Synthetic Bone Grafting in Foot and Ankle Surgery

Synthetic Bone Grafting in Foot and Ankle Surgery

Synthetic Bone Grafting in Foot and Ankle Surgery Vinod K. Panchbhavi, MD, FRCS (Eng) KEYWORDS  Calcium sulfate  Calcium phosphate  Synthetic bon...

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Synthetic Bone Grafting in Foot and Ankle Surgery Vinod K. Panchbhavi,

MD, FRCS (Eng)

KEYWORDS  Calcium sulfate  Calcium phosphate  Synthetic bone graft

SYNTHETIC BONE GRAFTS

Bone grafts are used by surgeons in the management of a wide variety of conditions, including tumors, trauma, and infection.1 Autografts have long been held as the gold standard for bone graft procedures because they contain osteogenic bone cells, marrow cells, and an osteoconductive collagen matrix suitable for new and existing bone-cell attachment and migration as well as osteoinductive proteins and factors endogenous to bone.2 In addition, autogenous bone is not antigenic but the harvesting of autogenous bone requires a second operation and can be associated with substantial donor site morbidity and complications. The common problems that have been reported include pain at the donor site, meralgia paraesthetica as a result of injury to the lateral femoral cutaneous nerve, injury of the superior gluteal artery, pelvic fracture, hematoma, infection, and gait disturbances.3–6 Furthermore, the amount of autogenous bone graft available for harvesting is limited and may be insufficient to fill large osseous defects. The quality of the harvested autogenous bone is also variable. One alternative to autograft is allograft, or tissue taken from a cadaver. With allografts limited supply is less of a problem but there is a potential for disease transmission from donor to recipient.7 Additional allograft complications have been reported at the 10-year mark, with as many as 30% to 60% of allograft implants encountering some sort of complication that may lead to failure of the structural allograft.8–10 Given the shortcomings of autografts and allografts and the growing demand for bone grafts, several alternative synthetic materials are being investigated. They share numerous advantages over autografts and allografts, including their unlimited supply, easy sterilization, and easy storage. The synthetic bone graft substitutes described later are mainly used for their osteoconductive abilities. The term osteoconduction refers to a process in which

The author has nothing to disclose. Division of Foot & Ankle Surgery, Department of Orthopedic Surgery, University of Texas Medical Branch, 301, University Boulevard, Galveston, TX 77555-0165, USA E-mail address: [email protected] Foot Ankle Clin N Am 15 (2010) 559–576 doi:10.1016/j.fcl.2010.07.004 1083-7515/10/$ – see front matter Ó 2010 Elsevier Inc. All rights reserved.

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the three-dimensional structure of a substance is conducive for the ongrowth and/or ingrowth of newly formed bone. Osteoconductive materials essentially provide a substrate, or matrix, that supports the migration, attachment, and proliferation of mesenchymal stem cells, which then differentiate into osteoprogenitor cells that form bone. These substances typically have a microscopic structure similar to that of cancellous bone as well as attractive surface kinetics. During osteoconductive bone ingrowth, capillaries, perivascular tissue, and osteoprogenitor cells migrate into the bone graft substitute; newly formed bone is produced within its porous spaces.11,12 Pore size and porosity are important characteristics of bone graft substitutes. No osseous ingrowth occurs with pore sizes of 15 to 40 mm. Osteoid formation requires minimum pore sizes of 100 mm; pore sizes of 150 to 500 mm are reported to be ideal for osseous ingrowth.13 However, some investigators have reported that pore size may be less critical than the presence of interconnecting pores for osseous ingrowth. Interconnecting pores prevent the formation of blind alleys, which are associated with low oxygen tension; low oxygen tension prevents osteoprogenitor cells from differentiating into osteoblasts.14 In addition to providing a mechanical buttress, these osteoconductive scaffolds may prevent soft tissue from occluding the space and hindering bone formation. Peltier and Jones15 showed that osteoconduction requires the bone graft substitute to have a resorption rate similar to the rate of new bone formation. If the rate of resorption is faster than the rate of bone growth, the new bone does not have a scaffold on which to travel. Conversely, if the graft material resorbs too slowly, it may stay in the osseous defect and block the ingrowth of new bone. Ceramics used as scaffolds for fracture repair can be subdivided into 3 main categories by their chemical reactivity following transplant: bioabsorbable ceramics, bioactive ceramics, and bioinert ceramics.16 Bioabsorbable and bioactive substances are able to physically bond directly to the host bed, whereas bioinert ones never actually bond to the bone. Nonbiodegradable polymers form another class of osteoconductive grafts.17 Bioabsorbable ceramics were the first synthetic materials used in bone transplantation. The ones that are commonly used include calcium sulfate, calcium phosphate, and tricalcium phosphate (TCP). These products vary considerably in their chemical composition, structural strength, and resorption/remodeling rates.18 They may be used selectively or in combination. The surgeon must understand the chemical composition, physical characteristics, and bioactivity of various synthetic substitutes and the differences between them to select a bone graft substitute that provides the properties desired for a specific clinical situation. Although bone graft substitutes are subject to varying degrees of regulatory scrutiny, specific proof of efficacy is not always required.19 Most bone graft substitutes currently marketed in the United States have been approved through a less stringent premarket notification (510[k]). In this process, the manufacturer must provide data showing that the new product is substantially equivalent to an already approved legally marketed device, which includes products commercially distributed before the May 28, 1976, Medical Device Amendment.19 Marketing claims are not always well supported by published data.20 There are a limited number of clinical studies and a lack of direct comparison studies between these products. In addition, the difficulty in showing new bone formation varies by anatomic region. Therefore, validation of the effectiveness of a bone graft substitute in one anatomic location may not be predictive of its performance in another. Thus, surgeons should avoid extrapolating available clinical evidence to other anatomic areas.

Synthetic Bone Grafting in Foot and Ankle Surgery

This article is a review of the chemical, physical, and biologic characteristics of synthetic bone graft substitutes used in foot and ankle surgery and of the available experimental and clinical studies. Calcium Sulfate

Calcium sulfate in the form of a hemihydrate is more commonly known to orthopedic surgeons as plaster of Paris, a material used for splinting and casting. When the hemihydrate form of calcium sulfate (CaSO4$0.5H2O) is mixed with water, a dihydrate known as gypsum (CaSO4$2H2O) is formed. The hemihydrate form of calcium sulfate (CaO4S), a bioabsorbable ceramic, is prepared by heating gypsum. Calcium sulfate is one of the oldest bone graft substitutes. Its reported use dates to 1892. Calcium sulfate was first used by Dreesmann21 to obliterate bone cavities caused by tuberculosis. Peltier22 became the first American to report on the use of calcium sulfate as a bone graft substitute. He established that calcium sulfate can be resorbed and replaced by bone in vivo. Peltier23 further concluded that the presence of calcium sulfate in a wound did not inhibit the formation of bone and that it was removed from the site of implantation irrespective of whether new bone formation occurred. Infection in wounds containing calcium sulfate was not complicated by sequestration of the material; it either drained out or was absorbed. Peltier and Jones15 found that calcium sulfate is safe to use in a variety of cavitary bone defects, that it is completely resorbed, and that regeneration of bone occurred in weeks to months. However, despite its initial success, the use of calcium sulfate was later associated with inconsistent results. This situation may have been due to impurities and a nonuniform structure of the calcium sulfate crystals. Subsequent improvements in the production of calcium sulfate have resulted in a high-grade material that is more suitable for surgical applications. Contemporary medical-grade calcium sulfate is inexpensive, can be sterilized and prepared easily, has an indefinite shelf life, and can be used in various sizes of osseous defects. Its resorption can also be monitored radiographically because it is radiopaque.24,25 Calcium sulfate works in an osteoconductive manner, providing a scaffold into which new bone can grow. Walsh and colleagues26 hypothesized that the mechanism of bone regenerative action of calcium sulfate is related to the local acidity produced during its resorption. These investigators postulated that in a confined cancellous defect, this local acidity results in demineralization of the adjacent bone, with a release of matrix-bound bone morphogenetic proteins that have a stimulatory effect on bone formation. It has been shown that osteoblasts attach to calcium salts. In cultures of rat bone, Sidqui and colleagues27 observed that osteoblasts attach to the surface of calcium sulfate pellets, and osteoclasts can resorb the mineral in vitro. A similar mechanism in vivo may be responsible for the resorption and rapid regeneration of bone defects by calcium sulfate.28 During the process of resorption, there is vascular infiltration, osteoid deposition, and ultimately restoration of the defect with new mineralized bone trabeculae. The new bone is seen layering on the microscopic residual of CaSO4 as it is substantially resorbed in the 6-week period.26,29,30 In a canine humeral model, Turner and colleagues31 studied bone regeneration around pellets of calcium sulfate. Six weeks after implantation, thin trabeculae of new bone spanned the space between pellets, and by 24 weeks the pellets had resorbed and the bone regeneration was qualitatively similar to that seen after autogenous bone grafting indistinguishable by volume or by histologic features from that of autograft-filled defects. New trabeculae of bone are easily distinguishable on radiographs from the amorphous calcium sulfate pellets.

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As with other calcium-based bone graft substitutes, CaSO4 is well tolerated, evoking minimal inflammatory or foreign body reaction.19,29–31 The rapid 6-week resorption period seems ideal for early bone repair.29–31 However, the rapid resorption may be responsible for the development in some clinical applications of serous drainage, which usually resolves spontaneously.32 It has been theorized that this serous drainage is the result of the osmotic effect of the calcium sulfate and that it subsides with calcium sulfate resorption.33 Calcium sulfate is available either as individual pellets or as a powder that can be mixed in solution to form an injectable paste or molded to form desired shapes. Its compressive strength is similar to that of cancellous bone.34 Some setting solutions for use with the powder are proprietary, and these solutions may differ between companies.33 Calcium sulfate is available in a variety of forms, the most common being hard pellets of calcium sulfate hydrate (eg, Osteoset, Wright Medical Technology, Arlington, TN, USA; JAX, Smith & Nephew, Memphis, TN, USA; Calceon, Synthes, Paoli, PA, USA). Calcium sulfate hemihydrate is a powder that hardens when mixed with a diluent. Minimally invasive injectable graft (MIIG, Wright Medical) is an injectable calcium sulfate that hardens in vivo, allowing for filling voids percutaneously. Boneplast bone void filler (Interpore Cross International, Irvine, CA) and Osteoset T (Wright Medical) can be fashioned into beads and impregnated with antibiotics for local antibiotic treatment, thereby providing a major advantage in the treatment of infected bone. Use of calcium sulfate alone or in combination to fill bone defects has been reported in several studies. Watson35 reported promising results on the use of injectable calcium sulfate in 5 patients who sustained tibial plateau fracture and in 3 patients with tibial pilon fracture. Borelli and colleagues36 used a mixture of autogenous iliac crest bone graft and calcium sulfate to treat 19 patients with long-bone nonunions and 7 with acute fractures with large osseous defects. Calcium sulfate was used as a bone graft expander in conjunction with internal fixation. Union was successful following initial surgical treatment in 85% of patients. When autogenous bone graft is being placed to restore absent cortical bone, calcium sulfate may be used to fill the deeper intramedullary area; the bone graft is placed on top so that it remains in contact with the surrounding muscular soft-tissue bed.33 Gitelis and colleagues37 reported healing in 21 of 23 patients with bony defects treated with calcium sulfate, either alone or in combination with demineralized bone matrix. Mirzayan and colleagues25 described healing in 13 of 13 patients in their series with defects that resulted from treatment of benign bone tumors or osteomyelitis. All of the defects healed in a centripetal fashion, in which the more peripherally placed calcium sulfate pellets were resorbed first and the more central pellets were the last to disappear. The average time to healing was 13.4 weeks (range, 5–24 weeks). The rate of healing depended on the size of the lesion. In one patient, some calcification developed in the adjacent soft tissues because some of the calcium sulfate pellets had spilled out of the cavity intraoperatively. This calcification was seen to have disappeared on a 6-month follow-up radiograph. Kelly and colleagues32 in a multicenter trial reported on use of calcium sulfate pellets alone or in combination with demineralized bone matrix, autograft, or bone marrow aspirate in 109 patients with bone defects caused by tumor (42%), trauma (36%), and other causes (22%), such as periprosthetic bone loss and fusion augmentation. These investigators found that patients who were treated with calcium sulfate pellets alone had a greater amount of bone ingrowth than those who were treated with a mixture of calcium sulfate pellets and other substances. Four patients developed serous wound drainage that was believed to be related to the calcium sulfate product.

Synthetic Bone Grafting in Foot and Ankle Surgery

Fracture stabilization in osteoporotic bones presents a special challenge. A variety of techniques are used to prevent failure of fixation and to improve purchase of implants. Injectable calcium sulfate has been used to augment purchase of the tibia pro fibular screws in internal fixation of an osteoporotic ankle fracture (Figs. 1–5).38 Calcium sulfate combined with antibiotics eliminates the dead space with gradual local release of antibiotics and has been used with good results in management of osteomyelitis, although this represents an off-label use of the product in the United States. McKee and colleagues39 studied 24 patients with infected nonunions and bone defects treated with a CaSO4 delivery system for local antibiotics. Infection was eradicated in 23 of the 24 patients and union was achieved in 10 of 16 nonunions. Postoperative draining sinuses present at the time of pellet resorption cleared spontaneously. It seems that the slow resorption of the CaSO4 pellets and elution of the antibiotics maintained a prolonged delivery of local antibiotics. The calcium sulfate also may have permitted or facilitated new bone formation within the infected defects. Calcium Phosphate

Calcium phosphate is available in a variety of forms and products, including ceramics, powders, and cements.40 The various forms of calcium phosphate cement have

Fig. 1. Preoperative radiograph of an osteoporotic ankle fracture. (Reproduced from Panchbhavi VK. Augmentation of internal fixation of osteoporotic ankle fracture using injectable bone substitute. Tech Foot Ankle Surg 2007;6:265; with permission.)

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Fig. 2. Intraoperative fluoroscopy image showing the cannula in the screw hole. (Reproduced from Panchbhavi VK. Augmentation of internal fixation of osteoporotic ankle fracture using injectable bone substitute. Tech Foot Ankle Surg 2007;6:266; with permission.)

different mechanical and biologic resorption characteristics.41 The injectable paste of inorganic calcium and phosphate hardens in situ and cures by a crystallization reaction in a nonexothermic reaction to form dahllite, a carbonated apatite similar to that found in the mineral phase of bone. The injectable nature of calcium phosphate cement was designed to facilitate percutaneous administration.33,42 On implantation, the cements sets and begins to harden, and the cement interdigitates with the adjacent bone, thus forming a solid structure that is more mechanically stable than either cancellous bone graft or hydroxyapatite granules. It is bioabsorbable and compatible in vivo.42 Compared with cancellous bone grafts and other bone graft substitutes, calcium phosphate, when hardened, has a higher compressive strength (4–10 times greater than cancellous bone) and may be useful in preventing subsequent displacement or depression of reduced articular fragments. In materials testing, calcium phosphate cement has showed excellent strength in compression and strength equivalent to cancellous bone in tension (2 MPa).43 But calcium phosphate cements do not provide a high level of structural support because they are brittle and have little tensile strength.44,45 Calcium phosphate first became available in the United States as Norian skeletal repair system (SRS) (Synthes, Paoli, PA, USA). It is now available from multiple manufacturers. Animal studies have shown that the material is gradually remodeled in a manner that is qualitatively similar to normal bone remodeling. Over time, calcium phosphate undergoes osteoclastic resorption, followed by the invasion of small blood vessels that become surrounded by circumferential lamellae of new bone.42 Animal studies have shown that 95% of calcium phosphate is resorbed in 26 to 86 weeks.46,47 Incomplete resorption after 6 months has been reported in animal studies,41 and in 3 of 4 patients there was no change in the radiographic or computed tomography

Synthetic Bone Grafting in Foot and Ankle Surgery

Fig. 3. Intraoperative radiograph showing calcium sulfate in the track along the screw holes. (Reproduced from Panchbhavi VK. Augmentation of internal fixation of osteoporotic ankle fracture using injectable bone substitute. Tech Foot Ankle Surg 2007;6:266; with permission.)

appearance of the cement at 18 months after the operation.48 In humans, the histology of retrieved femoral heads previously implanted with Norian SRS showed remodeling processes identical to those observed in animal studies.49 Unlike calcium sulfate, which is crystalline, independent of the rate of resorption, and a true salt that can dissolve into Ca21 and SO42 ions, calcium phosphate materials, although crystalline, are dependent on the rate of resorption and are true ceramics and therefore do not dissolve within the joint. As a result, they may cause cartilage wear if left exposed in the intracapsular space.50 Concerns therefore have been expressed about potential intraarticular extrusion of calcium phosphate when used in intraarticular fractures; however, no adverse sequelae have been reported when extrusion has occurred.51 There do not seem to be any early adverse

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Fig. 4. Follow-up mortise view radiograph at 12 weeks showing no evidence of implant failure or displacement and complete resorbtion of calcium sulfate. (Reproduced from Panchbhavi VK. Augmentation of internal fixation of osteoporotic ankle fracture using injectable bone substitute. Tech Foot Ankle Surg 2007;6:267; with permission.)

effects, such as inflammation, and foreign body responses, to these ceramics when they are in a structural block arrangement.51 However, small granules of material have been shown to elicit a foreign body giant cell reaction.52,53 Injectable calcium phosphate cements have been proposed as a tool to fill voids in metaphyseal bone, thereby improving host bone strength and the purchase of metal devices.49 The most commonly used are the Norian SRS cement (Norian Corp, Cupertino, CA, USA) and the Bone Source (Stryker Howmedica Osteonics, Rutherford, NJ, USA). These cements are available as 2 components, one in powder form and the other as liquid, which are mixed manually or with a mixing machine in the operating room. After mixing, they are similar to toothpaste in appearance and can be easily injected in the area of interest. A recent meta-analysis of 14 randomized, controlled trials, one of which involved calcaneal fractures, suggested that the use of calcium phosphate bone cement for the treatment of fractures is associated with the benefits of (1) less pain at the fracture

Synthetic Bone Grafting in Foot and Ankle Surgery

Fig. 5. Follow-up lateral view radiograph at 12 weeks showing no evidence of implant failure or displacement and complete resorbtion of calcium sulfate. (Reproduced from Panchbhavi VK. Augmentation of internal fixation of osteoporotic ankle fracture using injectable bone substitute. Tech Foot Ankle Surg 2007;6:267; with permission.)

site compared with that in controls managed with no bone graft or no bone graft substitutes and (2) a reduced risk for losing fracture reduction when compared with autogenous bone graft. The results of individual studies suggested improved functional outcomes in association with the use of calcium phosphate cement. This finding could be explained by the fact that patients in the calcium phosphate group had less pain and less risk for loss of reduction.54 Displaced intraarticular calcaneal fractures continue to be a therapeutic challenge for orthopedic surgeons. The goal of operative treatment is to restore the complex foot and ankle biomechanics by performing an anatomic reduction of the subtalar posterior facet and restoring calcaneal height and length.55,56 The difficulty often arises in maintaining this reduction postoperatively. In axial loading injuries that cause displaced intraarticular calcaneal fractures, the trabecular cancellous bone of the calcaneus is crushed. Operative reduction leaves a sizable bone void beneath the elevated posterior facet. Despite stable internal fixation, evidence indicates that the presence of a bone void predisposes the calcaneus to collapse, resulting in a loss of both posterior facet reduction and calcaneal height.57 Cancellous bone graft has not been shown to prevent collapse, and the biomechanical properties of polymethylmethacrylate (PMMA) make it an unattractive option.57,58 Thordarson and colleagues59 performed a cadaver study that showed improved compressive strength and stability of the fixation of experimentally created calcaneal fractures when the construct was augmented with Norian SRS1. These investigators

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compared intraarticular calcaneal fractures fixed with standard internal fixation with those in which the osseous defect was filled with bone graft or SRS. In the specimens treated with the combination of hardware and SRS cement, cyclic loading produced significantly less deformation. Schildhauer and colleagues60 reported a series of 36 joint depression-type calcaneal fractures that had been treated with internal fixation augmented by calcium phosphate cement. They found that patients who had been allowed to bear weight as early as 3 weeks after the surgery had no radiographic evidence of loss of reduction, and there was no significant difference in functional outcome scores between patients who had been allowed to begin bearing weight before 6 weeks and those who began it after 6 weeks. However, the investigators did note an 11% infection rate. Seventyfive percent of the infections developed in smokers, and histologic evaluation of tissue from those patients showed no giant cells or eosinophils to suggest a foreign body or allergic reaction. Although this infection rate is an important outcome to consider, the investigators concluded that cement augmentation of internal fixation of joint depression-type calcaneal fractures allowed earlier weight bearing with no change in postoperative outcomes. Recently, 2 European clinical studies have investigated the use of bioresorbable calcium phosphate paste (Biobon, the European equivalent of a-BSM (bone substitute material; Etex Corporation, Cambridge, MA, USA) in trauma surgery and articular calcaneal fractures.61,62 Calcaneal bone defects were filled with Biobon to augment internal fixation and were followed for 1 year. These studies showed that autogenous bone graft can be replaced by a resorbable calcium phosphate substitute for the use of filling bone voids and augmenting fixation. The bone substitute was biocompatible and resorbed within 6 months of implantation. Clinical studies concluded that Norian SRS allowed earlier postoperative weight bearing without compromising scoring on a calcaneal scoring measure. Csizy and colleagues63 provide a case report that describes the usefulness of Norian SRS in preserving Bo¨hler’s angle in a patient at 2 years under weight-bearing conditions. Despite this resistance to compression, little of the bone substitute had undergone osseous integration 2 years after implantation. Norian SRS is known to have a higher compressive strength than a-BSM (55 MPa vs 10–15 MPa), but it is absorbed less rapidly in vivo.61,64,65 Johal and colleagues66 studied whether open reduction and internal fixation (ORIF) augmented with an injectable bioresorbable calcium phosphate paste (a-BSM) is superior to ORIF alone in the treatment of calcaneal bone voids encountered after operative treatment of displaced intraarticular calcaneal fractures. These investigators randomized 47 patients with 52 closed displaced intraarticular fractures. ORIF alone was performed for 28 fractures and/or ORIF augmented with calcium phosphate in 24. The maintenance of Bo¨hler’s angle was evaluated at follow-up visits for more than 1 year. Secondary outcome measures included the Short Form (36) Health Survey and lower extremity measure every 6 months, and the Oral Analog Scale score at 2 years. These results support the use of an injectable calcium phosphate paste that hardens in situ to fill the bone void after a displaced intraarticular calcaneal fracture. There was no effect on general health, limb-specific function, and pain past 2 years and no associated complications with a-BSM use, supporting its safety as an addition to ORIF. The results of this study show that use of a-BSM leads to less calcaneal collapse after operative management once weight bearing is begun. They suggest the use of a bioresorbable calcium phosphate paste to fill the cancellous bone defect and augment ORIF to support the articular surface after a displaced intraarticular calcaneal fracture.

Synthetic Bone Grafting in Foot and Ankle Surgery

TCP

One of the commonly available resorbable ceramics is TCP. TCPs may be produced by either a conventional high-temperature ceramic process by heating nonmetallic mineral salts at temperatures greater than 1000 C, a process known as sintering, or a low-temperature aqueous chemical method. Coralline ceramics are formed by thermochemically treating coral with ammonium phosphate, leaving TCP with a structure and porosity that are similar to those of cancellous bone. TCP (Ca3[PO4]2) bone graft substitutes are composed of 39% calcium and 20% phosphorus by weight, and they have a range of multidirectional interconnected pores. TCP can assume one of 2 crystalline structures: a-TCP has a polygonal shape, whereas b-TCP is spherical, has a higher porosity, and can be packed more densely in a bone defect. b-TCP has a finer microarchitecture, which results in a faster resorption rate than that of a-TCP.47 Most commercially available TCP bone graft substitutes are of the b variety. Unlike calcium phosphate cements, which are pastes, TCP is available in either granular or block form. The compressive and tensile strength of b-TCP is similar to that of cancellous bone.41 It is brittle and weak under tension and shear forces. Tricalcium blocks are often used for noncontained defects. Because the compressive strength of both coralline hydroxyapatite and TCP is similar to that of cancellous bone, neither product is used in situations in which greater mechanical strength is required. TCP granules may be used as a bone graft extender. TCP undergoes resorption by dissolution and fragmentation in 6 to 18 months.67 Resorption of TCP occurs via osteoclasts without an inflammatory or giant cell response. The bone volume produced is always less than the volume of the TCP that is resorbed.67 Cameron68 evaluated the incorporation time of TCP by placing an 8.5- by 3-mm disk of the material into the cut surface of tibiae in a series of 20 patients undergoing total knee replacement. The disks of TCP could not be detected radiographically at 6 months, and the investigators concluded that TCP was a useful resorbable bone filler material. In a retrospective case series, 43 patients with traumatic bone defects or nonunion of the femur, tibia, calcaneus, humerus, ulna, or radius had treatment augmented with TCP. Ninety percent of the fractures and 85% of the nonunions had united at the time of follow-up, at an average of 12 months (minimum duration, 6 months). The investigators concluded that TCP was a useful substitute for cancellous bone.69 Composite Graft

Although most of the initial experimental and clinical work has been performed with products used in isolation as a single variable, these products may have qualities that are mutually beneficial when used in combination. Therefore, different combinations continue to be explored. Calcium sulfate 1 calcium phosphate

One concept of ideal synthetic bone void filler might combine the features of relatively rapid resorption of CaSO4 with the slower resorption of calcium phosphates (CaPO4). The calcium sulfate in the composite graft resorbs early but the calcium phosphate takes 180 days for complete resorbtion. A CaSO4-CaPO4 composite graft material might enhance vascular infiltration and replacement of the graft by new bone, thus promoting improved restoration of a bone defect. Early start and a slow rate of absorption promotes bone formation into the bolus of cement, and a portion of calcium phosphate continues to provide a scaffold, which eventually is incorporated into new bone.70

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Such a hybrid bone graft substitute in the form of a triphasic CaSO4-based injectable composite that incorporates a matrix of calcium sulfate dihydrate and dicalcium phosphate dehydrate with b-TCP granules (PRO-DENSE, Wright Medical Technology Inc, Arlington, TN, USA) has been tested in an animal experiment. The injectable CaSO4CaPO4 composite graft increased the amount and strength of restored bone when compared with conventional CaSO4 pellets after 13 and 26 weeks in a canine critical-sized bone defect model and when compared with specimens of normal bone.70 This CaSO4-CaPO4 composite graft may be advantageous in the treatment of benign bone tumors and in trauma applications, including distal radius, tibial plateau, and vertebral compression fractures, or other settings in which an enhanced amount and strength of restored bone using a highly biocompatible bone graft substitute are desirable. Such a composite graft in injectable form may also be used to increase purchase of hardware in osteoporotic bones in which bone failure, not implant breakage, is the primary mode of failure of internal fixation. Because bone mineral density correlates with the holding power of screws, osteoporotic bone often lacks the strength to hold plates and screws securely. Resistance to pull-out of a screw placed in bone depends on the length of the screw purchase, the thread of the screw, and the quality of the bone itself. A variety of substances have also been used to enhance screw purchase in bone, including bone auto- or allograft and bone cement. PMMA injection into the screw hole before pedicle screw insertion has been shown to dramatically improve axial pull-out resistance and the resistance to screw toggle caused by cyclic caudocephalic loading.71,72 However, it is not commonly used clinically because of intraoperative and long-term problems, including the risk for neural injury, risk for thermal necrosis during polymerization, cement extrusion into fracture site and joint,73,74 the toxicity of the polymerization reaction of PMMA,75 and complications of revision surgery and hardware removal.76,77 Furthermore, PMMA can physically block endosteal and periosteal new bone formation during fracture healing,78 and PMMA evokes the formation of a fibrous membrane at the bone-cement interface, which produces several cytokines and inflammatory mediators that lead to bone resorption,79–81 which is also caused by particulate PMMA wear debris.82 Retained PMMA can act as a stress riser,83 which increases the risk for refracture. CaSO4-CaPO4 composite graft may be a better alternative to PMMA to inject in screw holes before inserting the screws to increase the purchase of hardware implanted. It is not associated with exothermic necrosis of adjacent tissues. It is biocompatible, bioresorbable, and osteoconductive, and thus has the potential for replacement by new bone during healing and normal bone turnover. A cadaver study compared purchase of the tibia pro fibula screws inserted at the level of the syndesmosis with and without augmentation of drill holes with injectable calcium sulfate. A statistically significant difference was noted in displacement, failure load, and failure energy between augmented and nonaugmented screws; the augmented screws were considerably stronger. The force necessary to pull out augmented screws was 100% to 200% greater than the force necessary to pull out nonaugmented screws. In nonaugmented screws, failure occurred through simple stripping of the bone at the bone-screw interface, and there were no instances of fibula fracture. In the augmented group, failure occurred through stripping of the screw-cement interface; the fibula fractured at the screw site in 50% of specimens. The pull-out resistance of augmented screws was such that failure occurred in the bone before the implant failed.84 Calcium phosphate 1 osteoinductive matrix

Another type of combination is a composite graft that attempts to accelerate bone formation by adding osteoinductive factors to the osteoconductive matrix of calcium

Synthetic Bone Grafting in Foot and Ankle Surgery

phosphate (Collagraft, Zimmer, Warsaw, IN, USA; Healos, Orquest, Mountain View, CA, USA). A prospective randomized multicenter trial comparing autogenous bone grafting to a composite graft of calcium phosphate matrix and bovine collagen with autogenous bone marrow as an adjunct in the treatment of long-bone fractures showed no significant difference in union rate, functional outcomes, or complications in 249 fractures (213 patients) over a 2-year follow-up. The investigators concluded that a calcium phosphate composite graft was as effective as an autogenous iliac crest bone graft for the treatment of long-bone fractures requiring bone graft augmentation. However, because few such fractures are routinely bone grafted and because there were no control patients without any grafting, the overall usefulness of the grafting was unknown (level I evidence).85 Calcium phosphate 1 recombinant human bone morphogenetic protein 1 polymers

Growth factors have been added to injectable calcium phosphate ceramics either before setting of the cement or after complete setting.86,87 Because of the nonmacroporous structure of the calcium phosphate cement, one concern is that prolonged retention of entrapped proteins might result in the loss of their osteoinductive potential. If the recombinant human bone morphogenetic protein-2 (rhBMP-2) was loaded on a biodegradable polymer such as poly(DL-lactic-co-glycolic acid) and then combined with calcium phosphate, it would allow a controlled release of the growth factor from the microparticles, delivering a continuous level of bioactive protein to the surrounding tissues. An in vitro study on release kinetics showed that incorporation of rhBMP-2-loaded microparticles in calcium phosphate cement results in a sustained release of rhBMP-2 under neutral and acidic conditions.88 In an animal study, a single percutaneous injection of rhBMP-2–calcium phosphate matrix accelerated healing in nonhuman primate fibular osteotomy sites over a wide range of treatment times.89 SUMMARY

Multiple synthetic bone graft substitute options alone or in combination are available for use in patients to fill in a bone void caused by trauma or tumor, deliver high doses of antibiotics locally, improve purchase of hardware in osteoporosis, and accelerate healing. Although many of these products are used for similar indications, they differ considerably in their chemical composition, structural strength, and resorption or remodeling rates. Most available studies are nonrandomized case series the efficacy of which cannot be proved. There is a lack of direct-comparison studies between different types of bone graft substitutes. Indiscriminate use without clear indications results in unnecessary financial costs. When used in the correct circumstance, bone graft substitutes improve patient outcomes by decreasing the loss of reduction of intraarticular fractures and improving bone formation and fracture healing in areas affected by trauma. Future synthetic scaffold grafts offer the potential of performance superior to autograft because they can act as a scaffold for bone healing, be a source of mechanical stability, and if incorporated with bone induction factors provide stimulus for bone growth. REFERENCES

1. Fleming JE Jr, Cornell CN, Muschler GF. Bone cells and matrices in orthopedic tissue engineering. Orthop Clin North Am 2000;31:357–74. 2. Stevenson S. Biology of bone grafts. Orthop Clin North Am 1999;30:543–52.

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