Bone regeneration is often needed prior to dental implant treatment due to the lack of adequate quantity and quality of the bone after infectious diseases, trauma, tumor, or congenital conditions. In these situations, cell transplantation technologies may help to overcome the limitations of autografts, xenografts, allografts, and alloplastic materials. A database search was conducted to include human clinical trials (randomized or controlled) and case reports/series describing the clinical use of mesenchymal stem cells (MSCs) in the oral cavity for bone regeneration only specifically excluding periodontal regeneration. Additionally, novel advances in related technologies are also described. 190 records were identified. 51 articles were selected for full-text assessment, and only 28 met the inclusion criteria: 9 case series, 10 case reports, and 9 randomized controlled clinical trials. Collectively, they evaluate the use of MSCs in a total of 290 patients in 342 interventions. The current published literature is very diverse in methodology and measurement of outcomes. Moreover, the clinical significance is limited. Therefore, the use of these techniques should be further studied in more challenging clinical scenarios with well-designed and standardized RCTs, potentially in combination with new scaffolding techniques and bioactive molecules to improve the final outcomes.
Hard and soft tissues in the oral cavity are constantly being challenged. As a consequence of infectious oral diseases, trauma, tumor or cyst resection, or congenital and developmental conditions (i.e., cleft palate defects), tooth loss results in the alteration of basic functional, aesthetical, and psychological needs. Mastication, speech, swallowing, and thermal and physical protection of important anatomical structures (i.e., brain, nerves, arteries, and veins) are diminished [
Bone deficiencies in the oral cavity differ enormously in extension and etiology, ranging from localized alveolar bone loss due to periodontal disease to extensive bone atrophy as a consequence of a variety of syndromes, including traumatic injuries and bone resorption associated with a number of benign or malignant tumors. Extensive bone deficiencies, in particular, are really challenging in the clinical setting [
Bone regeneration requires the migration of specific cells to the healing area to proliferate and provide the biological substrate for the new tissue to grow. Soluble factors, different cell types, extracellular matrix (ECM), and matricellular proteins mediate and coordinate this process. Initially, angiogenic signals and new vascular networks provide the nutritional base for tissue growth and homeostasis. Simultaneously, a three-dimensional template structure based on a proper extracellular matrix is synthesized and organized. This template will, later, support and facilitate the process of bone formation and maturation. Once those structures are established, the regenerated bone will go on under the normal homeostatic and modeling-remodeling processes [
Although the exact mechanisms that regulate the bone regeneration process at the deepest biomolecular level are yet to be understood, several methods for predictable bone reconstruction have been proposed [
Schematic requirements for bone regeneration from a tissue engineering perspective.
Stem cells are unspecialized cells with the ability to proliferate and differentiate to multiple cell types when stimulated by both internal and external signals. Adult (somatic) stem cells that exhibit this plasticity are called pluripotent cells and can be found in bone marrow in the form of hematopoietic, endothelial, and mesenchymal (stromal) stem cells (MSCs). Other sources of MSCs in adult patients have been also identified such as adipose tissues (ASCs), lung, and teeth (perivascular niche of dental pulp and periodontal ligament) [
Principal types and uses of cells in oral tissue regeneration.
Cell type | Origin |
---|---|
Bone marrow stromal cells | Autograft |
Adipose stromal cells | Autograft |
Periodontal ligament cells | Autograft, allograft, xenograft |
Periodontal ligament stem cells | Allograft, autograft |
Therefore, the main purpose of this review is to identify the existing literature on clinical studies utilizing MSCs or ASCs to treat oral bone defects and to critically analyze their validity, methodology, and outcomes. Additionally, emerging strategies for the recruitment and transplantation of MSCs into bone defects will also be discussed.
A search of electronic databases including Ovid (MEDLINE), PubMed, and Cochrane Central for studies was performed in September 2014 by two examiners limited to articles published in English during the last 10 years performed on human subjects. The search build used was as follows: (“Mesenchymal Stem Cell Transplantation” [Mesh] OR “Adult Stem Cells” [Mesh] OR “Stem Cells” [Mesh] OR “Stem Cells Transplantation” [Mesh] OR “Tissue Therapy” [Mesh] OR “Bone Marrow Transplantation” [Mesh] OR “Bone Marrow” [All Fields] OR “stem cell therapy” [All Fields] OR “stem cell” [All Fields]) AND (“Sinus Floor Augmentation” [Mesh] OR “Bone Regeneration” [Mesh] OR “Alveolar Ridge Augmentation” [Mesh] OR “craniofacial bone regeneration” [All Fields] OR “craniofacial” [All Fields] OR “alveolar bone” [All Fields] OR “implant site development” [All Fields]) AND ((Controlled Clinical Trial [ptyp] OR Clinical Trial [ptyp] OR Randomized Controlled Trial [ptyp] OR Case Reports [ptyp] OR Comparative Study [ptyp] OR Validation Studies [ptyp] OR Evaluation Studies [ptyp]) AND “2004/09/12” [PDat]: “2014/09/12” [PDat] AND “humans” [MeSH Terms] AND English [lang]).
In addition, a manual search was conducted in related scientific journals and relevant papers that could contribute to the process of information collecting.
The following inclusion criteria to select the articles obtained after the search were as follows: human clinical trial (randomized or controlled) and case reports/series on the clinical application of MSCs in oral bone regeneration. On the other hand, articles were excluded if the technique applied was related to periodontal regeneration or was not associated with bone tissue reconstruction. Articles were first screened by analyzing the abstract. From those which were selected in this phase, full-text was obtained and analyzed for a second screening. Potential articles were independently reviewed in full-text by two examiners. The final decision on the included articles was made with mutual agreement of the two examiners.
Additionally, a critical review of relevant supportive technologies for bone regeneration in combination with MSCs has been conducted.
A total of 190 records were identified by the database and hand search and were assessed for eligibility. After reading the abstracts, 51 articles were selected for full-text assessment. Of those, only 28 were included in this review based on the inclusion criteria previously determined. From the 28 articles selected (Figure
Randomized clinical trials in the use of MSCs for oral bone tissue regeneration.
Reference | Stem cell type | Colection | Subculture | Origin |
|
Carrier | Defect type | Graft location | Cover | Control | Time for analysis | Analysis | Primary outcomes | Implants | Restoration | Follow-up after restoration | Implant survival rate | Complications |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Da Costa et al. [ |
MSC | BMA | No (whole aspirate) | IB | 5 + 5 | AB | Horizontal | AM | NO | AB | 6 m | CT + Hm | Alveolar thickness gain: 4.6 ± 1.43 versus 2.15 ± 0.47 mm (test versus control); vital bone: 60.7 ± 16.18 versus 41.4 ± 12.5% (test versus control) | Yes (40) | Yes | N/S | 100% | N/S |
|
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Gimbel et al. [ |
N/S | BMA | No (whole aspirate) | IB | 21 tests + 25 controls | CS | Cleft palate | AM | NO | IB | 1 d, 1 w, 3 w, 6 w, 6 m | Comfort and complications for donor site | Best results in test group followed by conventional iliac graft | No | No | N/A | N/A | Test: 2 granulation tissues; control: 1 oronasal fistula |
|
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Gonshor et al. [ |
MSC | CBA | No | N/S | 18: 8 bilats + 10 unilats (=26) | CBA | Sinus lift | PM | NO | Allograft | 3.6 ± 0.6 m | H + Hm + CT | Vital bone: 32.5 ± 6.8% (test) - 18.3 ± 10.6% (control) | Yes | No | N/S | N/S | 2 patients lost |
|
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Kaigler et al. [ |
MSC | BMA | Yes (automated Ixmyelocel-T) | IB | 12 + 12 | CS | Alveolar reconstruction | M and Mn | CM | CS + CM | 6 or 12 w | RX + |
Linear bone height: 55.3%–78.9 (6 w, control versus test); 74.6%–80.1% (12 w, control versus test) | Yes | Yes | 1 year | N/S | N/S |
|
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Pelegrine et al. [ |
MSC | BMA | No (whole aspirate) | IB | 15 + 15 | No | Alveolar reconstruction | AM | NO | No graft | 6 m | Clinical data + H + Hm | Horizontal bone loss: 1.14 ± 0.87 versus 2.46 ± 0.4 mm (test versus control); vertical bone loss: 1.17 ± 0.26 mm versus 0.62 ± 0.51 mm (test versus control); new vital bone: 45.47±7.21 versus 42.87 ± 11.33% | Yes (20) | Yes | N/S | 100% | 5 control sites required regraft at implant placement |
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Rickert et al. [ |
MNC | BMA | No (BMAC) | IB | 12 split mouths (24 sinuses) | BBM | Sinus lift | PM | CM | BBM + retromolar autogenous graft | 14.8 ± 0.7 w | Hm | New bone (test versus control): 17.7 ± 7.3% versus 12.0 ± 6.6% | Yes (66 nonsubmerged) | Yes | N/S | N/S | 3 implant failures |
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Sauerbier et al. [ |
MSC | BMA | No (BMAC) | IB | 7 patients (12 sites; test) + 4 (6; control) | BBM | Sinus lift | PM | CM | FICOLL | 3 m | H + Hm | Similar results for all parameters | Yes | Yes | 1 y | 98% | 1 implant lost in the test group |
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Sauerbier et al. [ |
MSC | BMA | No (BMAC) | IB | 26 patients (45 sinuses) 34 tests/11 controls | BBM | Sinus lift | PM | CM | BBM + Retromolar Autogenous graft | 3.46 ± 0.43 m test/3.34 ± 0.42 m control | CT + H + Hm | Radiographic volume gain: 1.74 ± 0.69 versus 1.33 ± 0.62 mL (test versus control); new bone formation: 12.6 ± 1.7 versus 14.3 ± 1.8% | No | No | N/S | N/A | 1 inferior alveolar nerve injury during autogenous graft harvesting |
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Wojtowicz et al. [ |
MNC | BMA | Nonprocessed BMA, CD34+ cells isolated from BMA or PRP | IB | 17 (9 CD34+/4 BMA/4 PRP) | BBM | Cystectomy | AMn | FM + CM | No graft | 1 & 3 m | RX | Similar trabeculae to nonregenerated bone in BMA and CD34+ groups | No | No | N/S | N/A | N/S |
MSC = mesenchymal stem cells; MNC = mononuclear cells; ASC = adipose stem cells; N/S = not specified; BMA = bone marrow aspirate; CBA = cellular bone allograft; BMAC = bone marrow aspirate concentrate; IB = iliac bone; AB = allogenic block; CS = collagen sponge; BBM = bovine bone marrow; AM = anterior maxilla; PM = posterior maxilla; M = maxilla; Mn = mandible; AMn = anterior mandible; CM = collagen membrane; FM = fibrin membrane; d = days; w = weeks; m = months; y = years; H = histology; Hm = histomorphometry; CT = computed tomography; RX = radiography; N/A = not applicable.
Case series/report in the use of MSCs for oral bone tissue regeneration.
Reference | Study design | Stem cell type | Collection | Subculture | Origin |
|
Carrier | Defect type | Graft location | Cover | Time for analysis | Analysis | Primary outcomes | Implants | Restoration | Follow-up after restoration | Implant survival rate | Complications |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Behnia et al. [ |
CS | MSC | BMA | Yes (2 w, manual, no induction) | IB | 2 | DBM + calcium sulfate | Cleft palate | AM | NO | 4 m | CT | Oronasal fistula closure; 25.6–34.5% bone defect fill | No | No | N/A | N/A | N/S |
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Behnia et al. [ |
CS | MSC | BMA | Yes (2 w, manual, no induction) | IB | 4 | HA/TCP + PDGF | Cleft palate | AM | FC | 3 m | CT | Oronasal fistula closure; 51.3% bone defect fill | No | No | N/A | N/A | N/S |
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Cerruti et al. [ |
CS | MNC | BMA | No (whole aspirate) | IB and SB | 32 | AB + PPP + PRP | Vertical, horizontal, sinus lift | AM and PM | N/S | 4 m | H + CT | Width: 6–14 mm (AM); height: ≈10 mm (AM) and 6 -> 15 mm (PM) | Yes | Yes | 4 years | 100% | 1 graft not integrated; 1 sinus infection |
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Hernández-Alfaro et al. [ |
CR | MSC | BMA | No (BMAC) | IB | 1 | DBB + BMP-2 | Ameloblastoma resection | PMn | CM | 9 m | CT + H | Adequate bone formation | Yes | Yes | 1 year | 100% | N/S |
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Hibi et al. [ |
CR | MSC | BMA | Yes (4 w, manual, osteogenic induction with 100 nM dexamethasone, 10 mM b-glycerophosphate, and 50 mg/mL ascorbic acid-2- phosphate) | IB | 1 | PRP | Cleft palate | AM | TM | 3–6–9 m | CT | 79.1% bone coverage | No | No | N/S | N/A | N/S |
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Lee et al. [ |
CR | MSC | BMA | Yes (4 w, manual, osteogenic induction by 50 |
IB | 1 | FDAB + Fibrin | Hemangioma resection | PMn | TM | 12 m | CT + H | New bone formation, graft contains live osteocytes, enough bone height for implant placement | Yes | No | N/S | N/S | N/S |
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Meijer et al. [ |
CR | MSC | BMA | Yes (manual, osteogenic induction by dexamethasone) | IB | 6 | HA | Sinus lift and other defects | PM and PMn | NO | 4 m biopsy/3, 6, 9, 15 m RX | RX + Clinical data + Hm | Adequate bone mainly induced by the carrier/adequate radiographic bone reconstruction | Yes | Yes | 15 m | N/S | 1 implant failure |
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Sándor et al. [ |
CR | ASC | SAT | Yes (3 w, manual, no induction) | AAW | 1 | B-TCP + BMP-2 | Ameloblastoma resection | AMn | NO | 10 m | Panoramic RX + Hm | Successful bone reconstruction, implant placement, and prosthetic rehabilitation | Yes | Yes | N/S | N/S | N/S |
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Sándor et al. [ |
CS | ASC | SAT | Yes (3 w, manual, no induction) | AAW | 3 | B-TCP + BMP-2 | Ameloblastoma resection | Mn | TM | 1w, 1–12 m | Clinical data + RX | Successful bone reconstruction, uneventful healing | 2 patients (7 implants) | Yes | 27–51 m | 86% | N/S |
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Sauerbier et al. [ |
CR | MSC | BMA | No (BMAC) | IB | 2 patients | BBM | Vertical, horizontal | PM | CM | 7 m or 4 m | H + RX | 51.6% and 20.0% new bone formation, respectively | Yes | Yes | 2 y | 100% | NO |
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Schmelzeisen et al. [ |
CR | N/S | BMA | No (BMAC) | IB | 1 (2 sinuses) | BBM | Sinus lift | PM | N/S | 3 m | Hm | 29.1% BBM; 26.9% NBF | No | No | N/S | N/A | N/S |
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Shayesteh et al. [ |
CR | MSC | BMA | Yes (4 w, manual, no osteogenic induction) | IB | 7 | HA/TCP | Sinus lift | PM | CM | 3 m, 1 y | RX + Hm | New bone: 41.34%; radiographic bone height: 2.25–12.08–10.83 (baseline-postgraft-1 y) | Yes (30) | Yes | 6 m | 93% | 2 implants lost before restoration |
|
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Smiler et al. [ |
CS | N/S | BMA | No (whole aspirate) | IB | 5 patients (7 sites) | Xenograft, allograft, or alloplastic graft ( |
Sinus lift or horizontal | PM | CM + TM | 4–7 m | H + Hm | 23–45% of new bone formation, no differences between carriers are statistically reported | No | No | N/S | N/A | N/S |
|
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Soltan et al. [ |
CS | N/S | BMA | No (whole aspirate) | IB | 5 | AB | Sinus lift or horizontal | AM and PM | N/S | 8–12 m | H + Hm | 89% new vital bone (54% bone, 46% marrow) | Yes | Yes | N/S | N/S | N/S |
|
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Soltan et al. [ |
CS | N/S | BMA | No (whole aspirate) | IB | 2 patients/6 sites | HA or particulate allograft | Horizontal | PM and PMn | N/S | 4–6 m | H + Hm | 34–45% new bone, no statistical differences reported | Yes | Yes | N/S | N/S | N/S |
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Ueda et al. [ |
CS | MSC | BMA | Yes (4 w, manual, osteogenic induction by dexamethasone, sodium |
IB | 6 |
|
Sinus lift | PM | TM | 6 m | Clinical data + CT | 7.3 ± 4.6 mm height gain | Yes (20) | Yes | 12 m | 100% | 2 sinus membranes perforation, with minor nasal bleeding |
|
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Ueda et al. [ |
CS | MSC | BMA | Yes (4 w, manual, osteogenic induction by dexamethasone, sodium |
IB | 14 (6 sinus lifts/8 onlay graftings) | PRP | Sinus lift or vertical | PM | Titanium reinforced CM for vertical ridge augmentation | 4.8 m | Clinical data + RX | 8.7 mm height gain in sinus; 5 mm in ridges | Yes | Yes | 2–5 y | 100% | 4 sinus membranes perforation |
|
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Wongchuensoontorn et al. [ |
CR | MSC | BMA | No (BMAC) | IB | 1 | IB | Mn fracture | PMn | CM | 4 m | Panoramic RX | Mandibular fracture consolidation | No | No | 4 m | N/A | N/S |
|
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Yamada et al. [ |
CR | MSC | BMA | Yes (4 w, manual, osteogenic induction by 100 nM dexamethasone, 10 mM sodium |
IB | 1 | PRP | Vertical, horizontal | PMn | CM + TM | 7 m | CT + H | 4.2 mm bone height gain, new mature bone formation | Yes (3) | Yes | 2 y | 100% | N/S |
CS = case series; CR = case report; MSC = mesenchymal stem cells; MNC = mononuclear cells; ASC = adipose stem cells; N/S = not specified; BMA = bone marrow aspirate; SAT = subcutaneous adipose tissue; BMAC = bone marrow aspirate concentrate; IB = iliac bone; SB = sternum bone; AAW = anterior abdominal wall; DBM = demineralized bone marrow; HA/TCP = hidroxyapatite/tricalcium phosphate; PDGF = platelet derived growth factor; PPP = platelet-poor plasma; PRP = platelet-rich plasma; AB = allograft block; DBB = demineralized bovine bone; BBM = bovine bone marrow; IB = iliac bone; AM = anterior maxilla; PM = posterior maxilla; AMn = anterior mandible; PMn = posterior mandible; M = maxilla; Mn = mandible; CM = collagen membrane; FM = fibrin membrane; FC = fibrin clot; TM = titanium mesh; d = days; w = weeks; m = months; y = years; H = histology; Hm = histomorphometry; CT = computed tomography; RX = radiography; N/A = not applicable.
Flow chart of the paper selection process.
Bone deficiencies in the oral cavity differ enormously in extension and etiology, ranging from localized alveolar bone loss due to periodontal disease to extensive bone atrophy as a consequence of a variety of syndromes, including traumatic injuries and bone resorption associated with a number of benign or malignant tumors. In these clinical scenarios, functional and esthetical rehabilitation by dental implants is an essential tool. However, a proper quantity and quality of bone is a prerequisite not always present [
Bone regeneration requires not only osteolineage populations to migrate, proliferate, and differentiate into the treated area but also, of extreme importance, angiogenesis to provide the adequate nutrients and environment in which the bone tissue can grow and develop [
The analysis of the published literature on the clinical use of MSCs for oral bone regeneration previous to dental implant placement highlights the lack of proper RCTs with comparable methodologies to extract proper overall conclusions. However, out of the 28 identified clinical studies, 25 report the use of iliac bone marrow aspirates (BMA) which reflects that this location is widely accepted as the current standard for aspirate harvesting [
However, there is no standardization in terms of the processing and handling of such aspirates. While some studies use an expansion and isolation protocol previous to the surgical implantation (with a variety of subculture times, culture supplementations, automated or manual processes, cell population selection, etc.), others do the aspirate intrasurgically (chairside) and use the whole aspirate or a commercially available concentration kit (to select endothelial progenitors, hematopoietic and mesenchymal stem cells, platelets, lymphocytes, and granulocytes) (BMAC Harvest Technologies Corporation, Plymouth, MA, USA). One RCT compared the use of nonprocessed BMA versus PRP or CD34+ cells (angiogenic cells isolated from a BMA). Radiographic results from this study confirmed the utility of BMA and CD34+ over PRP alone [
Another important difference amongst studies is the carrier used to deliver the cells. It ranges from alloplastic graft (
Additionally, different defects are being treated in these studies. Those defects range from extensive non-self-contained (cleft palate and tumoral postresection defects) to extensive self-contained (sinus lift), nonextensive self-contained (postextraction sockets), and nonextensive non-self-contained defects (vertical and horizontal alveolar ridge augmentation). Bone regeneration in these situations differs enormously from one to another.
Globally, the results in most of the available literature show the goodness of the technique by vague subjective indications of qualitative appreciations and some studies fail to report specific objective quantitative data. When they do, the reported data is not comparable either as it ranges from vertical, to horizontal, or volumetric measures. Additionally, these measures are presented in absolute magnitudes or % of gain or reduction depending on the study. On the other hand, the number of differences among the identified RCTs makes it difficult to make a fair global comparison. Only 2 of those RCTs are fairly comparable as they use similar methodologies for concentration process (chairside), cell origin (iliac crest), defect type (sinus lift), and control group (bovine bone + autogenous graft) [
Weighted mean percentage of vital bone from RCTs on sinus lift [
In summary, the main overall report findings were that the clinical application of stem cells for oral bone regeneration promotes better outcomes in terms of clinical, radiographic, and histological parameters. However, the clinical significance in the applications analyzed in those RCTs (mainly self-contained defects, that is, postextraction sockets and sinus floor elevation) is very limited. Therefore, it could be argued that (1) the use of stem cells is not necessary in small defects that can be successfully treated by other means and (2) the lack of conclusive advantages does not surpass the scientific doubts, morbidity, and potential complications that stem cell therapy may possess. Therefore, the generalizability for the use of stem cell therapy in the daily clinical setting is still to be confirmed and probably not recommended for many clinical cases. Its advantages are yet to be studied in more challenging scenarios, such as extensive non-self-contained defects (vertical alveolar bone augmentation, extensive bone deficiencies in postresection tumor defects, and cleft palate conditions) where they may show their greatest potential over current treatment options.
The clinical use of MSCs for oral bone regeneration is usually accompanied by supporting scaffolds and bioactive molecules to further increase the capabilities of cell-based therapies.
The main purpose of a scaffold is to provide a mechanical support for cell migration, proliferation, and activity by mimicking the ECM. They will stimulate the production and maturation of a new ECM that will eventually mineralize. A scaffold will ideally provide a template for the subsequent bone formation, which starts in the periphery and continues towards the inner part. In this process, porosity is of extreme importance since it will facilitate cell ingrowth and vascularization and the biodegradation process [
Conventional scaffolds naturally derived (autografts, allografts, and xenografts) or synthetic materials (alloplasts) are commonly used in bone regeneration and implant therapy [
Additive manufacturing is defined as the process of joining materials to make objects from 3D model data, usually layer upon layer, as opposed to subtractive manufacturing methodologies [
For bone regeneration, a large variety of ceramic, polymeric, and composite materials can be processed using 3D printing to control interconnected porosity [
Synthetic polymers in bone tissue engineering are very flexible [
Based on these properties, the use of 3D printing in fabricating scaffolds with live osteoprogenitor cells [
The delivery of growth factors and other bioactive molecules was the first approach into using a biological agent modifier for regeneration purposes [
In addition to the mentioned growth and/or transcription factors and regulators of osteogenesis, our group has recently initiated efforts in investigating the potential of two molecules that can be of interest in this topic as well. Osteopontin (OPN) is a highly phosphorylated sialoprotein abundant in the mineralized extracellular matrices of bones and teeth [
Osteopontin immunohistochemical detection on anorganic bovine bone particle (Bio-Oss). Note bone formation where intense interstitial expression of OPN is observed in a case of maxillary sinus floor elevation (micropolymer peroxidase-based method, original magnification ×20).
Another important attractor of MSCs to the bone healing area is Musashi-1. Musashi-1 is an osteogenic marker expressed in osteoblasts (cytoplasm and nuclei) and osteocytes (nuclei) (Figure
Immunohistochemical expression of Musashi-1 in fusocellular cells, osteoblasts, and osteocytes in a case of maxillary sinus floor elevation with anorganic bovine bone (micropolymer peroxidase-based method, original magnification ×20).
However, an important drawback of these described methods is the difficulty in activating the right process at the right location in the right cells at the right time for a sufficient amount of time, while minimizing adverse reactions [
In last decades, many different approaches have been attempted for the use of autologous platelet concentrates that serve as both carrier and metabolic stimulators through their high concentration of growth factors [
The 2 families of PRPs are first of all platelet suspensions, which can jellify after activation like a fibrin glue [
This classification is interesting to correlate with Figure
Specifically, within the context of this review, it is important to highlight the fact that L-PRF was tested with oral bone mesenchymal stem cells in vitro [
Bone regeneration based on tissue engineering approaches has a solid background for clinical application in human bone defects. The cell-based, scaffold, bioactive molecule delivery and gene-therapy methods interface and complement each other. However, some of these therapies are still at the preclinical level.
As presented in this paper, many different approaches and biologic agents are being studied. The major challenge for all of them is the timely and sequential organization of events that need to occur in the healing area. The aim is to promote the adequate processes at the precise moment without compromising the normal cell function and overall process. External “on demand” activation technologies are being developed. Additionally, the need for custom medical devices that can be adapted for the patient and the bone defect specific clinical needs will increase the use of 3D printing in the coming years. The association of these techniques with cell-based, bioactive molecules and gene-therapy approaches is a promising and exciting area of research.
However, the current published literature on the clinical application of stem cells for craniofacial bone regeneration is abundant but highly diverse, which reflects (1) the fact that these technologies are relatively new and, therefore, it is difficult to standardize findings and clinical applications; and (2) the number of different potential applications to successfully use cell therapy in the clinical practice is high but still needs to be scientifically proven.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors of this paper were partially supported by the Talentia Scholarship Program (Junta de Andalucía, Spain) (MPM), the International Team for Implantology through the ITI Scholarship Program (AL), and the Research Groups #CTS-138 and #CTS-583 (Junta de Andalucía, Spain) (All). This work has been also recommended by the PACT (Platelet and Advanced Cell Therapies) Forum Civitatis of the POSEIDO Academic Consortium (Periodontology, Oral Surgery, Esthetic and Implant Dentistry Organization).