Version May 2024
INTRODUCTION — Bone grafts fill bony voids or gaps of the skeletal system that may be the result of surgically created osseous defects (eg, tumor resection), related to osteonecrosis, or the result of trauma.
Bone grafting is commonly used in multiple surgical specialties including orthopedic surgery, neurosurgery, plastic surgery, and dental surgery. Almost two million bone grafting procedures are performed worldwide per year [1]. In the United States, over 500,000 bone graft procedures are performed annually, making bone grafts second only to blood transfusion as the most common tissue transplantation [2].
This topic will review the properties and categories of bone grafts and the basic principles of their use.
BONE GRAFT CHARACTERISTICS — Bone grafts are described based on their properties and clinical features. Based upon their properties, bone grafts may be regarded by the US Food and Drug Administration as drugs, a device, or a combination drug/device with appropriate regulation depending on the category (table 1).
Bone graft properties — Bone grafts have one or more of the following properties that describe the actions of the bone graft [3-5]. These include the following:
●Osteoconductivity – Osteoconductive materials provide a structural framework for bone growth.
●Osteoinductivity – Osteoinductive materials contain factors that stimulate bone growth through upregulation of osteoprogenitor cells.
●Osteogenicity – Osteogenic materials directly provide cells such as mesenchymal stem cells, osteoblasts, or osteocytes.
●Osteostimulation – Osteostimulative materials upregulate expression of osteogenic genes or proteins by mesenchymal stem cells.
●Bioactivity – Bioactive materials form a layer of bone-like mineral on their surface, which is proposed to aid the process of osteointegration.
Bone graft features — Another way to assess bone graft characteristics is through the graft's material features, which include porosity, resorption rate, origin, handling properties and physical features, ability to mix, immunogenicity, and composition [5].
●Porosity – Pore size and shape for bony incorporation.
●Origin – The origin of the graft, such as autograft (from the patient), allograft (human donor), xenograft (from nonhuman donor), and synthetic (manmade).
●Resorption rate – This describes how quickly a bone graft is resorbed by the human body. For example, autograft resorbs more quickly than anatomic bone growth.
●Handling properties and physical features – Grafts come in liquid or flowable forms, granules of various sizes, putties, strips, and on conduits such as sponges, among other formulations.
●Ability to mix – Some grafts can be mixed with blood, platelet-rich plasma, or bone marrow aspirate.
●Immunogenicity – Immunogenicity describes how the body reacts to a bone graft. This includes potential disease transmission, an inflammatory response, or immunomodulation to promote healing.
●Composition – Allografts contain cells. Synthetic grafts may contain silicate or bioglass. Bone morphogenic protein includes proteins.
CATEGORIES OF BONE GRAFT
Autograft — Autograft bone is the gold standard of bone graft. Autograft can be nonvascularized such as with cancellous bone, cortical bone, and bone marrow aspirate, or the bone graft can be harvested with a feeding artery (ie, vascularized bone graft). The immunogenic response to autograft is typically very low. However, drawbacks include limited blood supply with nonvascularized bone grafts and donor site morbidity, which is more prominent with vascularized bone grafts [2].
Nonvascularized bone grafts
Bone marrow aspirate — Bone marrow aspirate involves retrieving cells from the bone marrow, which is rich in mesenchymal stem cells and growth factors [6]. Limitations include the lack of osteoconductive properties, so it is often mixed with a carrier. Benefits include cost and osteogenic cells. Common sources include the anterior or posterior pelvis and the proximal or distal fibula.
Cancellous bone — Cancellous bone is the most commonly used form of autologous bone grafting because it is prevalent throughout the body and relatively easy to harvest [7,8]. Limitations include less structural support compared with cortical bone. High volumes of cancellous bone can be harvested with the use of a reamer/irrigator/aspirator. Often, cancellous bone is harvested near the surgical site, such as from the vertebrae for spine surgery, or the tibia, femur, or distal radius with extremity surgery.
Cortical bone — Cortical bone offers structural integrity. However, there is lower incorporation due to limited cellularity and healing through creeping substitution [7,8]. There is also the risk of donor site morbidity, for example meralgia paresthetica, which is an injury to the lateral femoral cutaneous nerve that can occur when harvesting iliac crest cortical bone graft [9]. Common sources include the anterior or posterior wing of the iliac crest.
Vascularized bone grafts — Vascularized bone grafts harvest the nutrient, metaphyseal, and/or additional perforating vessels to transfer with the bone graft. Benefits include the transfer of vascular supply, osteoprogenitor cells, and cortical and cancellous bone. This is technically challenging [7,8]. Common sources for vascularized bone grafts include the distal radius (based on the 1 to 2 intercompartmental super-retinacular artery branch of radial artery), a free fibular strut graft (based on the peroneal artery), or the free iliac crest graft (based on the deep circumflex iliac artery).
Extenders to autografts — The use of some materials potentially allows less autograft to be harvested, with the aim of decreasing the risk of donor site morbidity and pain [10]. As an example, allograft, demineralized bone matrix, or synthetic agents may be added as extenders to iliac crest autograft bone in surgical situations that require a higher volume of bone graft.
When a product is cleared by the US Food and Drug Administration as an "extender," this refers specifically to its use as an extender to autograft in the surgeon's hands. Some products do not require the surgeon to perform this function. In addition, there may be competing products within the same category with the same composition (particularly in synthetics) that have different indications from the FDA (ie, as an extender, as a standalone, or both) because some manufacturers will make the appropriate application, but others will not.
Allograft — Allograft is bone obtained from a human donor and that may be processed using a variety of techniques. The three types of bone allograft (fresh, fresh frozen, and freeze dried) have differing properties [2,8,11].
●Fresh allograft is washed but not sterilized of all cells and therefore has the highest risk of disease transmission or immune response of the allograft categories. The benefit is that it is osteoinductive.
●Fresh frozen undergoes more thorough cleaning, but still retains the osteoinductive properties. There is less of a risk of disease transmission.
●Freeze dried is the least immunogenic, with the lowest risk of immunogenicity, but it is purely osteoconductive. Treatment is via ethanol wash with or without gamma irradiation.
Demineralized bone matrices — Demineralized bone matrices (DBMs) are processed allografts that have undergone several phases of acid treatment and rinsing to remove the inorganic phases of bone and to deactivate biological contaminants such as viruses. The benefits include availability in many formations and are not as expensive as other categories. Limitations include variation of osteoconductive and osteoinductive properties between products and lot-to-lot, sterilization may inactivate or attenuate osteoinductive factors, and immunogenicity [8,11,12].
Cell-based allografts/matrices — Cell-based allografts contain native bone cells such as mesenchymal stem cells, osteoblasts, or pre-osteoblasts. The cells are kept alive by the addition of a cryoprotectant and freezing for storage. Cell-based matrices (CBMs) often also consist of a combination of cancellous allograft chips and/or DBM. Benefits include osteogenic properties and availability in a variety of formulations. Limitations include cost, risk of disease transmission, donor-dependent variation in efficacy, and need for an optimized infrastructure for freezing and thawing. In June 2021, the FDA issued a recall for a widely used cell-based allograft contaminated with tuberculosis [11,13-20].
Xenografts — Xenografts are a category of bone graft that is obtained from a nonhuman species. Coralline, obtained from marine coral, was first used in the 1970s as a bone graft substitute. Since that time, it has been combined with hydroxyapatite and used as a synthetic/xenograft bone graft combination [21]. (See 'Hydroxyapatite' below.)
Similarly, bovine bone is frequently used as an osteoconductive scaffold in allograft bone grafts [22].
Synthetic ceramic grafts — Synthetic ceramic grafts are artificially produced, not made from human tissue, and may be used as a standalone graft or an extender to autograft depending on their regulatory category [10].
First-generation — First-generation synthetic materials include calcium sulfate, hydroxyapatite, beta tricalcium phosphate, and biphasic calcium phosphate.
Calcium sulfate — Calcium phosphate, also known as "Plaster of Paris," was first used in the late 19th century to fill large bony defects. Calcium sulfate resorbs through chemical dissolution at a rate that is faster than the anatomic rate of bone resorption. Because of its cement-like structure, it can be used to fill large bony defects [23].
In clinical practice, surgeons may mix calcium sulfate with an antibiotic powder (eg, vancomycin, tobramycin) to make antibiotic beads, which can be packed into infected bone to provided extended treatment; the antibiotic continues to release as the beads dissolve. In some countries, this may be "off-label" use. Proprietary absorbable calcium sulfate antibiotic carrier products are also available.
Hydroxyapatite — Hydroxyapatite (HA) has been in use since the 1950s as a xenograft combined with sea coral (calcium carbonate) or bovine bone. Subsequently, synthetic HA was produced in the 1970. HA has high chemical stability and a very slow resorption rate, which may impair assessment of radiological fusion and/or impair the rate of bone healing. The benefits of HA include low cost, variety of formulations, and good porosity [24].
Beta tricalcium phosphate — Beta tricalcium phosphate (B-TCP) was first used as a bone graft in the 1980s. Like HA, this is available in a wide variety of formulations including granules, putties, and strips, can be manufactured with a range of porosity, and is cost effective. B-TCP is more degradable than HA; however, it does have an unpredictable biodegradation profile [25-27].
Biphasic calcium phosphate — Biphasic calcium phosphate (BCP) is a mix of HA and B-TCP and therefore has an intermediate resorption profile, which can be manipulated based on the ratio of HA to B-TCP. It has been in use in the US since the 1990s. BCP is available in a wide variety of formulations including granules, putties, and strips; can be manufactured with a range of porosity; and is cost effective [28].
Second-generation — Second-generation synthetics include silicated calcium phosphate and bioglass.
Silicated calcium phosphate — Silicated calcium phosphate (Si-CaP) is an ion-substituted calcium phosphate that entered the market in the US in the 2000s. Scientists substituted small amounts of silicate ions (<1 percent) for phosphate ions. Research suggests that silicate enhances bioactivity with increased activity and differentiation of bone cells in vitro, as well as faster bone ingrowth in vivo, although this has not translated into improved outcomes in human clinical studies. Many Si-CaPs are HA products, which have a slow resorption profile. As with the first-generation synthetics, this is available as granules, putties, or strips and has a wide range of porosity. It is more expensive that first-generation synthetics [28-31].
Bioglass — Bioglass contains silica, sodium, calcium, and phosphorus and is similar to glass. It entered the market in the 2000s. The ion release from bioglass can increase activity and differentiation of bone cells in vitro, can be osteoconductive by creating a calcium phosphate surface layer, and may have antibacterial effects. There have been reports of immunogenic reactions. It is available as granules, putties, or strips and is more expensive than first-generation synthetics [32].
Advanced — Advanced synthetics use enhanced surface topography to create bony ingrowth.
BCP <1 micrometer — The submicron needle-shaped surface of BCP <1 micrometer polarizes macrophages into a pro-healing M2 phenotype. The M2 macrophages are then able to cross-talk with mesenchymal stem cells, inducing an immune response that stimulates osteoprogenitor cells to form bone. BCP <1 micrometer has grown bone in muscular pouches without additional cells or growth factors in animal models and has proved equivalent to autograft in validated, clinically relevant sheep models [33,34]. Level 1 human trials are in progress.
Microporous BCP — Microporous BCP is a TCP with surface topography that has been shown to form bone in intramuscular sites. There have been reports of resorption leading to nonunion [35].
Growth factors — Depending on their FDA regulation class, growth factors can be used standalone or as extenders to bone grafts (eg, autograft, xenograft).
Peptides (P-15) — One xenograft of bovine bone is enhanced with synthetic peptide P-15 adsorbed to its surface. The peptide P-15 contains the cell-binding domain of collagen and modulates binding, activity, and osteogenic differentiation of bone cells that interact with the graft after implantation [36,37]. The instructions for use state "Peptide Enhanced Bone Graft must be used inside an allograft bone ring and with supplemental anterior plate fixation" [38].
Bone morphogenetic proteins — Recombinant human bone morphogenetic proteins (BMPs) are growth factors that must be combined with an osteoinductive carrier. BMP is an extender, but it is provided in a kit from the manufacturer so that the surgeon doesn't need to perform this function before implantation. BMPs signal to mesenchymal stem cells to initiate bone formation. Limitations include cost, as well as reported complications with on-label use, including ectopic bone formation [39].
Platelet-derived growth factor — Recombinant human platelet-derived growth factor is a recruiter of mesenchymal stem cells and an up-regulator of angiogenesis. This is mixed with B-TCP for osteoconductivity [40].
CLINICAL USES — Bone grafting is commonly used in multiple specialties including orthopedic surgery, neurosurgery, plastic surgery, and dental surgery [2,41-47]. Within these fields, common surgical applications for bone grafts include filling bony voids that result from:
●Elective arthrodesis surgery
●Traumatic injury
●Tumor resection
●Debridement for fracture nonunion or osteomyelitis
●Cancellous bony voids caused by avascular necrosis
Selection — Since the options for bone grafting are many and without robust comparison data, the selection of one category over another is based on anatomic and patient factors and the experience and preference of the surgeon. Any of the bone grafts described above may be used to manage any bone defect, although the application in certain situations may be "off label." Factors limiting use include availability (eg, autograft), cost (eg, bone morphogenetic protein), or lack of evidence for efficacy for a particular application.
Clinical scenarios
●Elective arthrodesis surgery – Filling bony voids for arthrodesis (ie, bone fusion) differs depending on anatomic location. For some anatomic regions (eg, carpal bones in the wrist, tibiotalar joint, tarsal and metatarsal joints in the foot), once the articular cartilage is removed, the gap between the bleeding cancellous bones that results is minimal (typically <5 mm) and easily filled, resulting in a favorable healing environment. By comparison, fusion involving the spine is more difficult because the gap that results following disc removal is large.
●Malunion and nonunion of fractures – Determining the type of nonunion can help direct bone graft usage in revision surgery. By definition, hypertrophic nonunions have adequate bone biology but inadequate stability in fixation; oligotrophic nonunions may have adequate bone biology but have inadequate reduction of the bony fragments; and atrophic nonunions have inadequate bone biology. As such, considering the type of nonunion and the adequacy of the native bone anatomy can direct the bone graft choice, bearing in mind that the hardware and fixation methods are also of paramount importance in these cases [48]. (See "General principles of fracture management: Early and late complications", section on 'Nonunion and malunion'.)
●Osteomyelitis – Bone graft substitutes can be used to provide local antimicrobial therapy. In a systematic review evaluating the effectiveness of antimicrobial bone graft substitutes in the treatment of osteomyelitis, primary and secondary outcomes from 15 observational studies were promising, with high clinical success rates at short-term follow-up [49]. The rates of eradication of infection varied from 80 to 100 percent, bone growth rates varied from 87.5 to 100 percent, and the bone graft substitute degradation was 100 percent in all studies except for one. However, the quality of the studies was overall low. (See "Nonvertebral osteomyelitis in adults: Treatment" and "Vertebral osteomyelitis and discitis in adults", section on 'Treatment'.)
●Extremity reconstruction after trauma – Because of the variability in fracture patterns, soft tissue injury associated with fracture, vascularity surrounding long bones, and healing patterns of long bones, axial skeleton, and extremities, there are no clear best practices when choosing a bone graft in trauma. Autograft from of iliac crest is widely selected as the standard; however, surgeons must make a case-by-case decision when choosing which bone graft, if any, to use for each individual fracture scenario [50]. (See "Surgical reconstruction of the upper extremity" and "Surgical reconstruction of the lower extremity".)
●Reconstruction after tumor resection – Bony defects from malignant tumor resection can represent a challenging reconstructive problem. The most commonly used bone grafts for these cases include allografts, vascularized fibular grafts, extracorporeally devitalized autograft, or segmental bone transplant [51]. (See "Surgical reconstruction of the upper extremity" and "Surgical reconstruction of the lower extremity" and "Surgical management of chest wall tumors" and "Surgical management of severe rib fractures".)
●Avascular osteonecrosis – The pathology of avascular necrosis relates to a failure of blood supply to nourish the bony environment, and as such, some authors advocate prioritizing a vascularized bone graft for reconstruction of these defects to restore viable bone, provide structural support, and re-establish blood supply [52]. (See "Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults" and "Acute and chronic bone complications of sickle cell disease", section on 'Osteonecrosis (avascular necrosis)'.)
●Posterolateral spine fusion – Fusion rates vary widely for the differing bone graft categories when applied to posterolateral spinal fusion (PLF) [10,26,27,32,35,39,53-56]. This is due in part to variability in techniques used for PLF and quality of the various studies, as well as the established difficulty of PLF specifically when compared with fusion procedures at other anatomic sites [25].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Severe blunt or penetrating extremity trauma" and "Society guideline links: General fracture and stress fracture management in adults".)
SUMMARY AND RECOMMENDATIONS
●Bone grafting – Bone grafting is commonly used in multiple surgical specialties to fill voids or gaps of the skeletal system that may be related to trauma, osseous defects created during surgery (eg, tumor resection), or the result of osteonecrosis. The type of bone graft used for filling a bony void depends upon the disease process, anatomic location, and size of the defect. (See 'Introduction' above and 'Clinical uses' above.)
●Characteristics of bone grafts – Bones grafts are characterized by one or more properties (eg, osteoconductivity, osteoinductivity, osteogenicity, osteostimulation, bioactivity) or other features (eg, origin, porosity, absorption rate, formulation, composition, mixability, immunogenicity). (See 'Bone graft characteristics' above.)
●Bone graft categories – Bone grafts can be derived from human (eg, autograft, allograft) or animal (ie, xenograft) tissues or be manmade (ie, synthetic; eg, hydroxyapatite, beta tricalcium phosphate, biphasic calcium phosphate, silicated calcium phosphate). Bone grafts can originate from cancellous or cortical bone and transferred in part, or in total, as nonvascularized or vascularized grafts. Allografts may be processed prior to implantation to reduce their immunogenicity. (See 'Categories of bone graft' above.)
●Bone graft extenders – Extenders potentially allow less autograft to be harvested, with the aim of decreasing the risk of donor site morbidity. These may include but are not limited to growth factors, peptides, and bone morphogenetic proteins. (See 'Extenders to autografts' above and 'Growth factors' above.)
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