Fracture repair undergoes a well-orchestrated biologic progression that involves a multitude of singling pathways that are regulated by certain local and systemic factors. Any aberration from this cascade can impede or halt the healing process. Amongst these complications come delayed unions, nonunions and malunions. Treatment of these firstly depends upon reparation of alignment, stable fixation and complementary techniques such as bone grafting or bone graft substitutes to further encourage bone healing. Worldwide, it is estimated that about 2.2million bone graft procedures are performed each year (1). The indications for their use include: malunions, nonunions, arthrodesis and reconstructive procedures. This paper will explore the various types of bone grafts and substitutes, their properties and the clinical scenarios in which you would use them.
Properties of Bone grafts
There are three components that allow for the success of bone graft materials in abetting the healing of fractures and formation of new bone: an osteoinductive matrix, which is a scaffold that supports the ingrowth of new bone, blood vessels and perivascular tissue, as well as its attachment of osteoprogenitor cells; osteoinductive proteins, refers to the recruitment and differentiation of pluripotent mesenchymal stem cells into bone forming osteoprogenitor cells- this is mediated by graft derived growth factors such as bone morphogenic protein (BMP). Osteogenesis refers to the process of bone formation after terminal differentiation of osteogenic progenitor cells into mature osteoblasts. These three processes create the signals, scaffolds and cells necessary for the initial phases of fracture healing and one or more of these factors is usually present in bone grafts/substitutes. (2)
Bone grafting stimulates the sequence of events similar to most tissue regeneration and can be seen in Figure 1.
Osteoclasts resorb necrotic graft material
Production of regenerative, angiogenic, and inflammatory factors
Cytokine release (PDGF, TGF-Beta and FGF)
Circulating progenitor cell recruitment
Pluripotent cells respond to local factors
These cells differentiate into osteoblasts that produce osteoid
Remodeling of callus (woven bone)
Coordinated activity of osteoblast bone formation and osteoclast bone resorption
Mineralization of osteoid
Woven replaced by lamellar bone
Figure 1: Process of tissue repair in fractures
Osteoblast cells on the surface of the graft may survive the transplantation and contribute to the healing, however, the grafts main contribution to the injury site is to act as an osteoinductive and osteoconductive substrate. These properties provide the necessary environment to allow proliferation, infiltration and differentiation of bone forming cells and eventual fracture healing. (3)
Types of Bone grafts
Possessing excellent osteoinductive growth factors, an osteoconductive matrix and osteogenic stem cells provide consistent results with regards to healing and integration therefore making it the ideal bone graft. Also graft versus host disease and any disease transmission is eliminated since it’s the patient’s own bone. This graft behaves primarily as osteoconductive substrate, effectively promotes the ingrowth of new vasculature and infiltration of new osteoblasts and osteoblast precursors (4-7).Osteoinductive factors released during the resorptive stage as well as cytokines released during the inflammatory stage may also contribute to the healing of the graft (8,9).
Autologous Cancellous Graft
This is the most commonly used bone graft source. This graft serves as a scaffold for the attachment of host cells and provides osteoconductive and osteoinductive features required for the laying down of new bone. However, this type of graft lacks immediate structural stability and strength therefore cannot support force transmission alone. Even though it lacks in mechanical strength, makes up for it in tremendous biologic activity – The lining of the trabeculae of the graft material are pluripotent progenitor cells capable of differentiation into osteoid producing cells (10). The large surface area leads to immediate graft incorporation via formation of new blood vessels and differentiation of progenitor cells to mature bone forming cells. Graft appears completely vascularized within first couple days. Cancellous graft also serves as a scaffold to be resorbed as the mature osteogenic cells lay down a new osteoid matrix (11). While cancellous graft does not provide structural support by itself, when aided by internal fixation, it can be used for areas of bone loss.
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Cancellous bone grafts consist of potions of spongy bone spicules with living bone cells. A variety of complications are associated with cancellous bone grafting. Not only is it common experience that the donor site is very painful and may delay ambulation, but the technique has been associated with bleeding, infection, nerve damage, arterial injury and iatrogenic fractures. Cancellous grafts are often harvested from the anterior or posterior iliac crest, as it supplies a large sum of bone. Other sources are Gerdy’s tubercle, distal part of radius and distal part of tibia (14).
Autologous Cortical Graft
This graft provides good structural support but has much weaker osteoconductive and osteoinductive properties, therefore is indicated when immediate structural support is needed. This graft has slightly inhibited long-term healing potential which is partly due to thickness of cortical matrix. This limits the diffusion of nutrients and subsequent neovascularization and osteogenesis. The density of the graft also limits the remodeling process as the bone incorporation process will rely on osteoclasts breaking down the bone rather than osteoblasts making new bone. This resorption phase during the first 6 months leads to progressive mechanical weakness which is eventually restored around a year after procedure. Remodeling proceeds and creeping substitution can require up to 2 years for completion (12). Cortical grafts are usually taken from the ribs, fibula and, mainly, from the iliac crest. Utilization of this graft also poses the same morbidity risks as the cancellous graft.
Vascularized Autologous Grafts
Autologous grafts can be transplanted with or without a vascular pedicle depending. Vascularized grafts differ in the rate of repair and the way in which remodeling in the bone occurs. The majority of these grafts are harvested from: the iliac crest with the deep circumflex artery, fibula with peroneal artery branches, medial femoral condyles with descending genicular artery branches, distal radius with supraretinacular artery branches and ribs with the posterior intercostal artery. Once implanted with its vascular pedicle, independent blood supply leads to significant biological activity and regeneration potential with retention of up to 90% of the grafts osteocytes. Dell et al. examined vascular versus non-vascularized graft necrosis based on amount of osteocytes present. At 2 weeks the vascularized graft remained mostly viable with the only area of necrosis noted at the periphery, while non-vascularized showed diffuse necrosis of medullary cavity taking 24 weeks to resemble the vascularized graft. The increase in osteocyte survival and early vascularity leads to rapid incorporation of the vascularized bone graft. Initial strength differences are due to the remodeling process. Nonvascularized incorporates through creeping substitution, vascularized grafts do not induce a robust inflammatory and angiogenic response compromising early mechanical strength (13).
Due to the morbidity associated with harvesting autologous bone graft and the limited quantity available when attempting to fill large defects, alternatives such as allogenic bone graft have gained in popularity. Annually, there are hundreds of thousands of allografts used around the world (15). Allografts are harvested from a number of sites including the pelvis, ribs and fibula. Allografts are frequently used in spinal surgery, joint arthroplasty and upper/lower-extremity arthrodesis (18). There are limitations associated with allograft efficacy and this may be due to how the grafts are prepared. As these grafts are not coming from the host, there is a risk of disease transmission. However, according to the American Association of Tissue Banks, no cases of HIV transmission have been reported in more than 2 million cases using allograft bone in the past 5 years (17).Still, to decrease this risk, allograft bone is prepared and sterilized via freeze drying, freezing or irradiation. Freeze drying significantly reduces immunogenicity via removal of water and vacuum packing tissues. For example, it reduces the osteoblast expression of the major histocompatibility complex (MHC) class 1 antigen. This blunts the host immune response that is modified by MHC antigens (16). Furthermore, Pecker et al (19). demonstrated that such treatment of the graft reduces its mechanical integrity thus reducing its load bearing capabilities. Irradiation has a similar effect on the mechanical strength, decreasing it in a dose dependent osteoinductive potential of the allograft by inducing the death of osteoprogenitor cells. Although slower than with autografts, allograft incorporation occurs through a similar process. Delayed incorporation is in part due to the paucity of donor progenitor cells, and partly due to the inhibitory host immune response to the allograft that inhibits osteoblastic differentiation- mononuclear cells have been demonstrated to line newly developing blood vessels. Thus, a limited initial revascularization, creeping substation and ultimate remodeling lead to a higher incidence of early fractures (20). The biologic nature of the recipient host bed is critical factor in facilitating allograft incorporation. Allograft bone incorporation occurs by sporadic appositional bone formation and is dependent on neo-angiogenesis. A well-vascularized bed aids in the incorporation process through a combination of revascularization, osteoconduction and remodeling. However, poor vascularization, as seen in some larger defects, leads to prolonged incorporation process and significant mechanical weakness (21). A technique first described by Wang and Weng to combat the relative inertness of cortical allografts involves placing harvested autologous iliac crest at the allograft-host bone interface. They treated 13 patients with femoral non-unions via ORIF with deep cortical allograft struts. Autologous bone grafts were inserted into the defect between the allograft and host femur. All the nonunions united at an average of 5 months. Therefore, this graft shows promise when augmented with other, more osteoinductive, grafts that may not have enough volume alone to repair the fracture. Allografts are also taken from various flat and long bones for the reconstruction of joint loss. From these areas you are able to take the full bone or just partial, segmental regions from them (22). These are used for limb salvage procedures or as cortical struts to buttress existing bone. These grafts are osteoconductive and provide immediate structural support.
Demineralized Bone Matrix
DBM is produced by acid extraction of allograft bone. It contains type 1 collagen, non-collagenous proteins and osteoinductive growth factors such as BMPs and TGF-Betas. However, similar to allografts, they provide little structural support. Nonetheless, the abundance of growth factors gives it more osteoinductive potential than allografts. There are various DBM formulations available based off manufacturing processes that include freeze-dried powder, granules, putty/gel and strips. Despite all this, there is minimal clinical data to support their efficacy. Furthermore, donor-to-donor variability in the osteoinductive capacity of DBM exists, resulting in the requirement that each batch of DBM be obtained from a single human donor. Bae et al. examined 10 production lots of a single DBM product, demonstrating significant variations in the BMP-2 and BMP-7 content, both of which have a core impact on fusion rates. Animal studies have demonstrated monocyte cell infiltration into the graft within 18 hours and cartilaginous differentiation of progenitor cells within the first week after DBM grafting. Cartilage mineralization ensues, followed by perivascular infiltration and the eventual formation of osteoblasts leading to complete resorption and bone formation(23). In humans, multiple case series have demonstrated DBM to be viable alternative in both acute and nonunion fractures, arthrodesis and implant fixation. Ziran et al (24). followed 107 patients treated with DBM and allograft cancellous chips for the treatment of acute fractures. He found that 87 fractures healed at a mean of 32 months. However, Ziran et al (25). also reviewed retrospectively, 41 patients with nonunions treated with human DBM and post-operative complications were high with 51% experiencing wound complications and of the 41 patients only 22 went to heal the nonunion without the need for additional bone grafting. The efficacy of DBM as a graft material remains unclear. Although widely available and known to contain BMP- there is very limited studies demonstrating the efficacy when used alone. However, when used in conjunction with autologous cancellous bone and stable internal fixation, it has a tremendous potential. (26). There are a few potential downsides to the matrix. As it is allogenic material, transmission of human immunodeficiency virus is a possibility. However, it has been reported that the decalcification portion of the process seems to inactivate and eliminate HIV (27). One manufacturer, Osteotech, states that there have not been any reported cases of disease transmission in 1.5 million procedures with the use of one particular preparation of the demineralized bone matrix. (28).
Bone Graft Substitutes
The main purpose of these is to provide Osteoconduction for the fracture. The ideal scaffold should have the appropriate 3-D structure to promote osteoconduction and allow osteointegration and invasion by cells and blood vessels. In addition, it should be biodegradable with biomechanical properties similar to the surrounding bone.
Calcium Phosphate Ceramics
These are osteoconductive materials produced by a process called sintering in which mineral salts are heated to 1000°C. These can be divided into slow and rapidly resorbing ceramics. This is important when considering whether the structure needs to provide long term structural support or if it is acting as a void filler that will be quickly replaced. These can provide osteoconduction without risk of disease transmission. In addition to osteoinduction these products are also osteointegrative, having the ability to form intimate bonds with tissue (29).
Hydroxyapatite is a slowly resorbing compound derived from both animal and synthetic sources. It is degraded by osteoclasts within 2 to 5 years. Hydroxyapatite has a very similar structure to trabecular bone, with pore diameters of between 200-500µm. A commercial hydroxyapatite, Apapore-60, has shown promise in acetabular defects. McNamara et al (31). demonstrated a 100% clinical survival for acetabular total hip reconstruction when using irradiated allograft one with hydroxyapatite. However, as a stand-alone implant for fixation in studies exploring distal radius fractures, hydroxyapatite did not show promising results (30).
TCP undergoes partial resorption and some of it may be converted to HA once implanted in the body. The composition of TCP is very similar to the calcium and phosphate part of human bone. This, combined with its porous nature, appears to facilitate incorporation with host bone with both animals and humans by 24 months. TCP is more porous and is resorbed faster than hydroxyapatite making it mechanically weaker in compression (32). McAndrew et al(33). investigated the suitability of TCP to treat bony defects in a series of 43 patients with fractures and 13 nonunions. After 1-year patients with fractured demonstrated 90% healing and 85% in those with nonunions. Similar to Hydroxyapatite, TCP has shown promise in acetabular grafting for hip revision surgery. Multiple biomechanical studies have demonstrated superior stability when TCP is used with allografts versus used alone. Because tricalcium phosphate has an unpredictable biodegradation profile it has not been popular as a bone-graft substitute (34). However, Bucholz et al. (1989) showed that tricalcium phosphate is effective for filling bone defects resulting from trauma benign tumors and cysts (35).
Calcium Sulfate, or Plaster of Paris, acts as an osteoconductive material which completely resorbs within 6 to 12 weeks as newly formed bone remodels and restores anatomic features and structural properties (36). Kelly et al. treated 104 patients with bone defects with calcium sulfate pellets alone or mixed with other bone graft substitutes. After 6 months, 44% of the pellets were resorbed and 88% of the defects were filled with trabeculated bone. (37)
The attainment of proper axial alignment, adequate stability and the preservation of vascular supply remain the most important factors for successful treatment of acute fractures as well as delayed unions and nonunions. In fractures that do not heal or that heal slowly, there is an abnormality in either the biology, mechanical environment or both. Therefore, unless the mechanical environment of the fracture site is optimized by increasing the stability of the fracture, manipulation of the biology at the fracture site with bone graft or bone-graft substitute will have limited success. The first step in matching the graft to the clinical problem is to decide whether the problem is a lack of osteoinduction and/or osteogenesis or one of structural bone loss requiring load-bearing graft.
The advantages of this type of graft is their excellent success rate, as well as the fact that they have a low risk of transmitting disease and histocompatibility. Yet, as mentioned above, there is a finite amount of autologous bone graft and there is the chance for donor site morbidity.
These grafts have osteoconductive, osteoinductive and osteogenic factors. They are the gold standard due to having all three of these components and can be used in a majority of incidences. However, this graft is unable to withstand much load bearing and due this cannot be used in defects that require immediate structural support. Examples of situations where you would use this graft include: If a non-union is present that is < 6cm, does not need structural integrity from the graft and a stimulus for new bone formation is needed, then the autologous cancellous graft is ideal. You can also use them to fill bone cysts or bone voids after reduction of depressed articular surfaces such as in tibial plateau fractures.
These grafts contain all three factors needed to help support new bone growth, however they are incorporated at a much lesser extent. Therefore, one would always prefer to go with cancellous instead as there is a higher outcome for healing. However, cortical grafts offer much more structural integrity and would be useful in diaphyseal defects that are too large to heal reliably with cancellous bone-grafting.
This graft has blood supply that is immediately restored, this makes it more viable due to the increased survival of graft osteocytes. Vascularized cortical autografts should be reserved for use in areas of marginal blood supply (such as the scaphoid femoral neck or talus) or for defects >12 cm, as vascularized grafts are superior to nonvascularized grafts in this case. This is indicated by failure rates of 25% and 50% respectively (38). Vascularized grafts are also indicated for reconstruction of defects where the microenvironment of the host is inadequate to initiate an effective biologic response. Examples include acute traumatic injuries with extensive soft tissue damage and impairment of blood supply, atrophic nonunions, and irradiated or severely scarred tissue. (39-41).
There a plentiful supply of this graft, though there is a chance of infection depending on the preparation process. This graft provides an osteoconductive scafflold, with little osteogenic potential due to death of osteocytes and other factors that occur in the preparation of the graft. Therefore, this graft would be best suited to being used to provide structural support of a fracture. They also have shown use when augmented with autologous grafts to fill larger defects when autologous graft is scarce.
DBM contains proteins and various growth factors in the extracellular matrix that account for its biologic activity, and these are made accessible to the host environment by the demineralization process. This gives the graft osteoinductive properties that help stimulate the production of new bone in fractures. Although, the amount of these proteins is variable between batches and also depending on the preparation method, which can reduce the number. This graft also offers very little structural support so would be most effective when used to activate bone formation skeletal defects that are not lacking in structural integrity, within bone cysts and cavities (42-43). Also, using this graft in combination with autologous bone provides an osteogenic advantage and has the possibility of enhancing the ability of a fixed volume of autologous graft to be more effective.
These grafts act mainly as osteoconductive scaffold with osteointegration. Their use is limited due to their low tensile strength. Uses of this gone graft substitute would be best as bone void fillers, especially when supplemented with another graft that has osteoinductive and osteogenic properties- such as autologous grafts or DBM. You would also have to use this graft in areas where the tensile strain is low as they do not offer structural support to the defect.
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