Growth Factors in Maxillofacial Bone Regeneration: A Narrative Review

INTRODUCTION

Despite important advances in surgical techniques, bone grafting materials, and implant-based rehabilitation, the regeneration of maxillofacial bone defects remains a major clinical challenge. These defects may occur after trauma, infection, cystic lesions, tumor surgery, periodontal destruction, tooth extraction, congenital deformities, or implant-related bone loss. Their management is not limited to filling an osseous void; it also requires restoration of bone volume, contour, ridge architecture, periodontal support, and functional stability for prosthetic or implant rehabilitation.^[1]

Bone regeneration is a coordinated biological process involving inflammation, recruitment of osteogenic and mesenchymal cells, angiogenesis, matrix deposition, mineralization, and later remodeling into mature bone.^[2] For successful healing, three elements are essential: Viable regenerative cells, a stable scaffold or matrix, and biological signals that regulate cell migration, proliferation, differentiation, and tissue maturation.^[3] Conventional grafting procedures mainly provide osteoconductive support and space maintenance. However, in complex defects, compromised healing sites, and larger reconstructive situations, a scaffold alone may not be sufficient to produce rapid and predictable bone regeneration.^[4]

Growth factors are signaling molecules that regulate important events in wound healing and bone repair, including chemotaxis, angiogenesis, osteoblast differentiation, extracellular matrix formation, and remodeling.^[4,5] In maxillofacial regeneration, these agents are used either as recombinant proteins or as autologous platelet-derived preparations. Recombinant systems include recombinant human platelet-derived growth factor-BB (rhPDGF-BB), recombinant human bone morphogenetic protein-2 (rhBMP-2), recombinant human bone morphogenetic protein-7 (rhBMP-7), and recombinant human fibroblast growth factor-2 (rhFGF-2).^[6,7] Autologous platelet-derived preparations include concentrated growth factor (CGF), plasma rich in growth factor (PRGF), platelet-rich fibrin (PRF), leukocyte PRF (L-PRF), and platelet-rich plasma (PRP).^[8-11] These materials are not passive fillers; rather, they act as biological mediators that may improve early healing, vascular ingrowth, bone formation, and graft maturation when used in suitable clinical situations.^[4,5]

Clinical use of growth factors has been reported in periodontal intrabony defects, peri-implant defects, extraction socket preservation, alveolar ridge augmentation, maxillary sinus augmentation, cystic jaw defects, mandibular reconstruction, alveolar cleft repair, and other oral and maxillofacial applications.^[12-18] Among these applications, rhPDGF-BB has shown the most consistent clinical support in periodontal regeneration, particularly when used with an appropriate carrier such as beta-tricalcium phosphate (β-TCP).^[13,14] Autologous platelet-derived preparations have shown encouraging adjunctive effects in ridge preservation, sinus augmentation, socket healing, and selected reconstructive procedures, although the magnitude of benefit varies considerably across studies.^[15-18]

A major reason for this variation is the lack of standardization in growth-factor protocols. Differences in preparation methods, centrifugation protocols, platelet and leukocyte concentration, activation methods, dose, carrier material, release kinetics, defect type, surgical technique, and follow-up duration can all influence clinical outcomes.^[10,19] For recombinant systems, dose and carrier selection are especially important, while autologous platelet concentrates may behave differently when used alone compared with when they are combined with bone substitutes or barrier membranes.^[20] Therefore, growth factors should not be interpreted as a single uniform treatment category. Their clinical value must be judged according to the specific biologic agent, delivery system, indication, and quality of supporting evidence.

Although many studies report favorable findings, the overall evidence base has important methodological limitations. Several clinical studies have small sample sizes, short follow-up periods, variable outcome measures, and heterogeneous defect characteristics. Some of the studies are randomized clinical trials, whereas others are retrospective studies, case series, or observational reports. These designs increase the possibility of selection bias, performance bias, detection bias, and reporting bias. In addition, many studies focus on surrogate outcomes such as radiographic bone density, early implant stability, or percentage bone fill, while fewer studies report long-term functional outcomes, implant survival, patient-reported outcomes, re-intervention rates, or histologic quality of regenerated bone.^[14,17,21] These limitations make it difficult to provide broad recommendations for routine clinical use.

At the same time, the field is rapidly evolving. Recent advances in stem cell-assisted regeneration, advanced biomaterials, bioactive scaffolds, hydrogels, nanostructured carriers, controlled-release delivery systems, and combined cell-scaffold-growth factor approaches have expanded the possibilities of biologically guided maxillofacial bone regeneration.^[22-26] These approaches aim to improve growth-factor retention, prolong release, enhance vascularization, and create a more favorable microenvironment for bone formation. However, many of these newer strategies remain at the experimental or early clinical stage. Their long-term safety, cost-effectiveness, and clinical superiority over established regenerative methods still require stronger evidence.

Therefore, this narrative review aims to discuss the biological basis, principal growth-factor systems, clinical applications, quality of evidence, methodological limitations, safety considerations, and emerging advances related to growth factors in maxillofacial bone regeneration. The review also attempts to provide clinically relevant recommendations regarding where these agents may be useful as adjuncts and where the current evidence remains insufficient for routine use.

GROWTH FACTORS IN MAXILLOFACIAL BONE REGENERATION

Growth factors function as biologic signals that guide maxillofacial bone healing by stimulating cell migration, proliferation, angiogenesis, matrix deposition, and tissue maturation. These biomolecular agents may be used alone, but they are more commonly combined with grafting materials, membranes, or scaffolds to support regeneration. Their clinical effect depends on the type of growth factor, dose, carrier material, release pattern, delivery system, defect environment, and surgical technique.^[3-5,22] Therefore, predictable bone healing should be understood as the combined result of appropriate case selection, defect management, scaffold stability, vascularity, and controlled use of bioactive materials.

Growth factors used in maxillofacial tissue engineering can be broadly divided into recombinant growth factors and autologous platelet-derived preparations. Among recombinant agents, rhPDGF-BB is the most studied and has shown the most consistent clinical results, especially in periodontal osseous defects.^[13,14] In periodontal defects, rhPDGF-BB-treated sites have demonstrated greater bone fill, clinical attachment gain, and long-term clinical stability than control sites.^[13,27] Other recombinant growth factors, such as rhBMP-2, rhBMP-7, and rhFGF-2, have also been investigated for periodontal and maxillofacial regeneration. However, the effects of rhBMPs are strongly influenced by dose and carrier selection, whereas rhFGF-2 has shown favorable results mainly in periodontal intraosseous defects.^[6,7,21] The principal growth-factor systems and their common indications are summarized in Table 1.

The second group consists of autologous platelet-derived preparations obtained from the patient’s own blood. These include CGF, PRGF, PRF, L-PRF, and PRP. These preparations contain multiple naturally released mediators, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), vascular endothelial growth factor, and insulin-like growth factor (IGF), which contribute to angiogenesis, soft-tissue healing, and bone repair.^[28,29] CGF has been evaluated for ridge preservation, sinus augmentation, periodontal regeneration, implant-site healing, and complex jaw defects.^{[18,28,30-32]} PRGF has shown encouraging results in intraoral bone grafting, alveolar ridge preservation, and post-extraction socket healing.^[8,33,34] The clinical results for PRF and PRP are more variable, but they generally appear more favorable when these preparations are used as adjuncts with grafting materials rather than as stand-alone regenerative agents.^[9,11,35]

The clinical performance of these preparations is influenced by differences in preparation and delivery protocols. For platelet-derived products, variations in centrifugation speed, centrifugation time, platelet concentration, leukocyte content, fibrin architecture, activation method, and handling technique can affect the concentration and release kinetics of growth factors. For recombinant molecules, dose, carrier material, retention at the defect site, and duration of release are critical determinants of efficacy and safety.^[10,19,22] These differences partly explain why similar growth-factor systems may produce different outcomes across studies and why direct comparison between studies is often difficult.

In clinical practice, growth factors are rarely used as isolated molecules. They are more commonly incorporated into a broader regenerative protocol using a scaffold, graft material, membrane, or delivery carrier. This is seen with rhPDGFBB combined with β-TCP for periodontal defects and with rhBMP-2 delivered through allograft-based carriers or absorbable collagen sponge systems.^[13,19,27] Similarly, CGF appears more predictable when used with particulate grafts such as deproteinized bovine bone mineral (DBBM), BioOss, or related bone substitutes rather than as a stand-alone material.^[16,32,36] Therefore, clinical decision-making should not be based only on the choice of growth factor, but also on the defect type, carrier system, release profile, surgical stability, and quality of evidence available for that particular indication.

CLINICAL APPLICATIONS AND CURRENT EVIDENCE

CURRENT LIMITATIONS, SAFETY, AND CLINICAL CONSIDERATIONS

Although many studies have reported promising outcomes, the available literature is not sufficiently homogeneous to recommend growth factors for all maxillofacial bone defects. Considerable variation exists in study design, sample size, defect type, carrier material, preparation protocol, outcome assessment, and follow-up duration. Follow-up periods range from short-term evaluations of a few weeks to longer follow-up extending over several months or years. Many clinical studies include small samples, while only a limited number of trials and systematic reviews provide stronger methodological support.^{[9,21,28,41,47,53]} This limits the strength of broad clinical recommendations and makes it necessary to interpret growth-factor outcomes according to specific indications rather than as a single treatment category.

The methodological quality of the available evidence is also variable. Randomized controlled trials provide the strongest support for selected applications, especially periodontal regeneration using rhPDGF-BB with β-TCP. However, many other applications are supported mainly by small clinical studies, split-mouth trials, retrospective analyses, case series, or defect-specific observational reports. These designs increase the possibility of selection bias, performance bias, detection bias, and reporting bias. In addition, several studies use surrogate outcomes such as radiographic bone density, percentage bone fill, implant stability, or short-term soft-tissue healing rather than long-term functional outcomes, histologic bone quality, implant survival, patient-reported outcomes, or need for re-intervention.^[14,17,21] Therefore, the current evidence should be considered encouraging but not uniformly strong across all clinical indications.

The efficacy of growth factors is influenced not only by their biological activity but also by the delivery system used at the surgical site. Ideally, the carrier should retain the growth factor, permit controlled release, provide space maintenance, support clot stability, and remain compatible with bone-forming cells. Studies have shown that rhBMP-2 delivered with allograft-based carriers may achieve greater mean bone regeneration than delivery through absorbable collagen sponge systems.^[19] Similarly, CGF has shown greater osseous regeneration when used with DBBM, Bio-Oss, or other bone substitutes rather than as a stand-alone material.^[16,36] These findings indicate that the carrier is not a passive component of treatment but a major determinant of the final regenerative response.

Variations in preparation protocol and dosage further contribute to inconsistent results. For autologous platelet-derived concentrates, differences in centrifugation speed, centrifugation time, tube type, platelet concentration, leukocyte content, fibrin architecture, activation method, and handling technique can alter the concentration and release pattern of growth factors. For recombinant preparations, dose, carrier binding, release kinetics, and local retention time are particularly important. Early clinical applications of rhPDGF-BB and recombinant human IGF-I showed that lower concentrations did not outperform control treatment, whereas higher concentrations achieved significant osseous fill.^[20] On the other hand, excessive concentrations of rhBMP-2 have been associated with marked gingival swelling and abnormal bone response.^[5] Therefore, growth factors cannot be evaluated by name alone; the specific agent, dose, preparation method, carrier system, release profile, and clinical indication must all be considered.

From a safety perspective, rhPDGF-BB has shown a favorable clinical profile, with no major local or systemic adverse effects reported in large periodontal studies and long-term follow-up.^[13,14,27] Autologous preparations such as CGF, PRGF, PRF, L-PRF, and PRP are generally considered biocompatible because they are prepared from the patient’s own blood and therefore carry minimal risk of immunogenic reaction or disease transmission.^[11,29] Several studies have also suggested that CGF and related platelet concentrates may reduce post-operative pain, swelling, and wound-related complications, particularly when used as adjuncts in graft-supported procedures.^[31,46] However, not all growth-factor-based approaches have the same safety margin. Recombinant systems, especially rhBMP-based protocols, require greater caution because adverse effects appear to be dose- and carrier-dependent.^[5]

Clinically, the present evidence supports selective rather than routine use of growth factors. rhPDGF-BB with β-TCP may be considered a useful adjunct in periodontal intrabony defects, particularly when defect morphology is favorable and cost is justified by the expected clinical benefit.^[13] CGF or PRGF combined with bone substitutes may be considered in ridge preservation or selected sinus augmentation procedures, especially when the aim is to improve early healing, soft-tissue response, or graft maturation.^[16,17] However, growth factors should not be viewed as replacements for sound surgical principles, stable graft containment, adequate vascularity, passive flap closure, infection control, and proper case selection.

The clinician must also consider practical factors such as cost, additional preparation time, availability of equipment, operator training, and the difference between statistically significant improvement and clinically meaningful benefit. Although systematic reviews support clinical superiority for rhPDGF-BB in selected periodontal defects, the absolute gain may be moderate in some outcomes.^[14] Therefore, the decision to use growth factors should be individualized according to defect type, patient risk profile, treatment objective, and strength of evidence for that indication. Future studies should use standardized preparation protocols, clearly defined dosages, uniform carrier systems, larger sample sizes, longer follow-up, and clinically relevant outcome measures.^[4,5,12,14] The main practical considerations are summarized in Table 5.

CONCLUSION

Growth factors appear to be useful adjuncts in maxillofacial bone regeneration, with the most consistent evidence seen for rhPDGF-BB in periodontal defects and encouraging results for autologous platelet-derived concentrates in ridge preservation, sinus augmentation, and selected reconstructive applications. However, their clinical effect is not uniform and depends largely on the specific biologic agent, carrier system, dosage, delivery method, defect type, and treatment protocol rather than on the presence of a growth factor alone. The current evidence is limited by heterogeneity in study designs, preparation protocols, sample sizes, follow-up duration, and outcome assessment. Therefore, growth-factor-based therapy should presently be considered a promising but indication-specific adjunct that may enhance regenerative outcomes in well-selected cases. Further standardized clinical studies with longer follow-up and clinically meaningful outcomes are required to clarify its most predictable applications.