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

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

doi:10.1590/0103-6440201902053

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Review Article • Braz. Dent. J. 30 (2) • Mar-Apr 2019 • https://doi.org/10.1590/0103-6440201902053 linkcopy

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

Authorship SCIMAGO INSTITUTIONS RANKINGS

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

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

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)

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

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

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

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[TFN1] 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)