Advancing bone regeneration: Clinical implications of synthetic biomaterials and fibrin derivatives

Abstract

Bone defects caused by trauma, infection, or congenital anomalies remain a significant challenge in orthopedic and dental practice, necessitating innovative strategies to enhance healing and functional restoration. This systematic review by Pagani et al synthesizes evidence on the synergistic role of synthetic biomaterials, such as hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP), combined with fibrin derivatives in bone regeneration. Analyzing 21 studies, the authors demonstrate that HA and β-TCP composites exhibit superior osteoconductivity and biocompatibility when integrated with fibrin sealants or platelet-rich fibrin, promoting cellular adhesion, osteogenic differentiation, and accelerated healing. While these studies underscore the potential of these biomaterial-fibrin hybrids, limitations such as variability in fibrin preparation, lack of long-term data, and insufficient standardization hinder clinical translation. This editorial contextualizes these findings within the evolving landscape of regenerative medicine, emphasizing the need for optimized formulations, interdisciplinary collaboration, and robust clinical trials to bridge laboratory innovation to bedside application.

Key Words: Biomaterials; Bone regeneration; Fibrin sealant; Hydroxyapatite; Regenerative medicine

Core Tip: The integration of synthetic biomaterials, for example hydroxyapatite and β-tricalcium phosphate, with fibrin derivatives enhances bone regeneration by improving scaffold stability, cellular recruitment, and mechanical support. While promising, clinical adoption requires standardized protocols, long-term outcome validation, and personalized approaches to address complex bone defects in aging and comorbid populations.

INTRODUCTION

Bone regeneration represents one of the most complex and clinically significant challenges in modern orthopedic and dental medicine[1,2]. Whether caused by traumatic injury, infection, tumor resection, or congenital anomalies, bone defects often result in prolonged disability, reduced quality of life, and substantial socioeconomic burdens. The innate regenerative capacity of bone, while remarkable, is limited in critical-sized defects-those exceeding the body’s intrinsic healing threshold-necessitating external interventions to restore structural integrity and function[3]. Traditional approaches, such as autologous bone grafting, remain the gold standard due to their osteogenic, osteoinductive, and osteoconductive properties[4]. However, these methods are fraught with limitations, including donor site morbidity, limited graft availability, and risks of infection or resorption[5]. Allografts and xenografts, though widely used, introduce additional concerns such as immunological rejection, disease transmission, and ethical dilemmas[6]. These challenges have catalyzed a paradigm shift toward synthetic biomaterials engineered to mimic the biochemical and mechanical properties of natural bone while circumventing the drawbacks of biological grafts.

THE RISE OF SYNTHETIC BIOMATERIALS IN BONE REGENERATION

Synthetic biomaterials, particularly calcium phosphate-based ceramics like hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP), have emerged as cornerstones of bone tissue engineering[7]. HA, a natural component of bone mineral, offers exceptional biocompatibility and osteoconductivity, serving as a scaffold for cell adhesion and extracellular matrix deposition. Its chemical similarity to native bone mineral facilitates ion exchange and surface remodeling, promoting integration with host tissue[8]. However, pure HA suffers from brittleness, slow degradation rates, and poor mechanical strength under load-bearing conditions, limiting its standalone utility in large defects[9]. β-TCP, conversely, exhibits faster resorption kinetics due to its higher solubility under physiological conditions, creating space for new bone formation[10]. Yet, its rapid degradation can outpace tissue ingrowth, leading to structural collapse in critical defects. To address these limitations, composite materials combining HA and β-TCP have gained traction. These biphasic calcium phosphate ceramics balance the sustained structural support of HA with the degradability of β-TCP, creating a dynamic microenvironment conducive to phased remodeling[11].

Beyond ceramics, synthetic polymers like poly (lactic-co-glycolic acid) and polyethylene glycol have been explored for their tunable degradation rates and mechanical flexibility[12]. However, their hydrophobic surfaces often impede cell adhesion, necessitating surface modifications or hybridization with bioactive molecules. The ideal bone substitute must thus reconcile conflicting requirements: Mechanical robustness to withstand physiological stresses, porosity to enable vascularization, biodegradability synchronized with tissue regeneration, and bioactivity to recruit progenitor cells and stimulate differentiation.

FIBRIN DERIVATIVES: BRIDGING BIOLOGY AND BIOMATERIALS

While synthetic biomaterials provide structural frameworks, their biological inertness often fails to replicate the dynamic signaling milieu of native bone. This gap has driven interest in fibrin-based biopolymers-natural matrices derived from the blood coagulation cascade-as adjuncts to enhance bioactivity[13]. Fibrin, a fibrous protein formed during clot formation, serves as a provisional matrix in wound healing, binding platelets, leukocytes, and growth factors like platelet-derived growth factor, vascular endothelial growth factor, and transforming growth factor-beta. Its role in hemostasis, cell migration, and angiogenesis makes it a compelling candidate for regenerative applications[14].

Platelet-rich fibrin (PRF), a second-generation platelet concentrate, has revolutionized tissue engineering by offering a autologous, cytokine-rich scaffold without anticoagulants or exogenous thrombin[15]. PRF’s dense fibrin network entraps platelets and leukocytes, enabling sustained release of growth factors over days to weeks[16,17]. Unlike traditional platelet-rich plasma, which requires biochemical activation, PRF forms through natural polymerization, preserving native cytokine ratios and reducing inflammatory responses. When combined with synthetic biomaterials, fibrin derivatives act as biological “glue,” enhancing scaffold stability, improving cell infiltration, and modulating immune responses. For instance, fibrin sealants have been used to bind HA/β-TCP granules into cohesive constructs, preventing migration and ensuring localized delivery of osteogenic signals[18].

Synergistic potential and mechanistic insights

The integration of synthetic biomaterials with fibrin derivatives creates a hybrid system that synergizes structural and biological functionalities. Preclinical studies demonstrate that HA/β-TCP scaffolds coated with fibrin or PRF exhibit accelerated vascularization and osteogenesis compared to standalone ceramics[18,19]. Fibrin’s porous architecture facilitates nutrient diffusion and waste removal, while its adhesive properties stabilize the scaffold-host interface, reducing micromotion-induced inflammation[20]. Mechanistically, fibrin matrices recruit mesenchymal stem cells (MSCs) via chemotactic gradients, promote their differentiation into osteoblasts through mechanotransductive signaling, and suppress excessive inflammation by polarizing macrophages toward a pro-regenerative M2 phenotype[21].

In critical-sized calvarial defects, for example, HA/β-TCP-fibrin composites have shown greater bone volume fraction (BV/TV) at 12 weeks compared to ceramic-only grafts[19]. Similarly, in periodontal applications, PRF-enhanced scaffolds improve alveolar ridge preservation by upregulating osteocalcin and collagen type I expression[22]. These effects are further amplified when fibrin is enriched with MSCs or osteoinductive agents like bone morphogenetic protein-2, highlighting the versatility of composite designs[23].

Persistent challenges and translational barriers

Despite promising results, clinical translation remains hindered by several unresolved issues[24]. Foremost among these is the lack of standardized protocols for fibrin derivative preparation. Variables such as fibrinogen concentration, thrombin activity, and crosslinking density vary widely across studies, leading to inconsistent scaffold porosity, degradation rates, and mechanical properties. For instance, high fibrinogen concentrations may reduce pore size, impeding cell migration, while excessive thrombin can trigger premature clot formation. Establishing international consensus guidelines for fibrin component sourcing, processing, and quality control is thus an urgent priority. Second, immune responses to fibrin derivatives-particularly xenogeneic components in commercial sealants-risk localized fibrosis or chronic inflammation, undermining integration. Third, most studies focus on short-term outcomes (≤ 6 months), leaving long-term durability, resorption kinetics, and ectopic calcification risks poorly characterized.

Additionally, the interplay between biomaterial topology and host biology is underexplored[25]. While macroporous scaffolds favor vascular invasion, nanoporous surfaces enhance protein adsorption and cell adhesion. Optimizing this hierarchical architecture requires advanced fabrication techniques, such as 3D printing or electrospinning, which remain cost-prohibitive in many clinical settings. Furthermore, patient-specific factors-age, comorbidities, defect location-profoundly influence outcomes but are rarely addressed in homogenized experimental models. Elderly patients, for example, exhibit reduced MSC populations and impaired angiogenic capacity, necessitating tailored biomaterial designs.

Future directions: From bench to bedside

To bridge these gaps, interdisciplinary collaboration is paramount. Material scientists, clinicians, and bioengineers must co-develop standardized protocols for fibrin-biomaterial composites, leveraging computational modeling to predict degradation-resorption equilibria. Incorporating “smart” stimuli-responsive materials-such as pH-sensitive polymers or enzyme-degradable linkers-could enable spatiotemporal control over growth factor release, mimicking natural healing cascades. Emerging technologies like 3D bioprinting offer unprecedented precision in scaffold fabrication, allowing patient-specific geometries infused with autologous cells or cytokines. For instance, bioprinted HA/β-TCP lattices embedded with PRF and MSCs could reconstruct complex craniofacial defects with anatomical fidelity[26]. Critically, advanced biomimetic strategies must replicate the hierarchical nanostructure of native bone. Natural bone’s mechanical resilience arises from the anisotropic arrangement of collagen fibrils mineralized with nanoscale HA crystals-a complexity unmatched by current bulk ceramic composites. Emerging techniques like electrospinning with nano-HA doping, magnetically aligned collagen/HA scaffolds, or 4D-bioprinting with shape-memory polymers maybe could achieve multiscale structural mimicry, enhancing graft biomechanics and osteogenic signaling.

Moreover, translational research must prioritize longitudinal clinical trials with stratified cohorts to evaluate efficacy across diverse populations. For elderly or comorbid patients, such as those with osteoporosis or diabetes, scaffold designs must address specific biological challenges. First, degradation rates should be tailored to accommodate reduced bone turnover activity; slower resorption is essential in these populations. Second, incorporating immunomodulatory cues-such as IL-4-loaded microspheres-can counteract chronic inflammation. Finally, combining patient-derived iPSC-MSCs with defect-specific 3D-printed HA/β-TCP-fibrin constructs offers a promising precision regeneration strategy.

In addition, regulatory agencies should establish clear guidelines for biomaterial-fibrin combinations, addressing safety, scalability, and cost-effectiveness. Finally, patient education and surgeon training programs are critical to fostering adoption, particularly in resource-limited regions where traditional grafts remain predominant.

CONCLUSION

In conclusion, the fusion of synthetic biomaterials and fibrin derivatives represents a transformative frontier in bone regeneration. By harmonizing structural integrity with dynamic bioactivity, these composites hold immense potential to overcome the limitations of conventional grafts. However, realizing these potential demands rigorous scientific inquiry, including longitudinal multicenter trials of at least 24 months to assess long-term safety, such as ectopic calcification and chronic inflammation, and functional integration in different cohorts stratified by age, comorbidities, and defect size. Pagani et al’s systematic review not only catalogs progress but also underscores the urgency of addressing translational bottlenecks to usher in a new era of regenerative orthopedics[27].