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Brazilian Dental Journal

Print version ISSN 0103-6440On-line version ISSN 1806-4760

Braz. Dent. J. vol.30 no.2 Ribeirão Preto Mar./Apr. 2019  Epub Apr 04, 2019

http://dx.doi.org/10.1590/0103-6440201902053 

Review Article

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

Luiz Alexandre Chisini1  2 
http://orcid.org/0000-0002-3695-0361

Marcus Cristian Muniz Conde2 
http://orcid.org/0000-0003-2662-3305

Guillermo Grazioli1 

Alissa Schmidt San Martin1 
http://orcid.org/0000-0002-2094-774X

Rodrigo Varella de Carvalho3 
http://orcid.org/0000-0002-2644-5820

Letícia Regina Morello Sartori1 

Flávio Fernando Demarco1 

1Graduate Program in Dentistry, School of Dentistry, UFPel - Universidade Federal de Pelotas, RS, Brazil

2Graduate Program in Dentistry, School of Dentistry, UNIVATES - Universidade do Vale do Taquari, Lajeado, RS, Brazil

3School of Dentistry, IMED - Faculdade Meridional, Passo Fundo, RS, Brazil


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 1. Since the discovery of mesenchymal stem cells (MSC) in several orals tissues 2,3,4,5, regenerative approaches have been investigated aiming to improve the translational potential of regenerative therapies 6. 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 7,8. Such MSC are able to originate mesodermal-derived cell line 9 providing, osteoblastic 6, odontoblastic 10,11 and periodontal cell lineages 12.

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 11. 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 13,14,15,16. 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 7,11.

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 17. Besides, PRP and PRF application as scaffolds have shown promising clinical results 18,19. 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 17. Choukroun et al. 20 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 21,22. 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 23,24. RCR is based on blood clot formation into the root canal, previously decontaminated with a triple antibiotic paste 23,25. 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 25,26.

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 27 named Scoping Review. Newly, numerous papers use Scoping Review to state the actual knowledge in a particular area to provide a concise qualitative analysis 25,28. 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 29. 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 25. 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 25.

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:

  • Are regenerative therapies in dentistry able to provide bone, periodontal and dental pulp regeneration in human?

  • Can the regeneration of bone periodontal and dental pulp be confirmed by histological analysis?

  • The retrieved records were uploaded into MendeleyTM, to delete duplicated studies. Two reviewers (LAC and MCMC) conducted independently the initial evaluation of titles and abstracts under the following inclusion criteria:

  • Studies: Clinical studies in humans, without language restriction;

  • Follow-up time: not limited;

  • Therapies: SC-BT, Cell-Based Therapy (C-BT) and GF-MT for bone, periodontal or pulp regeneration. The therapies aiming Root Canal Revascularization or applying PRP and PRF for tissue regeneration were also included;

  • Study design:

  • For SC-BT, C-BT and GF-MT: all clinical study design;

  • Root Canal Revascularization: all clinical design that that induced

  • Blood clotting or used PRP/PRF for RCR;

  • Regeneration applying PRP and PRF: only randomized clinical trial;

  • Reviews were excluded.

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 30,31,32,33,34,35 are presented in Table 1. Four accompaniments studies were identified (6,36-38). Figure 2 shows the distribution of included studies per years.

Table 1 Excluded studies and reasons for exclusion 

Studies Reason
Iwaia 200130; Iwaia 201131; Bose 2009 32; Not realized bleeding in the root canal
Okuda 2013 33 Not SC-BT
Yang 2010 34 Not Human
Peck 2012 35 Not growth-factor applying

Fig.1 PrismaFlowchart 

Figure 2 Studies included in the systematic scoping review according to year of publication 

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) 57, DPSC 6,12,36,58,59 and periodontal ligament stem cell (PDLSC) 60,61 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 74, Mononuclear Cells (MNC) 75,76 and Bone Marrow Aspirate Concentrates (BMAC) (77-85) were used also in Cell-based therapy (Fig. 3).

Table 2 Studies applying SC-BT for bone regeneration 

Year Author Cell Scaffold Growth Factor Patients Follow-up Parameters Outcome
2003 Schmelzeisen et al. 65 Periosteal Polymer fleece 2 4 months Histologic and clinical Mineralized tissue formed
2004 Warnke et al. 77 BMAC BioOss rhBMP7 1 Clinical and radiographic Mineralized tissue formed
2005 Ueda et al. 39 BMMSC PRP-b-TCP injectable 6 12 months Radiographic Mineralized tissue formed (7.3 ± 4.6 mm)
2007 Cerruti et al. 75 MNC PRP and Bone scaffod 32 8 months CT, histologic and clinical Mineralized tissue formed
2007 Soltan et al. 78 BMAC Allograft bone block 5 8 months Histologic and histomorphometry Mineralized tissue formed (54%)
2007 Smiler et al. 79 BMAC PepGen Putty or C-Graft 5 7 months Clinical and histologic Mineralized tissue formed; (45%)
2007 Zizelmann et al. 71 Osteoblast PLGA 10 3 months CT Mineralized tissue formed; High resorption of scaffolds
2008 Pradel et al. 72 Osteoblast Demineralized bovine bone matrix or from solvent-dehydrated mineralized bovine bone; and graft 6 1 year Histologic Mineralized tissue formed. Inflammation and some scaffold resorption was found in 5 months
2008 Shayesteh et al. 40 BMMSC b-TCP/hydroxyapatite 6 12 months Clinical, radiographic and histologic Mineralized tissue formed (41.3%)
2008 Yamada et al. 41 BMMSC PRP Injectable 12 2-6.3 years: 6.3/ 6.3/ 5.3/ 4.9/ 4.3/ 4.3/ 3.3/ 3.5/ 3.0/ 3.3/ 2.1/ 2.1/ 3.8/ 2.5/ 2.5/ 2.0 Orthopantomograms, histologic, CT Mineralized tissue formed; increases of 8.8 ± 1.6 mm
2009 Behnia et al. 62 MSC Demineralized bone mineral and calcium sulfate (Osteoset) 2 4 months CT Mineralized tissue formed (34.5%)
2009 D’Aquino et al. 58 DPSC Collagen sponge 7 3 months Histologic and radiographic Mineralized tissue formed
2009 Mangano et al. 73 Osteoblasts PLGA 5 6 months Clinical, histologic and CT Mineralized tissue formed; fast resorption of scaffold
2009 McAllister et al. 70 MSC and osteoprogenitor cells Bone graft 5 4.1 months Clinical, radiographic and histologic Mineralized tissue formed; (vital bone content of 33% - 22% to 40%-)
2010 Lee et al. 42 BMMSC Freeze-dried autobone tray and fibrin glue 1 7 months Histological, clinical and radiographic Mineralized tissue formed
2010 Sauerbier et al. 43 BMMSC FICOLL 4 4,1 months; clinical 2 years Histologic and clinical Mineralized tissue formed (19.9% Confidence interval 945% 10.9 to 29%)
2010 Soltan et al. 80 BMMAC Resorbable hydroxylapatite OR Allograft 2 4-6 months Histologic and radiographic Mineralized tissue formed (34% to 45%)
2010 Mangano et al. 69 Osteoblasts PLGA 1 6 months Histologic and CT Mineralized tissue formed (28.89% bone and 71.11% medullary spaces)
2011 Brunelli et al. 59 DPSC Collagen sponge 1 4 months Clinical, radiographic and histologic Mineralized tissue formed
2011 Graziano et al. 36 DPSC Collagen sponge 1 6 months Clinical and radiographic Mineralized tissue formed
2011 Montesani et al. 68 osteoblast and periosteal cells nonwoven polyglactin-910 fibers connected by poly-p-dioxanon bonding 2 12 months Clinical and radiographic Mineralized tissue formed
2011 Rickert et al. 49 BMMSC BioOsss and autogenous stem cells (Test); BioOsss mixed with autogenous bone (Control) 12 14.8 weeks 3-4 months Histologic Mineralized tissue formed; test group presented more bone formation than control
2011 Sauerbier et al. 81 BMAS Autogenous bone combination with a bovine bone mineral 26 biopsies 3-4 month Histologic Mineralized tissue formed (12.6% ± 1.7%)
2011 Schmelzeisen et al. 82 BMAC FICOLL 1 3 months Histologic Mineralized tissue formed (26.9%); no signs of inflammation
2012 Behnia et al. 63 MSC Synthetic biphasic bone substitute PDGF 3 3 months CT Mineralized tissue formed (51.3%)
2012 Hernández-Alfaro et al. 83 BMAC Bovine HA rhBMP-7 1 1 year Histologic, clinical and radiographic Mineralized tissue formed
2012 Soltan et al. 74 Concentrated of monocytes Demineralized allograft material 2 1 year Radiographic and histologic Mineralized tissue formed
2012 Nagata et al. 67 Periosteal Autogenous bone and PRP 25 1 year CT Mineralized tissue formed
2013 Giuliani et al. 6 DPSC Collagen sponge 7 3 years Histologic and radiographic Mineralized tissue formed
2013 Kaigler et al. 44 BMMSC Absorbable gelatin sponge N=12 Control=12 1 year Clinical, radiographic, CT and histologic Mineralized tissue formed; therapy accelerated alveolar bone regeneration
2013 Sandor et al. 57 ASC b-TCP rhBMP-2 1 10 months Histological Mineralized tissue formed
2013 Yamada et al. 46 BMMSC Membran + PRP Injetável 1 24 months Histological, CT and radiographic Mineralized tissue formed
2013 Yamada et al. 45 BMMSC PRP Injectable 3 months Clinical Mineralized tissue formed.; all patients improved bone tissue
2013 Zamiri et al. 47 BMMSC Bone Human cadavers (allograft) 3 6 months CT Mineralized tissue formed
2014 Marx et al. 84 BMAC Collagen sponge rhBMP-2 40 6 months Clinical, CT, radiographic and histologic Mineralized tissue formed; Patients that received cells presented more bone formation
2014 Rajan et al. 48 BMMSC b-TCP 1 biopsy 4 months; and 6 months follow-up CT and histologic Mineralized tissue formed; 80% of the original jawbone
2014 Rickert et al. 50 BMMSC BioOss + MSCs and BioOss + autogenous bone 12 1 year Clinical and radiographic Mineralized tissue formed; 3 implant (91%) failed in osteointegration
2014 Wildburger et al. 51 BMMSC Bio-Oss 7 3 and 6 months Histological and CT Mineralized tissue formed (13.5%)
2015 Bertolai et al. 52 BMMSC PRP and corticocancellous freeze-dried bone chips 20 3 months Histological and clinical Mineralized tissue formed
2015 Park et al. 53 BMMSC Bone from the iliac crest; collagenous membrane 1 1 year Clinical and radiographic Mineralized tissue formed
2015 Kaigler et al. 54 BMMSC b-TCP Test=13; Control=13 1 year Clinical, radiographic, and histologic Mineralized tissue formed (12.2% ±3.3)
2015 Pasquali et al. 85 BMAC Bio-Oss 8 6 months Histologic Mineralized tissue formed (55.15 ± 20.91)

beta-tricalcium phosphate (bb-TCP); polyglycolid-polylactid (PLGA); Synthetic polysaccharide (FICOLL); bovine bone mineral (BioOsss); hydroxyapatite (HA); Bone Morphogenetic Protein (rhBMP); Platelet Derived Growth Factor (PDGF); Computed Tomography (CT); Bone Marrow Mesenchymal Stem Cells (BMMSC); Bone Marrow Aspirate Concentrates (BMAC); Adipose stem cells (ASC); Dental Pulp Stem Cells (DPSC); Periodontal Ligament Stem Cells (PDLSC); Mesenchymal Stem Cells (MSC); Mononuclear Cells (MNC); Platelet-Rich Plasma (PRP); Platelet-Rich fibrin (PRF)

Table 3 Studies applying SC-BT for periodontal regeneration 

Year Author Cells Scaffold Growth factor Patients Follow-up Parameters Outcome
2006 Yamada et al. 55 BMMSC PRP Injectable - 1 1 year Clinical and Radiographic Bone defects reduced; Reduction on probing depths and gain on clinical attachment
2009 Okuda et al. 66 Periosteal PRP with HA granules - 3 6 months Clinical and Radiographic Radiographic deposition of bone, clinical attachment gain
2010 Feng et al. 60 PDLP Bone Grafting material Calcitite - 3 32-72 month Clinical Decrease in tooth movement and probing depth and attachment gain
2011 McAllister et al. 56 MMSC and osteoblast Allograft bone matrix from cadavers - 2 6 months Clinical and radiographic Radiographic bone deposition and decrease of probing depth
2013 Sankaranar et al. 76 MNC Thermo-reversible gelation polymer - 1 36 months Clinical and Radiographic Bone height was observed radiographically. Reduction of probing pocket depth, improve of clinical attachment
2014 Aimetti et al. 12 DPSC Collagen sponge - 1 1 year Clinical and radiographic Bone increase was observed by radiographic
2015 Yamada et al. 64 MSC PRP and Hyaluronic Acid - 1 Clinical Volume of papilla increase

beta-tricalcium phosphate (b-TCP); polyglycolid-polylactid (PLGA); Synthetic polysaccharide (FICOLL); bovine bone mineral (BioOsss); hydroxyapatite (HA); Bone Morphogenetic Protein (rhBMP); Platelet Derived Growth Factor (PDGF); Computed Tomography (CT); Bone Marrow Mesenchymal Stem Cells (BMMSC); Bone Marrow Aspirate Concentrates (BMAC); Adipose stem cells (ASC); Dental Pulp Stem Cells (DPSC); Periodontal Ligament Stem Cells (PDLSC); Mesenchymal Stem Cells (MSC); Mononuclear Cells (MNC); Platelet-Rich Plasma (PRP); Platelet-Rich fibrin (PRF).

Figure 3 Pooling of main results 

Bone regeneration based on SC-BT and C-BT provided increase of bone deposition when combined with xenogeneic and alloplastic materials 39,40,44,46,48,54,57,63,65,68,69,79. Synthetic poly (lactic-co-glycolic acid) (PLGA) presented fast resorption rates in the postoperative first weeks 71,73. Autografts 41,42,45,46,52,53 and allografts 47,52,70,74,75,78,84 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 49,77. Autologous bone without cell implantation also presented bone regeneration, however, the bone quality and vitality trend toward less when compared with SC-BT 54,73. Reported follow-ups ranged from three 63 to 75 months 41.

Figure 4 Main scaffolds reported in the included studies by origin classification. 

Five studies evaluated the influence of Bone Morphogenetic Protein (BMP) 2 57,84, BMP-7 77,83 or Platelet Derived Growth Factor (PDGF) 63 for constructs (MSC+Scaffolds) showing an improved potential of regeneration. Large reconstruction of bone defect - six 83, six to eight 84, seven 77, ten 57,14 53 and 15 cm 42 - 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 15,16,37,63,86,87,88,89,90,91,92,93 BMP-2 13,14,57,84,91,94,95,96,97,98,96, Plasma Rich in Growth Factors (PRGF) 97,98,99 and BMP-7 65,83. Such GF were reported as safe and effective in the treatment of periodontal and bone defects 87,88,92. 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 87. Wide bone mandible defects (5 to 12 cm) were regenerated by applying BMP-2 and beta-tricalcium phosphate (b-TCP) scaffolds 96. Histological analysis showed that density of blood vessels seems to be higher in tissues that utilize GF 13.

Table 4 Studies applying growth factor-mediated therapy 

Year Author Scaffold Growth Factor Patients Follow-up Parameters Outcome
2003 Nevins et al. 86 Demineralized freeze-dried bone allograft rhPDGF-BB 9 9 mths Clinical, radiographic and histologic Probing depth reduction (6.42 mm), clinical attachment level gain 6.17 mm, radiographic fill 2.14 mm; Histological evaluation show periodontal regeneration
2005 Nevins et al. 87 b-TCP rhPDGF-BB 180 6 mths Clinical and radiographic Improve bone fill, clinical attachment level and reduce gingival retraction
2006 McGuire et al. 92 b-TCP and collagen membrane rhPDGF 7 6 mths Clinical Favorable clinical results in all cases
2009 Mcguire et al. 93 b-TCP with a bioabsorbable collagen rhPDGF-BB 30 6 mths Clinical, radiographic and Histologic Recession depth reduction (-2.9 mm), root coverage (90.8%), recession width reduction. Regeneration of periodontal regeneration, cementum and bone.
2009 Schuckert et al. 94 Polycaprolactone and PRP rhBMP-2 1 6 mths Radiographic and histologic Radiographic evidence of bone confirmed by biopsy
2010 Schuckert et al. 95 b-TCP and PRP rhBMP-2 1 1 yr CT and histologic
2011 Jayakumar et al. 88 b-TCP rhPDGFBB 54 6 mths Clinical, radiographic Bone gain radiographic, clinical attachment gain and reduction on probing depth
2011 Nevins et al. 89 b-TCP rhPDGF-BB 3 5 mths Clinical, radiographic and histologic Bone gain radiograph and histologic
2011 Nevins et al. 90 Mineral collagen bone substitute rhPDGF-BB 16 5 mths Clinical, radiographic and Histologic Histological bone; histomorphometric shown more new bone with growth-factor
2011 Sohn et al. 97 Fibrin-rich blocks PRGF 53 10 mths Clinical, radiographic and Histologic Histological evidence of bone regeneration
2012 Anitua et al. 98 Bovine anorganic bone PRGF 5 5 mths Clinical, radiographic and histologic More vital bone was observed in growth factor group (21.4%) than control (8.4%) even less inflammation. Immunohistochemical show blood vessels
2012 Taschieri et al. 99 Deproteinized bovine bone matrix PRGF 8 6 mths Clinical and radiographic Less complication were observed in group treated with PRGF
2013 Desai et al. 96 b-TCP rhBMP-2 6 12/ 39/ 36/ 50/ 51/ 28 mths Clinical and radiographic From 6 patient one develop infection requiring new intervention
2013 Jensen et al. 91 Absorbable collagen sponge OR bone autograft/xenograft rhBMP-2 OR PDGF-bb 4 3 yrs/ 4 mths/ 4 mths/ 6 mths Clinical and radiographic Bone gain major than 13 mm in all patients
2013 Marx et al. 13 Collagen sponge; cancellous freeze-dried allogeneic bone; PRP rhBMP-2 20 6 mths Clinical, radiographic and histologic Bone formation (54%) and histological bone regeneration
2013 Nevins et al. 37 b-TCP PDGF-BB 83 36 mths Clinical and radiographic Long-term stable clinical and radiographic improvements;
2013 Sclar et al. 14 Collagen sponge, autogenous bone graft, bovine bone mineral, PRP, and guided bone regeneration rhBMP-2 1 1 yr Clinical, radiographic and CT Increase in bone deposition
2014 Maroo et al. 15 b-TCP rhPDGF 1 9 mths Clinical and radiographic Pocket defect was totally filled by mineral tissue
2014 Maroo et al. 16 b-TCP rhPDGF-BB 15 9 mths Clinical and radiographic Pocket depth reduction, clinical attachment gain, alveolar crest gain

beta-tricalcium phosphate (b-TCP); polyglycolid-polylactid (PLGA); Synthetic polysaccharide (FICOLL); bovine bone mineral (BioOsss); hydroxyapatite (HA); Bone Morphogenetic Protein (rhBMP); Platelet Derived Growth Factor (PDGF); Computed Tomography (CT); Bone Marrow Mesenchymal Stem Cells (BMMSC); Bone Marrow Aspirate Concentrates (BMAC); Adipose stem cells (ASC); Dental Pulp Stem Cells (DPSC); Periodontal Ligament Stem Cells (PDLSC); Mesenchymal Stem Cells (MSC); Mononuclear Cells (MNC); Platelet-Rich Plasma (PRP); Platelet-Rich fibrin (PRF)

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 23,100,101,102,103,104,405,106,107,108,109. Besides, tooth under revascularization could respond positively to thermal and electrical sensibility tests 110. Hoshino’s triple antibiotic paste (TAP), containing ciprofloxacin, metronidazole and minocycline, was the most applied intracanal medication 24,110,111,112,113,114,115,116,117,118,,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143, providing good infection control 144. 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 25. Thus, some studies have been investigating the substitution of minocycline by amoxicillin 100,145,146, cefaclor 23,147,148,149,150,151,152, clindamycin 153, tetracycline 154 and doxycycline 155,156,157 or utilization of Ca(OH)2158,159,160,161,162,163,164,165,166,167,168. Besides, some studies did not use intracanal medication 169,170,171,171). Although revascularization have been indicated for immature permanent teeth, recent studies demonstrated to be possible to perform revascularization in necrotic mature teeth 105,172. Few failures have been reported for teeth under revascularization, mainly due to crown fractures 131,165, root canal reinfection 102,173 and impossibility to induce the initial periapical bleeding 110. The tissue formed through revascularization presented blood vessels 131,174,175 with fibrous connective tissue 175 and areas with deposition of a cementum/bone-like tissue 131,165,173,175 without presence of dentin 175 or fibrous nerves 174. This way, the tissue presented more characteristics of a repair than regenerated tissue 175.

PRP and PRF in Tissue Reparation

Venous blood derivatives presented benefits when applied for bone, periodontal and pulp regeneration 18,19,24,128,144,155,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194. In this way, few studies did not observe improvement of regeneration results after PRP and PRF application 195,196,197,198. 60% of selected clinical trials (Table 5) evaluated regeneration induced by PRP-based therapies, while 28% evaluated PRF and 12% both.

Table 5 Clinical trials applying PRP and PRF for bone pulp and periodontal regeneration 

Year Author PRP/PRF Regeneration Scaffold /intervention Control Patients Follow-up Parameters Outcome
2004 Hanna et al. 176 PRP Periodontal Bovine derived xenograft Bone graft 30 6 mths Clinical and radiographic PRP improve the results: CAL and PD
2005 Okuda et al. 177 PRP Periodontal HA HA 35 12 mths Clinical and radiographic Group with PRP show better results
2008 Keceli et al. 195 PRP Periodontal Connective tissue graft Connective tissue graft 40 12 mths Clinical No differences with addiction of PRP
2008 Piemontese et al. 178 PRP Periodontal Demineralized freeze-dried bone allograft Demineralized freeze-dried bone allograft 30 12 mths Clinical and radiographic Greater changes in PD reduction and CAL
2009 Harnack et al. 196 PRP Periodontal b-TCP b-TCP 22 6 mths Clinical and radiographic PRP did not improve the results
2009 Pradeep et al. 18 PRP Periodontal PRP alone Open flap debridement 20 6 mths Clinical and radiographic PRP improve the results: CAL and PD
2009 Torres et al. 180 PRP Bone Anorganic bovine bone Anorganic bovine bone 87 24 mths Clinical, radiographic and histologic No differences; graft resorption was similar treatment and control
2009 Markou et al. 179 PRP Periodontal Demineralized freeze-dried bone allograft PRP alone 24 6 mths Clinical and radiographic PRP not improve significantly the treatment
2010 Alissa et al. 181 PRP Bone PRP - 20 3 mths Clinical and radiographic PRP show better bone trabecular pattern
2010 Arenaz-Búa et al. 182 PRP Bone Synthetic calcium HA or autologous bone OR PRP alone OR allogeneic demineralized bone matrix Anny material or PRP alone 82 6 mths Clinical and radiographic Greatest bone formation was observed in PRP + autologous bone
2010 Badr et al. 197 PRP Bone Bone graft Bone graft 22 5-6 mths Clinical Improve in the results was not observed with use of PRP
2011 Sharma et al. 184 PRF Periodontal PRF with conventional open-flap debridement Conventional open-flap debridement alone 42 9 mths Clinical and radiographic Highest percentage of bone fill was found in PRF group
2011 Yilmaz et al. 185 PRP Periodontal PRP PPP with Bovine-derived xenograft 20 12 mths Clinical and radiographic PPP demonstrated similar efficacy to PRP
2011 Thorat et al. 186 PRF Periodontal PRF Conventional open flap debridement alone 40 9 mths Clinical and radiographic PRF was better in all clinical and radiographic parameters
2012 Menezes et al. 187 PRP Periodontal Porous HA and PRP Porous HA 60 4 yrs Clinical and radiographic PRP improve the results
2012 Pradeep et al. 188 PRP and PRF Periodontal PRP or PRF with open-flap debridement or autologous Open-flap debridement alone 54 9 mths Clinical and Radiographic PD and CAL were better in PRF followed by PRP. Bone fill was more observed in PRF group
2013 Bajaj et al. 189 PRP and PRF Periodontal PRP or PRF with open-flap debridement Open-flap debridement alone 42 9 mths Clinical and radiographic CAL were better in PRF and PRP. No differences were observed among PRP and PRF
2013 Khairy et al. 198 PRP Bone PRP with autogenous bone Autogenous bone 15 6 mths Clinical, radiographic and histologic PRP group show more bone density
2013 Hauser et al. 190 PRF Bone PRF or PRF and socket filling Extraction alone 23 2 mths Clinical, radiographic and histologic PRF group shown better results
2014 Eskan et al. 191 PRP Bone PRP and resorbable polylactide membrane Resorbable polylactide without PRP 28 4 mths Clinical, radiographic and histologic PRP shown more bone gain
2015 Angelo et al. 192 PRF Bone Biphasic (60% HA/40% b-TCP) or monophasic (100% b-TCP) Bi or monophasic without PRF 82 8.3 mths Clinical, radiographic and histologic PRF shown superior mechanical stability to restored alveolar bone
2015 Narang et al. 144 PRP and PRF Pulp PRP and PRF revascularization Blood Clot revascularization 15 18 mths Clinical and radiographic PRF was superior that PRP. PRF and PRF were better than control group
2015 Pradeep et al. 19 PRF Bone and Periodontal PRF OR PRF with Metformin 1% OR Open-flap debridement with PRF plus 1% metformin Open-flap debridement alone 120 9 mths Clinical and radiographic PRF + 1% MF group showed greater improvements in clinical parameters
2015 Shah et al. 194 PRF Periodontal Open flap debridement and PRF Open-flap debridement + Demineralized freeze-dried bone allograft 20 6 mths Clinical and radiographic Better result observed in PRF group
2015 Kumar et al. 193 PRF Bone PRF 31 3 mths Clinical and radiographic Bone density was more in PRF group

beta-tricalcium phosphate (b-TCP); polyglycolid-polylactid (PLGA); Synthetic polysaccharide (FICOLL); bovine bone mineral (BioOsss); hydroxyapatite (HA); Bone Morphogenetic Protein (rhBMP); Platelet Derived Growth Factor (PDGF); Computed Tomography (CT); Bone Marrow Mesenchymal Stem Cells (BMMSC); Bone Marrow Aspirate Concentrates (BMAC); Adipose stem cells (ASC); Dental Pulp Stem Cells (DPSC); Periodontal Ligament Stem Cells (PDLSC); Mesenchymal Stem Cells (MSC); Mononuclear Cells (MNC); Platelet-Rich Plasma (PRP); Platelet-Rich fibrin (PRF); probing depth (PD), Clinical Attachment Level (CAL)

The higher follow-up reported was 4 years 187. Benefits of PRP 182 or PRF 190 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 188,189. Thus, PRP and PRF provided significant improvement, clinically and radiographically, in 3-wall periodontal intrabony defects 184,188. On the other hand, one study performing revascularization reported best results for PRF 144.

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 39,41,45,55,64 even as the use of PRP, when combined with biomaterials can facilitate the clinical manipulation of the materials for graft 182,198. 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 28,62,63.

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 58,73. Besides, PRP and PRF were able to improve bone deposition 198.

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 49. 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 98. 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 54,73. 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 7. 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 77 with gradually substitution of scaffolds for bone was frequently observed 36,49. 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 86,93. In contrast, no signs of periodontal regeneration were detected in control group 93. 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 4,199. GF-MT is considered easier to apply than SC-BT 7. 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 28,200.

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 41,46,52,55,64,66,67,75. 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 52. The use of PRP seems to increase the histological features proving good osteoconductive properties 180,191. Bone formation in sinus lifting was more efficient in group treated with PRP than in the control group (with inorganic bovine bone alone) 180. 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 52. In the same way, PRF alone presented a propensity to regenerate higher bone volume and quality, even as PRF combined with socket filling 190. 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 18,186,188.

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 71,73. Two studies evaluated the potential of osteoblastic cells seeded on PLGA scaffolds for bone regeneration, reported unfavorable results 71,73. 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%) 71. Polymeric scaffolds should be incorporated in metabolic routes to be replaced by cell-secreted extracellular matrix. However, this process should not be so fast 7. After adhesion and osteoblastic differentiation, bone remodeling is expected to happen parallel to new extracellular matrix formation 201. Histological analysis revealed high medullar spaces with few amount of regenerated bone 73. Therefore, the fast PLGA resorption rate seems to hamper proper bone regeneration 71,73. In contrast, collagen sponges, hydroxyapatite (HA) and b-TCP, as well as allogenic or xenogeneic bone has provided suitable bone stability 43,54,58,80,85. 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 38,131,165,173-175. 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 25. 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 25. 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 202. 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) 202. In fact, after performing revascularization, mineral deposition is observed into the root canal characterized as cementum/bone-like tissue, but not dentin 174. Thus, considering that application of SC-BT or GF-MT improves the quality of bone and periodontal formed 57,93, 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 25. 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 25. 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 25. 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 26.

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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Received: March 17, 2018; Accepted: July 02, 2018

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

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