FGF-2 in Bone Regeneration and Craniofacial Tissue Engineering: A Comprehensive Update

Abstract

Fibroblast growth factor-2 (FGF-2) has been investigated as a potential adjuvant to periodontal regeneration because it promotes angiogenesis, cellular proliferation, and osteogenesis. This review aims to provide a comprehensive update on recent research exploring the use of FGF-2 in periodontal regeneration. In recent years, FGF-2 has been delivered through various advanced methods, including hydrogels, nanoparticles, and scaffold-based systems. These systems enable sustained release and localized delivery, improving the therapeutic efficacy of FGF-2. Recent long-term studies suggest that FGF-2 may augment the efficacy of bone grafting. Nevertheless, FGF-2 has not been used due to several reasons, including the high production costs, optimal dosing strategies, and variability in patient responses to FGF-2 therapy. More recently, FGF-2 has been incorporated into scaffold materials to develop functionally graded membranes, which have demonstrated potential for sustained release of the growth factor into the periodontium, promoting effective tissue regeneration. Nevertheless, further research is required to optimize its application and ensure long-term efficacy and safety.

Keywords

guided bone regeneration - periodontitis - review (narrative)

Introduction

Guided tissue regeneration (GTR) involves the use of resorbable or nonresorbable membranes, along with grafts to stimulate the growth of periodontal tissues at periodontal defects or around dental implants.[1] [2] In the GTR procedure, a barrier membrane is placed (usually along with a grafting material) separating the gingival soft tissue and the bone or the surface of the tooth root, preventing the ingrowth of the soft tissue in to the defect, which in turn provides space for the regeneration of periodontal tissues.[3] Several materials have been used as GTR membranes and grafts, such as the nonresorbable expanded polytetrafluoroethylene, such as the degradable collagen.[4] Contemporary GTR materials have a customized porosity enabling selective cellular infiltration to enhance the regeneration of periodontal tissues.[5].

For GTR to be effective, the materials used must meet specific criteria.[6] The material must be biocompatible to prevent immune reactions and promote healing, while also serving as a barrier to prevent soft tissue from infiltrating the defect. It should also maintain the necessary space for tissue growth and possess sufficient mechanical strength to protect the regenerating tissues, especially in areas subjected to forces from chewing. For resorbable materials, the degradation rate must align with the healing process, providing support throughout tissue regeneration. Additionally, these materials should be easy to handle and cost-effective for practical clinical use.

GTR membranes are often combined with grafting materials such as autografts,[7] allografts,[8] xenografts,[9] and alloplasts.[10] Autografts, harvested from the patient's own body, provide superior biocompatibility and osteogenic potential but require a second surgical site. Allografts, sourced from other human donors, are processed and disinfected to reduce immunogenicity while retaining osteoconductive and osteoinductive properties. Xenografts, typically derived from bovine sources, serve as osteoconductive scaffolds, while alloplasts, which are synthetic materials like hydroxyapatite[11] [12] or tricalcium phosphate (TCP), offer biocompatible support for bone growth through osteoconduction. However, these materials have various drawbacks. For instance, autografts require an additional surgical procedure for harvesting the graft, allografts and xenografts (due to their human and animal sources) have ethical concerns, and may still cause immune reactions.

To overcome the drawbacks of traditional GTR materials, growth factors and drugs have been incorporated into bioresorbable membranes and grafts.[13] FGF-2 (basic fibroblast growth factor), an important regulator of wound healing,[14] has been integrated into these materials due to its ability to promote angiogenesis, cell proliferation, and differentiation.[15] FGF-2 can be stabilized and encapsulated into different materials so that it can be delivered in to the tissues in a controlled rate.[16] FGF-2 stimulates fibroblast and osteoblast activity, leading to the regeneration of alveolar bone and periodontal ligament (PDL).[17] [18] For example, bioresorbable collagen membranes embedded with FGF-2 facilitate the growth of periodontal tissues by enhancing cell migration and proliferation at the defect site.[19] [20] Similarly, FGF-2 has been added to bone grafting materials to accelerate osteoblast activity, resulting in faster and more effective bone regeneration.[21] Other growth factors, such as platelet-derived growth factor (PDGF) and bone morphogenetic proteins (BMPs), have also been incorporated into grafting materials, further promoting bone formation and wound healing.[5] These growth factors are released in a controlled manner as the bioresorbable membrane or graft degrades, providing a sustained local effect that supports natural tissue healing.

Literature Search Methodology

The author conducted a literature search via PubMed and Google Scholar to find potential articles of interest. The citations were uploaded onto Covidence and were screened by the author for eligibility. Eligible types of articles were clinical trials, animal studies, in vitro studies, and systematic reviews. In addition to the literature search on PubMed and Google Scholar, the author also conducted a targeted literature search on prominent journals such as Dental Materials, Periodontology 2000, Journal of Clinical Periodontology, Journal of Periodontology, and Journal of Dental Research. We excluded other narrative reviews, nonsystematic reviews, letters to the editor, and studies in languages other than English.

Current Applications of FGF-2 in Periodontal Regeneration

Clinical studies have demonstrated that FGF-2, often incorporated into hydrogels or other biomaterials, significantly improves the healing of periodontal defects by promoting new cementum, alveolar bone, and PDL formation.[22] In bone regeneration, FGF-2 has shown potential in enhancing fracture healing and bone graft integration by stimulating the proliferation of osteoprogenitor cells and supporting angiogenesis, both critical for bone regeneration.[23] Additionally, FGF-2 has been combined with scaffolds in tissue engineering approaches, where it aids in the formation of vascularized bone tissues, providing a viable strategy for treating large bone defects.[24] The growth factor's stimulatory effects on stem cell differentiation also make it an attractive candidate for use in advanced therapeutic applications such as GTR and bone augmentation procedures. Despite these promising outcomes, the controlled release of FGF-2, its dosage, and long-term effects remain areas of active research to optimize its therapeutic potential and ensure clinical safety and efficacy in periodontal and bone regeneration.[25]

Preclinical Studies on FGF-2

In vitro studies have demonstrated that FGF-2 plays a significant role in periodontal regeneration by stimulating the proliferation and migration of mesenchymal cells within the PDL.[26] FGF-2 has also been shown to enhance angiogenesis and osteogenesis—critical components of tissue regeneration.[27] These regenerative effects are amplified when FGF-2 is delivered with a scaffold, such as β-TCP or collagen matrices. The use of scaffolds provides a structural framework that stabilizes the blood clot, facilitates vascular invasion, and promotes the migration of regenerative cells.[28]

In vivo studies have further validated the regenerative potential of FGF-2 in periodontal therapy. Ishii et al conducted one of the earliest investigations using a split-mouth design in dogs, where gingival recession defects treated with FGF-2 alone or in combination with β-TCP demonstrated periodontal regeneration.[29] The combination group showed superior formation of new bone and cementum, suggesting that scaffolds enhance the clinical performance of FGF-2. Similarly, others reported enhanced cementum and bone formation when FGF-2 was delivered in a biodegradable sponge,[28] and Cha et al observed increased root coverage and tissue regeneration when FGF-2 was incorporated into a porcine collagen matrix.[30] These animal studies consistently support that FGF-2, particularly when combined with a scaffold, can inhibit epithelial downgrowth and promote regeneration of the periodontium, offering a promising strategy for root coverage and soft tissue engineering.

Recent Advances in FGF-2 Delivery Systems for GTR

One of the challenges with FGF-2 therapy has been its rapid degradation and short half-life in vivo.[31] To overcome this, recent innovations have focused on developing controlled-release delivery systems that ensure the sustained and localized release of FGF-2 at the site of injury.[32] Among these, hydrogels,[33] nanoparticles,[34] and multiscaffold-based systems[35] have gained prominence. Hydrogels, such as chitosan and collagen-based matrices, are particularly advantageous due to their biocompatibility, ease of modification, and ability to mimic the extracellular matrix, thereby enhancing cell attachment and proliferation.[16] Similarly, biodegradable polymeric nanoparticles, including those composed of poly(lactic-co-glycolic acid), have been developed to encapsulate FGF-2,[36] providing a sustained release profile and protection from enzymatic degradation. Scaffold-based systems, incorporating FGF-2 into three-dimensional porous matrices or electrospun nanofibers,[37] allow for the physical support of regenerating tissues while providing a continuous source of FGF-2 to promote cellular activities crucial for tissue regeneration. Additionally, advancements in surface modification techniques, such as the incorporation of bioactive molecules and the use of nanostructured coatings, have further improved the bioactivity and stability of FGF-2 delivery systems.[38]

Recent Clinical Trials on the Use of FGF-2 in GTR

For this review, we conducted an electronic search on PubMed for recent long-term clinical studies on the use FGF-2 for GTR. These studies are summarized below.

A recent clinical trial provided a 4-year extended follow-up of a randomized controlled trial (RCT) evaluating the long-term outcomes of recombinant human FGF-2 (rhFGF-2) combined with deproteinized bovine bone mineral (DBBM) compared with rhFGF-2 alone for treating periodontal intrabony defects.[39] In both groups, comparable gain in clinical attachment levels was observed (p > 0.05). Similarly, both groups also showed comparable reductions in probing pocket depth. Nevertheless, it was observed that radiographic bone fill (RBF) demonstrated a significant improvement in the FGF-2 group compared with DBBM alone, suggesting that rhFGF-2 combined with DBBM may significantly enhance bone regeneration, especially in poorly contained defects. Nevertheless, in 3-wall defects, no significant differences were observed between the groups, indicating that DBBM may offer an advantage in more complex or poorly contained defects.

Nakayama et al performed a retrospective study examining the impact of adjunctive procedures, specifically the modified papilla preservation technique (mPPT) and autogenous bone graft (AG), on the efficacy of rhFGF-2 therapy for periodontal regeneration.[40] This study involved 44 treatment sites where rhFGF-2 was applied, with clinical and radiographic outcomes assessed at 6 and 12 months postsurgery. Both treatment groups, those receiving adjunctive procedures and those without, experienced significant clinical improvements, including reductions in probing depth and gains in clinical attachment level. Notably, the RBF improvements were significantly greater in the groups that underwent treatment with AG and mPPT. Furthermore, the study found a positive correlation between the number of remaining bone walls and RBF, with contained bone defects (3- or 2/3-wall) exhibiting better outcomes compared with noncontained defects. Additionally, the mPPT technique demonstrated adjunctive benefits, showing statistically significant improvements in RBF at the 12-month mark, and multiple linear regression analysis indicated that mPPT had a more substantial impact on RBF than AG. When rhFGF-2 was combined with AG, the rate of bone filling was higher than with rhFGF-2 alone, achieving the highest bone fill percentages of 77.9% at 6 months and 76.3% at 12 months with full filling using autogenous bone.

Findings from of the above two studies and prior trials strongly suggest that FGF-2 improves the long-term efficacy of bone grafting and GTR.[39] [40] However, there are various areas in which there is potential of further research. Apart from a handful of studies, not many studies have looked at the efficacy of FGF-2 for more than a year. Furthermore, very few studies have reported presence or absence of adverse effects associated with the growth factor. Although the clinical trial by Seshima et al[39] looked at long-term results, they only included 3- and 2/3-walled defects—which are usually easier to treat.[41] So far, no large-scale multicenter or multinational studies have been conducted to assess the efficacy of FGF-2 in periodontal regeneration. Hence, its long-term efficacy is not yet ascertained. The outcomes of the two clinical studies included in this review are summarized in [Tables 1] and [2].

Table 1 Outcomes of the clinical trial by Seshima et al[39]

Parameter	rhFGF-2 alone	rhFGF-2 + DBBM	Significance
CAL gain (mm)	2.72 ± 1.43 mm	3.50 ± 1.41 mm	No significant difference (p > 0.05)
Radiographic bone fill (RBF)	41.5%	61.8%	Significant difference (p < 0.01)
PPD reduction (mm)	3.25 ± 1.38 mm	3.18 ± 1.55 mm	No significant difference (p > 0.05)
OHRQL-J scores (quality of life)	No significant changes	No significant changes	No significant intergroup difference
Success rate (CAL gain > 3 mm, PPD < 4 mm)	38%	69%	Higher success in the test group, but not statistically significant

Abbreviations: CAL, clinical attachment level; DBBM, deproteinized bovine bone mineral; OHRQL, Oral Health-related Quality of Life; PPD, probing pocket depth; rhFGF-2, recombinant human fibroblast growth factor-2.

Table 2 Outcomes of the retrospective study by Nakayama et al[40]

Key findings	Details
Study objective	Evaluate the adjunctive effects of modified papilla preservation technique (mPPT) and autogenous bone grafts (AG) in combination with rhFGF-2 therapy
Primary outcome	Radiographic bone fill at 6 and 12 months postsurgery
Secondary outcomes	Improvements in probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP)
Patient population	44 patients with chronic periodontitis. Exclusion of smokers, those with systemic diseases, and patients with furcation involvement or complicated defects
Main techniques assessed	mPPT and AG in combination with rhFGF-2
Improvements observed	Significant improvement in PD, CAL, and bone defects after surgeries
Correlation with bone fill at 6 months	Positive correlation with bone wall count, mPPT, and AG
Correlation with bone fill at 12 months	Positive correlation with mPPT and AG
Impact of mPPT	Demonstrated additional benefit, with significant improvements in radiographic bone fill at 12 months
Impact of AG	Significant increase in bone fill at both 6 and 12 months compared with non-AG treatment
Conclusion	Both mPPT and AG have significant adjunctive effects on rhFGF-2 therapy, with mPPT showing a stronger benefit at 12 months

Abbreviation: rhFGF-2, recombinant human fibroblast growth factor-2.

Challenges and Limitations in the Clinical Use of FGF-2

FGF-2 has shown promising results in stimulating the regeneration of periodontal tissues—including alveolar bone, cementum, and the PDL—by promoting cell proliferation, angiogenesis, and osteogenesis. It is particularly effective in treating intrabony and class II furcation defects, with RCTs demonstrating true periodontal regeneration.[42] However, its clinical availability is limited; it is approved for use in Japan (e.g., as Regroth)[43] but is not yet Food and Drug Administration (FDA)-approved in North America. In contrast, PDGF is widely used and commercially available, especially in the form of GEM 21S, an FDA-approved product that combines PDGF-BB with β-TCP.[44] PDGF is well-established in GTR and bone grafting procedures due to its chemotactic and mitogenic effects on fibroblasts and osteoblasts, as well as its ability to accelerate soft tissue healing. While both factors support periodontal regeneration, PDGF is more accessible and commonly used in clinical practice, whereas FGF-2 represents a promising but less widely adopted option due to regulatory limitations. Another obstacle is the development of an effective delivery system, as FGF-2 is highly sensitive to degradation, especially by proteolytic enzymes present at wound sites.[45] Nevertheless, although various strategies, such as controlled-release scaffolds and biomaterials, are being explored to improve the drug release, achieving the optimal release kinetics that maximize efficacy while minimizing degradation remains a challenge.[46]

Recent studies have focused to standardize and optimize the dose and concentration of FGF-2 released from scaffolds, because, while insufficient doses may be ineffective in regenerating tissues, excessive doses may enter the general circulation, leading to adverse effects..[47] In addition to these technical challenges, the cost of producing recombinant growth factors like FGF-2 is a considerable limitation.

To date, limited studies have focused to assess the impact of factors such as age, overall health, and local wound healing environment (for example, the presence of periodontal pathogens) on the efficacy of FGF-2. Therefore, future studies must focus on the impact of these confounding variables.

Emerging Research on FGF-2: Novel Approaches and Future Potential

More recently, research has focused on the use of FGF-2 in combination with other growth factors and biomaterials, for example, growth factors such as BMPs and materials such as chitosan and collagen to synergistically enhance tissue regeneration outcomes.[48] The different targets of the growth factors, combined with the different degradation rates of the membrane materials allow GTR systems designed at the nanometer level to target specific cells and tissues.

More recently, FGF-2 have been incorporated into functionally graded membranes (FGMs), which[49] are GTR membranes designed with a gradient in their composition and properties (such as porosity and fiber dimension), allowing for varying characteristics across their structure.[49] [50] FGMs may improve GTR by enhancing biocompatibility, promoting selective cellular attachment, infiltration and proliferation, and providing a controlled release of bioactive factors for sustained delivery that boosts tissue regeneration.[51] Moreover, these customizable mechanical properties enable the membrane to withstand physiological stresses, while optimized porosity facilitates selective cell.

Future potential for FGF-2 in GTR includes its integration into three-dimensional-printed scaffolds and personalized medicine approaches, where growth factor delivery is tailored to individual patient profiles based on genetic and epigenetic factors.[52] Additionally, ongoing research is investigating the use of FGF-2 in conjunction with cell-based therapies, such as the transplantation of FGF-2-treated stem cells, to further augment tissue regeneration.[53] As research continues to advance, FGF-2 holds considerable promise as a key component in the next generation of GTR therapies, potentially transforming the way clinicians approach the repair of periodontal and bone defects.

Conclusion

FGF-2 presents a promising avenue for enhancing periodontal regeneration outcomes. However, further research is essential to evaluate the long-term efficacy and safety of this growth factor. Additionally, studies focused on dose optimization are necessary to determine the ideal FGF-2 dosage for maximum therapeutic benefit. As research continues to advance, FGF-2 holds considerable potential as a key component in the next generation of GTR therapies, potentially transforming the way clinicians approach the repair of periodontal and bone defects.

Conflict of Interest

None declared.

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Artikel online veröffentlicht:
21. Januar 2026