Biological approaches and biomaterial-based solutions for bone reconstruction: A comprehensive review

Abstract

Reconstruction of bone defects remains a major challenge in contemporary orthopedic practice and related reconstructive fields, including dental applications, particularly in cases involving trauma, surgical resections, implants, and prostheses. Regenerative medicine has evolved through the integration of biological sciences, engineering, and technology to promote functional and predictable bone regeneration. Although autogenous grafts are still the gold standard because of their osteogenic, osteoinductive, and osteoconductive properties, their use is limited by donor site morbidity, extended surgical time, and volume constraints. Alternative grafts, such as allogeneic, xenogeneic, and synthetic materials, offer distinct advantages in terms of biocompatibility, resorption, and tissue integration. The development of advanced biomaterials, including bioactive scaffolds, has improved extracellular matrix mimicry, enhancing cell adhesion, vascularization, and mineralized tissue formation. This review aims to provide an integrative analysis of current biological and synthetic strategies for bone reconstruction in orthopedics and related fields, emphasizing their principles, properties, clinical applications, and limitations. Innovative approaches such as tissue engineering, cell therapy, and photobiomodulation with low-level laser therapy have shown promising outcomes in promoting osteogenesis and repair. The integration of biological approaches with synthetic solutions is emerging as a promising path toward more effective, individualized, and evidence-based regenerative treatments.

Key Words: Bone regeneration; Biomaterials; Orthopedics; Dentistry; Regenerative medicine; Low-level laser therapy; Photobiomodulation

Core Tip: Regenerative medicine combines biology, engineering, and technology to achieve predictable bone regeneration. While autogenous grafts remain the gold standard for their osteogenic properties, they pose limitations such as donor site morbidity and volume constraints. Alternatives like allogeneic, xenogeneic, and synthetic materials improve biocompatibility and tissue integration. Advanced biomaterials, including bioactive scaffolds, enhance extracellular matrix mimicry, supporting cell adhesion, vascularization, and mineralized tissue formation. Emerging strategies in tissue engineering, cell therapy, and photobiomodulation show promise for osteogenesis and repair. Integrating biological approaches with synthetic solutions offers a path toward individualized, effective, and evidence-based regenerative treatments in orthopedics.

INTRODUCTION

Bone tissue is a specialized connective tissue characterized by a highly vascularized, dynamic, and complex structure that undergoes continuous remodeling throughout an organism’s life[1]. Upon injury, bone has a remarkable capacity for regeneration and repair, enabling structural recovery without scar formation, a feature uncommon among other tissue types[2]. However, in certain situations, particularly in large or complex defects, the regenerative process is insufficient to fully restore the original structure. In these cases, additional interventions may be required to stimulate complete bone formation and ensure the functionality of the affected area[3].

In clinical practice, bone loss may result from trauma, degenerative diseases, or other pathological conditions, manifesting as resorption defects with horizontal, vertical, or combined patterns[4]. Consequently, medical (especially orthopedics) and dental research have focused on identifying both natural and synthetic materials capable of effectively replacing lost soft and hard tissues[5]. In orthopedic and reconstructive surgery, bone tissue remains one of the most commonly used materials for interventions, especially in pre-prosthetic procedures, treatment of congenital defects, and correction of dentofacial deformities[6]. Bone grafting is essential in these contexts to promote fracture union where osteotomies have been performed and to prevent collapse of bone segments in iatrogenic defects[7]. This approach is critical for functional restoration and for aesthetic rehabilitation, both vital for patient well-being[8].

To address these challenges, tissue engineering has emerged as a modern, inherently multidisciplinary field that integrates biology and engineering[9]. Its primary goals include creating and improving artificial implants and developing laboratory-synthesized tissues, cells, and molecules to stimulate biological functions or effectively replace damaged body parts, promoting structural and functional restoration[10].

There are currently four main types of bone grafts available for reconstruction: Autogenous grafts harvested from the patient; allogeneic grafts from genetically distinct donors of the same species; xenogeneic grafts derived from other animal species; and synthetic alloplastic biomaterials produced in laboratories[11]. Among these, autogenous grafts are widely recognized as the gold standard for bone regeneration due to their osteoconductive and osteogenic properties, lack of cytotoxicity, and mechanical stability[12]. Nevertheless, their use is often limited by donor site morbidity, defect size, and restricted tissue availability, driving research toward alternative biomaterials that offer effective, less invasive solutions for bone repair[13].

In this context, bone regeneration frequently involves the use of barrier membranes to stabilize blood clots and/or bone substitute materials, while preventing epithelial cell invasion into the regenerating area[14]. These membranes also protect against microbial contamination and promote an environment conducive to angiogenesis and osteogenesis, facilitating bone healing[15]. They act as selective barriers, maintaining space for osteoprogenitor cell migration and proliferation, and enhancing vascularization by transporting oxygen and undifferentiated mesenchymal cells to the defect site, contributing to functional and aesthetic restoration[16].

Membranes are classified as resorbable or non-resorbable. Non-resorbable types include expanded and dense polytetrafluoroethylene, titanium, titanium-reinforced expanded polytetrafluoroethylene, and polypropylene[17]. Resorbable membranes are typically composed of natural polymers such as collagen or synthetic polymers like polylactic acid and polyglycolic acid, which exhibit controlled biodegradability and promote tissue regeneration[15].

Within tissue engineering, alternatives to autogenous bone grafts include xenogeneic biomaterials, such as bovine bone that requires deproteinization, and alloplastic materials including bioactive ceramics, biologically or synthetically derived polymers, and composites, all studied as potential substitutes in bone regeneration and tissue repair[18-20].

Biopolymers find broad applications in medicine, including controlled drug release systems, wound healing, sutures, and scaffolds for tissue engineering[15]. In surgical applications, they play an important role in alveolar bone regeneration, especially through absorbable collagen and gelatin sponges[21]. These biomaterials have gained significant interest in bone tissue engineering due to their ability to provide structural support and modulate cell growth in regenerating regions[22].

Despite many advances, bone regeneration remains a major challenge in contemporary medicine regenerative. Thus, biopolymers are increasingly investigated as promising alternatives for bone repair therapies. Among natural polymers, proteins like collagen, gelatin, and fibroin; polysaccharides such as cellulose, chitin, chitosan, alginate, and hyaluronic acid; and polymers like polynucleotides, polyisoprenes (natural rubber), and polyesters such as poly (β-hydroxybutyrate), poly (β-hydroxyvalerate), and poly (hydroxybutyrate-co-valerate) stand out due to their structural and biocompatible properties[23,24].

In recent years, the use of biotechnology has grown significantly, driven by increased severe injuries from accidents, aging populations, age-associated diseases, and intense research efforts[25]. The global biomaterials market continues to expand annually, reflecting their broad applicability across healthcare. It is estimated that between 200000 devices and 700000 devices, including hip, knee, and shoulder prostheses, implants, and fixation plates, are regularly used, demonstrating their relevance in modern medicine[26].

Recent advances in bone regeneration have expanded the therapeutic arsenal available for orthopedic and reconstructive procedures[27]. Biomaterials have evolved from passive structural fillers to highly engineered scaffolds capable of modulating cellular behavior, controlling degradation rates, and enhancing vascularization. In parallel, biological therapies such as photobiomodulation, growth factors, and cell-based approaches have demonstrated promising results in accelerating bone healing and improving tissue quality. These developments highlight a growing trend toward more biologically responsive and clinically adaptable strategies[28,29].

Despite these advances, current literature remains fragmented, with studies often focusing exclusively on either biomaterial-based solutions or biological stimulation modalities[30]. There is a lack of comprehensive analyses that summarize the main types of biomaterials, their mechanisms of action, and their clinical performance alongside the biological strategies that may complement or enhance regeneration[31]. This fragmentation limits the ability of clinicians to make evidence-based decisions when selecting the most appropriate therapeutic approach[32].

Given the expansion of biomaterial applications, particularly in medical and dental fields, the demand for new materials and technological advances remains constant. The diversity of existing biomaterials, alongside emerging technologies and applications, requires frequent literature reviews to assist professionals in selecting the most appropriate materials according to technique and anatomical region[33].

Considering these advances and the gaps in published studies, a broader and more structured overview of current regenerative strategies is essential. A detailed synthesis of biomaterials, biological therapies, and emerging tissue engineering technologies can better support clinical decision-making and contribute to a more integrated understanding of bone reconstruction modalities.

Therefore, this article aims to provide a comprehensive overview of the main therapeutic strategies used in bone reconstruction within orthopedics and regenerative medicine, including biomaterials, tissue engineering approaches, biostimulatory therapies, and stem cells, summarizing their properties, clinical applications, limitations, and future perspectives.

INTEGRATIVE LITERATURE REVIEW

Biological aspects of bone tissue

Bone tissue is one of the most resistant structures in the human body, characterized by its high stiffness combined with a certain degree of elasticity. This property enables bones to support and dissipate mechanical forces, including tension and compression, ensuring its strength and functionality in structural support and protection. Furthermore, as a living tissue, bone comprises various cell types that play essential roles in its formation, remodeling, and repair[34].

Among these cells, osteoblasts, osteoclasts, osteocytes, and osteoprogenitor cells are particularly noteworthy. Osteoblasts synthesize and deposit the bone matrix, playing a direct role in bone formation and regeneration. In contrast, osteoclasts are multinucleated cells primarily involved in matrix resorption and are crucial for bone remodeling. Osteocytes arise from the differentiation of osteoblasts once they become embedded in the newly formed bone matrix, establishing an interconnected cellular network via cytoplasmic extensions[35]. Osteoprogenitor cells serve as a cellular reservoir and are activated under conditions of tissue injury. When stimulated, they differentiate into osteoblasts and contribute to the deposition of new bone matrix in areas requiring repair[36].

The continuous process of bone tissue formation and resorption is known as bone remodeling. This phenomenon is essential for enabling skeletal growth, microfracture repair, tooth movement, and the adaptation of bone to new physiological demands (Figure 1)[37].

Figure 1  Illustrative representation of the stages of bone remodeling, highlighting the sequential processes of resorption, reversal, and formation.

However, despite the significant regenerative capacity of bone tissue, in cases of extensive injuries or critical-size defects, the body is unable to promote spontaneous and effective regeneration. Faced with this limitation, the use of biomaterials becomes essential as temporary bone substitutes, providing structural support and favoring the tissue repair process[38].

Thus, bone neoformation is a biological process resulting from osteoblast activity that depends on several facilitating mechanisms. These mechanisms are directly related to the clinical conditions of the recipient site, type of grafted material, the proper understanding of clinical indications, precision of the surgical technique employed, and the origin of the grafting material[39].

Bone substitutes can be categorized according to their origin, biological properties, and mechanisms of action in the bone regeneration process. These mechanisms include osteoconduction, which provides a three-dimensional matrix for bone growth by supporting the migration of osteoprogenitor cells from the adjacent bone; osteoinduction, which stimulates and recruits undifferentiated mesenchymal cells, inducing their differentiation into osteoblasts and promoting bone tissue formation; and osteogenesis, which refers to the ability of certain biological materials to directly promote bone formation due to the presence of viable osteoblasts in the graft[40,41].

Similarly, biomaterials used in bone regeneration can be classified according to their origin and biological properties, as well as their mechanisms of action in the tissue repair process. Among the main mechanisms are: Osteogenesis, characterized by the ability of certain biological materials to promote direct bone tissue formation through viable osteoblasts present in the graft[42,43]; osteoinduction, which refers to the ability to stimulate the migration and differentiation of undifferentiated mesenchymal cells into osteoblasts or chondroblasts, favoring bone neoformation even in heterotopic sites; and osteoconduction, a property associated with inorganic grafts that provides a three-dimensional matrix for the deposition of new bone tissue, serving as a scaffold for the osteoprogenitor cell proliferation and migration from adjacent bone, promoting bone growth at the recipient site[44,45].

Biomaterials can also be classified based on their biological characteristics as: Biotolerant, which do not promote true osseointegration, resulting in the formation of fibrous connective tissue between the implant and bone tissue; bioinert, which allow bone formation in direct contact with the implant without triggering significant biological reactions between the implanted material and the bone bed; and bioactive, which induce physicochemical interactions between the implant and surrounding bone tissue. Regarding their physical characteristics, biomaterials can be classified as organic, inorganic or mineralized, demineralized, or fresh[46].

Therefore, to understand the use of biomaterials in bone reconstruction, it is essential to understand bone regeneration physiology, which depends on an adequate blood supply from the initial inflammatory response to the remodeling and bone resorption phases[47]. Moreover, biomaterials should promote mechanical stability and be compatible with the dimensions of the bone defect. The biological and physiological processes involved are influenced by both local and systemic factors. Thus, in addition to the aforementioned characteristics, these materials must allow the conduction of osteoblasts or osteoblastic precursor cells to the injured site, presenting osteoconductive and osteoinductive properties, supporting the periosteum, accelerating bone remodeling, and stimulating growth factor release[48].

Bone regeneration follows a well-organized sequence, beginning with an inflammatory phase marked by immune cell recruitment and the release of cytokines that initiate the repair process[49]. This is followed by granulation tissue formation and subsequent osteoid deposition by osteoblasts, which progressively mineralizes. Finally, the remodeling phase restores the structural arrangement of bone through the coordinated actions of osteoclasts and osteoblasts[50]. These sequential mechanisms demonstrate the dynamic and biologically demanding nature of bone repair[51].

Because each stage of bone healing depends on specific cellular and molecular events, the biological requirements of the regenerating tissue directly influence biomaterial design and selection[52]. For example, early angiogenesis requires a biomaterial with an interconnected porous architecture, while osteoblast activity is improved by surfaces with adequate bioactivity and protein adsorption capacity. These biological needs help determine the structural and chemical characteristics desired in bone substitutes[53,54].

Thus, understanding the mechanisms governing bone biology is essential for selecting appropriate bone substitutes[55]. Biomaterials must ensure mechanical stability during the early inflammatory phase, maintain space for tissue ingrowth, support osteoconduction during osteoid deposition, and undergo degradation at a rate compatible with new bone formation[56,57]. Therefore, properties such as porosity, chemical composition, collagen content, crystallinity, and resorption kinetics are designed to mimic or complement physiological processes, ensuring more predictable regenerative outcomes[58,59].

Classification of bone grafts

Autogenous grafts (autografts): Autografts are obtained from the patient themselves and are widely used in regenerative therapies due to their essential biological characteristics, particularly the high biocompatibility between donor and recipient sites[60]. The main advantages of autografts include rapid osteoconduction, the ability to transplant viable cells, osteogenic potential, and rapid revascularization, which significantly reduces the risk of transmitting infectious diseases. However, this therapeutic approach presents some limitations, such as postoperative discomfort, a more complex surgical procedure, the risk of aesthetic defects at the donor site, the possibility of paresthesia, and the tendency for partial graft resorption[61].

In reconstructive surgery, donor site selection for autogenous bone grafts depends on defect size and location. In the craniofacial region, intraoral sources are commonly used due to their anatomical accessibility and lower morbidity. The most commonly used intraoral donor sites include the mandibular symphysis, the mandibular ramus, and the maxillary tuberosity, which are frequently employed in clinical cases of reconstructive bone surgery[62]. For extensive bone defect reconstruction, extraoral regions such as the calvarium, iliac crest, rib, and tibia are widely used[63]. According to Reininger et al[64], bone fragments from the mandibular symphysis show superior reconstruction of alveolar defects. However, this area presents higher complication rates, with paresthesia from mental nerve injury being the most frequently reported complication.

Some authors, such as Urban and Monje[65], emphasize that autogenous bone is the only material that has all of the ideal properties for bone regeneration, fulfilling the three main mechanisms of this process: Osteogenesis, osteoconduction, and osteoinduction. The effectiveness of autogenous grafts in interacting with the recipient bed is attributed to the presence of osteoprogenitor cells in the transplanted bone fragment[66]. However, as discussed by Soni et al[67], the need for an additional surgical procedure to obtain the graft and its limited availability have restricted its use, encouraging the search for alternatives such as xenografts, allografts, and alloplasts[65].

Homologous grafts (allografts): Homografts have emerged as a promising alternative to autografts, as they eliminate the need for a donor site and exhibit both osteoconductive and osteoinductive properties[68]. These grafts are often indicated for atrophic maxillae reconstruction and are obtained from individuals of the same species, consisting of cortical bone, cancellous bone, or a combination of both. Additionally, they can be pre-shaped and subjected to various preservation processes such as lyophilization, demineralization, or freezing. The main advantage of this type of graft is the elimination of multiple surgical sites, thereby reducing surgical trauma to the patient. However, the limitations include dependence on tissue banks or donors, as well as the risk of transmission of infectious agents or immunological reactions, especially in fresh grafts[69]. According to Ferraz[11], although the decellularization process effectively reduces the immune response in allografts, it may also impair bone regeneration, making it slower and more challenging.

There is still no consensus in the literature regarding the ideal bone substitute, primarily due to the scarcity of controlled clinical trials[70]. However, both autogenous and homologous grafts show good survival and success rates in osseointegration protocols. In turn, allogeneic grafts have been widely used in combination with bone marrow aspirates through the bone marrow aspirate concentrate method, demonstrating favorable results[69]. A study conducted by Lavareda Corrêa et al[71] compared grafts with and without bone marrow aspirate and demonstrated that bone marrow-associated grafts showed better outcomes, particularly in terms of bone density and bone formation patterns.

Xenogeneic grafts (heterologous): Xenogeneic bone substitutes are derived from individuals of other species and have been widely used due to their high osteoconductive capacity. They are frequently reported in the literature within bone augmentation and reconstructive protocols[72]. The most commonly cited xenograft is deproteinized bovine bone mineral due to its favorable properties, including a composition and porosity similar to human bone, its prolonged residence time at the graft site, and its potential for association with biomaterials such as fibrin. However, a comparative study by Irdem et al[73] concluded that there are no significant advantages in using this material alone or in combination with other bone substitutes.

The bovine bone xenograft offers the advantage of minimizing inflammatory and immunological responses in patients due to deproteinized inorganic matrix. Its main function is to promote host bone cell proliferation, thus favoring new bone formation[74]. This material has been used in tooth cell transplantation, which involves the combination of the xenograft with bone marrow aspirate concentrate, the latter being a potent enhancer of bone regeneration[75].

Thus, heterologous grafts derived from lyophilized bovine bone are among the most commonly used in reconstructive bone procedures. Their production involves a physical-chemical sterilization process aimed at removing proteins in the bone tissue, resulting in the elimination of all organic components[76]. As a residue, hydroxyapatite crystals remain, playing a fundamental role in osteoblast adhesion and subsequent bone matrix deposition. This biomaterial, characterized by its mineralized and porous structure, is available in various formats, including blocks and granules, and may consist of either cortical or cancellous bone[77].

Despite their widespread use, bovine-derived heterologous grafts present some limitations, including the risk of infection and immunological rejection. Moreover, there is the possibility of prion transmission, infectious agents associated with the development of Bovine Spongiform Encephalopathy, commonly known as “mad cow disease”[78]. Another relevant drawback is the potential induction of an immune response with antibody production, which may compromise graft integration with the host tissue[79].

Synthetic grafts (alloplastics): Alloplastic biomaterials, synthetically produced in laboratories from hydroxyapatite and beta-tricalcium phosphate (β-TCP), are widely recognized for their quality and versatility as bone substitutes. Although they exhibit limited or no osteoinductive activity, their low resorption rates provide a stable and long-lasting environment, favoring the time required for new bone formation by the host tissue[80]. These biomaterials are frequently used in combination with other bone grafts due to their unlimited availability and lack of risk of transmitting infectious diseases, characteristics that make them highly advantageous[81,82]. Furthermore, studies by Liu et al[83] highlight that synthetic bone substitutes can satisfactorily repair bone defects, including applications in periodontal infrabony defects.

Hydroxyapatite is a natural bone mineral that can also be synthetically produced in the laboratory. This biomaterial is commercially available in various forms and is notable for its osteoconductive capacity. β-TCP has a phosphate and calcium composition similar to that of human bone tissue; however, it lacks osteogenic properties[84].

Additional studies have shown that the combination of hydroxyapatite and β-TCP in different proportions can influence resorption rate and bone formation, with combinations with higher β-TCP content tending to present greater biomaterial absorption and faster bone formation during healing. These characteristics make hydroxyapatite and β-TCP-based alloplastic biomaterials promising options for various clinical applications in the field of bone regeneration[85].

Complementary biomaterials and biostimulative therapies

Synthetic membranes: These biomaterials exhibit significant clinical acceptance and are frequently used in combination with autogenous, xenogeneic, or allogeneic bone grafts. Therefore, resorbable and non-resorbable membranes are widely indicated in guided bone regeneration (GBR) protocols[86]. These membranes act as selective barriers, preventing the migration of epithelial cells and connective tissue into the bone defect, thereby allowing osteogenic cell proliferation and vascularization at the site. This favors mineralized matrix deposition in the area of new bone formation[87].

In other words, the GBR technique optimizes bone graft integration by promoting its compaction and protection within the recipient site. This process creates a favorable environment for localized osteogenic activity, enhancing the formation of new bone tissue[88]. As a result, the membranes most commonly used in GBR protocols are manufactured from materials such as polytetrafluoroethylene, expanded polytetrafluoroethylene, collagen, polylactic acid, polyglactin 910, polyglycolic acid, calcium sulfate, microtitanium mesh, and polyurethane. Among these, expanded polytetrafluoroethylene is widely used due to its high resistance to degradation and low immunogenicity[89].

Resorbable collagen-based membranes have gained popularity among dental professionals because they eliminate the need for a second surgical procedure for removal. Moreover, they present low immunogenicity, adequate cellular adhesion, and effective hemostatic capacity features that support their use as barriers in GBR protocols[90]. These biomaterials significantly contribute to surgical site healing and bone tissue development during the early repair stages, being widely recognized for their proven biocompatibility[91].

The mechanical malleability of these membranes facilitates their adaptation to bone defects and handling during the clinical procedure. Additionally, their properties include semipermeability, allowing the diffusion of essential nutrients for repair, and enzymatic degradation, which enables fibroblast recruitment to the inflammatory site. This process is mediated by collagen fiber cleavage by collagenases, whose degradation products create a microenvironment favorable to the action of nonspecific proteases. These promote fibroblast migration and support tissue regeneration[92].

Fibrin-based autogenous therapies

Platelet-rich fibrin and platelet-rich plasma: Fibrin is a viscoelastic polymer whose mechanical and structural properties influence hemostasis and the development of thrombotic complications[93]. Its polymerization occurs through sequential reactions that form a porous three-dimensional network, whose structure determines clot resistance to blood flow, platelet contraction, and other dynamic forces[94]. This temporary matrix allows for cellular proliferation and organization, promoting tissue regeneration in injured or inflamed areas. Therefore, fibrin is widely applied in surgical procedures, including orthopedics, neurology, plastic surgery, periodontics, implant dentistry, and oral and maxillofacial surgery[93].

Platelet-rich fibrin (PRF) is derived from the patient’s own blood and is classified as an autogenous source, which significantly reduces the risk of immune rejection or allergic reactions and accelerates the healing process[95]. It is widely used in reconstructive surgery and GBR procedures, especially in cases of maxillary atrophy and sinus floor elevation due to its ability to promote soft tissue healing and stimulate the formation of newly formed bone tissue[96]. It is also employed in procedures aimed at post-extraction socket preservation, bone regeneration after cyst enucleation, sinus floor elevation, alveolar ridge maintenance, regenerative therapy in dental implants, and in the repair of intraosseous defects, furcation lesions, and periodontal plastic surgery interventions[97].

The PRF technique induces cell proliferation through growth factors in the plasma, which synergistically interact with the substitute biomaterial used in the procedure[98]. In addition to its favorable biological properties due to its autologous origin, PRF is widely available and low-cost, making it a viable option for patients[99].

However, despite the benefits of PRF in dentistry, some limitations must be considered. Its quality can vary due to differences in handling methods, preparation techniques, and professional expertise, which may influence its efficacy and clinical outcomes[100]. Moreover, not all dental procedures show the same benefits with PRF use, and in some cases, it must be combined with other biomaterials to enhance therapeutic effects. Finally, although PRF has gained popularity, there is still limited controlled and randomized clinical trials that confirm its effectiveness in specific dental applications (Figure 2)[95].

Figure 2 Comparative schematic representation between platelet-rich fibrin and platelet-rich plasma, emphasizing their structural and compositional differences. PRF: Platelet-rich fibrin; PRP: Platelet-rich plasma.

PRF in tissue regeneration should be highlighted. PRF contains higher concentrations of fibrin and leukocytes than platelet-rich plasma (PRP). Both enhance healing through the release of growth factors; however, PRF sustains this release over a prolonged period, offering long-lasting benefits and promoting faster tissue repair[101].

PRP is characterized by a high concentration of autologous platelets in a reduced volume of the patient’s plasma. It is obtained by collecting the patient’s blood, followed by a first centrifugation to isolate platelets without compromising their integrity[102]. A second centrifugation then separates platelets and white blood cells from the plasma. This two-step process allows for a higher platelet concentration from autologous blood[103].

Platelet granules release various growth factors that stimulate cell proliferation and differentiation, processes essential for osteogenesis. In addition to its pro-coagulant function, PRP plays a role in the initiation and maintenance of tissue repair, accelerating healing and improving its efficiency[104]. Nevertheless, PRP use requires the addition of external chemical agents, significantly increasing costs and complicating the handling process[105].

Given these considerations, PRF has emerged as a desirable option in tissue regeneration. In contrast to PRP, PRF contains higher concentrations of fibrin and leukocytes and has a simplified preparation technique. Although both promote healing through growth factor release, PRF promotes a more prolonged release, delivering long-term benefits and facilitating faster repair[101].

Low-level laser therapy: Laser technology (“Light Amplification by the Stimulated Emission of Radiation”) was introduced into dentistry in the 1960s and has since been widely used across various specialties. Its application encompasses both hard and soft tissues, proving effective in procedures such as caries prevention, treatment of dentin hypersensitivity, healing of herpetic lesions, removal of hyperplastic tissues, hemostasis, and frenectomies[106].

Photobiomodulation therapy, formerly known as low-level laser therapy (LLLT), is a non-thermal process based on the interaction of light with endogenous chromophores. This interaction triggers photophysical and photochemical events at cellular and molecular levels, promoting therapeutic effects such as analgesia, anti-inflammatory action, immune modulation, and stimulation of tissue regeneration[107].

Thus, it is a therapeutic modality that uses non-ionizing light sources within the visible and infrared spectra (600-1110 nm). When absorbed by the irradiated tissue, this light induces biochemical changes that result in growth factor production and increased cellular proliferation. Among the most relevant effects are stimulation of collagen synthesis, increased fibroblast and osteoblast activity, and angiogenesis, all essential for bone regeneration (Figure 3)[108].

Figure 3 Illustrative representation of the cellular effects of photobiomodulation therapy using low-level laser therapy. LLLT: Low-level laser therapy; ATP: Adenosine triphosphate.

These biological effects make photobiomodulation a promising avenue in regenerative medicine. It has been applied as an adjunct therapy in various clinical conditions, including medication-related osteonecrosis of the jaws, antimicrobial therapies, management of acute and chronic pain, and acceleration of orthodontic tooth movement[109]. In areas of fracture, bone defects, or post-extraction sites, laser therapy stimulates osteoblast recruitment and maturation along bone margins, enhances type I collagen expression, the predominant protein in the bone matrix, and promotes neovascularization essential to repair[110].

Recent studies also highlight the potential of photobiomodulation as an adjuvant therapy to biomaterials and scaffolds, promoting greater integration and acceleration of bone regeneration[111].

The effectiveness of photobiomodulation directly depends on variables such as wavelength, energy density, exposure time, and application frequency. Standardization of these parameters is essential to ensure reproducibility and consistent clinical outcomes, representing a current challenge in translating the therapy to broader clinical protocols[112].

Therefore, photobiomodulation with LLLT consolidates itself as a complementary therapeutic strategy with significant potential, substantially contributing to the modulation of the inflammatory response, acceleration of bone repair, and improvement of clinical outcomes in dental procedures[113].

Cell therapy - use of stem cells and advanced scaffolds in bone reconstruction: Tissue engineering represents one of the most innovative and promising approaches in the field of bone regeneration, especially in light of the limitations posed by conventional grafts. This multidisciplinary area aims to achieve the functional reconstruction of tissues through the combination of three essential elements: Regenerative cells, biomaterials (scaffolds), and biochemical or physical stimuli that promote regeneration[114].

Tissue engineering is defined as an interdisciplinary field that integrates biomaterials science, cell biology, and biochemical signaling to create functional tissue substitutes capable of restoring, maintaining, or improving damaged structures[115]. In the context of bone repair, tissue engineering relies on the synergistic interaction among three key components: Stem cells with osteogenic potential, three-dimensional scaffolds that provide structural support and guide tissue formation, and bioactive molecules that regulate cell behavior and promote osteogenesis. This triad forms the foundation of modern regenerative strategies, enabling controlled and predictable bone regeneration in critical-size defects[116,117].

Mesenchymal stem cells (MSCs), obtained from various sources such as bone marrow, adipose tissue, dental pulp, and periosteum, have been extensively studied due to their ability to differentiate into osteoblastic lineages and their role in modulating the inflammatory microenvironment through the release of trophic factors[118]. When associated with biocompatible and bioactive three-dimensional scaffolds, these cells can enhance bone formation in terms of quality and quantity, optimizing the process of neoformation in critical-size defects[119].

Scaffolds used in tissue engineering must exhibit appropriate physicochemical characteristics, such as controlled porosity, mechanical strength compatible with bone tissue, and degradation synchronized with new bone formation. Current advanced biomaterials that mimic the native extracellular matrix have been developed and can be functionalized with signaling molecules, osteoinductive peptides, and even nanoparticles that promote osteogenesis[120]. 3D printing of these scaffolds has enabled the fabrication of customized structures tailored to the morphofunctional needs of each bone defect[121].

Recent advances in tissue engineering have focused on optimizing scaffold–cell interactions and enhancing the biological functionality of implanted constructs. Bioengineered scaffolds incorporating growth factors, nano-structured surfaces, or controlled-release systems have demonstrated improved osteoinduction and vascularization[122]. Three-dimensional bioprinting technologies have also emerged as powerful tools, allowing the fabrication of patient-specific scaffolds with precise architecture and mechanical properties[123]. Additionally, the use of MSC-derived exosomes has gained attention as a cell-free therapeutic strategy, offering comparable osteogenic benefits with lower immunogenic risk. Together, these advances represent significant progress in the development of clinically applicable bone regeneration platforms[124,125].

Despite their therapeutic potential, the clinical use of stem cells and bioengineered scaffolds still faces significant challenges, such as standardization of cell isolation and expansion techniques, cell viability after transplantation, associated costs, and regulatory requirements for human application. Nevertheless, preclinical studies and early clinical trials have shown promising results, indicating the feasibility of incorporating these therapies into future bone regeneration protocols[126].

The clinical application of combined stem-cell and scaffold-based therapies has shown promising results in treating critical bone defects[127]. A recent systematic review (2024) reported that among 138 patients receiving MSC-loaded scaffolds for bone defects, all achieved bone healing with favorable safety and functional outcomes[126]. These findings demonstrate the practical effectiveness of integrating stem cells with osteoconductive scaffolds in promoting predictable bone regeneration in complex defects[128].

Thus, cell therapy and tissue engineering stand out as highly innovative and integrative strategies with the potential to transform the current approach to bone reconstruction in dentistry, offering personalized, less invasive solutions with greater predictability of clinical success[129].

Functionalized acellular periosteum for endogenous stem-cell recruitment: The periosteum plays a central role in natural bone regeneration due to its reservoir of osteoprogenitor cells and its ability to coordinate osteogenic activity[130]. Functionalized acellular periosteum has recently emerged as an innovative biomaterial capable of replicating key aspects of the native periosteal microenvironment[131].

By incorporating bioactive cues, these constructs promote endogenous stem-cell homing to the defect area, stimulate their differentiation into osteoblastic lineages, and enhance the intrinsic regenerative capacity of bone tissue[132]. Experimental models of critical-size defects demonstrate that this strategy supports robust matrix deposition, accelerates osteogenesis, and improves structural repair compared to conventional grafting alone[133,134]. Such findings reinforce the potential of engineered periosteal substitutes to serve as biologically instructive scaffolds that synergize natural healing mechanisms with advanced tissue-engineering approaches[135].

Hyaluronic acid–based multi-responsive hydrogels in infectious bone defects: Recent developments in hydrogel technology have enabled the creation of multifunctional materials designed to simultaneously combat infection and promote bone regeneration[136,137]. Hyaluronic acid-based hydrogel microspheres with multi-responsive properties have shown significant potential in treating Staphylococcus aureus-infected cranial defects[138].

These systems demonstrate the capacity to inhibit bacterial proliferation while supporting osteoblast adhesion, proliferation, and mineralization at the defect site, thereby providing a dual therapeutic effect that integrates antimicrobial action with osteogenic stimulation[139]. Their ability to adapt to local microenvironmental changes and deliver coordinated biological responses highlights their promise as advanced biomaterials for managing infectious bone defects and improving clinical outcomes in regenerative therapies[140-145].

To provide a clear overview of the main categories of bone graft materials, a we developed a comparative table summarizing their fundamental biological properties, advantages, limitations, and typical clinical applications. This comparison facilitates the understanding of how each graft option differs in behavior and clinical performance, supporting more informed decision-making in orthopedic and regenerative procedures[141-151] (Table 1).

Table 1 Horizontal comparison of the main categories of bone graft materials.

Ref.	Type of graft	Main properties	Advantages	Limitations	Typical clinical applications
[142,143]	Autograft	Osteogenic, osteoinductive, osteoconductive; no immune response	Gold standard; high predictability; rapid integration	Donor-site morbidity; limited volume	Large defects, non-unions, orthopedic reconstruction, maxillofacial surgery
[144,145]	Allograft	Mainly osteoconductive; may retain osteoinductive potential depending on processing	No second surgical site; wide availability	Possible immune reaction; slower integration; disease transmission risk	Orthopedic revision surgery, spinal fusion, large defects
[146,147]	Xenograft	Highly osteoconductive; stable porous structure; slow resorption	Excellent volume maintenance; good scaffold for bone growth	Very slow remodeling; no osteogenic potential	Alveolar ridge preservation, sinus lift, moderate orthopedic defects
[148,149]	Synthetic (HA, β-TCP, bioceramics)	Controlled porosity; adjustable resorption; bioinert or bioactive depending on composition	No risk of disease transmission; unlimited availability; tunable properties	Lower mechanical strength; variable integration depending on formulation	Filling small to medium defects, orthopedic revisions, periodontal/trauma defects
[150,151]	Composite biomaterials	Combine organic and inorganic components; mechanical reinforcement; enhanced bioactivity	Balanced resorption; improved handling; increased mechanical stability	Higher cost; variable performance depending on formulation	Load-bearing defects, trauma reconstruction, implant dentistry

HA: Hydroxyapatite; β-TCP: Beta-tricalcium phosphate.

RESULTS

The use of biomaterials for bone regeneration has proven essential in the rehabilitation of bone defects across various fields of orthopedic and reconstructive surgery, enabling the restoration of both function and esthetics of affected tissues. These materials exhibit a wide range of compositions, as well as physical, biological, and mechanical properties that directly influence their integration capacity, resorption rate, and clinical efficacy[25,150]. Currently, xenogeneic, alloplastic, and synthetic biomaterials are widely employed, each possessing specific characteristics that make them suitable for distinct clinical contexts and regenerative demands[38,151]. Therefore, the appropriate selection of these materials is crucial for the success of regenerative procedures, considering the complex interaction between the biomaterial, the host biological environment, and the mechanical requirements of the recipient site[152].

All bone substitute biomaterials of both natural and synthetic origin considered in this review are marketed in granular form, which allows optimal handling during surgical procedures and promotes effective osteoconduction by providing space for vascularization and new bone formation. However, beyond descriptive characteristics, their clinical effectiveness varies considerably according to origin, resorption dynamics, and mechanical behavior, requiring a comparative interpretation of evidence.

Naturally derived materials (bovine and porcine xenografts) demonstrated consistently high biocompatibility and predictable osteoconduction, largely due to their trabecular architecture and slow resorption profiles. Products such as Geistlich Bio-Oss^®, Cerabone^®, and Lumina-Bone Porous^® showed superior volumetric stability and long-term clinical performance in alveolar reconstruction and sinus augmentation, as documented in recent clinical and histological studies[144,153].

Collagen-preserving xenografts such as THE Graft^®, OsteoBiol Gen-Os^®, and Apatos^® exhibited integration within 6-12 months and supported cell adhesion due to their organic matrix. In contrast, sintered bovine grafts such as GenOx Inorg^® and OrthoGen Granules^® demonstrated enhanced mechanical stability and markedly slower resorption (> 24 months), making them suitable for areas subjected to higher functional loading. Composite biomaterials such as SmartBone^®, which incorporate collagen and biodegradable polymers into a bovine matrix, showed increased compressive strength and more rapid integration[154].

Synthetic and composite substitutes, including hydroxyapatite/β-TCP materials such as Nanosynt^®, GenPhos hydroxyapatite TCP^®, and BoneCeramic^®, provided tunable porosity and controllable resorption, enabling gradual bone replacement comparable to xenografts[155]. Bioactive materials such as BioGran^® (45S5 bioactive glass) promoted rapid angiogenesis and early bone formation, whereas calcium-based materials like Calcigen S^® exhibited accelerated resorption suitable for small, contained defects[156,157].

Allogeneic biomaterials such as Grafton DBM^® and MinerOss^® displayed osteoinductive potential and variable integration (3-12 months), although with mechanical limitations. In contrast, high-purity synthetic materials such as HAP-91^® and OsteoGen^® exhibited prolonged volumetric maintenance and low immunological risk, being suitable for alveolar and peri-implant reconstructions[158,159].

In contrast, synthetic and hybrid biomaterials offer greater control over physicochemical properties and resorption rates, allowing adaptation to the specific bone defect requirements and reduction of immunological risks. Hydroxyapatite/β-TCP composites exhibit osteoconductive behavior comparable to xenografts, but with more controlled resorption and no risk of biological transmission. Bioactive glasses such as 45S5 have gained prominence for simultaneously stimulating osteogenesis and angiogenesis, thereby accelerating regeneration in critical-size defects[160,161].

Moreover, recent studies indicate that the combination of biomaterials with growth factors and collagen membranes enhances bone regeneration by improving clot stability and promoting osteoblast differentiation[162,163]. This integrative approach reinforces the importance of personalized strategies in which biomaterial selection considers not only the defect size and location but also the patient’s biological profile and restorative treatment plan.

When comparing the materials, the literature indicates that xenogeneic grafts provide the most stable long-term volumetric outcomes due to their slow and predictable resorption, supported by extensive clinical and histological evidence[153,164]. In contrast, HA/β-TCP composites offer more controllable degradation profiles and faster remodeling, making them suitable for medium-sized defects requiring earlier replacement by native tissue[155]. Bioactive glass demonstrates superior early regenerative activity, promoting rapid angiogenesis and accelerated bone deposition, which is advantageous in defects requiring faster biological activation[156,157]. Meanwhile, allogeneic and high-purity synthetic substitutes show variable remodeling rates but low immunogenicity, serving as suitable options when biologic activity or structural maintenance is prioritized[158,159].

Taken together, these findings demonstrate that the choice of biomaterial should be guided by the match between material properties and clinical requirements. Slow-resorbing xenografts are preferable for esthetic areas and sites demanding long-term stability[153,165]; hydroxyapatite/β-TCP composites are appropriate for defects requiring balanced remodeling speed and structural support[155]; bioactive glass is beneficial in cases where rapid angiogenesis and early bone fill are needed[156,157]; and allogeneic or highly pure synthetic materials can be used when immunological safety or reduced donor-site morbidity are priorities[158,159].

Therefore, biomaterial selection should be individualized, taking into account structural characteristics, mechanical properties, and supporting clinical evidence. The future of bone tissue engineering is directed toward the development of hybrid and bioactive biomaterials capable of combining osteoconductivity, osteoinduction, and mechanical stability, thereby maximizing clinical success in bone regeneration and reconstructive orthopedic applications[154].

A number of studies have evaluated the biological and physicochemical characteristics of natural and synthetic bone substitutes, as well as their clinical performance in bone reconstruction[166-179]. Several experimental and clinical studies have investigated the effects of photobiomodulation and other biostimulatory therapies on bone repair[180-197].

Table 2[167-170,172-178,195-197] and 3[171,179-188] summarize the main characteristics of commercially available biomaterials, highlighting their composition, properties, integration mechanisms, and clinical applications, serving as a guide for evidence-based selection. Table 2 synthesizes biomaterials of natural origin, while Table 3 presents synthetic and composite biomaterials.

Table 2 Classification of bone substitute biomaterials according to information provided by the manufacturers: Biomaterials of natural origin.

Ref.	Commercial name/country/company	Composition	Physical properties	Biological properties	Mechanical properties	Resorption/integration	Clinical efficacy	Form/cost
[167]	Bonefill Porous®/Brazil/Bionnovation	Mineralized bovine spongy xenograft	White granules, irregular, porous	Biocompatible, osteoconductive, high interconnectivity	Lightweight, strong; maintains space and support	Slow and progressive (6-9 months)	Documented use in sinus lift, GBR, and alveolar filling	Granules (0.10-2.5 mm)/affordable
[168]	Cerabone®/Germany/Botiss	100% inorganic, calcined bovine bone	Purified ceramic; hard and stable particles	Biocompatible; osteoconductive; bone scaffold	High stability and strength	Very slow; progressive integration	Well-established use in peri-implant grafts, sinus lift, and bone augmentation	Granules and blocks (0.5-4 mm) high
[169]	Geistlich Bio-Oss®/Switzerland/Geistlich	Bovine xenograft	Porous, similar to human bone	Biocompatible, osteoconductive	Preserves volume and structure	Slow, promotes maintenance	Widely used in implant dentistry; proven clinical efficacy	Granules and blocks (0.25-2 mm) high
[172]	GenMix®/Brazil/Baumer	Inorganic bovine xenograft (cortical and cancellous matrix)	Dry granules, lightweight; high volumetric stability; good handling	Biocompatible; osteoconductive; promotes new bone formation; no transmission risk	Good initial strength; intermediate support	Slow and partial (some particles > 12 months); integration 6-9 months	Used in alveolar grafts, sinus lift, ridge augmentation; studies show predictability and maintenance	Granules (0.25 mm; 0.5 mm; 1.0 mm)/affordable cost
[195]	GenOx Inorg®/Brazil/Baumer	Inorganic bovine xenograft (mineral bone matrix, sintered)	Rigid, stable granules; resistant to rapid resorption; volume-maintaining	Biocompatible; osteoconductive; non-immunogenic; slow bone replacement	High initial strength; prolonged support; indicated for load-bearing areas	Very slow (> 24 months)	Used in sinus lifts, ridge augmentation, alveolar filling, and periodontal applications; proven efficacy	Granules (0.25 mm; 0.5 mm; 1.0 mm; 2.0 mm)/affordable cost
[170]	GenOx Org®/Brazil/Baumer	Organic and inorganic bovine matrix (type I collagen)	Lightweight, porous, and moldable; trabecular structure	Biocompatible, osteoconductive, potential osteopromotive effect	Lower resistance; suitable for low-load areas	6 months to 12 months	Effective in GBR, fillings, and esthetic areas; good remodeling	Granules (0.25-2 mm)/affordable
[173]	Lumina-Bone Porous®/Brazil/Critéria	Inorganic lyophilized bovine xenograft	Highly porous, bone-like	Biocompatible, osteoconductive	Preserves volume and structure	Slow (6-12 months or more)	Successful in reconstructions, sinus lift, and preservation	Granules (0.25-1 mm)/affordable
[174]	MinerOss XP®/United States/BioHorizons	Porcine xenograft (inorganic bone matrix)	Dry, sterile, irregular granules; high volumetric stability	Biocompatible; osteoconductive; good bone integration	Limited structural support; dimensional stability	Slow (6-9 months)	Widely used in GBR, sinus lift, alveolar preservation, and peri-implant defects; good volumetric maintenance and integration	Granules (0.25 mm; 1.0 mm; 2.0 mm)/high cost
[196]	OrthoGen Granules®/Brazil/Baumer	Bovine xenograft	Rigid granules; good volumetric stability; non-collapsing	Biocompatible; osteoconductive; guides bone growth; no rejection	Adequate structural support; maintains space; compatible with membranes/PRF	Very slow (up to 24 months)	Used in GBR, ridge augmentation, sinus lift, peri-implant, and post-extraction; studies show stability and osseointegration	Granules (0.25 mm; 0.5 mm; 1.0 mm; 2.0 mm)/affordable cost
[197]	OsteoBiol Apatos®/Italy/Tecnoss	Porcine or equine xenograft	Dry, rigid, trabecular granules	Biocompatible; osteoconductive; matrix for osteoprogenitor cells and new bone formation	High temporary resistance; good support and volume maintenance	Slow (9-12 months)	Effective for sinus lift, alveolar regeneration, and ridge augmentation; extensive clinical and histological evidence	Granules (0.25-2.0 mm)/moderate to high cost
[175]	OsteoBiol Gen-Os®/Italy/Tecnoss	Porcine or equine xenograft (cortical and cancellous bone + preserved collagen)	Natural trabecular structure; easy handling	Biocompatible; osteoconductive; native collagen promotes regeneration	Temporary structural support; maintains volume	Slow (6-12 months)	High efficacy; supported by multiple clinical and histological studies	Granules (0.25 mm; 1.0 mm; 2.0 mm)/intermediate cost
[176]	Osteosynt®/Brazil/EincoBio	Bovine xenograft (HA + β-TCP)	Dry, white granules; texture similar to cancellous bone; high volumetric stability	Biocompatible; osteoconductive; no inflammatory response; supports cell colonization and bone formation	Non-deformable; maintains space; limited mechanical load support	Slow (6-18 months)	Used in GBR, sinus lift, post-extraction sockets, and peri-implant defects; maintains volume; can be combined with membranes or PRF	Granules (0.25 mm; 1.0 mm; 2.0 mm), block, wedge, sphere/affordable cost
[177]	SmartBone®/Switzerland-Italy/IBI	Bovine xenograft (HA) + biodegradable polymers + type I collagen	Rigid trabecular structure	Biocompatible; osteoconductive; bioactive; rapid tissue integration	High compressive strength; excellent stability; can be fixed with plates or screws	Slow (6-18 months)	Recommended for load-bearing reconstructions in implantology, orthopedics, and oncology; extensive scientific documentation	Granules, blocks, and strips/high cost
[178]	THE Graf®/South Korea/Purgo	Porcine bone mineral matrix, similar to human bone	Interconnected pores, high hydrophilicity	Biocompatible, free of immunogenic agents, osteoconductive	Stable structure for regeneration	From 10 weeks	In vitro, in vivo and clinical studies	Granules/high

HA: Hydroxyapatite; β-TCP: Beta-tricalcium phosphate; PRF: Platelet-rich fibrin; GBR: Guided bone regeneration.

Table 3 Classification of bone substitute biomaterials according to information provided by the manufacturers: Synthetic and composite biomaterials.

Ref.	Commercial name/country/company	Composition	Physical properties	Biological properties	Mechanical properties	Resorption/integration	Clinical efficacy	Form/cost
[179]	Alobone poros®/Brazil/Osseocon	Synthetic: Low-crystallinity hydroxyapatite	Porous granules, promote vascularization	Biocompatible, osteoconductive, protein-free	Suitable for filling bone defects	Gradual, replaced by new bone	Positive results in sinus lift, ridge augmentation, and preservation	Granules (0.25-1 mm)/affordable
[180,181]	BioGran®/United States/Zimmer Biomet	Alloplastic; bioactive glass 45S5 (calcium sodium silicate)	Translucent white; microporous; high surface area	Biocompatible; osteoconductive; potentially osteoinductive; stimulates osteogenesis, angiogenesis, and HA formation	Stable in small to moderate defects; no structural support in load-bearing areas	Rapid (3-6 months); efficient	Good results in alveolar, peri-implant, periodontal, and sinus regeneration	Granules (0.3-0.35 mm)/moderate to high
[182]	Bonecerami®/Switzerland/Straumann	Alloplastic; 60% HA + 40% β-TCP	3D structure similar to cancellous bone	Biocompatible; osteoconductive; cell adhesion; no significant inflammatory response	Lightweight and stable; not indicated for high-load areas without protection	4-6 months; β-TCP resorbs first; HA maintains volume	High predictability in GBR, sinus lift, and alveolar filling; comparable to xenografts	Granules (0.5/1.0-2.0 mm)/moderate to high
[181]	Calcigen S®/United States/Zimmer Biomet	Alloplastic; calcium sulfate	Moldable (spheres, blocks, wedges); powder-liquid mix; sets in 4-6 minutes	Biocompatible; osteoconductive; promotes bone growth	Quick application; not indicated for load-bearing support	8-12 weeks	Used as filler in orthopedics and dentistry; conducive environment for bone regeneration	Powder for mixing/moderate to high
[171]	GenPhos HA TCP®/Brazil/Baumer	Synthetic: 70% HA + 30% β-TCP	Porous granules, similar to cancellous bone	Biocompatible, osteoconductive, protein-free	Good initial strength, lower than ceramics	Slow (7-9 months); gradual integration	Positive use in sockets, ridge augmentation, and peri-implant areas	Granules (0.5-0.75 mm)/affordable
[183]	Grafton DBM®/United States/Medtronic	Allogeneic; demineralized human bone + glycerol	Moldable; ready to use; adapts to irregular defects	Biocompatible; osteoconductive and potentially osteoinductive; stimulates osteogenesis and angiogenesis; forms HA in situ	Limited support; not indicated for load-bearing areas	3 months to 12 months (variable)	Widely used in reconstructions, implants, and orthopedics	Gel, paste, sponge, strip/high cost
[184]	HAP-91®/Brazil/JHS Biomaterials	Synthetic; pure synthetic HA	White, homogeneous granules; high volumetric stability; non-collapsing	Biocompatible; osteoconductive; non-immunogenic; promotes bone conduction	Good initial strength; adequate support for load and non-load areas; non-moldable	Very slow (18-24 months)	Indicated for alveolar grafts, sinus lift, GBR, peri-implant, and ridge augmentation; volumetric maintenance and osseointegration	Granules (0.15 mm; 0.3 mm; 0.5 mm; 1.0 mm; 2.0 mm)/affordable cost
[185]	MinerOss®/United States/BioHorizons	Allogeneic; human cortical and/or cancellous bone	Dry and rehydratable particles; easy adaptation	Biocompatible; osteoconductive; possible residual osteoinduction	Intermediate support	4 months to 9 months (variable)	Widely used in implant dentistry and GBR	0.25 mm to 1.0 mm; particulate (cortical, cancellous, or mix)/moderate to high cost
[186]	Nanosynt®/Brazil/National OsteoBiotec	Synthetic: 60% hydroxyapatite + 40% β-TCP	Porous nanostructure, high capillarity	Biocompatible, osteoconductive, non-immunogenic	Good initial stability; intermediate mechanics	Controlled/moderate; β-TCP resorbs in 4-6 months; HA persists	Good outcomes in preservation, bone augmentation, and peri-implant procedures; systematic reviews	Granules (0.25-2 mm)/affordable
[187]	OsteoGen®/United States/Intra-Lock	Alloplastic; synthetic HA	Dry, lightweight granules; maintains stability	Biocompatible; osteoconductive; non-immunogenic	Fragile; moderate support in cavities	6-9 months	Used in implants, post-extraction sockets, and periodontics; good but limited literature compared to others	Granules (0.3-0.5 mm), dry/Lyophilized; strips/Low to intermediate cost
[188]	Vitoss®/United States/Stryker Corp	Synthetic β-tricalcium phosphate (β-TCP)	Lightweight, porous, hydrophilic texture; easy to handle	Biocompatible; osteoconductive; stimulates vital bone formation	Fragile structure; compressible and adaptable but requires stabilization; not recommended for load-bearing sites	Moderate (4-9 months)	Effective in small to medium defects; indicated for trauma, spine, orthopedics, implantology, and periodontics	Granules and moldable putty/moderate to high cost

HA: Hydroxyapatite; β-TCP: Beta-tricalcium phosphate; GBR: Guided bone regeneration.

DISCUSSION

The analysis of the selected literature and commercial data demonstrates that biomaterials play a fundamental role in bone regeneration, particularly in orthopedic and reconstructive rehabilitation. These materials present diverse origins, compositions, and physicochemical characteristics that directly influence their integration capacity, resorption rate, and clinical performance. Among the main categories, xenogeneic, allogeneic, and synthetic biomaterials are the most frequently employed in regenerative bone medicine, each offering specific advantages depending on defect type and clinical demand[25,38,150-152].

Comparative analysis of the evaluated biomaterials demonstrates that their origin and chemical composition directly influence the biological response and rate of tissue replacement. Bovine and porcine xenografts remain the consolidated standard in bone reconstruction due to their high biocompatibility, trabecular structure similar to human bone, and slow resorption, which favors long-term volumetric stability[153,165]. This slow integration is particularly advantageous in esthetic procedures and in regions subjected to moderate loads, ensuring clinical predictability.

In contrast, synthetic and hybrid biomaterials offer greater control over physicochemical properties and resorption rates, allowing adaptation to the specific requirements of the bone defect and reducing immunological risks. Hydroxyapatite/β-TCP composites exhibit osteoconductive behavior comparable to xenografts, but with more controlled resorption and no risk of biological transmission. Bioactive glasses (such as 45S5) have gained prominence for simultaneously stimulating osteogenesis and angiogenesis, thereby accelerating regeneration in critical-size defects[155,160].

Moreover, recent studies indicate that the combination of biomaterials with growth factors and collagen membranes enhances bone regeneration by improving clot stability and promoting osteoblastic differentiation[162,163]. This integrative approach reinforces the importance of personalized strategies in which biomaterial selection considers not only the size and location of the defect but also the patient’s biological profile and the restorative treatment plan[187-191].

Emerging evidence also supports the synergistic combination of biomaterials with adjuvant biological therapies, such as collagen membranes, PRF, and low-level laser photobiomodulation. These associations enhance clot stability, modulate inflammation, and promote osteoblastic differentiation, thereby improving both the speed and quality of bone regeneration in orthopedic and reconstructive contexts[162,163,191]. The incorporation of growth factors or fibrin matrices accelerates vascularization and supports the balance between bone resorption and formation. Photobiomodulation (LLLT) acts through mitochondrial photoreceptors to increases ATP production and stimulates collagen and angiogenic factors, which synergize with scaffold-based regeneration[108,112,113,192-194].

However, despite the substantial technological progress, significant obstacles continue to limit the clinical translation of next-generation biomaterials. Most available products lack standardized manufacturing protocols, leading to variability in porosity, mechanical strength, and biodegradation profiles, which in turn affects the reproducibility of clinical outcomes. Regulatory barriers also remain substantial, particularly for hybrid and bioactive scaffolds that incorporate biologically active components, as their approval requires extensive safety and long-term biocompatibility evidence. Furthermore, cost, manufacturing complexity, and the need for specialized surgical handling continue to restrict the large-scale adoption of advanced biomaterials in routine bone reconstruction[154,195].

In addition, both natural and synthetic biomaterials present inherent limitations that must be acknowledged when interpreting current evidence. Although clinically predictable, xenogeneic grafts exhibit slow remodeling and long-term persistence of residual particles, which may limit their behavior in large defects or in patients requiring accelerated healing[20,38]. Conversely, synthetic ceramics and bioactive glasses offer controlled resorption but may lack the intrinsic biological signaling present in natural matrices, resulting in variable maturation of newly formed bone in some clinical scenarios[160,196]. These limitations illustrate why no single material fulfills all of the requirements for ideal bone regeneration, reinforcing the need for integrative, patient-specific strategies.

Despite these advances, the literature still presents significant gaps that limit the clinical translation of novel biomaterials. Most investigations remain preclinical, with heterogeneous methodologies and limited long-term follow-up. The scarcity of randomized clinical trials and standardized parameters hampers direct comparison among biomaterial types and regenerative strategies[197]. Future research must focus on multicenter clinical studies that assess histological integration, volumetric maintenance and patient-centered outcomes such as function, aesthetics, and long-term stability[25,155].

It is also important to recognize the methodological limitations of the present review. The available literature is highly heterogeneous, with variability in defect models, follow-up periods, biomaterial formulations, and evaluation methods, which restricts direct comparison among studies[154,197]. In addition, most of the evidence originates from preclinical or single-center clinical investigations, limiting the generalizability of outcomes. Because this review synthesizes published data without performing a meta-analysis, the conclusions rely on qualitative integration rather than quantitative effect estimates. These factors should be considered when interpreting the applicability of the findings to broad clinical practice[25].

Despite these limitations, the current body of evidence supports a paradigm shift in regenerative bone medicine from traditional, biologically passive materials to multifunctional, bioactive, and patient-specific scaffolds. The integration of synthetic matrices with osteoinductive molecules, stem cell–based therapies, and photobiomodulatory strategies constitutes a promising frontier for bone regeneration. The future of tissue engineering lies in hybrid systems capable of dynamic interaction with host tissues, ensuring enhanced predictability, safety, and individualized treatment outcomes in orthopedic and reconstructive bone regeneration[52,160].

FUTURE PERSPECTIVES

Future perspectives emphasize the continuous advancement of tissue engineering, focusing on the development of biomimetic three-dimensional scaffolds, 3D printing of customized matrices, bioactive biomaterials, and controlled-release systems for osteoinductive substances. Cell therapy, particularly those using MSCs, emerges as a promising frontier aiming at more functional, predictive, and personalized bone regeneration.

However, despite these advances, several research bottlenecks remain. For 3D-printed scaffolds, the main limitations involve insufficient mechanical resistance of polymer-based constructs, difficulties in reproducing hierarchical microarchitecture, and challenges in ensuring homogeneous vascularization throughout large defects. Overcoming these issues will require the integration of composite materials with tunable stiffness, optimization of pore geometry, and development of bioinks capable of supporting angiogenic signaling.

Regarding bioactive and osteoinductive biomaterials, major obstacles include the unpredictable release kinetics of growth factors, risk of ectopic mineralization, and limited long-term stability of functionalized surfaces. Breakthroughs in this area will depend on engineering stimulus-responsive carriers and refining controlled-release systems to synchronize degradation with new bone formation.

For cell-based therapies, current challenges include variability in MSC quality, high cost of cell expansion, and regulatory barriers that slow clinical translation. Future progress will require standardized manufacturing protocols, scalable bioprocessing methods, and the refinement of allogeneic MSC platforms to reduce costs while maintaining safety and therapeutic potency.

Future research directions include the development of 3D-printed scaffolds with controlled growth factor release, the use of nanobiomaterials with immunomodulatory properties, and the consolidation of clinical protocols involving allogeneic MSCs. These strategies represent feasible pathways for overcoming current technological limitations and strengthening the interface between basic science and clinical practice, ultimately enabling bone regeneration that is more efficient, predictable, and accessible.

CONCLUSION

Bone regeneration constitutes a fundamental pillar in reconstructive rehabilitation across various medical and surgical specialties, with biomaterials used as grafts being essential for the repair of bone defects of diverse etiologies. This review highlights the diversity of materials currently available in the market, exhibiting distinct physicochemical, biological, and clinical properties, each with specific advantages and limitations.

Autogenous grafts remain the gold standard due to their osteogenic, osteoinductive, and osteoconductive capabilities, although the need for a donor site and the associated morbidity represent significant limitations. Allogeneic and xenogeneic grafts, widely employed in clinical practice, are broadly available, easy to handle, and have demonstrated efficacy through their osteoconductive capacity. However, synthetic materials have gained ground owing to their high biocompatibility, absence of immunological risk, and controllable structural characteristics, although they generally exhibit limited osteoinductive activity. There is no universal biomaterial; optimal outcomes depend on aligning material characteristics with defect morphology and patient-specific biological conditions.

Therefore, the ongoing development and refinement of biomaterials, combined with the integration of innovative biotechnological approaches, represent a promising path toward increasingly safe, effective, and individualized therapies in bone reconstruction applied to orthopedics and regenerative medicine. Despite significant advances, important gaps remain, particularly regarding the standardization of clinical protocols involving synthetic biomaterials and combined therapies. Long-term randomized clinical trials are scarce, hindering validation of new materials and emerging technologies. Furthermore, there is a lack of studies directly comparing the performance of different biomaterials under specific clinical conditions, as well as cost-benefit analyses and assessments of long-term functional impact.