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Background:
Systematic Review

The Evolving Role of Stem Cells in Oral Health and Regeneration: A Systematic Review

by
Gianna Dipalma
1,2,†,
Grazia Marinelli
1,†,
Arianna Fiore
1,
Liviana Balestriere
1,
Claudio Carone
1,
Silvio Buongiorno
1,
Francesco Inchingolo
1,
Giuseppe Minervini
3,
Andrea Palermo
4,*,
Angelo Michele Inchingolo
1,2,‡ and
Alessio Danilo Inchingolo
1,‡
1
Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70121 Bari, Italy
2
Department of Biomedical, Surgical and Dental Sciences, Milano University, 20122 Milan, Italy
3
Multidisciplinary Department of Medical-Surgical and Odontostomatological Specialties, University of Campania “Luigi Vanvitelli,” 81100 Naples, Italy
4
Department of Experimental Medicine, University of Salento, 73100 Lecce, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally as co-first authors.
‡
These authors contributed equally as co-last authors.
Surgeries 2025, 6(3), 65; https://doi.org/10.3390/surgeries6030065
Submission received: 4 June 2025 / Revised: 21 July 2025 / Accepted: 29 July 2025 / Published: 30 July 2025
(This article belongs to the Special Issue Oral and Maxillofacial Surgery: Balance Between Innovative and Proven Procedures, Drugs and Materials, 2nd Edition)
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Versions Notes

Abstract

Background: Mesenchymal stem cells (MSCs), multipotent and immune-regulatory cells derived from tissues such as bone marrow, dental pulp, and periodontal ligament, emerged as promising agents in regenerative dentistry. Their clinical applications include endodontic tissue regeneration, periodontal healing, and alveolar bone repair, addressing critical challenges in dental tissue restoration. Methods: A systematic review was conducted following PRISMA guidelines and registered in PROSPERO. We searched PubMed, Scopus, and Web of Science databases for open-access, English-language clinical trials and observational studies published from 2015 to 2025. Studies focusing on the application of MSCs in dental tissue regeneration were included based on predefined eligibility criteria. Results: Out of 2400 initial records, 13 studies met the inclusion criteria after screening and eligibility assessment. Most studies investigated MSCs derived from dental pulp and periodontal ligament for regenerating periodontal tissues and alveolar bone defects. The majority reported improved clinical outcomes; however, variations in MSC sources, delivery methods, sample sizes, and follow-up periods introduced methodological heterogeneity. Conclusions: MSCs show significant potential in enhancing bone and periodontal regeneration in dental practice. Nonetheless, the current evidence is limited by small sample sizes, short follow-up, and inconsistent methodologies. Future large-scale, standardized clinical trials are required to validate MSC-based regenerative therapies and optimize treatment protocols.

1. Introduction

Mesenchymal stem cells (MSCs) have become central to the advancement of regenerative dentistry, owing to their multipotency, immunomodulatory properties, and accessibility from diverse autologous and allogeneic sources [1,2,3,4,5]. The translational potential of MSCs is being actively explored across various dental subspecialties, including bone augmentation, periodontal regeneration, endodontic revitalization, and post-extraction socket preservation. This special issue consolidates emerging clinical data and methodological innovations that underscore the evolving role of MSC-based therapies in dental tissue engineering [6,7,8,9,10].
Current clinical investigations demonstrated the capacity of MSCs—particularly those derived from bone marrow, adipose tissue, dental pulp, periodontal ligament, and peripheral blood—to promote predictable regeneration of mineralized and soft tissues [11,12,13,14,15]. For instance, the integration of bone marrow-derived MSCs with biphasic calcium phosphate scaffolds enabled the successful rehabilitation of severely atrophic mandibular ridges, supporting implant placement in previously non-restorable sites [16,17,18,19,20]. Likewise, stromal vascular fraction (SVF) derived from adipose tissue has shown promise in maxillary sinus floor augmentation without requiring ex vivo cell expansion, thus streamlining clinical workflows [21,22,23,24,25].
In periodontal applications, autologous periodontal ligament stem cells (PDLSCs), dental pulp stem cells (DPSCs), and peripheral blood-derived MSCs (PBMSCs) have been evaluated in conjunction with scaffold biomaterials and guided tissue regeneration protocols [26,27,28,29,30]. These studies yielded variable outcomes, reflecting the complexity of periodontal wound healing and the need for further refinement of cell delivery strategies and scaffold integration. Notably, the synergistic use of MSCs with bioactive matrices such as the platelet-rich fibrin matrix (PRFM) has shown enhanced clinical and radiographic parameters in preliminary studies (Figure 1).
The field of regenerative endodontics similarly expanded, with DPSCs being successfully utilized for the revascularization of necrotic mature teeth, challenging previous limitations of immature apexogenesis [31,32,33,34,35]. Emerging cell-free strategies, such as the use of MSC-derived exosomes, are also being investigated for their paracrine effects on tissue repair, offering a potentially safer and more scalable alternative to cell transplantation [30,36,37,38,39].
Despite these advances, significant barriers remain, including variability in cell sourcing, limited long-term clinical data, and challenges in protocol standardization [40,41,42,43,44]. Additionally, logistical constraints associated with cell expansion and regulatory considerations continue to impede the routine implementation of MSC-based therapies in clinical dentistry [45,46,47,48,49].
This systematic review critically examines recent progress in MSC-mediated regenerative strategies, highlights ongoing clinical challenges, and proposes future directions for enhancing therapeutic efficacy, reproducibility, and translational feasibility [50,51,52,53,54]. Through a multidisciplinary lens, the contributions aim to inform the development of standardized, evidence-based protocols that will drive the integration of biologically guided regeneration into mainstream dental practice.

2. Materials and Methods

2.1. PICO Question

The PICO approach is used to evaluate the effect of an intervention on a specific condition, in this case, the use of MSCs and their implications in dentistry.
In patients undergoing dental regenerative procedures (P), does the use of MSCs (from various sources) (I), compared to conventional treatments without MSCs (C), improve clinical and radiographic outcomes in bone, periodontal, or pulp tissue regeneration (O)?

2.2. Protocol and Registration

Our search was performed following the method of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and registered in the International Prospective Register of Systematic Review Registry guidelines (PROSPERO ID: 1044756).

2.3. Search Processing

The electronic databases PubMed, Scopus, and Web of Science were searched to find papers that matched our topic dating from 1 January 2015 up to 31 March 2025. The medical subject headings (MESH) terms entered in search engines were as follows: (“Stem Cell” OR “Stem Cells”) AND (“Dentistry” OR “Oral Health”) AND (“Regeneration” OR “Tissue Regeneration” OR “Repair” OR “Regenerative Medicine”) (Table 1).

2.4. Inclusion and Exclusion Criteria

The inclusion criteria were the following: (1) English language; (2) any type of observational study, i.e., retrospective cohort, prospective cohort, case-control, cross-sectional, and randomized controlled trials; (3) open access; and (4) articles concerning the use of stem cells and its implication in dentistry.
The exclusion criteria were the following: (1) other languages except English; (2) reviews and meta-analyses; (3) off-topic articles; (4) in vivo studies; and (5) in vitro studies.

2.5. Data Processing

The reviewers (A.F., L.B., and C.C.) screened the records according to the inclusion and exclusion criteria. Doubts have been resolved by consulting the senior reviewers (F.I.). The selected articles were downloaded into Zotero 6.0.36.

3. Results

3.1. Study Selection and Characteristics

A total of 2400 records were identified using the keywords (“Stem Cell” OR “Stem Cells”) AND (“Dentistry” OR “Oral Health”) AND (“Regeneration” OR “Tissue Regeneration” OR “Repair” OR “Regenerative Medicine”). When applicable, the automatic filters entered were only in English, only clinical studies, only humans, no reviews, and free full text. The consulted databases were PubMed (404), Scopus (1123), and Web of Science (873).
During the phase of screening, the inclusion and exclusion criteria were applied based on the analysis of the title and the abstract. Studies only focused the use of MSCs in dentistry.
After screening, 590 duplicated articles, 195 systematic reviews, and 206 in vivo/in vitro studies were excluded. Then, 1142 articles were excluded by the analysis of title and abstract, leading to 267 records assessed for eligibility. After eligibility, 13 studies (Table 2) were included in the final analysis. The process is summarized in Figure 2.

3.2. Quality Assessment and Risk of Bias of Included Articles

The assessment of the risk of bias in the included clinical studies revealed an overall moderate risk, with one study classified as having a high risk of bias. Common sources of bias included the presence of confounding factors, non-randomized participant selection, and limited clarity in outcome assessment methods. Several studies lacked proper blinding procedures, standardized protocols, and adequate strategies for managing missing data, all of which may have contributed to systematic bias. Despite these limitations, the majority of studies applied clinically appropriate methods for the use of MSCs. However, shortcomings in methodological transparency and the lack of control for potential confounders may weaken the strength of some conclusions. Overall, while the clinical evidence suggests encouraging outcomes for the use of MSCs in dentistry, the findings should be interpreted cautiously due to the moderate risk of bias. A summary of the risk of bias for each study is provided in Table 3.

4. Discussion

4.1. Clinical Applications of MSCs in Regenerative Dentistry

MSCs emerged as a cornerstone of regenerative dentistry due to their multipotency, immunomodulatory capabilities, and availability from multiple autologous sources, making them highly versatile in therapeutic applications [68,69,70,71,72]. Clinical studies across various dental applications explored MSCs derived from sources such as bone marrow, adipose tissue, peripheral blood, dental pulp, and periodontal ligament. Each source offers unique advantages and limitations depending on the specific regenerative needs of the patient [73,74,75,76,77].
The choice of source often depends on factors such as ease of harvest, cell yield, and patient-specific considerations, making personalized approaches essential in clinical practice. One notable study by Gjerde et al. demonstrated that bone marrow-derived MSCs, when combined with biphasic calcium phosphate, can significantly regenerate severely atrophied mandibular bone [55]. This approach enabled successful dental implant placement in previously compromised sites, emphasizing the role of MSCs in supporting osseous tissue engineering. The procedure was minimally invasive, showcasing not only the potential of MSCs in promoting bone regeneration, but also their capacity to enhance clinical outcomes in challenging cases [78,79,80,81,82].
Furthermore, the use of such biocompatible scaffolds aids in providing structural support and guides the regeneration process, which is crucial for predictable results.
Similarly, Castillo-Cardiel et al. investigated the use of adipose-derived MSCs (AMSCs) in promoting bone healing in mandibular fractures. The study showed faster ossification and better functional recovery compared to traditional care [57]. These findings were corroborated by Prins et al., who reported successful bone formation using freshly isolated stromal vascular fraction (SVF) from adipose tissue in sinus augmentation procedures [66]. Notably, the SVF method bypassed the need for in vitro expansion, making the procedure less time-consuming and more efficient from a clinical perspective, which could streamline the surgical workflow [83,84,85,86].
This advancement holds significant promise for clinical translation, as it reduces the complexity and cost of regenerative therapies.
Despite the promising findings, challenges remain in optimizing stem cell sourcing, preparation, and delivery protocols to ensure consistency in outcomes across different clinical settings. Addressing these challenges requires continued research into standardizing protocols, improving cell viability, and understanding patient-specific responses to therapies. Only through such efforts can MSC-based therapies achieve their full potential in routine dental regenerative practice [87,88,89].

4.2. Periodontal Regeneration: From Proof of Concept to Clinical Translation

The use of MSCs in periodontal regeneration is a rapidly evolving area, and several studies demonstrated their potential in treating intraosseous defects [90,91,92,93].
This growing body of research highlights the promising role of MSCs in restoring both the structure and function of periodontal tissues. PDLSCs are a particularly intriguing source, given their natural role in periodontal tissue regeneration [94,95,96,97,98]. A study by Chen et al. explored the combination of autologous PDLSCs with Bio-Oss® and guided tissue regeneration (GTR) materials [56]. Although the test group showed a trend toward improved clinical outcomes, the results are not statistically significant, underscoring the challenges in achieving consistent results with this approach [99,100,101,102].
These findings emphasize the importance of optimizing treatment protocols to harness the full potential of PDLSCs.
In contrast, Ferrarotti et al. demonstrated that DPSC micrografts significantly improved clinical attachment level (CAL), probing depth (PD), and radiographic bone fill, suggesting a more robust therapeutic efficacy for DPSCs in periodontal regeneration [63]. These findings provide further evidence of the potential of DPSCs as an effective tool in regenerative dentistry, particularly in cases of periodontal tissue loss [103,104,105,106,107].
The use of micrografts may enhance cell viability and local concentration, contributing to these positive outcomes.
Furthermore, Sreeparvathy et al. introduced the concept of the “Supercell”—a combination of peripheral blood MSCs (PBMSCs) and platelet-rich fibrin matrix (PRFM). Their study found significant improvements in both clinical and radiographic outcomes when PBMSCs were combined with PRFM, suggesting that even less commonly used stem cell sources, such as PBMSCs, can contribute meaningfully to periodontal regeneration when paired with optimized scaffolds and delivery systems [67].
Platelet derivatives, such as PRP and PRF, represent promising tools for enhancing the regenerative capacities of MSCs. According to high-impact scientific articles, these products contain numerous growth factors, including PDGF, TGF-β, and VEGF, which promote the proliferation, differentiation, and migration of MSCs, thereby improving their ability to regenerate damaged tissues. Furthermore, PRP and PRF help improve the local microvascular environment by stimulating angiogenesis, which is essential for the nutritional and oxygen support of the cells. These platelet derivatives also play an immunomodulatory role, modulating the inflammatory response and reducing the risk of rejection or excessive inflammatory processes that could compromise regeneration. The combined application of MSCs with platelet derivatives thus not only enhances cell survival and functionality, but can also accelerate healing and tissue regeneration processes [108].
However, despite these advances, studies such as that of Sánchez et al., which used PDLSCs seeded on a xenogeneic scaffold, showed no statistically significant advantage over using the scaffold alone [109,110,111,112,113]. This variance highlights the complexity of periodontal regeneration and the need for further refinement in cell preparation, scaffold materials, and clinical protocols [114,115,116,117,118]. As the field progresses, greater emphasis on personalized approaches and better standardization of protocols will be essential to maximize the therapeutic potential of MSCs in periodontal regeneration [119,120,121,122].

4.3. Endodontic and Post-Extraction Applications: Exploring New Frontiers

MSCs and their secretomes are not only being utilized in the regeneration of hard tissues, but also in endodontics and post-extraction management [123,124,125,126,127].
This broad applicability underscores the versatility of MSCs and their derivatives in addressing diverse dental challenges. One groundbreaking study by Nakashima et al. presented compelling case reports in which autologous DPSCs were used to restore pulp vitality in mature multirooted molars, a domain traditionally limited to apexogenesis in immature teeth [65,128,129,130,131,132]. This finding expands the scope of regenerative endodontics, suggesting that cell-based therapies could hold promise for treating more complex cases, potentially reducing the need for root canal treatments and improving patient outcomes [133,134,135,136,137].
Such advancements could lead to more conservative treatment options that preserve natural tooth structure and function.
Meanwhile, Jafari et al. explored the potential of exosomes from hUCMSCs, combined with chitosan, as a cell-free alternative for pulp tissue regeneration. The success of this approach in a single case study points to the promise of exosome-based therapies, which could overcome some of the logistical and immunological challenges associated with direct cell transplantation [60]. Exosomes, small vesicles containing bioactive molecules such as proteins and RNA, have been shown to facilitate tissue repair and regeneration, offering a potentially less invasive and more scalable approach to regenerative dentistry [138,139,140].
Additionally, Barbier et al. assessed the potential of dental pulp MSCs to reduce bone loss following tooth extraction using a split-mouth model [59]. However, the study found no significant radiographic benefit, suggesting that while MSCs hold potential, the current delivery protocols may need further optimization to achieve the desired clinical outcomes [141,142,143,144]. This highlights the importance of refining both cell-based and cell-free regenerative approaches to improve post-extraction healing and prevent complications such as alveolar bone resorption. Addressing these challenges will require a multidisciplinary approach integrating biomaterials science, cell biology, and clinical expertise [145,146,147,148,149,150].

4.4. Limitations and Future Directions

Despite the encouraging clinical outcomes of MSC-based therapies, several limitations must be considered before their broader adoption in clinical practice [151,152,153,154]. One key issue is the small sample sizes and short follow-up durations typically found in current clinical trials [155,156,157]. These factors limit the ability to draw definitive conclusions about the long-term safety and efficacy of MSC-based treatments [158,159,160,161,162]. In particular, the lack of histological evidence in human studies, due to ethical constraints, presents a challenge in accurately assessing true tissue regeneration and integration [163,164,165,166].
Moreover, the methodological variability in MSCs research—ranging from differences in stem cell sourcing, isolation techniques, scaffold materials, and defect types—compounds the difficulty in comparing results across studies. As a result, more rigorous and standardized clinical trials will be necessary to better understand the optimal conditions for MSC-based therapies [167,168,169,170,171].
Additionally, the cost and complexity of stem cell processing and delivery pose significant barriers to their widespread clinical implementation. Techniques such as ex vivo expansion and genetic manipulation, although promising, can be labor-intensive and expensive, making it difficult for some clinics to adopt these therapies routinely. This highlights the need for innovation in making these treatments more accessible and cost-effective [172,173,174,175,176].
A significant limitation of this review is the marked clinical heterogeneity among the included studies, particularly regarding the outcome measures used. The studies employed different outcomes to assess the effectiveness of the interventions, including clinical attachment level, bone density, and radiological parameters obtained through CBCT. This variability reflects differences in clinical evaluation protocols, technologies used, and the specific objectives of each trial.
Looking ahead, the future of regenerative dentistry will likely involve the standardization of protocols, multicenter randomized controlled trials, and extended follow-up periods to evaluate the long-term stability and clinical relevance of MSC-based therapies. Cell-free approaches, such as MSC-derived exosomes, are gaining increasing attention for their potential to offer regenerative outcomes with fewer regulatory and logistical hurdles. Moreover, the combination of MSCs with growth factor-rich matrices (e.g., PRFM) or the development of off-the-shelf, allogeneic cell products may provide a more consistent and accessible solution for clinical use [177,178,179,180].
An exciting future direction lies in the integration of advanced bioengineering technologies, such as 3D bioprinting and biomimetic scaffolds, to create patient-specific constructs that closely replicate native tissue architecture and function. The application of artificial intelligence and machine learning algorithms to optimize cell sourcing, treatment planning, and outcome prediction could further enhance personalized regenerative therapies. Additionally, exploring the synergistic effects of combining MSCs with novel immunomodulatory agents may unlock new pathways to improve tissue integration and healing.
By addressing the current limitations and optimizing delivery strategies, stem cell-based therapies could ultimately transform the field of regenerative dentistry, offering more predictable, effective, and minimally invasive treatments for a range of dental conditions [181,182,183,184,185,186].

5. Conclusions

MSCs show promise in regenerative dentistry, particularly for bone regeneration, periodontal therapy, and post-extraction healing. Despite positive clinical results, limitations such as small sample sizes, methodological variability, and short follow-ups hinder definitive conclusions. Future research should focus on standardized protocols, larger studies with longer follow-up, and cost-effective delivery methods. Additionally, cell-free approaches such as exosome therapies offer promising alternatives to overcome current challenges. A more personalized and evidence-based approach will be essential to fully integrate MSC therapies into routine dental practice.

Author Contributions

Conceptualization, G.D., G.M. (Grazia Marinelli) and A.M.I.; methodology, A.F., L.B., C.C. and S.B.; software, F.I., G.M. (Giuseppe Minervini), A.P. and A.D.I.; validation, G.D., G.M. (Grazia Marinelli) and A.M.I.; formal analysis, A.F., L.B., C.C. and S.B.; investigation, F.I., G.M. (Giuseppe Minervini), A.P. and A.D.I.; resources, G.D., G.M. (Grazia Marinelli) and A.M.I.; data curation, A.F., L.B., C.C. and S.B.; writing—original draft preparation, F.I., G.M. (Giuseppe Minervini), A.P. and A.D.I.; writing—review and editing, G.D., G.M. (Grazia Marinelli) and A.M.I.; visualization, A.F., L.B., C.C. and S.B.; supervision, F.I., G.M. (Giuseppe Minervini), A.P. and A.D.I.; project administration, A.F., L.B., C.C. and S.B.; funding acquisition, F.I. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
ADPMSCsAutologous Dental Pulp Mesenchymal Stem Cells
AMSCsAdipose-derived Mesenchymal Stem Cells
BCPBiphasic Calcium Phosphate
BMDBone Mineral Density
CALClinical Attachment Level
CBCTCone Beam Computed Tomography
DAPDouble Antibiotic Paste
DPSCsDental Pulp Stem Cells
EPTElectric Pulp Testing
GBRGuided Bone Regeneration
GTRGuided Tissue Regeneration
hUCMSCsHuman Umbilical Cord Mesenchymal Stromal Cells
HUHounsfield Units
IODsIntraosseous Defects
MSCsMesenchymal Stromal Cells
MSFEMaxillary Sinus Floor Elevation
ORIFOpen Reduction/Internal Fixation
PDProbing Depth
PBMSCsPeripheral Blood-derived Mesenchymal Stem Cells
PDL-MSCsPeriodontal Ligament Mesenchymal Stem Cells
PRFMPlatelet-Rich Fibrin Matrix
SB cellsSmall Blood Stem Cells
SVFStromal Vascular Fraction

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Surgeries 06 00065 g001
Figure 1. Stem cell extraction process.
Figure 1. Stem cell extraction process.
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Figure 2. PRISMA flow chart.
Figure 2. PRISMA flow chart.
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Table 1. Articles screening strategy.
Table 1. Articles screening strategy.
KEYWORDSA: Stem Cell; Stem Cells;
B: Dentistry; Oral Health; C: Regeneration; Tissue Regeneration; Repair; Regenerative Medicine
BOOLEAN INDICATORS“A” AND “B” AND “C”
 
TIMESPANFrom 1 January 2015 to 31 March 2025
 
 
 
ELECTRONIC DATABASESPubMed, Scopus and Web of Science
 
Table 2. Analysis of the studies included in the discussion section.
Table 2. Analysis of the studies included in the discussion section.
AuthorsType
of Study		PatientsAim
of Study		Materials and MethodsConclusions
Gjerde C., et al., 2018 [55]Clinical trial13 patients initially enrolled; 11 completed (aged 52–79, healthy, non-smokers)To evaluate the feasibility, safety, and efficacy of using autologous bone marrow-derived mesenchymal stromal cells (MSCs) combined with biphasic calcium phosphate (BCP) to regenerate mandibular bone.Bone marrow was aspirated from the iliac crest. These were combined with BCP granules and grafted onto resorbed mandibular ridges using a tenting technique with membranes.MSC and BCP
grafting protocol successfully
regenerated bone sufficient
for implant placement with no
adverse events. The procedure
was safe, feasible, and resulted in
high patient satisfaction.
Chen F., et al., 2016 [56]Randomized Clinical Trial30 patients with 48 periodontitis-affected teeth; 41 teeth ultimately treated (21 control, 20 test)To assess the safety and feasibility of autologous periodontal ligament stem cells (PDLSCs) combined with Bio-Oss® in treating periodontal intrabony defects.Patients were randomly assigned to two groups: Control (Bio-Oss® with GTR) and Cell (PDLSC sheets + Bio-Oss® + GTR). PDLSCs were isolated from patients’ extracted teeth and prepared under GMP. A 12-month follow-up was conducted with clinical and radiographic assessments, including bone defect depth and periodontal parameters (CAL, PD, and GR).PDLSC treatment was safe and
feasible with no serious adverse
effects. Both groups showed
significant bone gain, but
no statistically significant
difference between them.
Larger multicenter trials are
needed to confirm efficacy.
Castillo-Cardiel G., et al., 2016 [57]Single-blind RCT (pilot)20 male patients (10 AMSCs, 10 control)To evaluate the effectiveness of autologous mesenchymal stem cells (AMSCs) in enhancing bone regeneration in mandibular fractures.Patients with mandibular fractures were randomized into two groups: AMSCs + open reduction/internal fixation (ORIF), and ORIF alone. AMSCs were extracted from adipose tissue 24 h pre-surgery, processed in a lab, and applied at the fracture site. Radiographic (panoramic and CT) bone density was evaluated at weeks 4 and 12 post-surgery using ImageJ software (Version 1.54p). Grey levels were compared statistically.AMSCs significantly
improved bone regeneration,
with 36.48% higher ossification
at week 12 vs. control. The
application is safe, minimally
invasive, and promotes faster
recovery. The study supports
the potential of AMSCs as
a treatment in mandibular fractures.
Bajestan M.N., et al., 2017 [58]Randomized controlled trial18 adult patients (cleft palate or trauma)To evaluate the safety and efficacy of stem cell therapy (ixmyelocel-t) for the reconstruction of large alveolar defects in adults.Patients were randomized to receive either autogenous bone block grafts (control) or stem cell therapy using ex vivo expanded bone marrow-derived cells (ixmyelocel-t). Cells were harvested ~2 weeks before grafting. Grafts were evaluated 4 months later with Cone Beam Computed Tomography (CBCT) and clinical measures. Implant placement and stability were assessed. Secondary outcomes included complications, need for re-grafting, and patient satisfaction.Stem cell therapy was safe
and led to bone regeneration, but less
effective than conventional
bone grafts, especially in cleft
palate cases. Implants were
successfully placed in all control
patients, but only in 5 of 10 stem
cell patients. Optimization of
delivery and materials is needed
for broader clinical success.
Barbier L., et al., 2018 [59]Double-blind RCT, split-mouth30 patients (18–30 y.o., 60 third molars total)To assess whether autologous dental pulp mesenchymal stem cells (ADPMSCs) reduce bone resorption in post-extraction sockets of lower third molars.Each patient underwent bilateral third molar extraction. One socket was randomly assigned to receive ADPMSCs (Rigenera® Protocol) in a collagen matrix; the contralateral socket received collagen alone. CT scans were taken at day 0 and at 6 months to assess bone density (HU) and bone resorption (height of the interdental septum). Measurements were independently evaluated by two blinded neuroradiologists. Inter-observer agreement and statistical analysis were conducted with STATA 14.No statistically significant
differences in bone density
or bone resorption was found
between the stem cell-treated
sockets and controls. The study did not demonstrate that ADPMSCs
reduce bone resorption in
post-extraction third molar sites. Further studies are needed to confirm
their clinical efficacy.
Jafari N. et al., 2025 [60]Case report1 patient (40-year-old male) with irreversible pulpitis in the mandibular second premolarTo evaluate the regenerative potential of exosomes derived from human umbilical cord mesenchymal stromal cells (hUCMSCs) in a pulpectomized tooth.Exosomes were isolated from hUCMSCs.
Mixed with chitosan and applied to the root canal after pulpectomy.
Clinical and radiographic follow-ups at 1, 2, 4, 12, 16, and 24 weeks.
Assessments included vitality tests, CBCT, visual inspection, palpation, and periapical radiographs.		The treatment showed signs
of successful pulp regeneration
with no adverse clinical
symptoms. Radiographically,
progressive healing was
observed (initial periapical
radiolucency and periodontal ligament widening). hUCMSC-derived
exosomes demonstrated
potential as a regenerative therapy,
providing a promising alternative
to cell-based methods.
Further studies with larger
samples are needed to confirm
efficacy.
Feng S. et al., 2021 [61] Clinical trial9 adult patients (aged 29–81) with severe alveolar bone defects (D3 bone density); grouped into 3 dosage cohorts (low, medium, high)To evaluate the safety and tolerability of small blood stem cells (SB cells) for enhancing osseointegration in dental implants.SB cells (CD61−Lin−) were isolated from patients’ peripheral blood and purified.
Three dose levels were tested (105, 106, 107 cells per 0.25 mL DPBS).
Cells were combined with hydroxyapatite and collagen membrane during guided bone regeneration (GBR) before dental implantation.
CT scans and Hounsfield Unit (HU) scoring assessed bone mineral density (BMD) up to 24 weeks post-treatment.
Cytokines/chemokines were also monitored.		SB cell therapy was well tolerated with no serious
adverse events.
All patients showed increased
BMD and improved
osseointegration.
Cytokine profiles
suggest pro-regenerative
and immunomodulatory effects. Although the study lacked
a control group, results
support further investigation
in phase II trials for
regenerative applications in dental medicine.
Sánchez N. et al., 2020 [62]Clinical Trial20 patients (10 test, 10 control)To evaluate the safety and efficacy of embedding in a xenogeneic bone scaffold for periodontal regeneration.Patients with intrabony defects were assigned to a test group (or a control group.
Clinical, radiographic, and patient-reported outcomes were measured over 12 months. Blinding and standardized surgery were used.		The therapy was safe with no serious adverse events. There
was a trend toward
better clinical outcomes
in the test group, but no
statistically significant
differences were found.
Larger studies are needed
to confirm the benefit.
Ferrarotti F. et al., 2018 [63]Randomized controlled clinical trial29 patients (15 test, 14 control)To evaluate whether micrografts with dental pulp stem cells (DPSCs) in a collagen scaffold improve periodontal regeneration in intrabony defects.Patients with periodontitis and one deep intrabony defect requiring extraction of a vital tooth were enrolled. Test group received DPSCs from the extracted tooth on a collagen scaffold using the Rigenera system; control received scaffold alone. Clinical and radiographic evaluations were performed at baseline, 6 and 12 months.DPSCs significantly improved clinical outcomes
compared
to control. The therapy is
promising but limited by the
need for an intact tooth for
stem cell harvesting.
Further independent trials are needed to confirm these results.
Sobhnamayan F. et al., 2023 [64]Triple-blind randomized clinical trial26 pediatric patientsTo evaluate whether adding metformin to double antibiotic paste (DAP) enhances root regeneration in non-vital immature teeth.32 patients were enrolled; 6 excluded for incomplete follow-up. In total, 15 received DAP; 11 received DAP + 1% metformin. All underwent regenerative endodontic procedures with average 18-month follow-up. Clinical and radiographic outcomes (e.g., apical closure, root length/width) were assessed. Statistical analysis used chi-square test; p < 0.05 was considered significant.Adding metformin to DAP
significantly enhanced root
length and apical closure
compared to DAP alone.
All patients showed resolution
of apical periodontitis.
No canal obliteration
occurred in the metformin
group.
Nakashima M. et al., 2022 [65]Case report2 male patients (26 and 29 years old) with mature multirooted molarsTo assess the feasibility and outcome of pulp regenerative therapy using autologous DPSCs in mature multirooted molars.Extraction of nonfunctional third molars to isolate autologous DPSCs. DPSCs cultured under hypoxic conditions. After thorough disinfection (using nanobubble antibiotic irrigation).
Sealing was accomplished with Biodentine and composite resin. Follow-ups included electric pulp testing (EPT), CBCT, and blood/urine tests over 48 weeks.		The therapy showed no
adverse events or systemic
toxicity. Teeth responded
positively to EPT by week 4.
CBCT confirmed pulp
regeneration and absence
of periapical pathology.
Suggests the potential of
using DPSC-based therapy for mature multirooted teeth,
extending regenerative
endodontic possibilities
beyond single-rooted cases.
Prins H. et al., 2016 [66]Clinical trial10 patients undergoing maxillary sinus floor elevationTo assess the feasibility, safety, and potential efficacy of a one-step surgical procedure combining freshly isolated autologous SVF with calcium phosphate ceramics for bone regeneration.Adipose tissue was harvested via liposuction and processed with the Celution system to isolate SVF, which was seeded BCP carriers. Maxillary sinus floor elevation (MSFE) was performed with these constructs. Biopsies were taken 6 months later during implant placement. Outcomes included micro-CT and histomorphometric analysis for bone/osteoid/graft volume, plus clinical monitoring over 3 years.The procedure was safe
and feasible with no
adverse events.
SVF-treated sites showed
higher bone and osteoid volume
compared to control sites.
The results suggest
that SVF supplementation
enhances bone regeneration
and that this approach
could be a promising strategy
for future cell-based bone
regeneration therapies.
Sreeparvathy R. et al., 2025 [67]Randomized controlled clinical trial17 patients (12 men, 5 women), 34 mandibular defect sitesTo evaluate the regenerative capacity of combining PRFM with PBMSCs (Supercell) versus PRFM alone in periodontal intraosseous defects (IODs).Patients with bilateral mandibular three-wall IODs were treated with PRFM alone (control) or PRFM + PBMSCs (Supercell, test). Split-mouth design. Clinical and radiographic parameters recorded at baseline, 3, and 6 months. PRFM and PBMSCs were obtained from peripheral blood using a single-spin Merisis kit. Surgical procedures involved open flap debridement, defect filling, suturing, and follow-up.The Supercell group
showed significantly greater
reductions in probing pocket
depth and defect depth, and greater bone fill percentage than PRFM
alone at 6 months. No
significant difference in
early wound healing
index. The combination
therapy enhanced
periodontal regeneration and
inflammation resolution,
indicating that PBMSCs
improve the regenerative
effect of PRFM.
Table 3. Risk of bias of the articles [55,56,57,58,59,60,61,62,63,64,65,66,67].
Table 3. Risk of bias of the articles [55,56,57,58,59,60,61,62,63,64,65,66,67].
AuthorsD1D2D3D4D5D6D7Overall
Gjerde C. et al., 2018 [55]Surgeries 06 00065 i001Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002
Chen F. et al., 2016 [56]Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002
Castillo-Cardiel G. et al., 2016 [57]Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002
Bajestan M.N. et al., 2017 [58]Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003
Barbier L. et al., 2018 [59]Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i002
Jafari N. et al., 2025 [60]Surgeries 06 00065 i003Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i003
Feng S. et al., 2021 [61]Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002
Sánchez N. et al., 2020 [62]Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002
Ferrarotti F. et al., 2018 [63]Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i003Surgeries 06 00065 i003Surgeries 06 00065 i003
Sobhnamayan F. et al., 2023 [64]Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i003Surgeries 06 00065 i002
Nakashima M. et al., 2022 [65]Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i003
Prins H. et al., 2016 [66]Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i003
Sreeparvathy R. et al. 2025 [67]Surgeries 06 00065 i002Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i002Surgeries 06 00065 i003Surgeries 06 00065 i003Surgeries 06 00065 i003Surgeries 06 00065 i003
Domains: D1: Bias due to confounding, D2: bias arising from measurement of the exposure, D3: bias in selection of participants into the study (or into the analysis), D4: bias due to post-exposure interventions, D5: bias due to missing data, D6: bias arising from measurement of the outcome, and D7: bias in the selection of the reported result. Surgeries 06 00065 i001 high, Surgeries 06 00065 i002 some concerns, Surgeries 06 00065 i003 low.
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MDPI and ACS Style

Dipalma, G.; Marinelli, G.; Fiore, A.; Balestriere, L.; Carone, C.; Buongiorno, S.; Inchingolo, F.; Minervini, G.; Palermo, A.; Inchingolo, A.M.; et al. The Evolving Role of Stem Cells in Oral Health and Regeneration: A Systematic Review. Surgeries 2025, 6, 65. https://doi.org/10.3390/surgeries6030065

AMA Style

Dipalma G, Marinelli G, Fiore A, Balestriere L, Carone C, Buongiorno S, Inchingolo F, Minervini G, Palermo A, Inchingolo AM, et al. The Evolving Role of Stem Cells in Oral Health and Regeneration: A Systematic Review. Surgeries. 2025; 6(3):65. https://doi.org/10.3390/surgeries6030065

Chicago/Turabian Style

Dipalma, Gianna, Grazia Marinelli, Arianna Fiore, Liviana Balestriere, Claudio Carone, Silvio Buongiorno, Francesco Inchingolo, Giuseppe Minervini, Andrea Palermo, Angelo Michele Inchingolo, and et al. 2025. "The Evolving Role of Stem Cells in Oral Health and Regeneration: A Systematic Review" Surgeries 6, no. 3: 65. https://doi.org/10.3390/surgeries6030065

APA Style

Dipalma, G., Marinelli, G., Fiore, A., Balestriere, L., Carone, C., Buongiorno, S., Inchingolo, F., Minervini, G., Palermo, A., Inchingolo, A. M., & Inchingolo, A. D. (2025). The Evolving Role of Stem Cells in Oral Health and Regeneration: A Systematic Review. Surgeries, 6(3), 65. https://doi.org/10.3390/surgeries6030065

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