Parham Hazrati1†
Abdulmohsen Alanazi1†Abdusalam E. Alrmali1,2Pablo Galindo-Fernandez1
Hazar Kassem1Darnell Kaigler1,3*- 1Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, United States
- 2Department of Oral Medicine, Oral Pathology, Oral and Maxillofacial Surgery, University of Tripoli School of Dentistry, Tripoli, Libya
- 3Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, MI, United States
Craniomaxillofacial bone regeneration poses significant clinical challenges due to the anatomical complexity of this region and the inherent limitations of conventional reconstructive techniques. Stem cell-based therapies have emerged as a promising alternative in that stem cells harness the capacities of multilineage differentiation and paracrine signaling to enhance tissue regeneration. Nonetheless, the overall clinical efficacy of stem cell therapy remains a subject of debate. In this systematic review and meta-analysis, we aimed to comprehensively evaluate the safety and effectiveness of stem cell therapy in oral and craniofacial bone regeneration. A comprehensive search of PubMed/MEDLINE, Scopus, Embase, and Web of Science was conducted in July 2024, identifying 59 eligible prospective studies—including randomized controlled trials (RCTs), controlled clinical trials and single-arm studies—involving more than five participants each. Risk of bias was assessed using the Cochrane RoB 2 tool for randomized studies and ROBINS-I for non-randomized studies. The included studies encompassed a broad range of surgical indications, such as alveolar cleft repair, alveolar ridge augmentation, sinus floor augmentation, periodontal defect regeneration, mandibular fracture management, pathological bone defect repair, and temporomandibular joint disorders. Over three-quarters of studies utilized bone marrow aspirate (BMA) and/or mesenchymal stem cells (MSCs), either alone or combined with biomaterial scaffolds. Across diverse procedures, stem cell therapy was associated with clinical and histological benefits, especially in the quality and maturity of regenerated bone. Meta-analysis showed that the addition of stem cells significantly improved the histologic quality of regenerated bone (p = 0.0446), although this enhancement was not evident in radiographic assessments (p = 0.1094). Additionally, meta-analyses demonstrated that stem cell therapy did not result in significant improvements in periodontal clinical attachment level (CAL) gain (p = 0.0730) or linear bone height (p = 0.1858) and width (p = 0.8323) compared to conventional treatments. Notably, volumetric (3D) radiographic assessments indicated significantly enhanced bone volume regeneration in stem cell-treated groups (p = 0.0218). Overall, stem cell therapy shows promising potential in craniomaxillofacial bone regeneration, but heterogeneity among studies underscores the need for further standardized clinical trials to establish definitive benefits, as well as consistent reporting.
Systematic review registration: The protocol of this systematic review was registered on PROSPERO with the ID CRD42024619352.
1 Introduction
Achieving predictable craniomaxillofacial bone regeneration remains a significant challenge in reconstructive surgery and regenerative dentistry. Defects arising from trauma, congenital disorders, infections, or degenerative conditions present significant clinical complexities, largely due to the region’s highly variable anatomical features (Kinoshita and Maeda, 2013). On a global scale, head injuries affect approximately 47 million individuals, with 21.6 million new cases reported each year (James et al., 2018). Bone loss resulting from periodontal disease, oral cancer, tooth extraction, infection, or trauma can undermine facial appearance and essential oral functions such as chewing, speaking, and nutrition, thereby greatly diminishing patients’ quality of life (Bodic et al., 2005).
Conventional reconstructive treatment approaches face significant limitations. Autologous bone grafts, considered the gold standard for reconstruction, exhibit 20%–30% donor-site morbidity (including chronic pain and infection) and suffer up to 60% resorption in non-vascularized grafts (Thalakiriyawa and Dissanayaka, 2024). Guided tissue and bone regeneration (GTR/GBR) is compromised by material deficiencies: non-resorbable membranes [e.g., expanded polytetrafluoroethylene (ePTFE)] necessitate secondary removal surgeries (Thalakiriyawa and Dissanayaka, 2024), collagen membranes degrade too rapidly (<4 weeks) to support complete healing (Elsalanty and Genecov, 2009), and synthetic alternatives frequently provoke foreign-body reactions (Gil et al., 2023). Biomaterials such as hydroxyapatite and bioactive glass lack essential biological signals for functional interface regeneration (e.g., Sharpey’s fiber insertion), while growth factors like BMP-2 paradoxically suppress cementogenesis and induce root resorption (Aghali, 2021).
The craniomaxillofacial region encompasses diverse tissues — bone, mucosa, periodontal ligament (PDL), and cementum — each with distinct structural and biological properties. Specifically, periodontal regeneration proves exceptionally complex due to the periodontium’s intricate architecture, particularly its dual-tissue interfaces like the alveolar bone–PDL and PDL–cementum junctions (Majzoub et al., 2020). True regeneration requires not only tissue restoration but also seamless integration of these interfaces to reestablish functional integrity. Compounding these challenges, the oral environment introduces microbial contamination, masticatory forces, and restricted vascularization in defect sites (Cho et al., 2021).
Stem cell-based therapies represent a transformative approach in craniomaxillofacial and periodontal regeneration, offering solutions to limitations of traditional methods like donor-site morbidity, unpredictable resorption, and inadequate bioactivity (Huang et al., 2024). Unlike conventional grafts or biomaterials, stem cells exhibit the properties of self-renewal and multilineage differentiation, enabling regeneration of complex tissue architectures (Nguyen-Thi et al., 2023; Bartold et al., 2006). Mesenchymal stem cells (MSCs), for instance, can differentiate into osteoblasts for bone formation, cementoblasts for root cementum deposition, and fibroblasts for PDL fiber synthesis (Huang et al., 2009; Nguyen-Thi et al., 2023). This inherent plasticity allows simultaneous regeneration of critical interfaces (e.g., bone–PDL–cementum complex), which traditional materials often fail to restore (Qu et al., 2019).
Critical research gaps persist in regenerative dentistry, including technical limitations, procedural invasiveness, and prognostic uncertainty. Craniofacial bone regeneration is highly dependent on use of materials to treat defects in calvaria, facial bones, and temporomandibular joints (TMJ); despite some degree of functional restoration using these materials, anatomic and functional restoration often remains unrealized (Tevlin et al., 2014). Current bone biomaterials face challenges like premature resorption/persistence and limited efficacy in large/uncontained defects (Latimer et al., 2021; Dzobo et al., 2018). Since 2000, bioengineering advances have accelerated, spanning stem cell therapies (Kaigler et al., 2013b; Iwata et al., 2015; Gómez-Barrena et al., 2011; Queiroz et al., 2021).
The integration of stem cells with advanced biomaterial scaffolds further amplifies their regenerative potential. Biomimetic scaffolds can be engineered to closely mimic the composition and architecture of the native extracellular matrix, providing both structural support and critical cues for cell attachment, proliferation, and differentiation (Davidopoulou et al., 2024; Chen et al., 2024). Recent innovations, such as three-dimensional (3D) printing and electrospinning, have enabled the fabrication of patient-specific scaffolds with precisely controlled porosity, fiber alignment, and degradation profiles. These features not only facilitate the spatial organization of multiple cell types and the delivery of growth factors but also allow for the reconstruction of complex, multi-tissue interfaces that are essential for functional regeneration in the craniomaxillofacial region (Chen et al., 2024). For example, 3D-printed polycaprolactone scaffolds with microchannels have been shown to guide the alignment of periodontal ligament fibers, while smart hydrogels can provide sustained release of growth factors like fibroblast growth factor 2 (FGF-2) to promote angiogenesis and tissue integration over extended periods.
Despite these advances in biomaterial design and engineering, several challenges remain before stem cell-based therapies can be predictably integrated with the use of these biomaterials and ultimately translated into clinical practice. Ensuring the consistent quality and viability of stem cells during isolation, expansion, and delivery is critical for achieving reproducible outcomes. The development of delivery systems that can precisely target stem cells to defect sites, enhance their retention and survival, and promote their integration with host tissues remains an area of active research. Furthermore, the long-term stability and functional integration of regenerated tissues—particularly in the mechanically dynamic and microbiologically complex environment of the oral cavity—are essential for achieving durable clinical success. Patient-specific factors, such as age, systemic health conditions (including diabetes and immunosuppression), and lifestyle habits like smoking, can significantly influence the regenerative capacity of both transplanted and endogenous cells, adding an additional layer of complexity to treatment planning and outcome prediction (Shaikh et al., 2022; Huang et al., 2024).
This systematic review aims to evaluate the current evidence on the efficacy and safety of stem cell-based therapies for craniomaxillofacial and periodontal regeneration. By analyzing studies utilizing various stem cell sources and delivery methods across a range of clinical applications in oral and craniofacial regenerative procedures, this review seeks to provide a comprehensive overview of their potential benefits and limitations. Particular attention will be given to key clinical and histological outcomes such as new bone formation, clinical attachment level (CAL) gain in periodontal defects, vascularization of engineered bone, and long-term dimensional stability of regenerated tissues. Furthermore, this review will explore emerging trends in stem cell research—including advanced biomaterial design—that hold promise for advancing the field toward more predictable clinical outcomes.
2 Materials and methods
2.1 Protocol and registration
This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, as detailed in Supplementary Tables S1, S2 (Matthew et al., 2021). The protocol for this review was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the reference number CRD42024619352.
2.2 PICOST framework and focus question
The following elements were used in formulating the focus question of current review:
Population: Patients (humans) with congenital or acquired skeletal defect or deficiency in the maxilla or mandible.
Intervention: Application of stem cells or autogenous biologics containing stem cells in surgical regenerative approaches.
Comparison: Other regenerative approaches not involving stem cell therapy or none.
Outcomes: Primarily, the quantity or quality of the regenerated bone.
Study design: Any human prospective clinical study with equal to or more than 5 patients, such as prospective randomized or non-randomized controlled clinical trials, and single arm pre-post studies with a proper protocol.
Timeframe: Articles published at any point in time.
Based on the mentioned framework, the following focused question was considered:
“In prospective clinical studies including at least five patients with congenital or acquired maxillofacial skeletal defects, what is the effect of applying stem cells or stem cell-containing autogenous biologics in surgical regenerative approaches, compared to other regenerative methods not involving stem cells, in terms of the quantity and/or quality of regenerated bone?”
2.3 Search strategy
A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Embase electronic databases. The specific search queries used for each database are detailed in Table 1. All articles identified through the search queries and published or indexed in these databases up to 27 July 2024, were retrieved without any restrictions on publication type, language, or year of publication. In addition to reviewing the reference lists of articles deemed eligible for inclusion, issues of the following journals published since 2000 were also manually examined: British Journal of Oral and Maxillofacial Surgery, Clinical Advances in Periodontics, Clinical Implant Dentistry and Related Research, Clinical Oral Implants Research, Clinical Oral Investigations, International Journal of Oral and Maxillofacial Implants, International Journal of Oral and Maxillofacial Surgery, International Journal of Oral Implantology, International Journal of Periodontics and Restorative Dentistry, Journal of Clinical Periodontology, Journal of Craniofacial Surgery, Journal of Cranio-Maxillofacial Surgery, Journal of Dental Research, Journal of Maxillofacial and Oral Surgery, Journal of Oral and Maxillofacial Surgery, Journal of Oral Implantology, Journal of Oral Rehabilitation, Journal of Periodontology, Journal of Stomatology, Oral and Maxillofacial Surgery, and Oral and Maxillofacial Surgery.
Table 1. Search queries.
2.4 Eligibility criteria
2.4.1 Type of studies
Randomized controlled trials (RCTs), controlled (nonrandomized) clinical trials (CCTs), and single-arm prospective studies with equal to or more than 5 patients, were considered eligible. On the other hand, case reports, single-arm prospective studies with less than 5 patients, conference abstracts, protocols, hypothesis articles, and reviews were excluded.
2.4.2 Type of participants
Participants with congenital or acquired craniomaxillofacial bone deformities or defects, including alveolar ridge defects, cleft palate, TMJ disorders, were considered eligible. Cases of soft tissue defects unaccompanied by bone defects or deformities were deemed ineligible, for example cleft lip cases without alveolar or palatal cleft.
2.4.3 Type of intervention
Both cultured and expanded stem cells, as well as aspirates containing stem cells, were considered eligible for inclusion. In contrast, autologous platelet concentrates—such as platelet-rich fibrin (PRF), platelet-rich plasma (PRP), and concentrated growth factor (CGF)—were excluded.
2.4.4 Type of outcome measure
Primary outcomes included quality and quantity of the regenerated bone. Secondary outcomes encompassed patient reported outcomes and periodontal CAL gain.
2.5 Study screening and data extraction
The initial screening involved evaluating the titles and abstracts of studies based on the specified eligibility criteria. Following this step, the full texts of selected articles were obtained for a more comprehensive review. Both title/abstract and full-text screening processes were independently conducted by two reviewers (A.A. and H.K.), and any differences in their assessments were resolved through discussion with a third expert reviewer (A.E.A.). This collaborative approach aimed to minimize bias and maintain a high standard of data integrity throughout the review process. Inter-reviewer reliability was assessed via Cohen’s Kappa.
2.6 Data items and data extraction
Data extraction from the full-text articles was carried out by two authors (A.A. and P.H.), who input the following data items into predefined tables: 1) Bibliographic data (Author, year); 2) Type of study; 3) Type of procedure; 4) Type, donor tissue, and isolation technique of stem cells; 5) Number and demographics of patients; 6) Additional materials, such as bone grafts and membranes, used in the procedure; 7) Clinical, radiographic, histological, and any secondary outcomes; 8) Early and late complications; 9) Follow-up period. Discrepancies in the data extraction process were addressed in consultation with a third author (D.K.).
2.7 Risk of bias assessment
Two investigators (P.H. and A.E.A.) independently assessed the quality of the included studies using Cochrane RoB2 tool and ROBINS-I for randomized controlled trials (RCTs) and nonrandomized studies of intervention (NSRIs), respectively (Sterne et al., 2019; Sterne et al., 2016). Inconsistencies were resolved by consulting a third expert author (D.K.), and inter-reviewer agreement was evaluated using Cohen’s Kappa test.
2.8 Statistical analysis
A meta-analysis was conducted when at least three controlled studies, either RCTs or CCTs, reported a specific quantitative outcome for similar surgical procedures. Given the variability in outcome measurement scales and units across studies, standardized mean difference (SMD) was selected as the summary effect measure. Specifically, Hedges’ g was used to compute SMDs and their corresponding 95% confidence intervals (CIs), as it offers a bias-corrected and conservative estimate, particularly suitable for studies with small sample sizes (i.e., <20 participants per group). When original studies reported treatment effects using alternative metrics (e.g., mean difference or unadjusted SMD), all estimates were converted to Hedges’ g to ensure a unified effect size metric. Interpretation of effect sizes followed conventional thresholds: small (g = 0.2–0.5), medium (g = 0.5–0.8), and large (g > 0.8). The meta-analysis was performed using the metacont function from the meta package in RStudio (Version, 2024.12.1 + 563, RStudio PBC), with Hedges’ g as the effect size and the restricted maximum likelihood (REML) method for estimating between-study variance (tau2). Heterogeneity among studies was quantified using Cochrane’s Q, tau2, and Higgins’ I2 statistics, with I2 values above 75% considered indicative of substantial heterogeneity. Given the heterogeneity in surgical techniques, stem cell types, and follow-up durations across studies, a random-effects model was employed for all primary analyses. Subgroup analyses were also conducted based on follow-up duration, stem cell category used, and surgical procedure. These stratifications allowed for investigation of potential time-, cell-, or procedure-dependent effects of stem-cell-based therapies. A sensitivity analysis was conducted for each meta-analysis by excluding studies classified as having a high overall risk of bias, in order to assess the robustness of the pooled estimates. All statistical analyses and visualizations, including forest plots with subgroup breakdowns, were conducted by a single author (P.H.) using the meta and metafor packages in R. The significance level was set at 0.05 for all analyses, and confidence intervals for tau and I2 were computed using the Q-profile method (Balduzzi et al., 2019; Borenstein et al., 2021; Fritz et al., 2012; Schwarzer, 2007).
3 Results
3.1 Search results
As presented in Figure 1, after removing duplicates, 3,123 citations were screened by title and abstract, resulting in 65 studies selected for full-text screening. The inter-reviewer agreement was excellent in title/abstract screening step, with a Cohen’s Kappa value of 0.91 (95% CI: 0.86–0.96). Two of the initially eligible studies could not be retrieved. Among the 62 full-text articles assessed, four were excluded for the following reasons: two had fewer than five participants, one had a retrospective design, and one was a technical note (Supplementary Table S3). Ultimately, 59 studies were included in the review.
Figure 1. PRISMA flowchart of the review.
3.2 Risk of bias assessment
More than half of the included RCTs were judged to have some concerns regarding the overall risk of bias, while only eight RCTs were appraised as having a low overall risk of bias (Shabaan et al., 2023; Barbier et al., 2018; Castillo-Cardiel et al., 2017; Talaat et al., 2018; Apatzidou et al., 2021; Ferrarotti et al., 2018; Whitt et al., 2020; De Riu et al., 2019) (Figure 2). In contrast, seven RCTs were rated as having a high overall risk of bias (Khojasteh et al., 2017; Gimbel et al., 2007; Aloise et al., 2018; Mannelli et al., 2017; Marx and Harrell, 2014; Bertolai et al., 2015; Fayed et al., 2024). The most common source of bias among the RCTs was related to the randomization process. Similarly, among the non-randomized studies of interventions (NRSIs), nearly half were judged to have a moderate overall risk of bias based on the ROBINS-I tool (Figure 3). Six NRSIs were rated as having a high overall risk of bias (Mazzetti et al., 2018; Naujokat et al., 2022; D'Aquino et al., 2009; Baba et al., 2016; Katagiri et al., 2017; Shayesteh et al., 2008), whereas eight were considered to have a low overall risk of bias (Feng et al., 2021; Gjerde et al., 2018; Jain et al., 2016; Colangeli et al., 2018; Aimetti et al., 2018; Tzur et al., 2021; Prins et al., 2016; Yamada et al., 2013). Inter-reviewer agreement was substantial, with Cohen’s kappa values of 0.84 (95% CI: 0.76–0.92) and 0.81 (95% CI: 0.72–0.90) for the RoB 2 and ROBINS-I tools, respectively.
Figure 2. (A) Traffic light plot and (B) summary bar plot of the risk of bias among the included RCTs, assessed via RoB2 tool.
Figure 3. (A) Traffic light plot and (B) summary bar plot of the risk of bias among the included NRSIs, assessed via ROBINS-I tool.
3.3 Characteristics of the included studies
The studies included in this review were published between 2007 and 2024. With regard to study design, the majority were RCTs, accounting for 31 studies. Additionally, 16 were single-arm studies and 11 were CCTs. As illustrated in Figure 4, the included studies evaluated a wide range of regenerative procedures in dentistry and maxillofacial surgery. Alveolar ridge augmentation was assessed in 16 studies (Bambuliak et al., 2024; Naujokat et al., 2022; Feng et al., 2021; Pasquali et al., 2021; Akhlaghi et al., 2019; Khojasteh et al., 2019; Aloise et al., 2018; Barbier et al., 2018; Gjerde et al., 2018; Bajestan et al., 2017; Jain et al., 2016; Khojasteh and Sadeghi, 2016; Pelegrine et al., 2016; Kaigler et al., 2013a; D'Aquino et al., 2009; Cerruti et al., 2007) (Table 2). Likewise, 16 studies focused on maxillary sinus augmentation (Fatale et al., 2022; Asahina et al., 2021; Gupta et al., 2021; Tzur et al., 2021; Whitt et al., 2020; Katagiri et al., 2017; Prins et al., 2016; Bertolai et al., 2015; Kaigler et al., 2015; Pasquali et al., 2015; Payer et al., 2014; Rickert et al., 2014; Wildburger et al., 2014; Yamada et al., 2013; Rickert et al., 2011; Shayesteh et al., 2008) (Table 3). Eight studies evaluated alveolar cleft reconstruction (Shabaan et al., 2023; Mossaad et al., 2021; Mossaad et al., 2019; Al-Ahmady et al., 2018; Mazzetti et al., 2018; Bajestan et al., 2017; Khojasteh et al., 2017; Gimbel et al., 2007) (Table 4),similar to pathologic defect reconstruction that was evaluated in eight studies (Vignesh et al., 2019; Colangeli et al., 2018; Gali et al., 2018; Talaat et al., 2018; Kakabadze et al., 2017; Bertolai et al., 2016; Marx and Harrell, 2014; Sandor, 2012) (Table 5). Periodontal intrabony defect regeneration was investigated in six studies (Apatzidou et al., 2021; Sanchez et al., 2020; Aimetti et al., 2018; Ferrarotti et al., 2018; Baba et al., 2016; Chen et al., 2016) (Table 6). Temporomandibular disorder (TMD) treatment was examined only in four studies (Fayed et al., 2024; De Riu et al., 2019; Howlader et al., 2017; Sembronio et al., 2021) (Table 7). Mandibular fracture treatment was addressed only in two RCTs (Castillo-Cardiel et al., 2017; Mannelli et al., 2017) (Table 8). Only one study assessed two distinct procedures—alveolar cleft reconstruction and alveolar ridge augmentation—across two separate patient cohorts (Bajestan et al., 2017). Figure 4 summarize the study designs, procedures, categories and types of stem cells used, as well as the anatomical locations from which the stem cells were harvested.
Figure 4. Alluvial plot of the design, procedure, stem cell, stem cell family, and site of harvesting of stem cells among the included studies.
Table 2. Characteristics of the included studies evaluating alveolar ridge augmentation.
Table 3. Characteristics of the included studies evaluating maxillary sinus augmentation.
Table 4. Characteristics of the included studies evaluating alveolar cleft reconstruction.
Table 5. Characteristics of the included studies evaluating pathogenic defect reconstruction.
Table 6. Characteristics of the included studies evaluating periodontal intrabony defect reconstruction.
Table 7. Characteristics of the included studies evaluating temporomandibular joint disorders (TMD) treatment.
Table 8. Characteristics of the included studies evaluating mandibular fracture treatment.
3.4 Results of the individual studies according to the type of procedure
3.4.1 Alveolar ridge augmentation
The clinical outcomes indicated that various regenerative strategies, including bone fillers and stem cell-based approaches, led to high implant survival rates and effective bone regeneration. In several studies, there were no significant complications, with patients exhibiting good bone healing and minimal adverse events (Naujokat et al., 2022; Barbier et al., 2018). Additionally, soft tissue healing was generally good, with fewer complications and faster recovery in the test groups. In particular, the bone formation in patients treated with stem cells or biological materials was more pronounced (Kaigler et al., 2013a; Akhlaghi et al., 2019). Furthermore, the test groups showed less postoperative pain and swelling, suggesting that these advanced techniques may lead to a better patient experience during recovery (Aloise et al., 2018).
From a histological standpoint, the studies consistently showed superior bone formation in the test groups. Bone biopsies showed increased mineralized tissue and active osteoblast activity, which is indicative of successful bone regeneration (Kaigler et al., 2013a; Naujokat et al., 2022). The presence of newly formed bone with lamellar structure and well-organized osteoblasts was particularly noted in groups treated with bone marrow aspirate concentrate (BMAC) and growth factors (Aloise et al., 2018; Feng et al., 2021). Although one study observed minimal or no significant histological differences between groups, the overall trend pointed toward better bone healing and tissue integration in the experimental groups (Barbier et al., 2018).
Radiographically, the test groups demonstrated significant improvements in bone volume, height, and width compared to control groups. Bone resorption rates were lower, and increased bone density was noted at various time points, particularly at 6 months post-procedure (Naujokat et al., 2022). Additionally, many studies reported an increase in bone thickness, with CT scans showing well-integrated scaffolds and improved graft stability (Cerruti et al., 2007; D'Aquino et al., 2009). However, while these regenerative approaches resulted in favorable radiographic outcomes, some studies did not observe significant bone formation in all participants, particularly in cases where less effective graft materials or inadequate stem cell concentrations were used (Barbier et al., 2018).
3.4.2 Sinus augmentation
The use of stem cells in sinus augmentation procedures has shown promising results across various studies, particularly in terms of bone regeneration and implant stability. Clinically, several studies reported a high success rate of implant placement following sinus grafting with stem cell-enriched biomaterials. For instance, Gupta et al. and Yamada et al. both observed a 100% success rate in their test groups, with faster healing times and reduced postoperative complications (Yamada et al., 2013; Gupta et al., 2021). Similarly, Shayesteh et al. reported a 93% success rate, demonstrating that the incorporation of MSCs into bone grafts could enhance implant stability (Shayesteh et al., 2008). However, other studies did not report notable clinical outcomes but instead reported on histological and radiographic assessments (Fatale et al., 2022).
Histological analyses have consistently demonstrated improved bone regeneration in test groups where stem cells were used. Katagiri et al. found that lamellar bone formation was significantly higher in the MSC group, whereas control groups primarily exhibited woven bone (Katagiri et al., 2017). Similarly, Whitt et al. and Rickert et al. reported greater percentages of newly formed vital bone in their test groups (50.12% and 17.7%, respectively) compared to their controls (Whitt et al., 2020; Rickert et al., 2011). Fatale et al. also found a higher percentage of type I bone (44.45%) in MSC-treated sites versus 27.24% in the control group (Fatale et al., 2022). Moreover, some groups have observed enhanced bone regeneration in test groups, confirming the osteogenic potential of stem cells when combined with biomaterials like DBBM (Wildburger et al., 2014; Bertolai et al., 2015).
Radiographic evaluations further supported the superior performance of stem cell-enhanced grafts in promoting bone formation and stability. Several studies found significantly less bone resorption in test groups compared to controls (Gupta et al., 2021; Rickert et al., 2011). Increased bone height and density were frequently reported, with Yamada et al. documenting notable postoperative improvements in residual bone height. Likewise, Prins et al. and Payer et al. observed enhanced vertical bone height and implant stability in stem cell-treated groups (Prins et al., 2016; Payer et al., 2014). Interestingly, Katagiri et al. found no significant differences in radiographic HU between test and control groups, suggesting that while stem cells accelerate bone formation, their effect on bone mineral density may require further investigation (Katagiri et al., 2017).
3.4.3 Alveolar cleft reconstruction
Clinical outcomes consistently showed significant improvements in soft tissue healing, with several studies also reporting reduced post-operative pain and inflammation when using stem cells (Shabaan et al., 2023; Mossaad et al., 2021; Gimbel et al., 2007; Al-Ahmady et al., 2018; Mazzetti et al., 2018). Histological findings revealed increased bone density in groups treated with stem cells (Khojasteh et al., 2017). The presence of lamellar bone with active osteoblastic rims and minimal inflammation supports the hypothesis that stem cell-based methods enhance the formation of high-quality bone. However, some studies did not observe significant bone development, highlighting the need to evaluate additional factors influencing osteogenesis (Mazzetti et al., 2018).
Radiographic assessments were consistent with clinical and histological findings, demonstrating higher bone fill rates in the test groups compared to controls. Bone density measurements via computed tomography (CT) scans showed superior outcomes in regeneration groups employing stem cells, with reduced postoperative bone resorption and improved graft integration at the recipient site (Khojasteh et al., 2017; Mossaad et al., 2019). These results suggest that biomaterials and stem cell-based approaches may enhance long-term stability of the alveolar defect, although some studies did not confirm significant bone formation in all cases (Mazzetti et al., 2018).
3.4.4 Pathogenic defect reconstruction
Clinically, most studies reported high success rates and enhanced bone regeneration in stem cell-treated groups. For instance, in Kakabadze et al.’s study, one of the only two studies that did not use BMA and used MSC to treat pathogenic defects, observed a 100% success rate with significantly higher bone density in the test group (Kakabadze et al., 2017). Similarly, Marx and Harrell found that patients receiving BMA had a 100% success rate compared to 40% in control group. Vignesh et al. and Gali et al. both reported faster bone healing and improved overlying mucosal healing in BMA groups, further supporting the positive impact of stem cell therapy on defect reconstruction (Vignesh et al., 2019; Gali et al., 2018). Additionally, Bertolai et al. and Colangeli et al. confirmed successful bone regeneration in all patients treated with BMA, with no significant complications reported postoperatively (Bertolai et al., 2016; Colangeli et al., 2018).
Histologically, studies demonstrated that stem cell-enhanced grafts contributed to better-organized bone formation and vascularization. For example, George K. B. Sándor and Bertolai et al. observed well-organized bone regeneration with abundant vascular structures, suggesting improved integration of the newly formed bone (Bertolai et al., 2016; Sandor, 2012). Vignesh et al. identified the presence of bone marrow hematopoietic and mesenchymal elements in the test group, further confirming the osteogenic and angiogenic potential of stem cell therapy. Moreover, Kakabadze found significant new bone formation in MSC-treated sites, whereas the control group showed limited bone regeneration (Kakabadze et al., 2017). In contrast, Talaat et al. did not report specific histological findings, highlighting a gap in data that limits direct comparisons across all studies (Talaat et al., 2018).
Radiographic analyses consistently supported the clinical and histological findings, indicating increased bone density and volume preservation in stem cell-treated groups. Marx and Harrell reported that MSC therapy exhibited a higher bone density compared to control, which had a lower success rate (Marx and Harrell, 2014). Similarly, Vignesh et al. and Talaat et al. observed significant reductions in defect volume and increased bone density in test groups (Vignesh et al., 2019; Talaat et al., 2018). Colangeli et al. reported a mean bone density of 850 Hounsfield unit (HU) at 6 months postoperatively, further demonstrating the efficacy of BMA-based therapies in maintaining bone structure (Colangeli et al., 2018). Bertolai et al. and Kakabadze et al. also documented superior bone volume maintenance in stem cell-treated sites compared to controls (Kakabadze et al., 2017; Bertolai et al., 2016). However, Gali et al. noted some bone resorption at 3 months, suggesting that while stem cell therapy promotes initial bone regeneration, long-term stability may still require further investigation (Gali et al., 2018).
3.4.5 Periodontal intrabony defect reconstruction
Clinically, to treat intrabony defects, studies have reported significant reductions in probing depth (PD) and gains in CAL, albeit with variability in success rates. Apatzidou et al. found a 55.6% success rate in the stem cell group, defined as cases achieving at least 3 mm of CAL gain (Apatzidou et al., 2021), while Sánchez et al. observed a mean CAL gain of 1.44 mm, though the difference compared to the control group was not statistically significant (Sanchez et al., 2020). Ferrarotti et al. and Aimetti et al. reported greater improvements, with PD reductions of 4.9 ± 1.4 mm and 5.0 ± 1.3 mm, respectively, and CAL gains of 4.7 ± 1.6 mm in the test groups, indicating that MSC-based treatments may enhance periodontal healing (Ferrarotti et al., 2018; Aimetti et al., 2018). Baba et al. further confirmed significant gains in PD, CAL, and linear bone growth (LBG), suggesting a consistent clinical advantage in MSC-treated defects (Baba et al., 2016).
Histological analyses supported these clinical findings, demonstrating improved bone regeneration and osteogenic activity in MSC-treated defects. Apatzidou et al. reported enhanced bone regeneration in the stem cell group compared to controls (Apatzidou et al., 2021), while Chen et al. observed a more integrated graft structure and reduced connective tissue encapsulation in the test group, indicating superior osseointegration (Chen et al., 2016). Baba et al. identified high alkaline phosphatase (ALP) activity and elevated osteogenic markers, reinforcing the hypothesis that MSC-based therapy promotes active bone remodeling and regeneration. However, the lack of histological data in some studies (Aimetti et al., 2018; Ferrarotti et al., 2018; Sanchez et al., 2020) limits a comprehensive comparison across trials.
Radiographic outcomes further validated these findings, with most studies reporting increased bone fill and defect resolution. Apatzidou et al. documented bone fill at 12 months in both test and control groups (Apatzidou et al., 2021), while Ferrarotti et al. and Aimetti et al. reported mean radiographic bone fills of 3.9 ± 1.5 mm and 3.6 ± 1.9 mm, respectively, in MSC-treated sites, suggesting substantial periodontal regeneration (Ferrarotti et al., 2018; Aimetti et al., 2018). Chen et al. found that defects treated with periodontal ligament stem cells (PDLSCs) and deproteinized bovine bone mineral (DBBM) exhibited significantly greater bone fill compared to control sites (Chen et al., 2016). Baba et al. further confirmed that the test group showed superior linear bone growth compared to controls (Baba et al., 2016). However, Sanchez et al. did not find significant differences in radiographic bone fill between groups, indicating potential variability in outcomes depending on patient-specific factors and treatment protocols (Sanchez et al., 2020).
3.4.6 TMD treatment
Clinically, all four included studies consistently reported significant reductions in pain and improved mandibular mobility in patients receiving BMA or adiposte tissue aspirate (ATA)-based treatments. De Riu et al. observed a significantly greater reduction in pain in the test group compared to the control, suggesting a potential analgesic effect of BMA (De Riu et al., 2019). Similarly, Fayed et al. found that, after 1 week and 1 month, the test group showed significantly greater improvements in mandibular function and reduced discomfort relative to the control group (Fayed et al., 2024). Additionally, Howlader et al. documented a remarkable increase in mouth opening—from 4.14 mm to 34.57 mm post-treatment—highlighting the promise of stem cell therapy in restoring joint mobility and alleviating TMD symptoms (Howlader et al., 2017). The only study in this review that investigated microfragmented adipose tissue (MFAT) evaluated its use in combination with arthrocentesis and found greater improvements in both pain and mouth opening compared to arthrocentesis with hyaluronic acid injection alone (Sembronio et al., 2021).
Although histological data were absent in these studies, radiographic evaluations provided substantial evidence of bone regeneration and joint remodeling. De Riu et al. reported significantly greater bone formation in the BMA-treated group, supporting the role of stem cells in regenerating TMJ structures (De Riu et al., 2019). Fayed et al., through an 18-month postoperative radiographic evaluation, observed improved joint morphology in the test group, reinforcing the regenerative potential of BMA (Fayed et al., 2024). Similarly, Howlader et al. used CT and magnetic resonance imaging (MRI) to assess joint integrity, revealing enhanced bone structure and reduced joint degeneration in the BMA-treated group (Howlader et al., 2017).
3.4.7 Mandibular fracture
Clinically, Mannelli et al. observed after 3 months stable functional outcomes in all patients who were treated for fractures of the atrophic mandible, suggesting that bone marrow aspirate (BMA)-based therapy may contribute to enhanced fracture stability and recovery (Mannelli et al., 2017). Similarly, Castillo-Cardiel et al. reported a reduced recovery time in mandibular fracture cases treated with MSC-based treatments, with patients experiencing earlier functional improvements compared to the control group (Castillo-Cardiel et al., 2017).
Histological analyses were not conducted in these studies. Radiographically, both studies demonstrated favorable outcomes with stem cell therapy. Mannelli et al. reported stable long-term functional integrity in all patients, indicating that stem cell treatment may promote sustained bone healing (Mannelli et al., 2017). Castillo-Cardiel et al. conducted radiographic assessments at multiple time points, finding that by week four, the test group exhibited better callus formation and bone consolidation compared to controls (Castillo-Cardiel et al., 2017).
3.5 Meta-analysis
3.5.1 Periodontal clinical attachment level (CAL) gain
Four studies, three RCTs and one CCT, each reporting outcomes at both six and 12 months, were included in the meta-analysis of CAL gain (Figure 5). As shown in Figure 5A, a subgroup analysis based on the type of stem cell used revealed that the dental pulp stem cell (DPSC) subgroup demonstrated a significant CAL gain (SMD = 1.73, 95% CI = 0.82 to 2.63, p = 0.0002). In contrast, no significant effects were observed in the PDLSC and bone marrow mesenchymal stem cell (BMMSC) subgroups (PDLSC: SMD = −0.14, 95% CI = −1.74 to 1.47, p = 0.8660; BMMSC: SMD = 1.46, 95% CI = −0.87 to 3.80, p = 0.2201). Also, a significant heterogeneity in the results of studies employing BMMSC was noted (I2 = 94.5%, p < 0.0001). When stratified by follow-up duration (Figure 5B), substantial heterogeneity was observed within both subgroups as well as overall (p < 0.0001). No significant treatment effect of stem cell application was detected in either subgroup or in the overall estimate (6 months: SMD = 0.85, 95% CI = −1.25 to 2.94, p = 0.4300; 12 months: SMD = 1.49, 95% CI = −0.25 to 3.22, p = 0.0934; overall: SMD = 1.17, 95% CI = −0.11 to 2.46, p = 0.0730). As shown in Supplementary Figure S1, the sensitivity analysis excluding Baba et al.’s study did not alter the findings of this analysis (Baba et al., 2016).
Figure 5. Forest plots of CAL gain, subgrouped according to (A) type of stem cell and (B) follow-up period.
3.5.2 Quality of the regenerated bone
The quality of regenerated bone was evaluated using both histological and radiographic assessments in the included studies (Figure 6). A subgroup analysis based on surgical procedure, limited to studies using histology, showed that stem cell therapy did not significantly improve bone quality in either alveolar ridge augmentation (SMD = 2.35, 95% CI = −0.63 to 5.34, p = 0.1225) or sinus augmentation (SMD = 4.30, 95% CI = −2.86 to 11.46, p = 0.2393). However, the overall effect across all procedures was statistically significant (SMD = 2.57, 95% CI = 0.06 to 5.08, p = 0.0446), indicating a very large effect size (Figure 6A). Substantial and statistically significant heterogeneity was observed within both subgroups and overall (p < 0.0001). When the same studies were stratified by follow-up duration, the effect was significant, yet small, only among those with a 6-month follow-up (SMD = 1.03, 95% CI = 0.17 to 1.89, p = 0.0271). In contrast, studies with follow-up periods shorter than 6 months did not demonstrate a significant effect (SMD = 5.52, 95% CI = −1.88 to 12.92, p = 0.1437) (Figure 6B). Heterogeneity remained considerable and statistically significant in both follow-up subgroups. Excluding the two studies with a high overall risk of bias (Naujokat et al., 2022; Aloise et al., 2018) in the sensitivity analysis changed the statistical significance of the overall finding, as well as the effect observed in the 6-month follow-up subgroup (Supplementary Figure S2). A similar trend was observed in a separate meta-analysis including studies using radiography to evaluate regenerated bone’s quality (Figure 6C). The overall effect of stem cell therapy was insignificant (SMD = 3.18, 95% CI: -0.71 to 7.07, p = 0.1094); however, the effect was significant in 6 months subgroup (SMD = 1.66, 95% CI = 0.07 to 3.24, p = 0.0404). Substantial and significant heterogeneity was observed among the studies of both subgroups, as well as overall (p < 0.0001). Since all studies included in this analysis were rated as having either low risk or some concerns in the overall risk of bias, no sensitivity analysis was performed.
Figure 6. Forest plots of the quality of regenerated bone according to histology, subgrouped according to (A) type of procedure, (B) follow-up period. (C) Forest plots of the quality of regenerated bone according to radiography, subgrouped according to follow-up period.
3.5.3 Quantity of the regenerated bone
Stratified according to follow-up period (Figure 7A), studies evaluating regenerated bone quantity with radiography demonstrated significant heterogeneity (less than 6 months of follow-up: I2 = 65%, p = 0.0138; 6 months of follow-up: I2 = 82.9%, p < 0.0001; overall: I2 = 77.2%, p < 0.0001). Even though the effect was not significant in either of the less than 6 months or 6 months subgroups (less than 6 months of follow-up: SMD = 0.37, 95% CI: -0.66 to 1.40, p = 0.4836; 6 months of follow-up: SMD = 1.02, 95% CI: -0.01 to 2.06, p = 0.0523), the overall effect of stem cell therapy was significant (SMD = 0.75, 95% CI = 0.02 to 1.48, p = 0.0434). As presented in Figure 7B, when the studies were stratified according to the dimension of measuring the regenerated bone, in both linear subgroups—vertical and horizontal—had insignificant effect sizes (vertical: SMD = 0.72, 95% CI = −0.35 to 1.79, p = 0.1858; horizontal: SMD = 0.08, 95% CI = −0.65 to 0.81, p = 0.8323). However, a very large effect size was observed in the three-dimensional subgroup (SMD = 1.99, 95% CI: 0.29 to 3.68, p = 0.0218), in spite of having substantial and significant heterogeneity (I2 = 85.3%, p = 0.0001). When the two studies with high risk of bias (Khojasteh et al., 2017; Aloise et al., 2018) were excluded in the sensitivity analysis, the overall effect became insignificant, while the significant effect observed in the volumetric gain subgroup remained unchanged (Supplementary Figure S3).
Figure 7. Forest plots of the quantity of regenerated bone according to radiography, subgrouped according to (A) follow-up period, (B) dimension of change.
4 Discussion
This systematic review and meta-analysis provides a comprehensive evaluation of current clinical evidence regarding the use of stem cell-based therapies for oral and craniofacial bone regeneration. By synthesizing data from 59 prospective studies encompassing diverse clinical indications—including alveolar cleft repair, ridge augmentation, sinus augmentation, periodontal intrabony defects, and TMJ disorders—this review offers a comprehensive perspective on the therapeutic applications of stem cells across the craniofacial region. The majority of included studies reported favorable outcomes, demonstrating that stem cell-based interventions can enhance both the quality and quantity of regenerated bone compared to conventional methods. Notably, pooled meta-analytic findings further corroborated these benefits, with stem cell therapies being consistently associated with superior volumetric bone regeneration and improved histological bone quality. These results underscore the growing potential of stem cell-centered strategies to address the limitations of traditional grafting approaches in periodontal, alveolar, and craniofacial reconstruction. In a recent systematic review, Hung et al. included clinical studies published between 2013 and 2023 evaluating the effect of stem cell therapy on the regenerative outcomes of procedures on maxillofacial bone tissues (Hung et al., 2024). They included seven studies, all of those meeting the eligibility criteria of the present study are included in this review, and highlighted the efficacy, safety, and effectiveness of stem cell-based approaches (Hung et al., 2024). Similarly, Dipalma et al. conducted a systematic review encompassing 12 studies, including clinical and laboratory studies, and concluded that although MSC-based therapies represent a promising frontier in maxillofacial bone regeneration, the broad variability in study methodologies, stem cell preparation protocols, and outcome measures highlights the importance of establishing more standardized approaches (Dipalma et al., 2025). It is noteworthy that despite other systematic reviews being recently conducted, the number of studies employing a meta-analysis to quantify the effect of stem cell therapy on craniofacial bone regeneration are scarce. To our knowledge, the only meta-analysis which has been conducted in this area was conducted by Eini et al. and they reported that stem cells combined with scaffolds improve bone regeneration (Eini et al., 2023). In addition to multiple meta-analyses for different outcome measures, the current study also includes various subgroup analyses aimed at addressing the sources of heterogeneity frequently observed among the studies. However, true heterogeneity in designs and materials, along with the scarcity of certain categories of stem cells, study designs, or follow-up periods, limited the possibility of further subgroup analyses, as these often resulted in single-study subgroups, which the Cochrane Handbook for Systematic Reviews explicitly discourages (Deeks et al., 2023).
Tissue engineering for bone regeneration is founded on three fundamental pillars: stem cells, scaffolds, and biological agents (Hao et al., 2021). A substantial body of translational, in vitro, and preclinical animal research has elucidated the mechanisms through which stem cell-based therapies contribute to bone formation and regeneration (Arvidson et al., 2011; Garg et al., 2017; Baniameri et al., 2025). These studies consistently demonstrate the osteogenic and immunomodulatory potential of stem cells, particularly when delivered within an optimized microenvironment. Concurrently, extensive research is underway to evaluate approaches aimed to enhance the osteoinductive and osteoconductive properties of scaffolds and biological agents, aiming to create more favorable conditions for stem cell survival, differentiation, and integration. Together, these three components form the core of regenerative strategies designed to mimic and support native bone healing processes (Nokhbatolfoghahaei et al., 2025; Mohaghegh et al., 2024).
Safety—often a central concern in stem cell-based regenerative interventions—was consistently reported across the included studies (Asahina et al., 2021; Katagiri et al., 2017; Howlader et al., 2017; Bajestan et al., 2017; Feng et al., 2021; Gjerde et al., 2018; Castillo-Cardiel et al., 2017; Sanchez et al., 2020). No serious complications attributable to stem cell application were observed beyond common postoperative effects such as pain, swelling, or minor bleeding. These findings are in agreement with earlier reviews that have supported the favorable safety profile of stem cell therapies in maxillofacial applications (Nguyen-Thi et al., 2023; Liu et al., 2022; Tatullo et al., 2015). This is consistent with a large body of research demonstrating that stem cell-based therapies are generally safe across a wide range of medical fields, including not only oral and craniofacial procedures but also orthopedic and other surgical applications (Trounson and McDonald, 2015). In addition to its safety, a substantial body of medical literature supports the benefits of adjunctive stem cell therapy in bone regeneration and repair. Consistent with the findings of our review, which focused exclusively on craniofacial bone regeneration and demonstrated the effectiveness of stem cell therapy in managing mandibular fractures, previous studies have also reported significant benefits in the treatment of osteoporotic vertebral compression fractures and non-union of long bone fractures (Zhang et al., 2024; Thurairajah et al., 2021; Kaspiris et al., 2022; Yi et al., 2022).
Beyond their capacity for direct differentiation, stem cells also play a pivotal role in creating a pro-regenerative microenvironment. Through the secretion of a diverse array of bioactive factors — including cytokines, chemokines, and growth factors such as vascular endothelial growth factor (VEGF), FGF-2, and BMP-2 — stem cells modulate local inflammation, promote the formation of new blood vessels, recruit host progenitor cells, and orchestrate the intricate cellular interactions required for effective healing (Da Silva et al., 2025; Zheng et al., 2019). These paracrine effects are crucial for overcoming the hostile conditions often present in large or chronically inflamed defects, where impaired vascularity and persistent inflammation can otherwise compromise regeneration (Latimer et al., 2021; Valdivia et al., 2017). For instance, the immunomodulatory properties of MSCs enable them to suppress the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interlukin-1beta (IL-1β), thereby shifting the local environment from one that is destructive to one that is conducive to tissue repair (Valdivia et al., 2017; Zheng et al., 2019). Additionally, stem cell-derived factors can enhance matrix remodeling, restore the balance between matrix metalloproteinases (MMPs) and their inhibitors, and even exert antimicrobial effects that help protect regenerating tissues from infection (Bartold et al., 2019; Liu et al., 2019).
In addition to resulting in accelerated and enhanced abundance and volume of regenerated bone, the quality of regenerated bone is a crucial component of assessing success of regenerative therapies. As presented in many of the included studies (Pasquali et al., 2021; Pasquali et al., 2015; Aloise et al., 2018; Whitt et al., 2020), the regenerated bone following application of stem cells exhibits enhanced vascularity and compactness, both of which play critical roles in long-term success of any regenerative approach, specifically involving dental implants.
One of the main strengths of the present review is the inclusion of all prospective clinical studies with a minimum of five patients, regardless of surgical technique or treated anatomical site. This inclusive approach allowed for the presentation of a broad and integrative overview of stem cell use in diverse oral and craniofacial regenerative therapies. However, this comprehensiveness introduced substantial heterogeneity across the included studies in terms of design, patient population, types of stem cells utilized, therapeutic approaches, and follow-up durations. As a result, comparability across studies was limited, and pooled estimates require cautious interpretation. Subgroup analyses were conducted, where applicable, to address this variation. Additionally, this review exclusively evaluated regenerative outcomes of bone tissue within the craniofacial region. Extrapolation of these findings to other craniofacial tissues, such as cementum, or to non-craniofacial sites, such as long bones, requires further validation.
Of the 32 included RCTs and 27 NRSIs, only eight in each category were judged to have a low overall risk of bias. The main sources of bias were related to inappropriate random sequence generation and confounding. Although the number of studies with high risk of bias was relatively small—seven assessed with RoB2 and six with ROBINS-I—the reliance on studies with unclear risk of bias may have influenced the findings of this review. Despite including 59 studies, the considerable heterogeneity in outcome measures, study designs, and procedures prevented us from conducting a meta-regression to evaluate the effect of overall and domain-specific risk of bias on the effect size. Nevertheless, we performed sensitivity analyses by excluding studies with high overall risk of bias. Excluding studies with unclear or moderate risk was not feasible, as too few remained for meaningful analysis. With the exception of the meta-analysis on radiographic bone quality, all other analyses included studies with high overall risk of bias. While the results for CAL gain were not affected by excluding high-risk studies, the findings for both histologic bone quality and radiographic bone quantity were sensitive to their inclusion. When these high-risk studies were removed, only the effect of stem cell therapy on volumetric radiographic bone quantity remained statistically significant (Supplementary Figure S3). It is also important to note that we employed SMD using Hedges’ g as the summary statistic, which corrects for small sample bias and is inherently conservative. Applying an additional restriction by excluding studies with high risk of bias, on top of this conservative effect, may represent a double conservatism, making it particularly difficult to detect significant results. The pool of included studies makes it clear that future research on stem cell therapy in craniofacial bone regeneration should place greater emphasis on adhering to established standards for conducting clinical trials, particularly with respect to random sequence generation and allocation concealment.
To the best of the authors’ knowledge, this is the first systematic review and meta-analysis to evaluate the effects of stem cell therapy across the full spectrum of oral and craniofacial surgical procedures. Quantitative synthesis was performed to provide pooled effect estimates, offering a consolidated view of treatment outcomes. Due to the variability in measurement scales and reporting formats across studies, SMD using Hedges’ g was adopted instead of raw mean difference (MD) to enable meaningful comparisons across heterogeneous outcomes. The comprehensiveness of this review enables a broader understanding of how stem cell therapies are being applied clinically and the outcomes being reported. At the same time, it highlights ongoing challenges, particularly the need for greater consistency in study protocols, outcome measures, and reporting standards. Future investigations would benefit from standardized methodologies, including consistent definitions of clinical endpoints, rigorous stem cell characterization, and extended follow-up periods. Such efforts will enhance comparability, reduce heterogeneity, and improve the overall quality and applicability of evidence in this growing field of regenerative therapy.
5 Conclusion
Stem cell therapy has demonstrated promising outcomes in regenerative approaches targeting oral and craniofacial bones. However, heterogeneity in protocols and designs of the studies limits generalizability and impedes drawing robust conclusions. According to the results of our meta-analyses, stem cell therapy results in higher volume of regenerated bone, although in 2-dimensional planes—vertical and horizontal, it did not yield in better results. Also, meta-analysis showed that histologically stem cell therapy results in a regenerated bone with higher quality, however, this observation could not be confirmed in meta-analysis of radiographic evaluations. Finally, almost 75% of the studies included in this report had either moderate or high overall risk of bias, which further reduces the quality of evidence; therefore, conducting more high-quality clinical trials is necessary to determine the true potential and benefit of stem cell-based approaches for oral craniofacial bone regeneration.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.
Author contributions
PH: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review and editing. AlA: Conceptualization, Data curation, Investigation, Methodology, Writing – original draft, Writing – review and editing. AsA: Conceptualization, Methodology, Writing – original draft, Writing – review and editing. PG-F: Writing – original draft, Writing – review and editing. HK: Investigation, Writing – original draft, Writing – review and editing. DK: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing – original draft, Writing – review and editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the National Institute of Dental and Craniofacial Research, National Institute of Health (NIDCR/NIH) R01DE028657 (DK) and the Major M. Ash Professorship Fund (DK).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fbioe.2026.1677400/full#supplementary-material
References
Aghali, A. (2021). Craniofacial bone tissue engineering: current approaches and potential therapy. Cells 10, 2993. doi:10.3390/cells10112993
Aimetti, M., Ferrarotti, F., Gamba, M. N., Giraudi, M., and Romano, F. (2018). Regenerative treatment of periodontal intrabony defects using autologous dental pulp stem cells: a 1-Year Follow-Up case series. Int. Journal Periodontics and Restorative Dentistry 38, 51–58. doi:10.11607/prd.3425
Akhlaghi, F., Hesami, N., Rad, M. R., Nazeman, P., Fahimipour, F., and Khojasteh, A. (2019). Improved bone regeneration through amniotic membrane loaded with buccal fat pad-derived MSCs as an adjuvant in maxillomandibular reconstruction. J. Cranio-Maxillofacial Surg. 47, 1266–1273. doi:10.1016/j.jcms.2019.03.030
Al-Ahmady, H. H., Abd Elazeem, A. F., Ahmed, N. E.-M. B., Shawkat, W. M., Elmasry, M., Abdelrahman, M. A., et al. (2018). Combining autologous bone marrow mononuclear cells seeded on collagen sponge with nano hydroxyapatite, and platelet-rich fibrin: reporting a novel strategy for alveolar cleft bone regeneration. J. Cranio-Maxillofacial Surg. 46, 1593–1600. doi:10.1016/j.jcms.2018.05.049
Aloise, A. C., Pasquali, P., Sperandio, M., Scavone De Macedo, L. G., Teixeira, M. L., Pelegrine, A. A., et al. (2018). Use of bone marrow aspirate Concentrate (BMAC) associated with hyperbaric oxygenation therapy in maxillary appositional bone reconstruction. A randomized clinical trial. Symmetry-Basel 10, 533. doi:10.3390/sym10100533
Apatzidou, D. A., Bakopoulou, A. A., Kouzi-Koliakou, K., Karagiannis, V., and Konstantinidis, A. (2021). A tissue-engineered biocomplex for periodontal reconstruction. A proof-of-principle randomized clinical study. J. Clin. Periodontology 48, 1111–1125. doi:10.1111/jcpe.13474
Arvidson, K., Abdallah, B. M., Applegate, L. A., Baldini, N., Cenni, E., Gomez-Barrena, E., et al. (2011). Bone regeneration and stem cells. J. Cell Mol. Med. 15, 718–746. doi:10.1111/j.1582-4934.2010.01224.x
Asahina, I., Kagami, H., Agata, H., Honda, M. J., Sumita, Y., Inoue, M., et al. (2021). Clinical outcome and 8-Year Follow-Up of alveolar bone tissue engineering for severely atrophic alveolar bone using autologous bone marrow stromal cells with platelet-rich plasma and β-Tricalcium phosphate granules. J. Clin. Med. 10, 5231. doi:10.3390/jcm10225231
Baba, S., Yamada, Y., Komuro, A., Yotsui, Y., Umeda, M., Shimuzutani, K., et al. (2016). Phase I/II trial of autologous bone marrow stem cell transplantation with a three-dimensional woven-fabric scaffold for periodontitis. Stem Cells Int. 2016, 6205910. doi:10.1155/2016/6205910
Bajestan, M. N., Rajan, A., Edwards, S. P., Aronovich, S., Cevidanes, L. H. S., Polymeri, A., et al. (2017). Stem cell therapy for reconstruction of alveolar cleft and trauma defects in adults: a randomized controlled, clinical trial. Clin. Implant Dent. Relat. Res. 19, 793–801. doi:10.1111/cid.12506
Balduzzi, S., RüCKER, G., and Schwarzer, G. (2019). How to perform a meta-analysis with R: a practical tutorial. Evid. Based Ment. Health 22, 153–160. doi:10.1136/ebmental-2019-300117
Bambuliak, A., Bandrivsky, Y., Kuzniak, N., Tkachyk, S., Perebyinis, P., and Lopushniak, L. (2024). Efficacy of the use of a therapeutic composition containing stem cells in the augmentation of the alveolar ridge according to the indicators of bone remodeling markers in the saliva. Romanian J. Stomatology 70, 27–31. doi:10.37897/rjs.2024.1.8
Baniameri, S., Aminianfar, H., Gharehdaghi, N., Yousefi-Koma, A.-A., Mohaghegh, S., Nokhbatolfoghahaei, H., et al. (2025). Tissue engineering 3D-Printed scaffold using allograft/alginate/Gelatin hydrogels coated with platelet-rich fibrin or adipose stromal vascular fraction induces osteogenesis in vitro. J. Cell. Physiology 240, e31497. doi:10.1002/jcp.31497
Barbier, L., Ramos, E., Mendiola, J., Rodriguez, O., Santamaria, G., Santamaria, J., et al. (2018). Autologous dental pulp mesenchymal stem cells for inferior third molar post-extraction socket healing: a split-mouth randomised clinical trial. Med. Oral Patol. Oral Y Cirugia Bucal 23, e469–e477. doi:10.4317/medoral.22466
Bartold, P. M., Shi, S., and Gronthos, S. (2006). Stem cells and periodontal regeneration. Periodontol. 2000 40, 164–172. doi:10.1111/j.1600-0757.2005.00139.x
Bartold, M., Gronthos, S., Haynes, D., and Ivanovski, S. (2019). Mesenchymal stem cells and biologic factors leading to bone formation. J. Clin. Periodontol. 46 (21), 12–32. doi:10.1111/jcpe.13053
Bertolai, R., Catelani, C., Aversa, A., Rossi, A., Giannini, D., and Bani, D. (2015). Bone graft and mesenchimal stem cells: clinical observations and histological analysis. Clin. Cases Mineral Bone Metabolism 12, 183–187. doi:10.11138/ccmbm/2015.12.2.183
Bertolai, R., Catelani, C., Signorini, M., Rossi, A., and Giannini, D. (2016). Mesenchymal stem cells in post-surgical cavities of large maxillary bone lesions. Clin. Cases Mineral Bone Metabolism 13, 214–220. doi:10.11138/ccmbm/2016.13.3.214
Bodic, F., Hamel, L., Lerouxel, E., Baslé, M. F., and Chappard, D. (2005). Bone loss and teeth. Jt. Bone Spine 72, 215–221. doi:10.1016/j.jbspin.2004.03.007
Borenstein, M., Hedges, L. V., Higgins, J. P., and Rothstein, H. R. (2021). Introduction to meta-analysis. Hoboken, NJ: John Wiley & Sons. doi:10.1002/9780470743386
Castillo-Cardiel, G., LóPEZ-Echaury, A. C., Saucedo-Ortiz, J. A., Fuentes-Orozco, C., Michel-Espinoza, L. R., Irusteta-JiméNEZ, L., et al. (2017). Bone regeneration in mandibular fractures after the application of autologous mesenchymal stem cells, a randomized clinical trial. Dent. Traumatology Official Publication Int. Assoc. Dent. Traumatology 33, 38–44. doi:10.1111/edt.12303
Cerruti, H. F., Kerkis, I., Kerkis, A., Tatsui, N. H., Da Costa Neves, A., Bueno, D. F., et al. (2007). Allogenous bone grafts improved by bone marrow stem cells and platelet growth factors: clinical case reports. Artif. Organs 31, 268–273. doi:10.1111/j.1525-1594.2007.00374.x
Chen, F. M., Gao, L. N., Tian, B. M., Zhang, X. Y., Zhang, Y. J., Dong, G. Y., et al. (2016). Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: a randomized clinical trial. Stem Cell Res. Ther. 7, 33. doi:10.1186/s13287-016-0288-1
Chen, H., Song, G., Xu, T., Meng, C., Zhang, Y., Xin, T., et al. (2024). Biomaterial scaffolds for periodontal tissue engineering. J. Funct. Biomater. 15, 233. doi:10.3390/jfb15080233
Cho, Y. D., Kim, K. H., Lee, Y. M., Ku, Y., and Seol, Y. J. (2021). Periodontal wound healing and tissue regeneration: a narrative review. Pharm. (Basel) 14, 456. doi:10.3390/ph14050456
Colangeli, W., Riccelli, U., Giudice, A., Barca, I., Caruso, D., Novembre, D., et al. (2018). Jaw bones regeneration using mesenchymal stem cells. A single-center experience. Ann. Ital. Chir. 89, 20–23.
D'Aquino, R., De Rosa, A., Lanza, V., Tirino, V., Laino, L., Graziano, A., et al. (2009). Human mandible bone defect repair by the grafting of dental pulp stem/progenitor cells and collagen sponge biocomplexes. Eur. Cells Mater. 18, 75–83. doi:10.22203/ecm.v018a07
Da Silva, K., Kumar, P., and Choonara, Y. E. (2025). The paradigm of stem cell secretome in tissue repair and regeneration: present and future perspectives. Wound Repair Regen. 33, e13251. doi:10.1111/wrr.13251
Davidopoulou, S., Karakostas, P., Batas, L., Barmpalexis, P., Assimopoulou, A., Angelopoulos, C., et al. (2024). Multidimensional 3D-Printed scaffolds and regeneration of intrabony periodontal defects: a systematic review. J. Funct. Biomater. 15, 44. doi:10.3390/jfb15020044
De Riu, G., Vaira, L. A., Carta, E., Meloni, S. M., Sembronio, S., and Robiony, M. (2019). Bone marrow nucleated cell concentrate autograft in temporomandibular joint degenerative disorders: 1-year results of a randomized clinical trial. J. Cranio-Maxillofacial Surg. 47, 1728–1738. doi:10.1016/j.jcms.2018.11.025
Deeks, J. J., Bossuyt, P. M., Leeflang, M. M., and Takwoingi, Y. (2023). Cochrane handbook for systematic reviews of diagnostic test accuracy. John Wiley and Sons.
Dipalma, G., Marinelli, G., Palumbo, I., Guglielmo, M., Riccaldo, L., Morolla, R., et al. (2025). Mesenchymal stem cells in oral and maxillofacial surgery: a systematic review of clinical applications and regenerative outcomes. J. Clin. Med. 14, 3623. doi:10.3390/jcm14113623
Dzobo, K., Thomford, N. E., Senthebane, D. A., Shipanga, H., Rowe, A., Dandara, C., et al. (2018). Advances in regenerative medicine and tissue engineering: innovation and transformation of medicine. Stem Cells Int. 2018, 2495848. doi:10.1155/2018/2495848
Eini, E., Ghaemi, A., and Rahim, F. (2023). “Bone using stem cells for maxillofacial bone disorders: a systematic review and meta-analysis,” in Advances in mesenchymal stem cells and tissue engineering, 2023//2023. Editor P. V. PHAM (Cham: Springer International Publishing), 119–135.
Elsalanty, M. E., and Genecov, D. G. (2009). Bone grafts in craniofacial surgery. Craniomaxillofac Trauma Reconstr. 2, 125–134. doi:10.1055/s-0029-1215875
Fatale, V., Pagnoni, S., Pagnoni, A. E., Passarelli, P. C., Netti, A., Lajolo, C., et al. (2022). Histomorphometric comparison of new bone formed after maxillary sinus lift with lateral and crestal approaches using periostal mesenchymal stem cells and beta-tricalcium phosphate: a controlled clinical trial. J. Craniofac Surg. 33, 1607–1613. doi:10.1097/SCS.0000000000008319
Fayed, H. M., Khairy, M. A., Eldahshan, D., Sabry, D., and Ahmed, W. A. (2024). Bone marrow aspirate concentrate - a novel approach to alter the course of temporomandibular joint osteoarthritis (a clinical study). J. Stomatology, Oral Maxillofacial Surgery 125, 101644. doi:10.1016/j.jormas.2023.101644
Feng, S. W., Su, Y. H., Lin, Y. K., Wu, Y. C., Huang, Y. H., Yang, F. H., et al. (2021). Small blood stem cells for enhancing early osseointegration formation on dental implants: a human phase I safety study. Stem Cell Res. Ther. 12, 380. doi:10.1186/s13287-021-02461-z
Ferrarotti, F., Romano, F., Gamba, M. N., Quirico, A., Giraudi, M., Audagna, M., et al. (2018). Human intrabony defect regeneration with micrografts containing dental pulp stem cells: a randomized controlled clinical trial. J. Clinical Periodontology 45, 841–850. doi:10.1111/jcpe.12931
Fritz, C. O., Morris, P. E., and Richler, J. J. (2012). Effect size estimates: current use, calculations, and interpretation. J. Exp. Psychol. Gen. 141, 2–18. doi:10.1037/a0024338
Gali, R. S., Chinnaswamy, R., Devireddy, S. K., Shaik, M. V., Kumar, R. V. K., Kanubaddy, S. R., et al. (2018). Concentrated bone marrow aspirate-coated hydroxyapatite for reconstruction of small-to-moderate-sized mandibular defects caused by the removal of benign pathologies. Contemp. Clin. Dent. 9, 535–540. doi:10.4103/ccd.ccd_745_18
Garg, P., Mazur, M. M., Buck, A. C., Wandtke, M. E., Liu, J., and Ebraheim, N. A. (2017). Prospective review of mesenchymal stem cells differentiation into osteoblasts. Orthop. Surg. 9, 13–19. doi:10.1111/os.12304
Gil, A. C. K., Prado, M. M., Rocha, L. R. D., Benfatti, C., Schuldt Filho, G., and Almeida, J. (2023). In vitro evaluation of membranes for regenerative procedures against oral bacteria. Braz Dent. J. 34, 57–65. doi:10.1590/0103-6440202305060
Gimbel, M., Ashley, R. K., Sisodia, M., Gabbay, J. S., Wasson, K. L., Heller, J., et al. (2007). Repair of alveolar cleft defects: reduced morbidity with bone marrow stem cells in a resorbable matrix. J. Craniofacial Surg. 18, 895–901. doi:10.1097/scs.0b013e3180a771af
Gjerde, C., Mustafa, K., Hellem, S., Rojewski, M., Gjengedal, H., Yassin, M. A., et al. (2018). Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial. Stem Cell Res. Ther. 9, 213. doi:10.1186/s13287-018-0951-9
Gómez-Barrena, E., Rosset, P., MüLLER, I., Giordano, R., Bunu, C., Layrolle, P., et al. (2011). Bone regeneration: stem cell therapies and clinical studies in orthopaedics and traumatology. J. Cell Mol. Med. 15, 1266–1286. doi:10.1111/j.1582-4934.2011.01265.x
Gupta, A. S., Aurora, J. K., Dubey, K. N., Chauhan, H., Saxena, M., and Ganvir, S. R. (2021). A comparative evaluation of bone regeneration using mesenchymal stem cells versus blood coagulum in sinus augmentation procedures. Natl. Journal Maxillofacial Surgery 12, 349–356. doi:10.4103/njms.njms_358_21
Hao, Z., Xu, Z., Wang, X., Wang, Y., Li, H., Chen, T., et al. (2021). Biophysical stimuli as the fourth pillar of bone tissue engineering. Front. Cell Dev. Biol. 9, 790050. doi:10.3389/fcell.2021.790050
Howlader, D., Vignesh, U., Bhutia, D. P., Pandey, R., Kumar, S., Chandra, T., et al. (2017). Hydroxyapatite collagen scaffold with autologous bone marrow aspirate for mandibular condylar reconstruction. J. Cranio-Maxillofacial Surg. 45, 1566–1572. doi:10.1016/j.jcms.2017.06.022
Huang, G. T., Gronthos, S., and Shi, S. (2009). Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine. J. Dent. Res. 88, 792–806. doi:10.1177/0022034509340867
Huang, T. H., Chen, J. Y., Suo, W. H., Shao, W. R., Huang, C. Y., Li, M. T., et al. (2024). Unlocking the future of periodontal regeneration: an interdisciplinary approach to tissue engineering and advanced therapeutics. Biomedicines 12, 1090. doi:10.3390/biomedicines12051090
Hung, M., Sadri, M., Katz, M., Schwartz, C., and Mohajeri, A. (2024). A systematic review of stem cell applications in maxillofacial regeneration. Dent. J. (Basel) 12, 315. doi:10.3390/dj12100315
Iwata, T., Washio, K., Yoshida, T., Ishikawa, I., Ando, T., Yamato, M., et al. (2015). Cell sheet engineering and its application for periodontal regeneration. J. Tissue Eng. Regen. Med. 9, 343–356. doi:10.1002/term.1785
Jain, A., Singh, M., Ganapathy, K. P., Ramola, V., Passi, D., and Jain, K. (2016). Evaluation of two socket healing procedures with and without mesenchymal stem cells: a comparative study. Natl. J. Maxillofac. Surg. 7, 159–165. doi:10.4103/0975-5950.201366
James, S. L., Abate, D., Abate, K. H., Abay, S. M., Abbafati, C., Abbasi, N., et al. (2018). Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet 392, 1789–1858. doi:10.1016/S0140-6736(18)32279-7
Kaigler, D., Pagni, G., Park, C. H., Braun, T. M., Holman, L. A., Yi, E., et al. (2013a). Stem cell therapy for craniofacial bone regeneration: a randomized, controlled feasibility trial. Cell Transplant. 22, 767–777. doi:10.3727/096368912X652968
Kaigler, D., Silva, E. A., and Mooney, D. J. (2013b). Guided bone regeneration using injectable vascular endothelial growth factor delivery gel. J. Periodontol. 84, 230–238. doi:10.1902/jop.2012.110684
Kaigler, D., Avila-Ortiz, G., Travan, S., Taut, A. D., Padial-Molina, M., Rudek, I., et al. (2015). Bone engineering of maxillary sinus bone deficiencies using enriched CD90+ stem cell therapy: a randomized clinical trial. J. Bone Mineral Res. 30, 1206–1216. doi:10.1002/jbmr.2464
Kakabadze, A., Mardaleishvili, K., Loladze, G., Karalashvili, L., Chutkerashvili, G., Chakhunashvili, D., et al. (2017). Reconstruction of mandibular defects with autogenous bone and decellularized bovine bone grafts with freeze-dried bone marrow stem cell paracrine factors. Oncol. Lett. 13, 1811–1818. doi:10.3892/ol.2017.5647
Kaspiris, A., Hadjimichael, A. C., Vasiliadis, E. S., Papachristou, D. J., Giannoudis, P. V., and Panagiotopoulos, E. C. (2022). Therapeutic efficacy and safety of osteoinductive factors and cellular therapies for long bone fractures and non-unions: a meta-analysis and systematic review. J. Clin. Med. 11, 3901. doi:10.3390/jcm11133901
Katagiri, W., Watanabe, J., Toyama, N., Osugi, M., Sakaguchi, K., and Hibi, H. (2017). Clinical study of bone regeneration by conditioned medium from mesenchymal stem cells after maxillary sinus floor elevation. Implant Dentistry 26, 607–612. doi:10.1097/ID.0000000000000618
Khojasteh, A., and Sadeghi, N. (2016). Application of buccal fat pad-derived stem cells in combination with autogenous iliac bone graft in the treatment of maxillomandibular atrophy: a preliminary human study. Int. J. Oral Maxillofac. Surg. 45, 864–871. doi:10.1016/j.ijom.2016.01.003
Khojasteh, A., Kheiri, L., Behnia, H., Tehranchi, A., Nazeman, P., Nadjmi, N., et al. (2017). Lateral ramus cortical bone plate in alveolar cleft osteoplasty with concomitant use of buccal fat pad derived cells and autogenous bone: phase I clinical trial. Biomed. Res. Int. 2017, 6560234. doi:10.1155/2017/6560234
Khojasteh, A., Hosseinpour, S., Rezai Rad, M., Alikhasi, M., and Zadeh, H. H. (2019). Buccal fat pad-derived stem cells with anorganic bovine bone mineral scaffold for augmentation of atrophic posterior mandible: an exploratory prospective clinical study. Clin. Implant Dent. Relat. Res. 21, 292–300. doi:10.1111/cid.12729
Kinoshita, Y., and Maeda, H. (2013). Recent developments of functional scaffolds for craniomaxillofacial bone tissue engineering applications. Sci. World J. 2013, 863157. doi:10.1155/2013/863157
Latimer, J. M., Maekawa, S., Yao, Y., Wu, D. T., Chen, M., and Giannobile, W. V. (2021). Regenerative medicine technologies to treat dental, oral, and craniofacial defects. Front. Bioeng. Biotechnol. 9, 704048. doi:10.3389/fbioe.2021.704048
Liu, J., Ruan, J., Weir, M. D., Ren, K., Schneider, A., Wang, P., et al. (2019). Periodontal bone-ligament-cementum regeneration via scaffolds and stem cells. Cells 8, 537. doi:10.3390/cells8060537
Liu, P., Zhang, Y., Ma, Y., Tan, S., Ren, B., Liu, S., et al. (2022). Application of dental pulp stem cells in oral maxillofacial tissue engineering. Int. J. Med. Sci. 19, 310–320. doi:10.7150/ijms.68494
Majzoub, J., Barootchi, S., Tavelli, L., Wang, C. W., Travan, S., and Wang, H. L. (2020). Treatment effect of guided tissue regeneration on the horizontal and vertical components of furcation defects: a retrospective study. J. Periodontol. 91, 1148–1158. doi:10.1002/JPER.19-0529
Mannelli, G., Arcuri, F., Conti, M., Agostini, T., Raffaini, M., and Spinelli, G. (2017). The role of bone marrow aspirate cells in the management of atrophic mandibular fractures by mini-invasive surgical approach: single-institution experience. J. Cranio-Maxillofacial Surg. 45, 694–703. doi:10.1016/j.jcms.2017.01.007
Marx, R. E., and Harrell, D. B. (2014). Translational research: the CD34+ cell is crucial for large-volume bone regeneration from the milieu of bone marrow progenitor cells in craniomandibular reconstruction. Int. J. Oral Maxillofac. Implants 29, e201–e209. doi:10.11607/jomi.te56
Matthew, J. P., Joanne, E. M., Patrick, M. B., Isabelle, B., Tammy, C. H., Cynthia, D. M., et al. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372, n71. doi:10.1136/bmj.n71
Mazzetti, M. P. V., Alonso, N., Brock, R. S., Ayoub, A., Massumoto, S. M., and EçA, L. P. (2018). Importance of stem cell transplantation in cleft lip and palate surgical treatment protocol. J. Craniofac Surg. 29, 1445–1451. doi:10.1097/SCS.0000000000004766
Mohaghegh, S., Nokhbatolfoghahaei, H., Baniameri, S., Farajpour, H., Fakhr, M. J., Shokrolahi, F., et al. (2024). Physicochemical and biological characterization of gelatin/alginate scaffolds reinforced with β-TCP, FDBA, and SrHA: insights into stem cell behavior and osteogenic differentiation. Int. J. Biomaterials 2024, 1365080. doi:10.1155/2024/1365080
Mossaad, A., El Badry, T., Abdelrahaman, M., Abdelazim, A., Ghanem, W., Hassan, S., et al. (2019). Alveolar cleft reconstruction using different grafting techniques. Open Access Macedonian J. Med. Sci. 7, 1369–1373. doi:10.3889/oamjms.2019.236
Mossaad, A. M., Al Ahmady, H. H., Ghanem, W. H., Abdelrahman, M. A., Abdelazim, A. F., and Elsayed, S. A. (2021). The use of dual energy X-Ray bone density scan in assessment of alveolar cleft grafting using bone marrow stem cells Concentrate/platelet-rich fibrin regenerative technique. J. Craniofacial Surg. 32, E780–E783. doi:10.1097/SCS.0000000000007772
Naujokat, H., Loger, K., GüLSES, A., FlöRKE, C., Acil, Y., and Wiltfang, J. (2022). Effect of enriched bone-marrow aspirates on the dimensional stability of cortico-cancellous iliac bone grafts in alveolar ridge augmentation. Int. J. Implant Dent. 8, 34. doi:10.1186/s40729-022-00435-1
Nguyen-Thi, T. D., Nguyen-Huynh, B. H., Vo-Hoang, T. T., and Nguyen-Thanh, T. (2023). Stem cell therapies for periodontal tissue regeneration: a meta-analysis of clinical trials. J. Oral Biol. Craniofac Res. 13, 589–597. doi:10.1016/j.jobcr.2023.07.001
Nokhbatolfoghahaei, H., Baniameri, S., Tabrizi, R., Yousefi-Koma, A.-A., Dehghan, M. M., Derakhshan, S., et al. (2025). Pre-vascularized porous gelatin-coated β-tricalcium phosphate scaffolds for bone regeneration: an in vivo and in vitro investigation. Vitro Cell. and Dev. Biol. - Animal 61, 67–80. doi:10.1007/s11626-024-00973-5
Pasquali, P. J., Teixeira, M. L., De Oliveira, T. A., Scavone De Macedo, L. G., Aloise, A. C., and Pelegrine, A. A. (2015). Maxillary sinus augmentation combining bio-oss with the bone marrow aspirate concentrate: a histomorphometric study in humans. Int. J. Biomaterials 2015, 121286. doi:10.1155/2015/121286
Pasquali, P. J., Andre Dall'Agnol, R., Garcia Rezende, L., and Martinez, E. F. (2021). Clinical, histological, and scintigraphic comparative study of the use of mandibular bone marrow and peripheral blood in bone neoformation. Int. J. Dent. 2021, 4867574. doi:10.1155/2021/4867574
Payer, M., Lohberger, B., Strunk, D., Reich, K. M., Acham, S., and Jakse, N. (2014). Effects of directly autotransplanted tibial bone marrow aspirates on bone regeneration and osseointegration of dental implants. Clin. Oral Implants Res. 25, 468–474. doi:10.1111/clr.12172
Pelegrine, A. A., Teixeira, M. L., Sperandio, M., Almada, T. S., Kahnberg, K. E., Pasquali, P. J., et al. (2016). Can bone marrow aspirate concentrate change the mineralization pattern of the anterior maxilla treated with xenografts? A preliminary study. Contemp. Clin. Dent. 7, 21–26. doi:10.4103/0976-237X.177112
Prins, H. J., Schulten, E. A. J. M., Ten Bruggenkate, C. M., Klein-Nulend, J., and Helder, M. N. (2016). Bone regeneration using the freshly isolated autologous stromal vascular fraction of adipose tissue in combination with calcium phosphate ceramics. Stem Cells Transl. Med. 5, 1362–1374. doi:10.5966/sctm.2015-0369
Qu, H., Fu, H., Han, Z., and Sun, Y. (2019). Biomaterials for bone tissue engineering scaffolds: a review. RSC Adv. 9, 26252–26262. doi:10.1039/c9ra05214c
Queiroz, A., Albuquerque-Souza, E., Gasparoni, L. M., De FrançA, B. N., Pelissari, C., Trierveiler, M., et al. (2021). Therapeutic potential of periodontal ligament stem cells. World J. Stem Cells 13, 605–618. doi:10.4252/wjsc.v13.i6.605
Rickert, D., Sauerbier, S., Nagursky, H., Menne, D., Vissink, A., and Raghoebar, G. M. (2011). Maxillary sinus floor elevation with bovine bone mineral combined with either autogenous bone or autogenous stem cells: a prospective randomized clinical trial. Clin. Oral Implants Res. 22, 251–258. doi:10.1111/j.1600-0501.2010.01981.x
Rickert, D., Vissink, A., Slot, W. J., Sauerbier, S., Meijer, H. J. A., and Raghoebar, G. M. (2014). Maxillary sinus floor elevation surgery with BioOss® mixed with a bone marrow concentrate or autogenous bone: test of principle on implant survival and clinical performance. Int. J. Oral Maxillofac. Surg. 43, 243–247. doi:10.1016/j.ijom.2013.09.006
Sanchez, N., Fierravanti, L., Nunez, J., Vignoletti, F., Gonzalez-Zamora, M., Santamaria, S., et al. (2020). Periodontal regeneration using a xenogeneic bone substitute seeded with autologous periodontal ligament-derived mesenchymal stem cells: a 12-month quasi-randomized controlled pilot clinical trial. J. Clin. Periodontology 47, 1391–1402. doi:10.1111/jcpe.13368
Sandor, G. K. B. (2012). Tissue engineering of bone: clinical observations with adipose-derived stem cells, resorbable scaffolds, and growth factors. Ann. Maxillofacial Surgery 2, 8–11. doi:10.4103/2231-0746.95308
Sembronio, S., Tel, A., Tremolada, C., Lazzarotto, A., Isola, M., and Robiony, M. (2021). Temporomandibular joint arthrocentesis and microfragmented adipose tissue injection for the treatment of internal derangement and osteoarthritis: a randomized clinical trial. J. Oral Maxillofac. Surg. 79, 1447–1456. doi:10.1016/j.joms.2021.01.038
Shabaan, A. A., Salahuddin, A., Aboulmagd, I., Ragab, R., Salah, K. A., Rashid, A., et al. (2023). Alveolar cleft reconstruction using bone marrow aspirate concentrate and iliac cancellous bone: a 12-month randomized clinical study. Clin. Oral Investig. 27, 6667–6675. doi:10.1007/s00784-023-05276-9
Shaikh, M. S., Shahzad, Z., Tash, E. A., Janjua, O. S., Khan, M. I., and Zafar, M. S. (2022). Human umbilical cord mesenchymal stem cells: current literature and role in periodontal regeneration. Cells [Online] 11, 1168. doi:10.3390/cells11071168
Shayesteh, Y. S., Khojasteh, A., Soleimani, M., Alikhasi, M., Khoshzaban, A., and Ahmadbeigi, N. (2008). Sinus augmentation using human mesenchymal stem cells loaded into a beta-tricalcium phosphate/hydroxyapatite scaffold. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 106, 203–209. doi:10.1016/j.tripleo.2007.12.001
Sterne, J. A., HernáN, M. A., Reeves, B. C., Savović, J., Berkman, N. D., Viswanathan, M., et al. (2016). ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 355, i4919. doi:10.1136/bmj.i4919
Sterne, J. A. C., Savović, J., Page, M. J., Elbers, R. G., Blencowe, N. S., Boutron, I., et al. (2019). RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366, l4898. doi:10.1136/bmj.l4898
Talaat, W. M., Ghoneim, M. M., Salah, O., and Adly, O. A. (2018). Autologous bone marrow concentrates and concentrated growth factors accelerate bone regeneration after enucleation of mandibular pathologic lesions. J. Craniofacial Surgery 29, 992–997. doi:10.1097/SCS.0000000000004371
Tatullo, M., Marrelli, M., and Paduano, F. (2015). The regenerative medicine in oral and maxillofacial surgery: the most important innovations in the clinical application of mesenchymal stem cells. Int. J. Med. Sci. 12, 72–77. doi:10.7150/ijms.10706
Tevlin, R., Mcardle, A., Atashroo, D., Walmsley, G. G., Senarath-Yapa, K., Zielins, E. R., et al. (2014). Biomaterials for craniofacial bone engineering. J. Dent. Res. 93, 1187–1195. doi:10.1177/0022034514547271
Thalakiriyawa, D. S., and Dissanayaka, W. L. (2024). Advances in regenerative dentistry approaches: an update. Int. Dent. J. 74, 25–34. doi:10.1016/j.identj.2023.07.008
Thurairajah, K., Briggs, G. D., and Balogh, Z. J. (2021). Stem cell therapy for fracture non-union: the current evidence from human studies. J. Orthop. Surg. 29, 23094990211036545. doi:10.1177/23094990211036545
Trounson, A., and Mcdonald, C. (2015). Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17, 11–22. doi:10.1016/j.stem.2015.06.007
Tzur, E., Ben-David, D., Gur Barzilai, M., Rozen, N., and Meretzki, S. (2021). Safety and efficacy results of BonoFill First-in-Human, phase I/IIa clinical trial for the maxillofacial indication of sinus augmentation and mandibular bone void filling. J. Oral Maxillofac. Surg. 79, 787–798.e2. doi:10.1016/j.joms.2020.12.010
Valdivia, E., Mendoza-Azpur, G., Pando, J., Cornejo, H., Carrasco, A., Nevins, M., et al. (2017). Tissue engineering therapy for atrophic maxilla using minimally manipulated CD90 and CD105 bone marrow stem cells: a case report. Int. Journal Periodontics and Restorative Dentistry 37, 355–361. doi:10.11607/prd.3119
Vignesh, U., Mehrotra, D., Howlader, D., Kumar, S., and Anand, V. (2019). Bone marrow aspirate in cystic maxillofacial bony defects. J. Craniofac Surg. 30, e247–e251. doi:10.1097/SCS.0000000000005200
Whitt, J., Al-Sabbagh, M., Dawson, D., Shehata, E., Housley-Smith, M., Tezanos, A., et al. (2020). Efficacy of stem cell allograft in maxillary sinus bone regeneration: a randomized controlled clinical and blinded histomorphometric study. Int. J. Implant Dent. 6, 25. doi:10.1186/s40729-020-00222-w
Wildburger, A., Payer, M., Jakse, N., Strunk, D., Etchard-Liechtenstein, N., and Sauerbier, S. (2014). Impact of autogenous concentrated bone marrow aspirate on bone regeneration after sinus floor augmentation with a bovine bone substitute – a split-mouth pilot study. Clin. Oral Implants Res. 25, 1175–1181. doi:10.1111/clr.12228
Yamada, Y., Nakamura, S., Ueda, M., and Ito, K. (2013). Osteotome technique with injectable tissue-engineered bone and simultaneous implant placement by cell therapy. Clin. Oral Implants Res. 24, 468–474. doi:10.1111/j.1600-0501.2011.02353.x
Yi, H., Wang, Y., Liang, Q., and Mao, X. (2022). Preclinical and clinical amelioration of bone fractures with mesenchymal stromal cells: a systematic review and meta-analysis. Cell Transplant. 31, 09636897211051743. doi:10.1177/09636897211051743
Zhang, S., Lee, Y., Liu, Y., Yu, Y., and Han, I. (2024). Stem cell and regenerative therapies for the treatment of osteoporotic vertebral compression fractures. Int. J. Mol. Sci. 25, 4979. doi:10.3390/ijms25094979
Zheng, C., Chen, J., Liu, S., and Jin, Y. (2019). Stem cell-based bone and dental regeneration: a view of microenvironmental modulation. Int. J. Oral Sci. 11, 23. doi:10.1038/s41368-019-0060-3
Glossary
ALP Alkaline phosphatase.
ASC Adipose tissue stem cell.
ATA Adipose tissue aspirate.
BFPMSC Buccal fat pad mesenchymal stem cell.
BMA Bone marrow aspirate.
BMAC Bone marrow aspirate concentrate.
BMMSC Bone marrow mesenchymal stem cell.
BMMNC Bone marrow mononuclear cell.
BMNCC Bone marrow nucleated cell concentrate.
β-TCP Beta-tricalcium phosphate.
CAL Clinical attachment level.
CBCT Cone beam computed tomography.
CCT Controlled clinical trial.
CGF Concentrated growth factor.
CI Confidence interval.
CT Computed tomography.
DBBM Deproteinized bovine bone mineral.
DEXA Dual-energy X-ray absorptiometry.
DPSC Dental pulp stem cell.
ePTFE Expanded polytetrafluoroethylene.
FGF-2 Fibroblast growth factor 2.
GBR Guided bone regeneration.
GTR Guided tissue regeneration.
HAM Human amniotic membrane.
HSC Hematopoietic stem cell.
HU Hounsfield unit.
IL-1β Interleukin-1 beta.
LBG Linear bone growth.
MD Mean difference.
MFAT Microfragmented adipose tissue.
MMP Matrix metalloproteinase.
MMSC Multipotent mesenchymal stem cell.
MNC Mononuclear cell.
MRI Magnetic resonance imaging.
MSC Mesenchymal stem cell.
NA Not applicable/available.
NRSI Non-randomized studies of intervention.
PD Probing depth.
PDL Periodontal ligament.
PDLSC Periodontal ligament stem cell.
PMSC Periosteal mesenchymal stem cell.
PPD Pocket probing depth.
PRF Platelet-rich fibrin.
PRISMA Preferred reporting items for systematic reviews and meta-analyses.
PROSPERO International prospective register of systematic reviews.
PRP Platelet-rich plasma.
RCT Randomized controlled trial.
REML Restricted maximum likelihood.
RoB2 Cochrane’s risk of bias tool version 2.
ROBINS-I Risk of bias in non-randomized studies of interventions.
SBSC Small blood stem cell.
SCG Super cell glue.
SMD Standardized mean difference.
SVF Stromal vascular fraction.
TMD Temporomandibular disorder.
TMJ Temporomandibular joints.
TNF-α Tumor necrosis factor-alpha.
TRC Tissue repair cell.
VEGF Vascular endothelial growth factor.
3D Three-dimensional.
Keywords: stem cells, bone regeneration, dental implants, maxillofacial injuries, maxillofacial abnormalities, alveolar bone grafting, sinus floor augmentation
Citation: Hazrati P, Alanazi A, Alrmali AE, Galindo-Fernandez P, Kassem H and Kaigler D (2026) Clinical stem cell therapy in oral and craniofacial bone regeneration: a systematic review and meta-analysis. Front. Bioeng. Biotechnol. 14:1677400. doi: 10.3389/fbioe.2026.1677400
Received: 31 July 2025; Accepted: 05 January 2026;
Published: 23 January 2026.
Edited by:
Qinggang Dai, Shanghai Jiao Tong University, ChinaReviewed by:
Ali Mentes, Marmara University, TürkiyeAdili Alimujiang, Jinan University, China
Azal Hadi Al-Masoody, University of Alkafeel, Iraq
Copyright © 2026 Hazrati, Alanazi, Alrmali, Galindo-Fernandez, Kassem and Kaigler. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Darnell Kaigler, ZGthaWdsZXJAdW1pY2guZWR1
†These authors have contributed equally to this work