Oral Bone Tissue Regeneration: Mesenchymal Stem Cells, Secretome, and Biomaterials
Abstract
:1. Introduction
2. Mesenchymal Stem Cells and Regenerative Medicine
3. Biomaterials and Scaffold Characteristics for Bone Tissue Engineering
4. Biomaterials and Mesenchymal Stem Cells for Bone Tissue Engineering
4.1. In Vivo Studies Using MSCs and Scaffolds for Bone Regeneration
4.2. In Vivo Studies Comparing Different Biomaterials or Scaffold Features in Association with MSCs for Bone Regeneration
4.3. In Vivo Studies Using Scaffolds Enriched with Biomolecules and MSCs for Bone Regeneration
4.4. In Vivo Studies Using Scaffolds Enriched with Genetically Modified or Pre-Treated MSCs for Bone Regeneration
4.5. In Vivo Studies Using Scaffolds Enriched with MSCs from Different Sources for Bone Regeneration
5. Future Perspective: Cell-Free Approach
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
MSCs | Mesenchymal stem cells |
ECM | Extracellular matrix |
BMSCs | Bone marrow-derived MSCs |
OMSCs | Oral mesenchymal stem cells |
DPSCs | Dental pulp stem cells |
SCAPs | Stem cells from the apical papilla |
PDLSCs | Periodontal ligament stem cells |
GMSCs | Gingival-derived MSCs |
DFSCs | Dental follicle stem cells |
TGSCs | Tooth germ stem cells |
ABMSCs | Alveolar bone-derived MSCs |
CM | Conditioned medium |
EVs | Extracellular vesicles |
VEGF | Vascular endothelial growth factor |
TGF-β | Transforming growth factor β |
BMPs | Bone morphogenetic proteins |
ESB | European Society for Biomaterials |
HA | Hydroxyapatite |
β-TCP | Β-tricalcium-phosphate |
Col | Collagen |
PLA | Polylactic acid |
PCL | Polycaprolactone |
PLLA | Poly(l-lactic acid) |
PDLA | Poly(d,l-lactic acid) |
PLGA | Polylactic-co-glycolic acid |
PGA | Polyglycolic acid |
C/ABB | Chitosan/anorganic bovine bone |
JBMMSCs | Jaw bone marrow-derived MSCs |
PDA | Polydopamine |
HCCS | HA Col calcium silicate |
CGFs | Concentrated growth factors |
NIPAM | N-isopropylacrylamide |
DMAc N | N′–dimethylacrylamide |
Hana | HA nanoparticles |
TEP | Tissue-engineered periosteum |
PDLCs | Periodontal ligament cells |
SHED | Stem cells from human exfoliated deciduous teeth |
OPG | Osteoprotegerin |
ADMSCs | Adipose-derived MSCs |
PLDL | l-lactide and dl-lactide |
PDL | dl-lactide |
DSPP | Dentin sialo-phosphoprotein |
DMP1 | Dentin matrix protein-1 |
MMP20 | Enamelysin/matrix metalloproteinase 20 |
PHEX | Phosphate-regulating gene with homologies to endopeptidases on X Chromosome |
SrHAB | Strontium-substituted HA-based bioceramic scaffold |
EPCs | Endothelial progenitor cells |
pDNA | Plasmid DNA |
BGN | Bioactive glass nanoparticle |
CPCs | Calcium phosphate cements |
iPSMSCs | Induced pluripotent stem cell-derived MSCs |
NAC | N-acetyl-l cysteine |
Trb3 | Tribbles homolog 3 |
PRF | Platelet-rich fibrin |
PVDF-TrFE/BT | Poly(vinylidene-trifluoroethylene)/barium titanate |
hUVECs | Human umbilical vein endothelial cells |
hUCMSCs | Human umbilical cord MSCs |
hiPSC-MSCs | MSCs from induced pluripotent stem cells |
hESC-MSCs | Embryonic stem cells |
PVA | Polyvinyl alcohol |
HAB | HA-based bioceramic |
PMSCs | Periosteum-derived MSCs |
ABM | Anorganic bone mineral |
EXO | Exosomes |
MBG | Mesoporous bioactive glass |
PEI | Polyethyleneimine |
PEI-EVs | Polyethyleneimine-engineered EVs |
VEGFR2 | VEGF receptor 2 |
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Biomaterial | MSCs | Species | Model | Results | Ref. |
---|---|---|---|---|---|
C/ABB scaffold | JBMMSCs | Beagle dogs | Infrabony defects | New bone and cementum formation | [49] |
PDA-laced HCCS | Osteogenic aggregated BMSCs | Sprague Dawley rats | Critical-sized calvarial defects | New bone formation was visible in scaffold with MSCs, while the scaffold without MSCs showed limited osteoconductivity | [50] |
Bio-Oss® | BMSCs | Beagle dogs | Maxillary sinus floor augmentation | Newly formed bone in groups treated with Bio-Oss® and BMSCs may be more mature | [51] |
Laponite® crosslinked with NIPAM and DMAc loaded with HA nanoparticles | BMSCs | Wistar rats | Femur defect model | In young male rats, bone defect repair seemed to be less effective when l-pNIPAM-co-DMAc seeded with MSCs was injected. In aged rats, an increase in runx2 was found in rats treated with l-pNIPAM-co-DMAC with HAna and MSC, suggesting an improved osteogenicity | [52] |
PCL, Col, and nano-HA | BMSCs | Mice | Femur defect model | Combined with a bone allograft restored donor-site periosteal bone formation, reversing the poor biomechanics of bone allograft healing | [53] |
Matrigel | Tonsil-derived MSCs | Sprague Dawley rats | Osteoradionecrosis | Bone regeneration and mineral density were better in the group transplanted immediately after trauma | [54] |
PCL | Gingival cells, BMSCs, and PDLC | Sheep | Periodontal defect model | The PDLC group showed an enhanced bone formation | [55] |
Fibrinogen and gelatin | Endothelial cells and MSCs | Sprague Dawley rats | Critical-sized calvarial defects | When the cells in the scaffolds were separated by a distance of <200 μm, an elevated number of blood vessels was shown and major bone regeneration | [56] |
HA | SHED | Wistar rats | Alveolar bone defect model | Improved alveolar bone defect regeneration | [57] |
HA matrix with PLGA | DPSCs | New Zealand rabbits | Bilateral mandibular critical-sized defects | Induced new bone formation and angiogenesis. The scaffold without DPSCs was less efficacious | [58] |
TCP–PLGA scaffolds | Osteogenic differentiated ADMSCs | Miniature pigs | Mandibular defect model | Increased bone volume and osteocalcin deposition; the scaffold without cells was less efficacious | [59] |
Alginate-based hydrogel modified with dopamine and methacrylate residues and with HA microparticles | GMSCs | Beige nude XID III (nu/nu) mice; Sprague Dawley rats | Subcutaneous model; Peri-implantitis model | Induced a complete bone regeneration | [60] |
Self-crosslinking thiolated hyaluronic acid/type I Col I blend hydrogel and biphasic calcium phosphate ceramics | BMSCs | New Zealand rabbits | Osteochondral defect model | The BMSCs/chondrocyte scaffold promoted bone regeneration | [61] |
Biomaterial | MSCs | Species | Model | Results | Ref. |
---|---|---|---|---|---|
Polyamide, PLGA, or decellularized amniotic membrane | ADMSCs | Rabbits | Calvarial defects | Polyamide scaffolds showed the best results | [62] |
PLDL, PDL, and HA/TCP | DPSCs | Immunocompromised mice | Subcutaneous implantation | PLDL, PDL, and HA-TCP enriched with DPSC seemed to be promising scaffolds for odontogenic regeneration | [63] |
Col membrane with and without TCP material | BMSCs | Sprague Dawley rats | Critical-sized calvarial defects | The hardness of the new bone was similar to the native bone in groups with the Col membrane with and without cells. The bone in the group treated with Col membrane, TCP, and BMSCs showed a greater elasticity | [64] |
20% HA/80% TCP, 60% HA/40% TCP, or Bio-Oss | ABMSCs | Mice | Ectopic transplantation model | ABMSCs with both HA/TCP scaffolds increased bone regeneration; Bio-Oss did not induce new bone formation when loaded with ABMSCs | [65] |
Alginate hydrogels containing BMP-2 | SHED | C57BL/6 mice | Subcutaneous | Scaffold with smaller pores and greater elasticity was found to potentially induce greater bone regeneration | [66] |
Nanofibrous PLLA scaffolds with different pore sizes | BMSCs | Mice | Subcutaneous implantation | Bone volume increased with the increase of pore size | [67] |
PDA-laced HCCS scaffolds with different pore dimensions | MSCs | Sprague Dawley rats | Critical-sized calvarial defects | New bone formation was observed after the implantation of the scaffold with pores of the size of 500 μm; instead, the scaffolds with 250 μm pores induced only a minimal bone formation | [68] |
βTCP with or without nano-diamond particles | BMSCs | Merino sheep | Lateral augmentation of the mandible | βTCP with nano-diamond particles induced more bone formation; MSC addition resulted in little difference | [69] |
HA-based bioceramic scaffold 10% of strontium | BMSCs | NOD.CB17-PrkdcSCID/Jmice; sheep | Ectopic bone formation; femoral critical-sized defects | The scaffolds containing 10% of strontium induced bone formation and osteogenic differentiation of MSC | [70] |
Scaffold | MSCs | Enrichment | Species | Model | Results | Ref. |
---|---|---|---|---|---|---|
TCP scaffolds | BMSCs with endothelial progenitor cells | PLGA microspheres releasing VEGF | Mongrels | Mandibular defects | Bone formation was greatest in the VEGF/MSC scaffold, followed by the VEGF/MSC/EPC and MSC/EPC scaffolds | [71] |
Alginate-chitosan beads | MSCs | BMP-2 or basement membrane proteins | Mice | Cranial defect | Induced bone repair | [72] |
Nano-HA (nHA)/Gel/Gel microsphere | BMSCs | BMP-6 | Sprague Dawley rats | Critical-sized calvarial defects | The new bone was larger with the BMP-6-loaded scaffolds | [73] |
nHA/Col I/multi-walled carbon nanotube | BMSCs | BMP-9 | Sprague Dawley rats | Critical-sized calvarial defects | The enrichment with BMP-9 increased bone formation | [74] |
Heparin-conjugated Col hydrogel reinforced by 3D printed β-TCP-based bioceramic | DPSCs | BMP-2 | Male Fischer 344 rats | Subcutaneous implantation | A greater new bone formation was found when heparin was present. BMP-2 increased the expression of genes involved in osteogenesis | [75] |
PCL biomembranes | BMSCs | BMP-2 | Nude mice | Maxillary bone lesion | BMSCs and BMP-2 accelerated the bone remodeling process | [76] |
Nanofibrous PCL scaffold | BMSCs | pDNA encoding for human BMP-2 | Sprague Dawley rats | Calvarium defect | Increased the regenerated bone volume, and this composite induced the formation of more dense bone-like structures | [77] |
Scaffold | MSCs | Species | Model | Results | Ref. |
---|---|---|---|---|---|
Col gel | BMSCs transfected with BMP-2 plasmid DNA | Sprague Dawley rats | Calvarium critical-sized defect | Improved in bone regeneration | [79] |
HA scaffold | BMSCs for OPG delivery | Sprague Dawley rats | Critical-sized bone defects were created in the rat mandibles | The genetically modified BMSCs group showed the greatest level of mineralized new bone | [80] |
Bio-Oss | DMP1-transduced BMSCs | Beagles | Maxillary sinus floor augmentation | Promoted of new bone formation | [81] |
Calcium phosphate cements | Pre-osteoinduced or BMP-2 transduced iPSMSCs in alginate microbeads | Nude rats | Cranial bone defects | New bone area fraction was greater when iPSMSCs transduced with BMP-2 were used, followed by pre-osteoinduced iPSMSCs | [82] |
Col sponge | BMSCs pre-treatment with N-acetyl-L cysteine | Sprague Dawley rats | Femur bone defect | Pre-treatment of BMSCs with NAC before transplantation enhanced bone regeneration | [83] |
β-TCP | miRNA-21-modified BMSCs | Labrador dogs | mandibular defect model | A greater volume of new bone formation was found in the miRNA-21 group compared to the control group | [84] |
Hydrogels made of fibrin and plasmonic gold nanoparticles | BMP-2-expressing MSCs | C3H/HeNRj mice | Critical-sized calvarial defects | Formed of new mineralized tissue. | [85] |
Biphasic calcium phosphate (MBCP) blocks | PDLSC pretreatment of recombinant human BMP-2 | BALB/c nude mice | Subcutaneous transplantation | rhBMP-2 pretreated hPDLSC sheets showed greater mineralized tissue formation and Col ligament deposition compared to not pretreated cells | [86] |
Apatite/PLGA scaffold | Trb3 overexpressing MSCs | CD-1 nude mice; Sprague Dawley rats | Calvarial defect model; critical-sized mandible defects | Induced bone regeneration | [87] |
Scaffold | MSCs | Species | Model | Results | Ref. |
---|---|---|---|---|---|
Dentin matrix and HA/TCP | platelet-rich fibrin PDLSCs and JBMSCs | Nude mice | Simulated periodontal space comprising human treated dentin matrix and HA/TCP frameworks | PDLSC sheets developed into periodontal ligament-like tissues, while the JBMSC sheets tended to predominantly produce bone-like tissues | [88] |
PVDF-TrFE/BT membrane | BMSCs or ADMSCs differentiated toward osteoblastic cells | Wistar rats | Calvarial defect | Osteoblastic cells from BMSCs with the PVDF-TrFE/BT membrane increased bone formation, bone volume, bone volume percentage, bone surface, and trabecular number, while those derived from ADMSCs were not able to enhance bone repair | [89] |
CPC scaffold | hUVECs and hUCMSCs, BMSCs, hiPSC-MSCs, or hESC-MSCs | Rats | Critical-sized cranial defect | The coculture of hUVEC with hUCMSCs, hiPSC-MSCs, and hESC-MSCs showed new bone and vessel density similar to the coculture of hUVEC with BMSCs. | [90] |
PVA-PCL-HA-based bioceramic | BMSCs or DPSCs | NOD-SCID mice | Ectopic bone formation | New bone formation was found | [91] |
PCL | PMSCs and BMSCs | Sprague Dawley rats | Femoral critical-sized bone defect | New bone formation was found in the group implanted with the PMSC-enriched scaffold, while no healing was observed when the scaffold was seeded with BMSCs | [92] |
Anorganic bone mineral coated with a biomimetic Col peptide (ABM-P-15) | DPSCs and BMSCs | MF1 Nu/Nu mice | Intraperitoneal transplantation | DPSCs showed a better osteogenic capacity | [93] |
NanoBone scaffold | GMSCs and BMSCs | New Zealand rabbits | Tibiae bone defects | The transplantation of GMSCs and BMSCs loaded onto the NanoBone showed better bone regeneration compared to the scaffold without cells. Interestingly, no difference was found in the new bone formed by the scaffolds loaded with GMSCs or BMSCs | [94] |
Secretome | MSC Source | Biomaterial | Species | Model | Results | Ref. |
---|---|---|---|---|---|---|
CM or cytokine cocktail that mimics the CM | BMSCs | Atelocollagen sponge | Wistar/ST rats | Calvarial bone defects | Bones regenerated thanks to the recruitment of endogenous stem cells and endothelial cells | [110] |
CM | MSCs | Atelocollagen | Wistar/ST rats | Calvarial bone defect model | New bone formation | [111] |
CM | BMSCs | Col sponge | Sprague Dawley rats; BALB/C mice | Calvaria defect model; inflammatory bone loss | Enhanced bone volume | [112] |
CM | SHED | Atelocollagen sponge | Deficient mice (BALB/c-nu) | Calvarial bone defect model | Enhanced bone regeneration and angiogenesis | [113] |
CM | BMSCs cultured under cyclic stretch stimulation | Col sponge | Mice | Calvarial defect model | Bone regeneration and angiogenesis were enhanced by CM obtained from the cyclic stretch culture group | [114] |
CM | GMSC and PDLSC | Col membrane | Wistar rats | Periodontal defect model | Newly formed bone and reduced inflammation | [115] |
EXO | Adipose-derived stem cells | Polydopamine-coating PLGA | BALB/C mice | Calvarial critical-sized defect | Promoted MSC migration and homing into the new bone | [116] |
EXO | MSCs | Col/III sponges | Sprague Dawley rats | Periodontal defect model | Regenerated bone and periodontal tissues | [117] |
EXO overexpressing miR-375 | Adipose-derived stem cells overexpressing miR-375 | Hydrogel consisting of thiol-modified hyaluronan, HA and thiol-modified heparin | Sprague Dawley rats | Calvarial defects | Enhanced bone regeneration | [118] |
EXO | BMSCs | Atelocollagen sponges | Wistar rats | Calvarial critical-sized defect | Bones regenerated and angiogenesis occurred | [119] |
EXO | DPSCs | Tri-block PLGA–PEG–PLGA micro-spheres incorporated into a nanofibrous PLLA scaffold | C57BL/6 mice | Calvarial Defect | Bone tissue regenerated | [120] |
Small EVs | BMSCs | Gelatin blended with Laponite | Sprague Dawley rats | Periodontitis rat model | Alveolar bone loss, inflammatory infiltration, and collagen destruction diminished | [121] |
EVs | BMSCs were genetically modified to constitutively express BMP-2 | Collagen tape | Rats | Calvarial bone defect | Increased bone regenerative potential | [122] |
EXO | BMSC in osteoinductive condition | Mesoporous bioactive glass | Rats | Critical-sized calvarial defect | New bones formed and regenerated | [123] |
EVs | BMP 2 expressing MSCs | Alginate hydrogel linked with the RGD domain of fibronectin | Rats | Calvarial bone defect model | Enhanced bone regeneration | [124] |
EVs, or PEI-engineered EVs | GMSCs | PLA | Wistar rats | Calvarial defect | The scaffold containing PEI-EVs, with or without cells, were able to improve bone healing | [125] |
CM | GMSCs | PLA scaffold | Wistar rats | Calvarial defect | Good osteogenic capacity was observed | [126] |
CM, EVs, or EVs engineered with PEI | PDLSCs | Col membrane | Wistar rats | Calvarial defect | Increased bone regeneration in association with vascularization | [127] |
CM | PDLSCs | Evolution membrane | Wistar rats | Calvarial defect | Good osteogenic ability was observed | [128] |
EVs | GMSCs | PLA | Wistar rats | Calvarial defect | Bone regeneration and vascularization were observed | [129] |
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Gugliandolo, A.; Fonticoli, L.; Trubiani, O.; Rajan, T.S.; Marconi, G.D.; Bramanti, P.; Mazzon, E.; Pizzicannella, J.; Diomede, F. Oral Bone Tissue Regeneration: Mesenchymal Stem Cells, Secretome, and Biomaterials. Int. J. Mol. Sci. 2021, 22, 5236. https://doi.org/10.3390/ijms22105236
Gugliandolo A, Fonticoli L, Trubiani O, Rajan TS, Marconi GD, Bramanti P, Mazzon E, Pizzicannella J, Diomede F. Oral Bone Tissue Regeneration: Mesenchymal Stem Cells, Secretome, and Biomaterials. International Journal of Molecular Sciences. 2021; 22(10):5236. https://doi.org/10.3390/ijms22105236
Chicago/Turabian StyleGugliandolo, Agnese, Luigia Fonticoli, Oriana Trubiani, Thangavelu S. Rajan, Guya D. Marconi, Placido Bramanti, Emanuela Mazzon, Jacopo Pizzicannella, and Francesca Diomede. 2021. "Oral Bone Tissue Regeneration: Mesenchymal Stem Cells, Secretome, and Biomaterials" International Journal of Molecular Sciences 22, no. 10: 5236. https://doi.org/10.3390/ijms22105236