Fracture healing is dependent on a delicate balance between biology and biomechanical stability. Despite attempts to minimize damage to the blood supply of the fracture fragments during surgery, the sequential activation of cells and bioactive molecules necessary for fracture healing can still be disrupted. When this sequential activation is interfered, a nonunion often develops. To aid in the healing of some acute fractures and nonunions, bone grafts and bone graft alternatives—specifically autologous bone grafts, allografts, synthetic bone grafts, and osteoinductive proteins—are available.
The ability for grafts to promote healing depends on their osteoconductive, osteogenic, osteoinductive, and osteopromotive qualities. Osteoconduction refers to the ability of a substance to serve as scaffolding for new bone growth. Osteogenesis refers to osteoblastic cells that may be present in the graft substance that are able to contribute to new bone growth. Osteoinduction refers to growth factors and cytokines present within the grafts that are able to stimulate differentiation of osteoprogenitor cells into osteoblasts. Osteopromotion refers to the ability of a substance to enhance osteoinduction without being osteoinductive on its own.1 Each bone graft type and bone graft alternative possesses some combination of these qualities. This review outlines the benefits of autografts, the most suitable sites for harvesting bone grafts, the timing of bone graft procedures, the potential risks and benefits of grafting in the face of infection, and the currently available bone graft extenders.
BONE GRAFT: IS ANYTHING AS EFFECTIVE AS AUTOGRAFT?
The iliac crest bone graft (ICBG) is the gold standard for cancellous autografts in cases in which fracture healing rather than void filling is required. It is corticocancellous with osteoconductive, osteoinductive, and osteogenic properties. Hernigou et al2 demonstrated that ICBG is rich in colony-forming cells, and the number of progenitor cells directly correlates with healing. In a comparison of 3 bone graft harvest sites, Takemoto et al3 demonstrated that bone graft obtained from the iliac crest had increased expression of bone morphogenetic proteins (BMPs), BMP receptors, and other factors as compared with proximal tibia or humerus bone. Despite the relative advantages of ICBG, it is not without limitations. The main concern with its use is donor site morbidity. ICBG also leads to increased time in the operating room, and an increased length of hospital stay.4,54,5 For certain patients with compromised bone or inadequate volume for grafting, bone graft substitutes may be preferable.
Substitutes to bone grafting include bone bank allograft, demineralized bone matrix (DBM), osteoconductive materials, and osteoinductive proteins. The orthopaedic community has extensive experience with bone bank allograft, with the first clinical tissue bank opening in 1949.6 Allografts do however carry the risk of rejection and disease transmission. There are also issues of inconsistent incorporation and late resorption. An alternative to bone bank allograft is DBM. DBM is prepared from an allograft with the inorganic material removed. Urist7 demonstrated that DBM implanted intramuscularly resulted in new bone formation. Since then, DBM has been shown to be osteoconductive but only weakly osteoinductive.
Synthetic osteoconductive materials are a common alternative to bone graft in orthopaedic practice, and include hydroxyapatite, coralline hydroxyapatite, CaPO4 and CaSO4 cements, and collagraft. Hydroxyapatite possesses a porous structure comparable to the cancellous bone and functions as an effective osteoconductive matrix. The mineralization and remodeling of this material can lead to formation of mature bone. Coralline hydroxyapatite is a similar product, in which coral is converted to pure crystalline hydroxyapatite. It possesses good compressive strength, but has low tensile strength and limited remodeling potential. Both hydroxyapatite and coralline hydroxyapatite function strictly as osteoconductive materials, lacking osteogenic and osteoinductive properties. Calcium-based bone cements are osteoconductive and primarily used for filling metaphyseal defects. They have adequate compressive strength, but lack resistance to torsional and shear forces, and come at a very high cost.8 They are also associated with resorption, leading to wound drainage.9 In situations in which osteoconduction is not the primary concern, but osteoinduction is required, BMPs are available.
The genetic sequences of BMPs were first identified by Wozney et al.10 Specific functions of the 14 subtypes of BMP were later identified by Cheng et al.11 Of the various subtypes, BMP-2 and BMP-7 have shown success in human trials.12 In addition, Einhorn et al13 demonstrated that injection of BMP-2 accelerated the healing of femoral fractures in animal models, with injected animals having larger and more vascular callus formation. BMP-7 has also exhibited promising results in animal models. Makino et al14 showed that test fractures that were stripped of periosteum healed when treated with BMP-7, whereas control fractures developed nonunion. Friedlaender et al15 conducted clinical trials in which 124 patients with tibial nonunion were randomly treated with intramedullary nailing and either ICBG or BMP-7. No difference in outcomes was observed between both groups. Giannoudis et al demonstrated a potential synergistic effect between ICBG and BMP-7 in a small cohort with 100% union rate, postulating that autograft provides the cell population whereas BMP-7 activates the provided cells.16,1716,17 A 2010 Cochrane review doubts the cost-effectiveness of BMPs and suggests that they are unlikely to be cost-effective for tibial nonunion as a primary treatment.18
Autogenous bone graft remains the only clinically available graft option that is osteogenic, osteoconductive, and osteoinductive.19 However, osteoconductive materials may work as bone void fillers. Bone graft substitute development is largely driven by autograft limitations, not increased effectiveness. The iliac crest remains the best location to obtain autogenous bone graft.
EFFICACY OF AUTOGRAFTS: DO HARVEST SITES MATTER?
A number of different harvest sites have been described for harvesting autograft bone, including the iliac crest, distal femur, proximal tibia, distal tibia, proximal humerus, and distal radius. Intramedullary reamings from the femur or tibia and vascularized bone grafts from the fibula, rib, or iliac crest have also been used in the past as sources of autologous bone. Among these, the most commonly used are the iliac crest and morselized bone graft from the femoral diaphysis.
A number of criteria are relevant when evaluating the quality of an autograft source. First, the components of the fracture-healing process provided by the graft should be assessed, including osteoconduction, osteoinduction, osteogenesis, and vascularity. Second, there are practical issues, such as the volume of graft obtainable and the ability to obtain structural support from the graft (eg, tricortical iliac crest). Third, the morbidity and potential complications associated with harvest should be considered. Finally, the clinical results/efficacy and cost of the graft source are of clear importance.
There is emerging evidence to suggest that bone harvested from the iliac crest contains factors and cells that stimulate angiogenesis and vascularity.20,2120,21 In terms of graft volume, the crest is superior to other conventional sites of harvest. Recently, there has been a substantial amount of research and clinical interest in a potential “ new standard” using the reamer–irrigator–aspirator (RIA), which is a novel system for harvesting intramedullary reamings from the canal of the femur or tibia. Recent evidence suggests that RIA graft possesses equivalent osteoconductive and angiogenic properties as ICBG, with potentially superior osteoinductive and osteogenic properties.20–2220–2220–22
Clinical evidence suggests that RIA results in larger volumes of graft with potentially less harvest site morbidity and pain compared with ICBG.23−2623−2623−2623−26 A recent randomized trial of ICBG (anterior or posterior) versus RIA graft for the treatment of long bone nonunions or bone defects was performed in 133 patients.27 The authors reported no difference in union rates between the 2 grafts, with significantly less donor site pain with RIA. In addition, they found significantly more graft volume with RIA compared with anterior ICBG and significantly shorter operative time when RIA was compared with posterior ICBG.
In summary, although ICBG remains the gold standard for autogenous bone grafting, there is emerging evidence to support the use of RIA bone graft that can provide large volumes of graft in an efficient manner, with potentially less harvest site morbidity. The cost of RIA remains an issue, and further prospective comparisons of the 2 graft sources, including economic evaluations, are warranted.
BONE GRAFT TIMING: WHAT IS THE MOST OPTIMAL TIME?
The optimal timing for bone grafting is not well supported by any contemporary high-quality evidence. There is great variability in clinical scenarios that affect a surgeon's choice of timing. There are essentially 3 options: immediate bone grafting (at the time of the index surgery), subacute bone grafting (performed at a second surgery but still in the acute phase of treatment), or delayed bone grafting (weeks after a primary surgery). Currently, for many high-energy injuries or critical bone loss situations, delayed bone grafting is selected. This choice is based on both theoretical concerns about the negative effects of high levels of inflammation during acute graft applications and theoretical benefits of the revascularization of graft recipient sites.28,2928,29
With the structural damage of an acute fracture, there is local vasoconstriction, hypoxia, and acidosis. Most significantly, there is an intense inflammatory cell infiltrate, and macrophages are present in the local milieu to signal repair and remove necrotic debris. Histologic studies of bone graft sites verify 2 distinct but overlapping stages of intense inflammation with bone resorption concurrent with the onset of new bone growth.30 Comparatively, an allograft creates more and more sustained inflammation than does an autograft. In these studies, inflammation is seen for up to 4 weeks. If there is concern about the role of acute inflammation in affecting incorporation or resorption of bone, this initial 4-week window might be problematic.
The technique of an induced membrane for management of critical bone defects has strongly influenced approaches to contemporary cancellous grafting in trauma surgery. After the initial experience and basic science work, secondary grafting of defects after membrane induction is typically performed 4–6 weeks after index surgery. Subsequent studies suggest that an induced membrane may have higher levels of biological activity before that time point, but the exact time course remains unclear.31–3431–3431–3431–34
Concerns about early inflammation and its negative effects on graft incorporation may be flawed. Although, in general, there is a current trend toward delayed bone grafting approaches, there is no clear evidence supporting long delays, and thus more acute approaches require further consideration.
GRAFTING IN THE SETTING OF INFECTION: STRATEGIES
The presence of infection is a genuine issue with regard to being able to use a bone graft. This applies for autologous and heterologous (nonviable) tissue and spacers used as implants.
There are 3 major considerations when using a bone graft in the setting of infection:
- The ability of the surrounding tissue to provide the biologic background for healing;
- The biomechanical stability present to enable the biologic reactions that promote ingrowth;
- Finally, if 1 and 2 are present, one has to decide whether a 1- or 2-stage surgery should be performed.
The best example of 1-stage surgery is chronic infection of the spine. In many instances, radical evacuation of the infected region and replacement of the vertebra are performed in one operation. This is followed by antibiotic treatment consistent with the findings of the intraoperative specimen.
For infection in the extremities, 1-stage surgery is usually too risky because of issues with vascularity and soft tissue coverage. In many cases, bone defects occur and are accompanied by both poor vascularity and poor soft tissue coverage. Moreover, the presence of cortical bone in the extremities is important, as it requires a longer recovery period for healing. In a 2-stage approach, initial therapy requires radical debridement of the infected bone and soft tissues. The induced membrane technique is then the current method of choice for 2-stage procedures. In the first phase, polymethylmethacrylate (PMMA) cement is combined with antibiotics and inserted as a spacer into the bone defect. After 6– 8 weeks, healing of the soft tissues is typically achieved. Histologic and animal data have clearly shown that upon removal of the cement spacer, well-vascularized tissue, or an induced membrane, surrounds the area. In chronic infections, there is usually no foreign body reaction to the PMMA spacer, as would be expected with other foreign bodies, such as prosthetic implants.35,3635,36
An autologous bone graft can then be used if no drainage, development of a sinus, or other signs of infection develop. The induced membrane acts as a biologic chamber, preventing resorption of the bone graft and promoting the vascularization and formation of bone through growth and other osteoinductive factors. This seems to be the case even after irradiation or specific bone diseases, such as congenital pseudarthrosis.
BONE GRAFT EXTENDERS: WHICH ONES WORK?
When using bone graft extenders, the surgeon should bear in mind 2 primary considerations. The first is the desired function of the extenders. Sometimes the goal is to increase the volume of the autograft or replace the autograft entirely, whereas other times, it is to increase the bioactivity of the graft and make the graft more “potent.” There are many “extenders” and all have varying properties depending on the surgical goal. The other pertinent consideration is the location of the graft in terms of metaphyseal versus diaphyseal bone, and the presence of a contained or uncontained defect. The augmentation material must match the biologic, mechanical, and anatomic requirements of the pathologic location of the graft. One material does not work for every graft enhancement situation, and thus multiple materials are available to augment fracture healing through a myriad of biologic pathways.
Some of the most widely used extenders are the calcium ceramics, specifically calcium phosphate and calcium sulfate. Ceramics can be combined with autografts to serve as graft extenders, or can be placed by themselves as conductive substrates for metaphyseal defects. Calcium sulfate has a crystalline-independent rate of incorporation and degrades through a chemically mediated pathway. CaSO4 behaves as a “true salt” in a fluid, dissolving into its respective Ca2+ and SO42− ions. This ionic load produces an osmotic effect in an uncontained defect and generates wound drainage when used in a situation with poor soft tissue coverage. Calcium sulfate exhibits a rapid degradation rate with an associated loss of compressive strength, and is therefore limited in its application for bone defect management. The best use of this material therefore seems to be as a carrier for adjuvant antibiotics used in the treatment of osteomyelitis in contained defects.37–4437–4437–4437–4437–4437–4437–4437–44
Calcium phosphate substitutes are osteoconductive, but are not osteoinductive unless other osteoinductive/osteopromotive substances are added to the graft material. Adding an osteoinductive factor to an osteoconductive calcium phosphate matrix creates a composite graft and can theoretically increase bone formation. Many clinical series use composite ceramic grafts, combining the scaffolding properties of calcium phosphate materials with biologic elements to stimulate cell proliferation and differentiation. These materials have variable rates of osteointegration and compressive strength based on their crystallite size, stoichiometry, and inherent porosity. When combined with autogenous ICBG, these ceramics function as graft extenders, yielding results comparable to those obtained with autograft alone.45–4745–4745–47
DBM is highly osteoconductive because of its particulate nature, large surface area, and complex 3-dimensional architecture. Osteoinductive growth factors including BMPs and other inductive factors are also present. These properties make this material highly desirable as a graft extender when mixed with autograft or marrow aspirate. Numerous studies suggest that particulate DBM enriched with bone marrow may be comparable to autograft for treating long bone fractures and nonunions. Furthermore, studies examining the use of autograft plus DBM have consistently found that a reduced amount of harvested autograft is required, with no loss in graft efficacy, confirming the use of DBM as a bone graft extender.2,48–502,48–502,48–502,48–50
Despite numerous promising substitutes, autogenous bone from the iliac crest remains the gold standard for bone grafts, as it possesses osteogenic, osteoconductive, and osteoinductive properties. When performing the grafting procedure, a 2-stage surgery using the induced membrane technique facilitates the preferred delayed grafting approach and is effective in the presence of infection. Finally, if a graft extender is required, then calcium ceramics—in particular, calcium phosphate combined with ICBG or DBM enriched with bone marrow—have been shown to be comparable to using autograft alone.
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