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Review Article
- Current concepts and applications of bone graft substitutes in orthopedic surgery
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Jae Ho Cho
, Hyung Keun Song -
Journal of Musculoskeletal Trauma 2025;38(4):169-177.
DOI: https://doi.org/10.12671/jmt.2025.00248
Published online: October 24, 2025
Department of Orthopedic Surgery, Ajou University School of Medicine, Suwon, Korea
- Correspondence to: Hyung Keun Song Department of Orthopedic Surgery, Ajou University School of Medicine, 164 World Cup-ro, Yeongtong-gu, Suwon 16499, Korea Tel: +82-31-219-5220 Email: ostrauma@ajou.ac.kr
• Received: July 14, 2025 • Accepted: July 23, 2025
© 2025 The Korean Orthopaedic Trauma Association
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract
- Bone defects, which often arise from high-energy injuries, infections, tumor resections, or nonunions, represent a persistent challenge in orthopedic trauma surgery. Autologous bone grafting remains the gold standard due to its unique combination of osteogenic, osteoinductive, and osteoconductive properties. However, issues such as donor site morbidity, limited graft volume, and increased surgical time have driven the development of bone graft substitutes. These substitutes vary widely in origin, composition, biological activity, and mechanical characteristics, encompassing allografts, xenografts, synthetic materials, and biologically enhanced constructs. This review outlines the fundamental biological principles underlying bone regeneration—including osteogenesis, osteoinduction, and osteoconduction—and addresses additional key factors such as biocompatibility, biodegradability, and mechanical strength. Current bone graft materials are classified by biological origin and functional characteristics, with an emphasis on their use in trauma surgery. Particular attention is given to the clinical applications, indications, and limitations of allograft-based solutions (such as structural allografts and demineralized bone matrix), synthetic ceramics (including calcium phosphate and bioactive glass), and biologically enhanced options, such as recombinant growth factors and stem cell therapies. In trauma settings, graft selection must be tailored to the characteristics of the defect, mechanical demands, the biological environment, and patient-specific factors. Integration with surgical technique and fixation is crucial for optimizing outcomes. Although modern substitutes show promise, none fully replicate the complex biology of autografts. Looking ahead, emerging technologies such as 3D printing, nanotechnology, and smart biomaterials offer exciting possibilities but face translational challenges. This review aims to provide practicing orthopedic surgeons with a concise, evidence-based overview of bone substitute options and their roles in trauma care. By applying core biological principles and clinical judgment, surgeons can better navigate the expanding array of graft materials to improve outcomes for patients with complex skeletal defects.
Introduction
The management of bone defects presents one of the most challenging aspects of contemporary orthopedic practice [1,2]. These defects, whether arising from high-energy trauma, oncological resection, infectious processes, or developmental anomalies, often require sophisticated reconstructive approaches to restore both structural integrity and functional capacity. The complexity of these cases has intensified as our understanding of bone biology has evolved, yet the fundamental challenge remains: how to effectively replace lost bone tissue while minimizing patient morbidity [3,4].
For decades, autologous bone grafting has dominated the field as the undisputed gold standard. Its success stems from the unique combination of osteogenic cells, inductive growth factors, and conductive matrix that no other material can fully replicate. However, the clinical reality often falls short of this theoretical ideal. Donor site complications affect up to 20% of patients, ranging from minor discomfort to chronic pain syndromes. The available volume is frequently inadequate for large defects, and the additional surgical time and blood loss can be prohibitive in compromised patients [4,5].
This clinical dilemma has catalyzed decades of research into alternative materials. The result is a diverse landscape of bone substitutes, each with distinct properties and applications [6,7]. From the early use of processed cadaveric bone to sophisticated bioengineered constructs, the field has witnessed remarkable innovation. Yet this diversity also creates confusion for practicing surgeons who must navigate an increasingly complex array of options [8,9].
The purpose of this review is to provide a practical framework for understanding bone graft substitutes in the context of orthopedic trauma surgery. Rather than presenting an exhaustive catalog of available materials, we focus on the fundamental principles that govern their selection and use, emphasizing clinical relevance over theoretical considerations.
This was a literature-based study; therefore, neither approval by the institutional review board nor informed consent was required.
Biological foundations of bone grafting
Successful bone grafting depends on three interconnected biological processes that work in concert to restore skeletal integrity. Understanding these mechanisms is crucial for rational graft selection and realistic outcome expectations (Table 1).
Osteogenesis represents the direct contribution of viable bone-forming cells to the healing process. These cells, primarily osteoblasts and their precursors, are capable of synthesizing new bone matrix immediately upon implantation. This mechanism is unique to autologous grafts, where living cells survive the transplantation process and contribute directly to bone formation. The osteogenic potential of autograft explains its superior performance in challenging clinical scenarios, particularly when host biology is compromised [1,5].
Osteoinduction involves a more complex cascade of cellular events. Growth factors and bioactive molecules within the graft material recruit host mesenchymal stem cells and stimulate their differentiation into bone-forming cells. This process is mediated by members of the bone morphogenetic protein (BMP) family, along with other signaling molecules such as transforming growth factor-beta and insulin-like growth factors. The osteoinductive capacity of a material depends largely on the preservation of these proteins during processing, which explains the variability in clinical performance among different preparations [10,11].
Osteoconduction provides the structural framework for bone regeneration. The graft material serves as a three-dimensional scaffold that facilitates cell migration, vascular ingrowth, and subsequent bone deposition. This mechanism is perhaps the most predictable and is shared by most bone substitutes, regardless of their origin. However, the effectiveness of osteoconduction depends on factors such as pore size, interconnectivity, and surface chemistry, which vary significantly among different materials [3,7].
While the traditional triad provides a useful framework, modern bone grafting must also consider additional factors that influence clinical success. Biocompatibility extends beyond simple tissue acceptance to encompass the complex interplay between the graft material and the host immune system. Some materials may trigger chronic inflammatory responses that ultimately compromise healing, while others may be rapidly cleared by macrophages before meaningful bone formation can occur [12,13].
Biodegradability presents a delicate balance between mechanical support and biological remodeling. The ideal graft material should be gradually replaced by new bone tissue, but the timing of this replacement is critical. Premature degradation can lead to mechanical failure, while persistence of non-resorbing material may interfere with normal bone remodeling and create long-term complications [3,14].
Mechanical properties become particularly important in load-bearing applications. The graft must provide adequate strength to withstand physiological forces while maintaining porosity for vascular ingrowth. This represents a fundamental engineering challenge, as these requirements are often contradictory. Dense materials may offer superior strength but poor vascularization, while porous materials may facilitate healing but lack mechanical integrity [9].
The traditional classification of bone grafts based on their biological origin—autograft, allograft, xenograft, and synthetic—remains useful but increasingly oversimplified. Modern materials often combine elements from multiple categories, creating hybrid products that defy simple categorization (Table 2) [6,7].
Autografts continue to represent the biological gold standard, despite their limitations. The harvest site significantly influences graft properties, with cancellous bone from the iliac crest offering superior osteogenic potential compared to cortical bone from the fibula. However, even autografts exhibit variability based on patient age, health status, and harvest technique [1,5].
Allografts have evolved far beyond simple cadaveric bone transplantation. Modern processing techniques can selectively preserve or remove specific components, creating materials with tailored properties. Fresh-frozen allografts retain some osteoinductive capacity but carry higher immunological risk, while freeze-dried preparations offer improved handling characteristics at the cost of reduced biological activity [2,4,15].
Xenografts remain controversial, with significant variation in acceptance across different regions and cultures. Despite extensive processing to remove cellular components, concerns about immunogenicity and disease transmission have limited their widespread adoption in orthopedic applications [8].
Synthetic materials represent the most diverse category, ranging from simple calcium phosphate ceramics to complex composite structures. The advantage of synthetic materials lies in their consistency and unlimited availability, but they generally lack the biological activity of natural grafts [7,9].
Contemporary bone substitute materials
The use of human cadaveric bone has a long history in orthopedic surgery, but modern allograft processing has transformed these materials into sophisticated biological tools. Structural allografts continue to play a crucial role in reconstructive surgery, particularly for large segmental defects where mechanical support is paramount. These grafts undergo processing to reduce immunogenicity while preserving mechanical properties, but they lack the cellular components necessary for osteogenesis [2,15].
The incorporation of structural allografts follows a predictable pattern that differs significantly from autograft healing. Initial mechanical support is provided by the processed bone matrix, but gradual remodeling occurs through creeping substitution. This process can take years to complete and may never fully restore the mechanical properties of native bone. Nevertheless, structural allografts remain invaluable for specific applications where alternatives are limited [4].
Demineralized bone matrix (DBM) represents a more processed form of allograft with distinct properties and applications. The demineralization process removes the mineral component while preserving the organic matrix, including growth factors responsible for osteoinduction [16]. However, the biological activity of DBM varies considerably based on donor characteristics, processing methods, and storage conditions. This variability has led to the development of numerous commercial preparations, each with distinct handling characteristics and claimed biological activities. The clinical performance of DBM depends heavily on the host environment and the specific preparation used. In well-vascularized sites with good biological potential, DBM can stimulate significant bone formation. However, in compromised environments, its effectiveness may be limited. The addition of various carriers and enhancers has attempted to improve consistency, but clinical outcomes remain somewhat unpredictable [12].
The development of synthetic bone substitutes has been driven by the desire to create materials with predictable properties and unlimited availability. Calcium phosphate ceramics represent the most mature category of synthetic bone substitutes, with decades of clinical experience supporting their use [3,7]. Hydroxyapatite (HA) closely mimics the mineral component of natural bone, providing excellent biocompatibility and osteoconductive properties. However, its slow resorption rate means that it may persist in the body for years, potentially interfering with normal bone remodeling [6]. This characteristic makes HA suitable for applications where long-term structural support is desired, but problematic when rapid incorporation is needed.
Beta-tricalcium phosphate (β-TCP) offers a more favorable resorption profile, with gradual dissolution that more closely matches the rate of new bone formation. This property makes it attractive for applications where complete replacement by host bone is desired. However, the mechanical properties of β-TCP are generally inferior to HA, limiting its use in load-bearing applications [3].
Biphasic calcium phosphate attempts to combine the advantages of both materials by incorporating both HA and β-TCP in a single product. The ratio of these components can be adjusted to tailor the resorption characteristics to specific clinical needs. Despite this theoretical advantage, clinical studies have not consistently demonstrated superior performance compared to single-phase materials [7].
Bioactive glass represents a different approach to synthetic bone substitutes, with the ability to form direct chemical bonds with bone tissue. The dissolution of bioactive glass creates a locally alkaline environment that may stimulate osteoblast activity while inhibiting bacterial growth. These properties make bioactive glass potentially attractive for infected or contaminated sites, although clinical experience remains limited compared to calcium phosphate ceramics [8].
The limitations of purely synthetic materials have led to the development of biologically enhanced substitutes that combine synthetic scaffolds with biological components. BMPs represent the most clinically significant example of this approach [10,11].
Recombinant human BMP-2 (rhBMP-2) has demonstrated remarkable osteoinductive capacity in clinical trials, with the ability to stimulate bone formation even in challenging biological environments. The mechanism involves recruitment of mesenchymal stem cells and their differentiation into osteoblasts through well-characterized signaling pathways. However, the clinical experience with rhBMP-2 has been mixed, with concerns about dose-dependent side effects and cost-effectiveness limiting its widespread adoption [10,17]. The delivery system for BMPs is as important as the growth factor itself. Collagen sponges provide a biocompatible carrier that allows for localized delivery, but the release kinetics may not be optimal for all applications. Alternative delivery systems, including synthetic polymers and ceramic matrices, are being investigated to improve the efficacy and safety profile of BMP-based products.
Stem cell-based approaches represent an emerging frontier in bone grafting, with the potential to provide autologous osteogenic cells without the morbidity of bone harvest [18]. Mesenchymal stem cells can be harvested from various sources, including bone marrow, adipose tissue, and peripheral blood, then expanded in culture and delivered on appropriate scaffolds [18,19]. However, the clinical translation of stem cell therapies faces significant regulatory and practical challenges.
Platelet-rich plasma (PRP) and related blood-derived products have gained popularity as adjuncts to bone grafting procedures. The theoretical rationale is compelling, as these products contain concentrated growth factors and cytokines that may enhance healing. However, the clinical evidence for PRP in bone grafting remains inconsistent, with significant variation in preparation methods and outcome measures complicating interpretation of results [20].
Clinical applications in trauma surgery
The decision to use bone substitutes in trauma surgery requires careful consideration of multiple factors that extend beyond simple defect size (Table 3). Segmental bone loss remains the most straightforward indication, particularly when the defect exceeds 2‒3 cm in length or when autograft volume is insufficient [2]. However, the definition of "critical size defect" varies with location, patient age, and biological environment [1].
Metaphyseal defects present unique challenges that often favor the use of bone substitutes. These defects commonly occur in periarticular fractures where subchondral support is crucial for joint congruity [21,22]. The cancellous bone environment is generally favorable for graft incorporation, but the mechanical demands require materials that can provide immediate structural support [7].
Nonunion management represents a complex clinical scenario where bone substitutes may play a crucial role. The biological environment in established nonunions is often compromised, with poor vascularity and fibrous tissue formation. In such cases, the choice of bone substitute must consider both the need for biological stimulation and the mechanical requirements for stability [14].
Infection-related bone loss poses particular challenges for bone substitute selection. The presence of bacteria or their biofilms can compromise graft incorporation and lead to persistent infection. Some materials may be more susceptible to bacterial colonization than others, and the timing of grafting relative to infection control becomes critical [20].
The selection of bone substitutes must be individualized based on patient characteristics that influence healing potential. Age significantly affects both the biological response to grafts and the mechanical demands placed on them [5]. Elderly patients may have reduced osteogenic potential but also lower functional demands, while young patients may require materials that can withstand high activity levels [19].
Comorbidities such as diabetes, smoking, and immunosuppression can profoundly impact graft performance. These conditions may compromise the biological response to osteoinductive materials while also affecting the mechanical properties of healing bone [4,16]. In such cases, the choice of bone substitute may need to favor materials with proven performance in compromised hosts [13].
Anatomical location influences both the mechanical requirements and the biological environment for graft incorporation. Weight-bearing sites require materials with superior mechanical properties, while non-weight-bearing locations may prioritize biological activity over structural strength [9]. The local vascularity and soft tissue coverage also affect the choice of appropriate materials [12].
The success of bone substitutes depends heavily on their integration with sound surgical principles. Mechanical stability remains paramount, as even the most biologically active graft will fail without adequate fixation [3]. The choice of fixation method should consider the properties of the graft material and the expected timeline for incorporation [3,20].
Soft tissue management becomes particularly important when using bone substitutes, as these materials may be more susceptible to infection or extrusion compared to autograft. Adequate soft tissue coverage and tension-free closure are essential for successful outcomes [20].
Timing considerations may favor staged procedures in contaminated or infected cases. The biological environment must be optimized before grafting, which may require debridement, antibiotic therapy, or other preparatory measures [10]. The use of temporary spacers or external fixation may be necessary to maintain alignment and stability during the preparatory phase [14].
The clinical performance of bone substitutes must be evaluated within the context of realistic expectations. Time to union may be prolonged compared to autograft, particularly for materials that rely primarily on osteoconduction [3]. Patients should be counseled about the expected timeline for healing and the potential need for protected weight-bearing [5].
Functional outcomes may differ from those achieved with autograft, particularly in load-bearing applications. While bone substitutes may achieve radiographic union, the mechanical properties of the healed bone may not fully restore normal function [9]. This consideration is particularly important in young, active patients with high functional demands [19].
Complication rates vary significantly among different bone substitute materials and clinical applications. Some materials may have higher rates of infection, delayed union, or failure compared to autograft. These risks must be weighed against the potential benefits of avoiding donor site morbidity [15,16].
Future directions and emerging technologies
Despite significant advances in bone substitute technology, several fundamental challenges remain unresolved. The biological activity of current materials often falls short of autograft performance, particularly in challenging clinical scenarios [23]. While synthetic materials offer excellent biocompatibility and handling characteristics, they generally lack the complex biological signals that drive robust bone formation [15].
Mechanical properties represent another area where current materials often compromise. The ideal bone substitute should provide immediate structural support while gradually transferring load to newly formed bone. Achieving this balance requires sophisticated engineering that current materials have not fully realized [3].
Cost-effectiveness remains a significant concern for many bone substitute materials. While the direct costs of these products may be justified by avoiding donor site morbidity, the overall economic impact must consider factors such as operative time, hospital stay, and complication rates [12]. Few materials have demonstrated clear cost advantages over autograft when all factors are considered.
Regulatory pathways for bone substitutes vary significantly depending on their classification and intended use. This variability creates challenges for manufacturers and clinicians, as the approval process may not adequately address the unique characteristics of each material. The result is a marketplace with inconsistent standards and unclear comparisons between products [10].
Three-dimensional printing has emerged as a promising technology for creating customized bone substitutes with precise control over geometry and porosity [21,22,24]. Patient-specific scaffolds can be designed based on imaging data, potentially improving fit and integration. However, the clinical benefits of this customization remain to be demonstrated, and the costs may be prohibitive for routine use [17].
Smart materials that respond to biological signals represent an exciting frontier in bone substitute development. These materials could potentially release growth factors or other therapeutic agents in response to specific cellular or enzymatic signals, providing more precise control over the healing process. However, the complexity of these systems presents significant challenges for clinical translation [9].
Genetic engineering approaches offer the potential to deliver therapeutic genes directly to the graft site, potentially enhancing osteogenesis without the need for expensive protein drugs. However, the safety and efficacy of genetic therapies remain to be established, and regulatory approval is likely to be complex and lengthy [12].
Nanotechnology applications in bone grafting include the development of nanostructured surfaces that may enhance cell adhesion and differentiation. Nanoparticles can also serve as delivery vehicles for drugs or growth factors, potentially improving the efficacy of biologically enhanced materials. However, the long-term safety of nanomaterials in the human body remains a concern [6,25].
The path from laboratory innovation to clinical application faces numerous obstacles that have slowed the development of next-generation bone substitutes. Regulatory requirements for bone substitutes vary depending on their classification, with some materials requiring extensive clinical trials while others may be approved through less stringent pathways [10]. This variability creates uncertainty for manufacturers and may not adequately ensure patient safety [14].
Clinical trial design for bone substitute evaluation presents unique challenges. Unlike pharmaceutical drugs, bone substitutes are often used in combination with other treatments, making it difficult to isolate their specific effects. The heterogeneity of clinical indications and patient populations further complicates trial design and interpretation [20].
Manufacturing standardization remains a significant challenge for biologically active bone substitutes. The inherent variability in biological materials, combined with complex processing requirements, can lead to batch-to-batch variation that affects clinical performance [13]. Developing quality control methods that ensure consistent biological activity while maintaining cost-effectiveness is an ongoing challenge [4].
Reimbursement policies for bone substitutes vary widely and may not reflect their clinical value. The lack of standardized outcome measures and economic analyses makes it difficult for payers to assess the cost-effectiveness of these materials. This uncertainty can limit patient access to potentially beneficial treatments [23].
Conclusions
The landscape of bone graft substitutes in orthopedic trauma surgery has evolved dramatically over the past several decades, offering surgeons an increasingly sophisticated array of options for managing complex bone defects. While autologous bone grafting remains the gold standard for most applications, the limitations of autograft have driven the development of numerous alternative materials, each with distinct advantages and applications.
The successful use of bone substitutes requires a thorough understanding of their biological properties, mechanical characteristics, and clinical limitations. No single material can replicate all the properties of autograft, and the choice of substitute must be tailored to the specific clinical scenario. The integration of bone substitutes with sound surgical principles, appropriate fixation, and realistic outcome expectations is essential for achieving successful results.
Looking forward, the field continues to evolve with promising developments in biotechnology, materials science, and regenerative medicine. However, the translation of these innovations into clinical practice faces significant challenges related to regulation, cost, and clinical validation. The next generation of bone substitutes will likely combine multiple approaches, potentially including synthetic scaffolds, biological enhancers, and cellular components.
For practicing orthopedic surgeons, staying current with developments in bone substitute technology while maintaining a critical perspective on their clinical value is essential. The decision to use bone substitutes should be based on sound scientific principles, clinical evidence, and patient-specific factors rather than marketing claims or theoretical advantages. When used appropriately, bone substitutes can significantly enhance the surgeon's ability to manage complex bone defects while minimizing patient morbidity.
The future of bone grafting lies not in finding a single perfect substitute for autograft, but in developing a comprehensive understanding of how different materials can be optimally applied to specific clinical scenarios. This nuanced approach, combined with ongoing technological innovation, promises to further improve outcomes for patients with complex bone defects in the years to come.
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Author contribution
Conceptualization: HKS. Data curation: JHC. Project administration: HKS. Writing-original draft: JHC. Writing-review & editing: HKS. All authors read and approved the final manuscript.
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Conflict of interests
Hyung Keun Song is a managing editor of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
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Funding
None.
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Data availability
Not applicable.
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Acknowledgments
None.
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Supplementary materials
None.
Article Information
Table 1.
Biological properties of bone graft materials
Table 2.
Summary of common bone graft substitutes
Table 3.
Clinical considerations in choosing bone graft substitutes
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XML DownloadCurrent concepts and applications of bone graft substitutes in orthopedic surgery
Current concepts and applications of bone graft substitutes in orthopedic surgery
| Property | Definition | Key example |
|---|---|---|
| Osteogenesis | Contribution of living cells to new bone formation | Autograft |
| Osteoinduction | Induction of osteoprogenitor cells to differentiate into osteoblasts | DBM, BMP-2 |
| Osteoconduction | Passive scaffold for new bone ingrowth | Allograft, ceramics |
| Biocompatibility | Lack of immune reaction or toxicity | Most clinical substitutes |
| Biodegradability | Resorption in synchrony with bone formation | Calcium sulfate, β-TCP |
| Mechanical support | Ability to withstand load-bearing forces | Structural allografts, some ceramics |
| Type | Source | Biological activity | Mechanical strength | Common use case |
|---|---|---|---|---|
| Autograft | Patient | Osteogenesis, induction, conduction | High | All types of defects |
| Allograft | Human donor | Osteoconduction, weak induction | Variable | Large defects, structural support |
| Xenograft | Animal | Mainly osteoconduction | Low–moderate | Void filling, dental/maxillofacial |
| Synthetic ceramic | Synthetic | Osteoconduction (some osteoinduction in vitro) | Variable | Void filler, non-load-bearing defects |
| Bioactive glass | Synthetic | Osteoconduction + surface stimulation | Low | Infection-prone or irregular cavities |
| BMP-enhanced | Biologic | Strong osteoinduction | Not applicable | Fusion promotion, difficult healing sites |
| Clinical scenario | Preferred graft type | Key consideration |
|---|---|---|
| Small metaphyseal defect | Allograft, synthetic ceramic | Osteoconduction sufficient; low load-bearing |
| Large segmental defect | Autograft±BMP, structural allograft | Mechanical strength needed; consider augmentation |
| Poor bone healing potential | BMP-enhanced, DBM | Requires osteoinduction |
| Infection-prone area | Bioactive glass, antibiotic-loaded graft | Antimicrobial activity desirable |
| Pediatric case | BMP should be avoided; autografts or resorbables are used instead | Safety concerns with growth |
| Revision surgery or fusion failure | BMP-2, autografts | High induction needed |
Table 1. Biological properties of bone graft materials
DBM, demineralized bone matrix; BMP-2, bone morphogenetic protein-2; β-TCP, beta-tricalcium phosphate.
Table 2. Summary of common bone graft substitutes
BMP, bone morphogenetic protein.
Table 3. Clinical considerations in choosing bone graft substitutes
BMP, bone morphogenetic protein; DBM, demineralized bone matrix.
