Clinical evidence on bone tissue engineering for craniomaxillofacial reconstruction: a narrative review

Introduction

Background

Bone defects caused by tumor resections, non-union fractures, infectious processes, and/or skeletal developmental anomalies are among the main causes of disability and reduced quality of life (1,2). Autogenous bone grafts remain the clinical gold standard; however, their use is frequently limited by complications including donor-site morbidity, unpredictable resorption, and infection (3-5). As alternatives, biomaterials of different natures have been developed and applied, either alone or in combination, as bone substitutes (5-7). Previous studies have highlighted the role of biomaterials in in modulating tissue response, contributing to the understanding of the cellular and molecular mechanisms involved in bone biology, but this knowledge has not yet resulted in the regeneration of critical-sized defects (8). Over recent decades, researchers have explored strategies that combine biomaterials with growth factors and cells from different sources, composing a multidisciplinary science called Tissue Engineering. This field integrates principles of engineering and biological sciences to restore, maintain or improve tissue functions, including that of bone (9). Within this context, bone tissue engineering (BTE) has emerged as a promising alternative, offering bio-inspired strategies for the regeneration of bone defects (5,10,11).

In the craniomaxillofacial (CMF) region, the reconstruction of such defects represents a challenge due to anatomical complexity, aesthetic relevance, and functional demands inherent to this area (5). The unique biological and structural characteristics of CMF bones that distinguish them from long bones, including embryological, anatomical, and biomechanical features, need to be carefully considered when selecting treatment strategies for bone defects and fractures in these regions, since these characteristics determine distinct growth patterns and repair mechanisms (5).

Embryologically, most CMF bones originate from neural crest cells and develop through intramembranous ossification, a process in which mesenchymal stromal cells (SCs) differentiate directly into osteoblasts (12). The intramembranous ossification proceeds with minimal callus formation, necessitating stable fixation of bone fragments to support proper healing (12). Anatomically, CMF bones, including the mandible, consist primarily of inner and outer cortical plates separated by intervening trabecular or diploic bone, rather than a central medullary cavity typical of long bones, reflecting differences in microarchitecture and marrow volume. The mandibular blood supply is derived predominantly from the inferior alveolar and periosteal vessels, with region-dependent endosteal contributions, in contrast to the dominant nutrient artery supply observed in long bones. In addition, craniofacial SC niches are distributed within periosteal and sutural regions (13). Consequently, CMF bone defects rely more heavily on early revascularization and the migration of osteoprogenitor cells from the periosteum and sutures, supporting the use of porous biomaterials combined with pro-angiogenic factors (14,15). Furthermore, the presence of specialized functional structures, such as alveolar bone and the periodontal ligament, imposes additional requirements on regenerative strategies. The restoration of occlusal function requires not only bone regeneration but also the reconstruction of periodontal attachment and precise three-dimensional architecture (16).

Rationale and knowledge gap

Fundamentally, BTE is built on the triad of scaffolds, cells, and signaling molecules, each playing a synergistic role in creating functional bone tissue that mimics the native extracellular matrix and guides tissue regeneration. However, for successful therapy application in the CMF region, the anatomical and functional principles described above need to be considered. Despite significant advances in the field, the literature still lacks a narrative review that consolidates these multidisciplinary insights, particularly addressing the unique biological and structural features of the CMF region in BTE strategies.

Objectives

This review aims to summarize and critically evaluate the clinical advances in BTE for CMF reconstruction, highlighting the cell types, the main materials used as scaffolds, growth and signaling factors, clinical outcomes and the main challenges and future perspectives shaping this field. We present this article in accordance with the Narrative Review reporting checklist (available at https://fomm.amegroups.com/article/view/10.21037/fomm-2025-1-54/rc).

Methods

Search strategy

An electronic search of articles was conducted using Web of Science, PubMed and Scopus using a Boolean search with the following keywords: (“Tissue Engineering”) AND (craniomaxillofacial OR craniofacial OR maxillofacial OR mandibul* OR maxill* OR calvarial OR cranial) AND (“clinical trial” OR “randomized controlled trial”). Studies published in English over the past 20 years (2005–2025) that met the predefined criteria and applied filters were included. Eligible study designs comprised case reports, clinical studies, clinical trials (Phase I–IV), controlled clinical trials, randomized clinical trials, and observational studies investigating BTE approaches involving the use of cells, scaffolds, and/or growth factors. Additionally, a manual search of the reference lists of included studies was performed, and one relevant manuscript indexed in PubMed, but not retrieved in the initial database search, was included. Exclusion criteria were in vitro studies; studies conducted on animals; reviews and/or systematic reviews. The search strategy is summarized in supplemental files (Tables S1,S2).

Studies selection

Duplicate records were identified and removed both automatically and manually using the web application Rayyan prior to the screening process (17). Then, titles and abstracts were independently screened by two independent reviewers (E.P.F. and B.A.M.). Any discrepancies between reviewers were resolved through discussion and consensus. In cases where consensus could not be reached, a third reviewer was consulted to make the final decision (H.F.F.O.). Studies were excluded if they did not meet the predefined inclusion criteria, including in vitro studies, in vivo animal studies, studies that did not involve the use of cells or biomaterials, and all types of literature reviews. Manuscripts with insufficient abstract information were considered in the next step. The same reviewers read the selected manuscripts to ensure that they met the inclusion criteria (Figure 1).

Figure 1 PRISMA flow diagram illustrating the identification, screening, eligibility, and inclusion of studies in the narrative review.

Data extraction

The data extracted were categorized into the following items: authors, study type, sample size, SCs source, growth factor, scaffold, reconstructed area, main findings and conclusions. The following sections presents the data from the manuscripts included and discuss each component of the BTE triad and how recent advances have been adapted for CMF regeneration (Tables 1,2).

Results and discussion

Thirty-seven papers met the inclusion criteria and were included in the review. A flowchart outlining the search process, study selection, and the main reasons for the exclusion of the manuscript are shown in Figure 1. Tables 1,2 summarize the main data and clinical evidence for the use of SCs associated with scaffolds and/or growth factors in BTE for the reconstruction of CMF defects. These included randomized controlled trials, case series, and case reports employing various cell populations, scaffolds, and growth factors.

Cell sources for CMF bone regeneration

The cellular component of BTE is predominantly based on adult SCs, due to their central role in osteogenesis and immunomodulatory properties (55,56). Studies indicate that autologous SCs exhibit good osteogenic capacity and high compatibility with the local microenvironment, supporting their application in CMF reconstruction (18,20,23). In addition, some reports describe the use of allogeneic cells without major complications (29,52).

Among autologous cell sources, iliac crest bone marrow-derived SCs still represent the gold standard (18,20,21,23-25,27,28,30,32,35,36,39,42,47-53). Four studies employed heterogeneous bone marrow cell mixtures different concentration of expanded CD90+, CD14+ and mononuclear cells (23,25,53) while one study investigated varying concentrations of CD34+ cells (24). Bone marrow aspirate comprises a heterogeneous population of cells, and the isolation of CD90+ and CD14+ populations, markers of mesenchymal stem cells, appears to improve therapeutic outcomes, particularly in larger defects (24). Although CD34 has traditionally been considered a marker of the hematopoietic lineage, evidence indicates that this maker is characteristic of progenitor cells, whose characterization depends on the expression of additional features. Thus, in the bone marrow, the detection of CD34 reflects a heterogeneous population composed of osteoblastic and hematopoietic progenitor cells, which may contribute to local vascularization at the defect site (57).

Alternative SCs sources have been proposed, including adipose tissue, dental pulp, periodontal ligament, alveolar bone and periosteum (19,22,26,31,33,34,37,40,41,43,44,54). Oral-derived SCs are particularly attractive for CMF applications due to their developmental proximity and niche compatibility. The use of differentiated osteoblasts offers the advantage of immediate functional activity; however, this approach is limited by reduced proliferative capacity, decreased viability after implantation, and difficulties in obtaining sufficient cell numbers for the treatment of critical-sized defects (20,35,40). As an alternative, induced-pluripotent stem cells have been described as having a theoretically unlimited proliferative and differentiation potential, making them potent candidates for large-scale BTE (58). Nevertheless, safety concerns, challenges in controlling lineage-specific differentiation, and regulatory constraints continue to hinder their clinical translation (59).

For BTE purposes, cells could be expanded after harvesting prior to implantation. The included studies reported expansion protocols with shared general protocols but varying in specific media formulations and culture periods, ranging from 1 day to 8 weeks (18,20,21,23,25,30,33-35,37-39,41,43,45-47,52,54). In contrast, other used bone marrow aspirate without laboratory manipulation (19,28,49,50). Cell density varied widely among studies, reflecting differences in clinical indications and scaffold types (18,32,35,39,40), and higher cell densities have been associated with improved clinical outcomes in terms of bone volume, in large defects (24,40).

To ensure the regenerative contribution of cells, characterization of cell phenotype, viability or differentiation potential before and/or after seeding in scaffolds is fundamental. However, some studies reported these data (20,22,23,25,30-32,40,41,43,53,54). Considerable variability was also observed in collection, expansion, and seeding protocols. Cell-scaffold incubation times ranged from immediate mixing prior to implantation to pre-incubation periods of 30 minutes to 2 weeks (19,30,53,54). Importantly, most studies reported adherence to Good Manufacturing Practice (GMP) standards to ensure procedural safety and minimize contamination risks. Overall, the safety profile of cell-based approaches was favorable, with reported adverse events being mostly mild, transient, and not directly attributable to the cellular component (34,43,44,53). No study reported serious treatment-related adverse events or systemic complications attributable to cell therapy.

Challenges and perspectives

Despite the promise of adult SCs for BTE applications, their use still faces significant barriers. Key barriers include cellular heterogeneity among donors, variability in osteogenic potential, limitations in in vitro expansion without phenotypic loss, determination of optimal cell density for different biomaterials, and difficulties related to cell viability, vascularization, and integration within the defect environment. Clinical effectiveness of SCs appears inversely related to defect size and complexity, while for large or critical-sized defects, outcomes were less evident. This can be attributed to several factors, including insufficient vascularization, scaffold properties, cell isolation techniques, cell density, and post-implantation viability. Therefore, comprehensive evaluation of all components of BTE constructs is essential. In addition, regulatory requirements and the high costs associated with standardized GMP-compliant cell processing remain major obstacles to large-scale clinical translation. Nonetheless, advances in understanding cellular microenvironments, the development of bioengineering for safe genetic manipulation, and the use of bioactive are expected to enhance the predictability, safety, and efficacy of cell-based regenerative therapies.

Scaffolds and biomaterials for CMF bone regeneration

Scaffolds act as temporary matrices that support cell attachment, proliferation, and differentiation while providing mechanical stability and degrading in synchrony with new bone formation (10,11). Ideally, scaffolds should reproduce both the architectural features and the biochemical composition of the native bone matrix. In CMF applications, scaffold design becomes even more critical due to the region’s anatomical, functional, and biological complexity. In addition, the inherently limited vascularization of CMF bone further complicates regeneration, reinforcing the need for scaffolds capable of supporting rapid vascularization and cellular integration to achieve successful reconstruction (14).

Studies on BTE in the CMF region employed wide variety of scaffold materials, which are summarized in Table 1. Beta tricalcium phosphate (β-TCP) has been the most frequently used material either alone or in combination with biphasic calcium phosphate and/or hydroxyapatite (HA) and bioactive glasses (18,19,21,23,30,32,39,43,44,48,51-54). However, most reconstructed defects were characterized by the presence of bony walls, such as those found in maxillary sinus augmentations and alveolar defects, which inherently provide mechanical support and containment (19,21,23,30,39,48,51). Ceramic and ceramic-based composites as HA, β-TCP, and bioactive glasses, mimic the mineral phase of the extracellular matrix and promote osteoconduction, but they generally lack mechanical properties. Hybrid scaffolds combining combine multiple materials have therefore been proposed to balance mechanical performance and biological activity (10,60).

Allografts were used in some studies, showing promising clinical outcomes despite the risk of immunological rejection and transmission of infectious diseases (24,29,31,49). Natural polymers, such as collagen and platelet-rich plasma (PRP) matrices have been used as both cell carriers and biologically active scaffolds (20,24,25,28,33,36-38,47). Although collagen and PRP offer excellent biocompatibility, their limited mechanical strength restricts their use to less critical load-bearing areas, such as the jaws and alveolar sockets, unless combined with more mechanically robust biomaterials (38). It has been debated as to whether they should be considered scaffolds or primarily vehicles for the delivery of cells and/or growth factors (61). Synthetic polymers, such as poly(lactic-co-glycolic acid) (PLGA), provide improved mechanical properties but often lack intrinsic bioactivity (60). Reported failures were largely attributed to insufficient mechanical stability, even when PLGA-based constructs were combined with reinforcing sheets (52).

Xenogeny particles, as demineralized bone matrix, were used either alone or combined with other graft materials (22,26,27,37,41,42,45). One study used a fabricated cross-linked serum-matrix (40), while only one study reported the use of advanced manufacturing with precisely controlled porosity and fiber lay-down patterns (52). This approach represents a shift toward patient-specific construct design using computer-aided design and manufacturing technology (52).

Despite satisfactory results, most reconstructed defects were confined by surrounding bony walls, thereby reducing the need for three-dimensional structures that can support excessive loads during repair. One study reported high failure rate after sinus lifting procedure (34). Complex defects were treated with BTE using particulate scaffolds in combination with meshes or fixation devices to restore local anatomy and provide mechanical support (18,24,32,43,50,54). One study evaluated bone formation in periodontal defects, where the contamination rate is higher due to exposure to the oral cavity; and no adverse events were observed (22). However, as the microbiota was not assessed, these outcomes cannot be directly attributed to the presence or absence of cells or biomaterials.

Challenges and perspectives

Achieving an optimal balance between structural stability and tissue ingrowth remains challenging. Furthermore, successful regeneration of large CMF defects depends heavily on rapid and effective vascularization, a requirement that many current available scaffolds fail to meet. The high microbial load of the oral and facial environment further increases the risk of postoperative infection, emphasizing the need for antimicrobial strategies that do not compromise scaffold biocompatibility. From a biological perspective, scaffolds must not only support osteogenesis but also modulate immune responses and promote stem cell recruitment and survival, while minimizing reliance on high doses of growth factors or complex cell-based therapies, which are associated with safety concerns, high costs, and regulatory barriers. Consequently, strategies involving the controlled delivery of biomolecules, bioactive peptides, extracellular vesicles, and immunomodulatory materials are increasingly seen as promising approaches that reduce dependence on complex BTE constructs. The choice of scaffold material significantly influences clinical outcomes, and the selection of materials for reconstructing larger CMF defects requires careful reconsideration. In such cases, advanced manufacturing approaches are emerging as viable solutions, ranging from GMP-compliant production of cell-seeded constructs to computer-aided design and three-dimensional printing technologies that enable patient-specific scaffold fabrication. Notably, the physical properties of these constructs vary considerably depending on anatomical location, defect size, and functional requirements. Finally, the integration of digital surgical planning, the selection of materials with established clinical safety profiles, and the simplification of regulatory requirements are key factors for accelerating the translation of engineered scaffolds from research settings to routine CMF clinical applications.

Growth and signaling factors for CMF bone regeneration

Growth factors, such as bone morphogenetic proteins (BMP), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) among others, play crucial roles in osteoinduction and angiogenesis, and are therefore essential for bone formation and remodeling (62). Overall, most of the studies do not incorporate exogenous growth factors, reporting instead that signaling molecules could be released endogenously by transplanted cell; on the other hand, one study cultured the cells with FGF before implantation (30). Five studies used human recombinant BMP-2 (24,31,44,50,54) and two studies used PRPs a source for signaling factors (49,51). Notably, many clinical studies have failed to consistently confirm the osteoinductive effects of BMPs, especially in large lesions (63). These limited outcomes have been attributed to their short biological half-life of growth factors, high costs, the lack of controlled delivery systems for sustained release, and potential adverse effects, while others suggest that failure may result from an unfavorable microenvironment characterized by an insufficient number of responsive cells, especially when compared with autogenous bone graft (63,64).

Challenges and perspectives

Despite their central role in bone regeneration, the clinical translational of growth factor for BTE in CMF reconstruction faces some challenges. The development of delivery systems capable of maintaining effective local concentrations to replicate the natural signaling cascade for coordinated bone formation has not been achieved (64,65). To overcome these limitations, future BTE strategies should focus on integrating growth factors with biomaterial carriers that enable sustained and localized delivery, while mimicking physiological signaling patterns (61). There is also growing interest in multimodal approaches that combine GFs with cellular therapies or endogenous signal amplification, with the aim of creating regenerative microenvironments with sufficient responsive cells and vascular support to improve outcomes in large or complex CMF defects. Continued refinement of delivery platforms and rigorous clinical evaluation will be crucial to realizing the full therapeutic potential of growth factors in CMF tissue engineering.

Vascularization strategies for CMF bone regeneration

Angiogenesis plays a critical role in graft survival at CMF sites by ensuring adequate vascularization, nutrient delivery, and integration with host tissue (66), and insufficient vascular supply has been identified as a key factor limiting the success of BTE approaches (35). Only a limited number of studies have investigated in situ vascularization on BTE using an arteriovenous loop or axial vascularization to reconstruct a large mandibular or skull defects (50,54). Although these approaches relied primarily on vascularization originating from donor sites rather than from cells or angiogenic factors incorporated within the BTE construct itself, the favorable outcomes observed in the reconstruction of large CMF defects underscore the importance of maintaining or enhancing local vascular supply. In addition, one clinical study evaluated the use of different densities of CD34⁺ cells, reporting improved bone regeneration with higher cell concentrations (24), suggesting a potential role of circulating progenitor cells in enhancing vascularization and subsequent bone formation. Collectively, these findings highlight that, although most clinically applied strategies currently depend on external vascular sources, adequate vascularization remains a decisive factor for successful regeneration in large CMF defects.

Challenges and future directions

Ensuring the blood supply remains one of the most critical and persistent challenge in CMF bone regeneration, especially for large-volume grafts, where only diffusion is incapable to sustain cell viability and tissue integration. As noticed by the clinical studies included in this review, current approaches largely rely on vascularization originating from surrounding tissues or surgically introduced vascular axes, which may limit its clinical use.

Future strategies are therefore being developed to promote intrinsic vascularization within BTE constructs. These include the fabrication of scaffolds with pre-formed vascular-like networks, the co-culture of osteogenic and endothelial cells to enhance coupled osteogenesis and angiogenesis, and the controlled delivery of angiogenic growth factors such as VEGF. In addition, advanced manufacturing techniques, including bioprinting, are being explored to spatially organize cells and biomolecules to mimic native tissue architecture. Despite promising preclinical results, these approaches still face significant translational challenges, including regulatory constraints, scalability, and the need for robust clinical validation. Future research should focus on well-designed clinical studies to evaluate the safety, efficacy, and long-term outcomes of these strategies in CMF reconstruction.

Clinical outcomes on CMF bone regeneration

Clinical outcomes on bone formation varied considerably among studies, reflecting the wide heterogeneity in defect size, anatomical location, and reconstruction strategies, as summarized in Table 2. Significant bone formation was consistently reported, with several studies demonstrated bone augmentation in area, volume and heigh, resulting in successful dental implant installation and integration, with functional outcomes maintained over follow-up periods ranging from 3 months to 7 years (36,37,39,41,42,47,49).

Some studies with control groups provided comparative data with autogenous bone (18,20-22,26-28,33,34,45), with conflicting data. Only two reported better bone formation in the BTE group compared to autograft (18,45), while five found no statistically significant differences between the two approaches (20,22,26,27,41). On the other hand, two studies reported higher bone formation on control compared with BTE, with reduced bone formation compared to autografts (21,34). These variable results could be due to several factors, including differences in experimental design, sample size, evaluation time, defect type, cell source, and the scaffold. These studies usually reported reduced donor site morbidity on BTE patients compared to iliac crest harvesting.

The majority of the studies reported safety profiles characterized by the absence of serious adverse events, short hospitalization times, and reduced treatment-related costs. Minor complications, including wound dehiscence, graft exposure and transient pain, were managed with conservative measurements. However, two studies reported the need for reintervention due to increased bone resorption following cranial reconstruction procedures (43,52).

Some main factors were identified as contributors to successful outcomes, including the composition of cells (23,24), the presence of a vascular supply specially in larger defects (50,54), and the characteristic of the defects: bone augmentation after sinus lift, and on the repair of alveoli or periodontal defects, which contain bone walls that, in turn, lead to the formation of new bone. On the other hand, studies evaluating BTE in larger defects with loss of bone continuity demonstrated clearer therapeutic advantages of cell-based approaches (18,24). This pattern suggests that cell therapy only brings clear benefit when the defect size exceeds the intrinsic regenerative capacity of bone.

Across studies, several limitations were identified. Sample-related including small sample sizes, lack of proper control, and restricted exploration of cell sources and experimental variables. Cell-related limitations involved heterogeneity of cell populations, insufficient or variable cell concentration, poor regenerative potential of human tissues, low viscosity of cell suspensions causing leakage, and challenges in large-scale cell preparation. Scaffold-related limitations included inadequate mechanical strength and variability in cell attachment between scaffold types. Cost-related limitations from the need for specialized large-scale facilities, harvesting procedures, and regulatory compliance. Methodological limitations included reliance on image analyses, difficulty distinguishing native from newly formed bone due to remodeling, potential bias in histomorphometric evaluation, and masking of cell effects when autogenous bone was used.

Overall, the clinical evidence indicates that BTE strategies can support bone regeneration across a range of CMF defects. In sinus augmentation, BTE constructs combining SCs combined with β-TCP or bovine bone mineral consistently yield sufficient bone for implant placement (19,26,37,39,42,47,48,51). For alveolar ridge augmentation, BTE with appropriate scaffolds can achieve superior bone volume gains over conventional block grafts, accelerating regeneration and reducing the need for secondary grafting (18,20,33,49). In contrast, reconstruction of large mandibular defects appears to require a more comprehensive cellular and biological environment, highlighting the limitations of point-of-care cell concentration alone in extensive defects. In cranial reconstruction, persistently high reoperation rates underscore the challenges posed by inadequate construct rigidity in the pulsatile intracranial setting, indicating a need for rigid scaffold support or alternative strategies (43,52). Finally, in alveolar cleft reconstruction, tissue-engineered approaches achieve ossification comparable to autogenous bone grafts without donor site morbidity, although evidence for their effectiveness in large defects remains limited and warrants further investigation (20,28,41,45).

The findings of this review should be interpreted considering several limitations inherent to the included literature. Overall, the available clinical evidence is characterized by heterogeneity in study design, including a predominance of case series and case reports, small sample sizes, and a limited number of randomized clinical trials. Considerable variability was observed in cell sources, scaffold materials, growth factors and clinical indications, which precludes direct comparison across studies and limits the ability to draw definitive conclusions. In addition, inconsistencies in reporting protocols, cell characterization, outcome measures, and follow-up periods further hinder data standardization and reproducibility. The frequent absence of appropriate control groups and the reliance on imaging-based assessments may also introduce bias and affect the outcomes. Despite these limitations, this review presents strengths. A structured search strategy was conducted across multiple databases, and study selection followed transparent criteria, enhancing the reproducibility of the methodology. The inclusion of different levels of clinical evidence allows for a broad overview of current translational applications of BTE in CMF reconstruction. Furthermore, this review provides an integrated analysis of key components of BTE, cells, scaffolds, and growth factors, highlighting their interactions and clinical implications. Nonetheless, limitations of this review include the restriction to English-language publications, the inclusion of lower levels of evidence, and the inability to perform a quantitative synthesis due to heterogeneity among studies. Therefore, further well-designed, large-scale randomized clinical trials with standardized protocols are needed to strengthen the evidence base and support the clinical translation of BTE strategies.

Conclusions

BTE has emerged as a promising and clinically relevant approach for the reconstruction of CMF defects. However, the current clinical evidence is predominantly based on case reports and case series, which limits the strength of the available conclusions. Clinical studies suggest that tissue-engineered constructs combining cells and scaffolds may support bone regeneration in specific CMF applications, particularly in contained defects such as sinus augmentation, alveolar ridge reconstruction, and alveolar cleft repair. In contrast, outcomes reported in large and load-bearing defects remain heterogeneous, reflecting the influence of multiple factors, including vascularization, mechanical stability, and defect-specific anatomical conditions.

Persistent challenges continue to limit clinical translation, including variability in cell-based approaches, inconsistent scaffold performance, uncertain efficacy of growth factor delivery, as well as regulatory and cost-related constraints. Consequently, while preliminary clinical experiences are encouraging, the predictability, safety, and scalability of BTE approaches have yet to be established through well-designed clinical trials. Future advances in this field will depend on the development of mechanically robust and bioactive scaffolds, strategies to enhance vascular integration, improved standardization of cell-based therapies, and the adoption of clinically feasible manufacturing and regulatory pathways. Within these limitations, the present review provides a synthesis of the currently available clinical evidence and highlights key gaps that should be addressed in future research to better define the role of BTE in CMF reconstruction.

Acknowledgments

An AI language model (ChatGPT, GPT 4.1 version, OpenAI) was used solely for proofreading and improving readability, using the following prompt: “Revise the paragraph below from my manuscript to ensure fluency, quality, and academic rigor. Improve clarity and readability and correct grammatical or stylistic errors. Do not add new content or alter the meaning of the original text. Maintain the references as cited in the text and preserve the academic tone”. Two AI-assisted tools (Rayyan and Elicit AI) were used to support data extraction from included studies. The authors manually reviewed and confirmed all extracted data, and the final dataset reflects only author-verified information.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Fernando P.S. Guastaldi, Yannick M. Sillmann and Henrique Hadad) for the series “Revolutionizing Craniomaxillofacial Regeneration: 3D Printing, Bone Tissue Engineering, and AI-Driven Innovations” published in Frontiers of Oral and Maxillofacial Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://fomm.amegroups.com/article/view/10.21037/fomm-2025-1-54/rc

Peer Review File: Available at https://fomm.amegroups.com/article/view/10.21037/fomm-2025-1-54/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://fomm.amegroups.com/article/view/10.21037/fomm-2025-1-54/coif). The series “Revolutionizing Craniomaxillofacial Regeneration: 3D Printing, Bone Tissue Engineering, and AI-Driven Innovations” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Costa L, Badia X, Chow E, et al. Impact of skeletal complications on patients' quality of life, mobility, and functional independence. Support Care Cancer 2008;16:879-89. [Crossref] [PubMed]
2. Global , regional , and national burden of bone fractures in 204 countries and territories, et al. Lancet Healthy Longev. 2021;2:e580-92.
3. Chiapasco M, Casentini P, Zaniboni M. Bone augmentation procedures in implant dentistry. Int J Oral Maxillofac Implants 2009;24 Suppl:237-59. [PubMed]
4. Moura LB, Carvalho PHA, Xavier CB, et al. Autogenous non-vascularized bone graft in segmental mandibular reconstruction: a systematic review. Int J Oral Maxillofac Surg 2016;45:1388-94. [Crossref] [PubMed]
5. Kawecki F, Clafshenkel WP, Fortin M, et al. Biomimetic Tissue-Engineered Bone Substitutes for Maxillofacial and Craniofacial Repair: The Potential of Cell Sheet Technologies. Adv Healthc Mater 2018;7:e1700919. [Crossref] [PubMed]
6. Baldwin P, Li DJ, Auston DA, et al. Autograft, Allograft, and Bone Graft Substitutes: Clinical Evidence and Indications for Use in the Setting of Orthopaedic Trauma Surgery. J Orthop Trauma 2019;33:203-13. [Crossref] [PubMed]
7. De Pace R, Molinari S, Mazzoni E, et al. Bone Regeneration: A Review of Current Treatment Strategies. J Clin Med 2025;14:1838. [Crossref] [PubMed]
8. Winkler T, Sass FA, Duda GN, et al. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: The unsolved challenge. Bone Joint Res 2018;7:232-43. [Crossref] [PubMed]
9. Langer R, Vacanti JP. Tissue engineering. Science 1993;260:920-6. [Crossref] [PubMed]
10. Zhang L, Yang G, Johnson BN, et al. Three-dimensional (3D) printed scaffold and material selection for bone repair. Acta Biomater 2019;84:16-33. [Crossref] [PubMed]
11. Jagadale S, Damle M, Joshi MG. Bone Tissue Engineering: From Biomaterials to Clinical Trials. Adv Exp Med Biol 2025;1479:73-115. [Crossref] [PubMed]
12. Chai Y, Jiang X, Ito Y, et al. Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 2000;127:1671-9. [Crossref] [PubMed]
13. Lin Z, Fateh A, Salem DM, et al. Periosteum: biology and applications in craniofacial bone regeneration. J Dent Res 2014;93:109-16. [Crossref] [PubMed]
14. Tian T, Zhang T, Lin Y, et al. Vascularization in Craniofacial Bone Tissue Engineering. J Dent Res 2018;97:969-76. [Crossref] [PubMed]
15. Eichholz KF, Freeman FE, Pitacco P, et al. Scaffold microarchitecture regulates angiogenesis and the regeneration of large bone defects. Biofabrication 2022;14:10. [Crossref] [PubMed]
16. Bartold PM, Gronthos S, Ivanovski S, et al. Tissue engineered periodontal products. J Periodontal Res 2016;51:1-15. [Crossref] [PubMed]
17. Ouzzani M, Hammady H, Fedorowicz Z, et al. Rayyan-a web and mobile app for systematic reviews. Syst Rev 2016;5:210. [Crossref] [PubMed]
18. Sanz M, Gjerde C, Gjertsen BT, et al. Bone Augmentation of Atrophic Alveolar Ridges Using a Synthetic Bone Substitute With Mesenchymal Stem Cells: A Randomized, Controlled Clinical Trial. Clin Oral Implants Res 2025;36:1498-514. [Crossref] [PubMed]
19. Fatale V, Pagnoni S, Pagnoni AE, et al. 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 2022;33:1607-13. [Crossref] [PubMed]
20. Kadry W, Eldeftar M, Nassar Y, et al. Clinical, volumetric and densitometric evaluation of tissue engineered constructs for secondary alveolar cleft reconstruction: A randomized clinical trial. J Craniomaxillofac Surg 2021;49:1141-50. [Crossref] [PubMed]
21. Bajestan MN, Rajan A, Edwards SP, et al. Stem cell therapy for reconstruction of alveolar cleft and trauma defects in adults: A randomized controlled, clinical trial. Clin Implant Dent Relat Res 2017;19:793-801. [Crossref] [PubMed]
22. Chen FM, Gao LN, Tian BM, et al. Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: a randomized clinical trial. Stem Cell Res Ther 2016;7:33. [Crossref] [PubMed]
23. Kaigler D, Avila-Ortiz G, Travan S, et al. Bone Engineering of Maxillary Sinus Bone Deficiencies Using Enriched CD90+ Stem Cell Therapy: A Randomized Clinical Trial. J Bone Miner Res 2015;30:1206-16. [Crossref] [PubMed]
24. Marx RE, Harrell DB. 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 2014;29:e201-9. [Crossref] [PubMed]
25. Kaigler D, Pagni G, Park CH, et al. Stem cell therapy for craniofacial bone regeneration: a randomized, controlled feasibility trial. Cell Transplant 2013;22:767-77. [Crossref] [PubMed]
26. Hermund NU, Stavropoulos A, Donatsky O, et al. Reimplantation of cultivated human bone cells from the posterior maxilla for sinus floor augmentation. Histological results from a randomized controlled clinical trial. Clin Oral Implants Res 2012;23:1031-7. [Crossref] [PubMed]
27. Sauerbier S, Rickert D, Gutwald R, et al. Bone marrow concentrate and bovine bone mineral for sinus floor augmentation: a controlled, randomized, single-blinded clinical and histological trial--per-protocol analysis. Tissue Eng Part A 2011;17:2187-97. [Crossref] [PubMed]
28. Gimbel M, Ashley RK, Sisodia M, et al. Repair of alveolar cleft defects: reduced morbidity with bone marrow stem cells in a resorbable matrix. J Craniofac Surg 2007;18:895-901. [Crossref] [PubMed]
29. Gonshor A, McAllister BS, Wallace SS, et al. Histologic and histomorphometric evaluation of an allograft stem cell-based matrix sinus augmentation procedure. Int J Oral Maxillofac Implants 2011;26:123-31. [PubMed]
30. Kagami H, Inoue M, Agata H, et al. A Clinical Study of Alveolar Bone Tissue Engineering Using Autologous Bone Marrow Stromal Cells: Effect of Optimized Cell-Processing Protocol on Efficacy. J Clin Med 2022;11:7328. [Crossref] [PubMed]
31. Tzur E, Ben-David D, Gur Barzilai M, et al. 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 2021;79:787-798.e2. [Crossref] [PubMed]
32. Gjerde C, Mustafa K, Hellem S, et al. Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial. Stem Cell Res Ther 2018;9:213. [Crossref] [PubMed]
33. Nagata M, Hoshina H, Li M, et al. A clinical study of alveolar bone tissue engineering with cultured autogenous periosteal cells: coordinated activation of bone formation and resorption. Bone 2012;50:1123-9. [Crossref] [PubMed]
34. Voss P, Sauerbier S, Wiedmann-Al-Ahmad M, et al. Bone regeneration in sinus lifts: comparing tissue-engineered bone and iliac bone. Br J Oral Maxillofac Surg 2010;48:121-6. [Crossref] [PubMed]
35. Meijer GJ, de Bruijn JD, Koole R, et al. Cell based bone tissue engineering in jaw defects. Biomaterials 2008;29:3053-61. [Crossref] [PubMed]
36. Yamada Y, Nakamura S, Ito K, et al. Injectable tissue-engineered bone using autogenous bone marrow-derived stromal cells for maxillary sinus augmentation: clinical application report from a 2-6-year follow-up. Tissue Eng Part A 2008;14:1699-707. [Crossref] [PubMed]
37. Springer IN, Nocini PF, Schlegel KA, et al. Two techniques for the preparation of cell-scaffold constructs suitable for sinus augmentation: steps into clinical application. Tissue Eng 2006;12:2649-56. [Crossref] [PubMed]
38. Pradel W, Eckelt U, Lauer G. Bone regeneration after enucleation of mandibular cysts: comparing autogenous grafts from tissue-engineered bone and iliac bone. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101:285-90. [Crossref] [PubMed]
39. Asahina I, Kagami H, Agata H, et al. 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 2021;10:5231. [Crossref] [PubMed]
40. Redondo LM, García V, Peral B, et al. Repair of maxillary cystic bone defects with mesenchymal stem cells seeded on a cross-linked serum scaffold. J Craniomaxillofac Surg 2018;46:222-9. [Crossref] [PubMed]
41. Tanikawa DYS, Pinheiro CCG, Almeida MCA, et al. Deciduous Dental Pulp Stem Cells for Maxillary Alveolar Reconstruction in Cleft Lip and Palate Patients. Stem Cells Int 2020;2020:6234167. [Crossref] [PubMed]
42. Fuerst G, Strbac GD, Vasak C, et al. Are culture-expanded autogenous bone cells a clinically reliable option for sinus grafting?. Clin Oral Implants Res 2009;20:135-9. [Crossref] [PubMed]
43. Thesleff T, Lehtimäki K, Niskakangas T, et al. Cranioplasty with Adipose-Derived Stem Cells, Beta-Tricalcium Phosphate Granules and Supporting Mesh: Six-Year Clinical Follow-Up Results. Stem Cells Transl Med 2017;6:1576-82. [Crossref] [PubMed]
44. Sándor GK. Tissue engineering of bone: Clinical observations with adipose-derived stem cells, resorbable scaffolds, and growth factors. Ann Maxillofac Surg 2012;2:8-11. [Crossref] [PubMed]
45. Pradel W, Lauer G. Tissue-engineered bone grafts for osteoplasty in patients with cleft alveolus. Ann Anat 2012;194:545-8. [Crossref] [PubMed]
46. Mangano C, Piattelli A, Mangano A, et al. Combining scaffolds and osteogenic cells in regenerative bone surgery: a preliminary histological report in human maxillary sinus augmentation. Clin Implant Dent Relat Res 2009;11 Suppl 1:e92-102. [Crossref] [PubMed]
47. Ueda M, Yamada Y, Kagami H, et al. Injectable bone applied for ridge augmentation and dental implant placement: human progress study. Implant Dent 2008;17:82-90. [Crossref] [PubMed]
48. Shayesteh YS, Khojasteh A, Soleimani M, et al. Sinus augmentation using human mesenchymal stem cells loaded into a beta-tricalcium phosphate/hydroxyapatite scaffold. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:203-9. [Crossref] [PubMed]
49. Filho Cerruti H, Kerkis I, Kerkis A, et al. Allogenous bone grafts improved by bone marrow stem cells and platelet growth factors: clinical case reports. Artif Organs 2007;31:268-73. [Crossref] [PubMed]
50. Eweida A, Morsi M, Abouelnaga S, et al. In situ axial vascularization for regeneration of challenging mandibular defects, a feasibility trial and case report with long-term results. J Craniomaxillofac Surg 2025;5:881-7. [Crossref] [PubMed]
51. Ueda M, Yamada Y, Ozawa R, et al. Clinical case reports of injectable tissue-engineered bone for alveolar augmentation with simultaneous implant placement. Int J Periodontics Restorative Dent 2005;25:129-37. [PubMed]
52. Morrison DA, Kop AM, Nilasaroya A, et al. Cranial reconstruction using allogeneic mesenchymal stromal cells: A phase 1 first-in-human trial. J Tissue Eng Regen Med 2018;12:341-8. [Crossref] [PubMed]
53. Rajan A, Eubanks E, Edwards S, et al. Optimized cell survival and seeding efficiency for craniofacial tissue engineering using clinical stem cell therapy. Stem Cells Transl Med 2014;3:1495-503. [Crossref] [PubMed]
54. Mesimäki K, Lindroos B, Törnwall J, et al. Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int J Oral Maxillofac Surg 2009;38:201-9. [Crossref] [PubMed]
55. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-7. [Crossref] [PubMed]
56. Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2008;2:313-9. [Crossref] [PubMed]
57. Sidney LE, Branch MJ, Dunphy SE, et al. Concise review: evidence for CD34 as a common marker for diverse progenitors. Stem Cells 2014;32:1380-9. [Crossref] [PubMed]
58. Lou X. Induced Pluripotent Stem Cells as a new Strategy for Osteogenesis and Bone Regeneration. Stem Cell Rev Rep 2015;11:645-51. [Crossref] [PubMed]
59. Rana D, Kumar S, Webster TJ, et al. Impact of Induced Pluripotent Stem Cells in Bone Repair and Regeneration. Curr Osteoporos Rep 2019;17:226-34. [Crossref] [PubMed]
60. Qi J, Yu T, Hu B, et al. Current Biomaterial-Based Bone Tissue Engineering and Translational Medicine. Int J Mol Sci 2021;22:10233. [Crossref] [PubMed]
61. Wang Z, Wang Z, Lu W, et al. Novel biomaterial strategies for controlled growth factor delivery for biomedical applications. NPG Asia Mater 2017;9:e435.
62. Urist MR, Silverman BF, Büring K, et al. The bone induction principle. Clin Orthop Relat Res 1967;53:243-83. [PubMed]
63. Ripamonti U, Ferretti C. The Biological and Clinical Grand Challenges For Craniomandibulofacial Reconstruction: The Dream of Bone Tissue Engineering. J Craniofac Surg 2025;36:2893-903. [Crossref] [PubMed]
64. Oliveira ÉR, Nie L, Podstawczyk D, et al. Advances in Growth Factor Delivery for Bone Tissue Engineering. Int J Mol Sci 2021;22:903. [Crossref] [PubMed]
65. Khojasteh A, Behnia H, Naghdi N, et al. Effects of different growth factors and carriers on bone regeneration: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:e405-23. [Crossref] [PubMed]
66. Saran U, Gemini Piperni S, Chatterjee S. Role of angiogenesis in bone repair. Arch Biochem Biophys 2014;561:109-17. [Crossref] [PubMed]