and osteoblastic differentiation, bone remodeling is expected to happen parallel to new extracellular matrix formation ²⁰¹201 Gong T, Xie J, Liao J, Zhang T, Lin S, Lin Y, et al. Nanomaterials and bone regeneration. Bone Res2015;3:15029.. Histological analysis revealed high medullar spaces with few amount of regenerated bone 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.. Therefore, the fast PLGA resorption rate seems to hamper proper bone regeneration 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.^,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.. In contrast, collagen sponges, hydroxyapatite (HA) and b-TCP, as well as allogenic or xenogeneic bone has provided suitable bone stability 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.^,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.^,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.^,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.^,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.. It can be justified by the fact that these scaffolds possess components derived from natural bone tissue.

Although the studies demonstrate that it is possible to regenerate bone and periodontal tissue, the same is not true regarding pulp tissue. Thus, some points should be highlight and discussed about the characteristics of dental pulp to understood this fact. The blood supply in the pulp chamber is practically insignificant due the dimensions of the apical foramen that do not allow an adequate revascularization of the constructs; hence, it makes the regeneration of this tissue more difficult. In this sense, it is seems not yet possible regenerate a pulp-like tissue able to deposit dentin, following revascularization ³⁸38 Torabinejad M, Faras H, et al. A clinical and histological report of a tooth with an open apex treated with regenerative endodontics using platelet-rich plasma. J Endod 2012;38:864-868.^,131131 Martin G, Ricucci D, Gibbs JL, Lin LM, et al. Histological findings of revascularized/revitalized immature permanent molar with apical periodontitis using platelet-rich plasma. J Endod2013;39:138-144.^,165165 Shimizu E, Ricucci D, Albert J, Alobaid AS, Gibbs JL, Huang GTJ, et al. Clinical, radiographic, and histological observation of a human immature permanent tooth with chronic apical abscess after revitalization treatment. J Endod 2013;39:1078-1083.^,173173 Lin LM, Shimizu E, Gibbs JL, Loghin S, Ricucci D, et al. Histologic and histobacteriologic observations of failed revascularization/revitalization therapy: a case report. J Endod2014;40:291-295.

174 Meschi N, Hilkens P, Lambrichts I, Van den Eynde K, Mavridou A, Strijbos O, et al. Regenerative endodontic procedure of an infected immature permanent human tooth: an immunohistological study. Clin Oral Investig 2016;20:807-814.^-175175 Becerra P, Ricucci D, Loghin S, Gibbs JL, Lin LM, et al. Histologic study of a human immature permanent premolar with chronic apical abscess after revascularization/revitalization. J Endod2014;40:133-139.. Conventional revascularization did not apply expanded MSC or GF; solely underlies on stem cell from apical papilla migration towards the formed blood clot inside root canal ²⁵25 Conde MC , Chisini LA , Sarkis-Onofre R, Schuch HS, Nor JE , Demarco FF , et al. A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. Int Endod J 2017;50:860-874.. In this way, the biological mechanisms coordinating migration and differentiation of stem cell from apical papilla are not clearly understood, as well as the real harm provided by pulp necrosis above these cells ²⁵25 Conde MC , Chisini LA , Sarkis-Onofre R, Schuch HS, Nor JE , Demarco FF , et al. A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. Int Endod J 2017;50:860-874.. Real-time polymerase chain reaction analysis showed that blood collected from root canal during revascularization, presented higher expression of MSC markers CD73 and CD105 (up to 600-fold) than systemic blood ²⁰²202 Lovelace TW, Henry MA, Hargreaves KM, Diogenes A. Evaluation of the delivery of mesenchymal stem cells into the root canal space of necrotic immature teeth after clinical regenerative endodontic procedure. J Endod 2011;37:133-138.. However, the increase of MSC markers was selective, since there wasn’t any change in expression of mRNA transcripts encoding dentin sialophosphoprotein and alkaline phosphatase (molecules considered as odontoblast markers) ²⁰²202 Lovelace TW, Henry MA, Hargreaves KM, Diogenes A. Evaluation of the delivery of mesenchymal stem cells into the root canal space of necrotic immature teeth after clinical regenerative endodontic procedure. J Endod 2011;37:133-138.. In fact, after performing revascularization, mineral deposition is observed into the root canal characterized as cementum/bone-like tissue, but not dentin ¹⁷⁴174 Meschi N, Hilkens P, Lambrichts I, Van den Eynde K, Mavridou A, Strijbos O, et al. Regenerative endodontic procedure of an infected immature permanent human tooth: an immunohistological study. Clin Oral Investig 2016;20:807-814.. Thus, considering that application of SC-BT or GF-MT improves the quality of bone and periodontal formed 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.^,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., the use of these therapies (SC-BT and GF-MT) could be combined with revascularization to increase the quality of the formed tissue. Although none study was identified employing cells or growth factors in revascularization, we can hypothesize that use of these therapies could comprise interesting strategies for pulp regeneration. Moreover, the increase observed in length and width of root canal has been provided by a repaired tissue, this mineral deposition can be responsible for good longevity rates in teeth submitted to revascularization, justifying the use of this therapy ²⁵25 Conde MC , Chisini LA , Sarkis-Onofre R, Schuch HS, Nor JE , Demarco FF , et al. A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. Int Endod J 2017;50:860-874.. A recent review evaluating 75 studies (367 teeth) corroborated with presents results showing a success rate of 94.3% in teeth submitted to revascularization with a mean of follow-up 17.6 months ²⁵25 Conde MC , Chisini LA , Sarkis-Onofre R, Schuch HS, Nor JE , Demarco FF , et al. A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. Int Endod J 2017;50:860-874.. Although these results are provided from case reports and case of series studies, the authors suggest that revascularization should be considered as treatment option in cases of necrosis of immature permanent teeth ²⁵25 Conde MC , Chisini LA , Sarkis-Onofre R, Schuch HS, Nor JE , Demarco FF , et al. A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. Int Endod J 2017;50:860-874.. Moreover, revascularization does not requires the instrumentation of root canal , since bacteriological control is chemically achieved, reducing the tooth structure loss cooperating with the increase on survival rate ²⁶26 Wigler R, Kaufman AY, Lin S, Steinbock N, Hazan-Molina H, Torneck CD, et al. Revascularization: a treatment for permanent teeth with necrotic pulp and incomplete root development. J Endod2013;39:319-326..

While promising results have been observed applying regenerative therapies in dentistry, these results are mostly based in clinical cases and small clinical trials, which limits the extrapolation of the data. Thus, this should be interpreted with caution. Besides, literature presents short follow-ups, generally under 1 year. Therefore, it is important to keep researching and publishing initial clinical cases as well as reporting the possible failures that may happen. Moreover, large randomized clinical trials should be conducted primarily investigating different scaffolds, cells and growth factors and their interactions with different regenerated tissues.

In conclusion, the regenerative therapies in dentistry are able to regenerate bone and periodontal tissue. No evidence of dental pulp regeneration was observed. Stem Cell-Based Therapy provide histological evidence to bone regeneration while GF-MT regenerate bone and periodontal tissues. PRP and PRF were able to promote bone regeneration with histological confirmation.

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