A Guide To Orthobiologics In Podiatric Surgery
In our ongoing quest to find viable graft alternatives in bone fracture and primary osseous repair, the technology of orthobiologic bone substitutes continues to evolve. Traditionally, we have looked for replacement bone from sources within the patient’s own body. Indeed, autograft is widely considered the gold standard for grafting. While autograft bone is superior in its ability to provide osteogenic mesenchymal stem cells, it does have a couple of inherent problems, namely, a limited supply and morbidity associated with harvesting from donor sites. Accordingly, we have brought together a panel of experts with broad and practical experience in using state-of-the-art alternatives to traditional bone autografts for bone defect management in podiatric surgery. In addition to discussing their use of orthobiologics as graft enhancers, the panelists review key indications for the three classes of orthobiologic materials and offer pertinent insights on bioceramic materials. They also speculate about the future potential of orthobiologics. Here are their thoughts. Question Mark Dollard, DPM: What are the unique uses or surgical techniques in which you currently use orthobiologic materials as graft enhancers or expanders? Answer Glenn Weinraub, DPM, has used orthobiologics extensively and touts the use of autologous platelet gel concentrate (PGC) systems for their many applications. He notes that he impregnates all allogenic bone graft material with the platelet gel concentrate. Doing so enhances local inductivity, according to Dr. Weinraub. Dr. Weinraub also utilizes PGC on split thickness skin grafts, noting that the concentrate mimics the first phase of graft take. He says surgeons may also mix PGC with demineralized bone matrix (DBM) materials. D. Scot Malay, DPM, routinely uses DBM in combination with either calcium phosphate or calcium sulfate bioceramic at the donor site after harvesting cancellous bone graft. He also employs this combination after evacuation and curettage of a solitary or aneurysmal bone cyst. Another “very valuable” byproduct of the PGC system is its fibrinogen rich but platelet poor content, notes Dr. Weinraub. He adds that the combination of PGC with thrombin is an excellent natural hemostatic agent. Dr. Weinraub cites research by Mooar, et. al., who demonstrated a significant decrease in pain level and narcotic use as well as less change in hemoglobin and hematocrit in the early post-op period when surgeons used platelet poor plasma in total knee replacement surgery.1 When it comes to bone graft substitutes, surgeons would use them in place of corticocancellous and/or cancellous allograft or autograft bone, according to Thomas Zgonis, DPM. He says one may use bone graft substitutes for patients who have a prolonged history of nicotine use and autoimmune diseases including diabetes mellitus. Kieran Mahan, DPM, concurs, noting that he will use orthobiologic materials for fusions and “in situations in which there might be difficulty healing.” Dr. Zgonis has used orthobiologics to stimulate a fracture site that has failed to heal by conventional means and to stimulate bone healing in an arthrodesis site on a diseased joint. Whenever an osseous defect or interface cleft is present during an arthrodesis or bone grafting procedure, Dr. Malay notes he will use DBM in combination with either calcium phosphate or calcium sulfate. Surgeons may place DBM gel into arthroscopic ankle fusion sites under direct arthroscopic visualization, adds Dr. Weinraub. Dr. Weinraub notes that one may use the aforementioned PGC for backfill of large half-pin sites with an antibiotic-impregnated, ceramic-like triphosphate. Luis Leal, DPM, notes that he utilizes orthobiologics for potential packing defects that may occur during deformity correction with open osteotomies or arthrodesis of the hindfoot and ankle. Dr. Mahan adds that he has utilized orthobiologic materials for the Evans osteotomy. While he notes that the Evans osteotomy generally heals quite well, Dr. Mahan says using orthobiologic materials “accelerates the healing and allows earlier weightbearing.” In particular, Dr. Mahan has used Healos (DePuy) with autogenous bone marrow from the proximal or distal tibia, noting that his experience with this combination over the past two years has been “excellent.” “New bone formation occurs much more quickly around the allogenic graft for the Evans and the graft itself incorporates much more rapidly,” explains Dr. Mahan. “Earlier healing could allow the graft to resist loss of correction during incorporation.” Dr. Mahan has also used a new material called Platform (EBI) in two cases. He cites the human bone product’s “excellent” handling properties. Dr. Zgonis will also use orthobiologics to promote bone healing response in a revisional surgery for malunion or nonunion, or to regenerate bone that has been lost to infection, surgery, autoimmune disease or trauma. Dr. Leal incorporates orthobiologic materials when treating compression fractures, such as calcaneal fractures or pilon fractures, and crush injuries of the ankle in which there has been bone loss. Dr. Malay uses his aforementioned DBM combination to pack osseous defects or grossly evident crevices during open reduction internal fixation (ORIF) of comminuted fractures. Dr. Leal says he rarely uses orthobiologic materials for Charcot reconstruction or in any situation in which there is a sufficient amount of local bone graft to be harvested. Question Dr. Dollard: What criteria do you use to determine which clinical circumstances warrant or which patients are candidates for any of the three classes of orthobiologic materials: osteogenic, osteoinductive or osteoconductive agents? Answer For Dr. Zgonis, the current standard for bone grafts is the autograft, which involves osteogenic stimulation and characteristics of both osteoconductivity and osteoinductivity. Osteogenic grafting is desirable for most patients, concurs Dr. Leal. Dr. Zgonis says surgeons may harvest living, bone-forming cells from the iliac crest, femur, proximal or distal tibia, and/or the foot. Purchasing a separate inductive agent is usually unnecessary, especially if the donor site is healthy, points out Dr. Leal. Drs. Leal and Zgonis also note that one may transfer bone-forming cells from the patient’s bone marrow in order to facilitate osteogenic stimulation. Dr. Mahan utilizes osteogenic agents for fusions, difficult areas of healing, non-unions and for those patients with poor healing potential (i.e. smokers, people with diabetes). Other patients may have poor healing potential as well, according to Dr. Weinraub. He says these patients include: people with rheumatoid arthritis and a history of DMARD use; those who have low serum alkaline phosphatase and albumin levels; people who have nutritional deficits; and those with suspect compliance in regard to post-op instructions. Dr. Malay concurs. He usually employs a combination of DBM and bioceramic materials to repair fractures in people who smoke, for nonunions and when he performs osteotomies for patients who have a history of previous nonunion or delayed union. When it comes to adult cases of nonunion repair, Dr. Malay says he will add a proximal tibial bone marrow aspirate to help facilitate osteogenesis. One would primarily reserve osteoconductive materials for packing of bone defects such as donor defects that occur after harvesting bone grafts, according to Dr. Mahan. Dr. Zgonis notes that osteoconductive agents provide a scaffold upon which new osteoblasts and bone cells can migrate and grow into a healthy bone tissue. Furthermore, he says osteoconductive agents can act as spacers and limit the amount of fibrous or connective tissue in the bone gaping. Osteoinductive agents aid in inducing osteoprogenitor cells into osteoblasts via various growth factors in the body, according to Dr. Zgonis. While inductive agents may be necessary for “critical gaps where local bone or bone marrow is limited,” Dr. Leal cautions that these agents still need an adequate cell source. In regard to osteoinductive agents, Dr. Mahan says he would use them to supplement the use of osteogenic or osteoconductive materials. “Knowing the three general categories of bone grafting, one can properly select the orthobiologic agent based on the tensile, bending strength and torsion of the required site,” sums up Dr. Zgonis. Dr. Malay emphasizes appropriate, adjunctive use of orthobiologics. “Orthobiological materials are not, in and of themselves, a solution to bone healing,” advises Dr. Malay. “They are used in conjunction with appropriate osteosynthesis techniques, stimulated osteogenesis, immobilization and avoidance of disruptive weightbearing.” He reminds clinicians that orthobiologic use is dependent upon the needs of the individual patient. Dr. Malay also emphasizes that having an intact blood supply to the bone is essential for orthobiologic use. In addition to the aforementioned indications for possible use of orthobiologics, Dr. Weinraub says surgeons may want to consider the materials when one has done everything possible regarding a fixation construct but the construct is still not optimal. “In these cases, the judicious use of an orthobiologic could tip the scale in the favor of predictable healing,” adds Dr. Weinraub. Question Dr. Dollard: In choosing a bone graft substitute, what key characteristics are critical for bone graft structure and stability as they behave in the phases of bone healing? Answer Porosity and pore size are critical to permit good bone healing and controlled graft resorption, according to Drs. Leal and Mahan. “Graft should not resorb too quickly and should not leave soft tissue with low mechanical integrity,” maintains Dr. Leal. “A graft with controlled or gradual resorption will not increase inflammation beyond what is considered normal, and should provide a structure for long-term remodeling.” Dr. Mahan points out that pore sizes similar to cortical bone require a prolonged absorption time, which is not beneficial in most areas of the foot. Pore size for bioceramics generally ranges between 10 to 100 microns, notes Dr. Malay. He says it is critical for these agents to mimick the pores of cancellous bone. “This enables cellular migration and capillary ingrowth into the bioceramic,” explains Dr. Malay. Dr. Zgonis notes surgeons employ ceramic-based bone graft substitutes as optimal synthetic scaffolds for delivering osteoprogenitor cells and osteoinductive growth factors. Most common biosynthetic ceramics include porous, coralline-tricalcium phosphates, calcium sulfate, collagen composites and bioactive glass, according to Dr. Zgonis. In addition to the aforementioned pore size, Dr. Zgonis says other key physical characteristics of these agents include biocompatibility, biodegradation and their biomechanical properties. For example, while calcium phosphates are based on the primary inorganic bone mineral calcium hydroxyapatite, Dr. Zgonis notes they are very brittle and have less tensile strength than bone. Dr. Malay cites the “inductive influence” of DBM, noting that it facilitates the differentiation of mesenchymal stem cells into osteoblasts and chondroblasts, the migration of new stem cells and the release of growth factors at the site of bone healing. However, Dr. Weinraub cautions surgeons to pay close attention to how much bone morphogenic protein (BMP) is in the DBM product they choose. Citing a study by Blume, et. al., Dr. Weinraub says the authors studied 113 lots of various DBM products and discovered wide variation in the amount of actual BMP contained in many of these preparations.2 Accordingly, he notes surgeons should only use DBM products that have been tested for adequate quantities of active BMP. When using a bone marrow aspirate, Dr. Malay says one may place undifferentiated stem cells, as well as osteocytes and chondrocytes, at the site of bone healing. However, he notes the concentration of cells in the aspirate can vary. Question Dr. Dollard: How efficient are current bioceramic materials (CsPo4, CaSO4, hydroxyapatite) in providing prolonged structural integrity in graft defects by virtue of their material strength or resorption rate? How do you determine when incorporation has been successfully completed? Answer Dr. Mahan says calcium sulfate is a good material for packing and as a carrier vehicle for antibiotics. He adds that the rapid resorption of the agent is very compatible with these purposes. Dr. Zgonis notes the average resorption rate of calcium sulfate materials within the bony defect ranges between six to 12 weeks depending upon bolus size. In comparison, he says the average resorption rate for calcium phosphate is six to 12 months. Calcium sulfate materials lose their mechanical properties upon their degradation and using them in weightbearing surfaces is “questionable,” notes Dr. Zgonis. In regard to calcium sulfate products such as OsteoSet (Wright Medical) and TCP ceramics with high porosities, Dr. Leal believes they “resorb too quickly for any good healing to occur.” Dr. Leal also notes that hydroxyapatite (HA) resorbs too slowly and will not allow for long-term remodeling and incorporation. Several types of calcium phosphate materials, including coralline hydroxyapatite and tricalcium phosphate, provide a more structural strength to the bone graft substitute, according to Dr. Zgonis. However, he notes these products require high temperatures for scaffold formation similar to that of trabecular bone, are often brittle and are also questionable in weightbearing surfaces. While Dr. Weinraub continues to be impressed by the “back table” structural strength of some of the biphasic calcium phosphate materials, he says it is a mistake to rely on any of these materials to “provide a sole source of prolonged structural stability.” Dr. Mahan agrees. While he says HA and tricalcium phosphates are useful in packing defects, Dr. Mahan says a combination of orthobiologic materials and properties is key to success. “The three key aspects of osteogenesis, osteoconduction and osteoinduction should ideally be present,” maintains Dr. Mahan. Grafts with some structural stability and controlled architectures (i.e. Therics grafts) can achieve good incorporation, points out Dr. Leal. In Dr. Malay’s experience, only carbonated apatites offer useful structural strength and the only one with which he is familiar is Norian® (Synthes). Dr. Malay says Norian is a rapidly setting, injectable agent that hardens in about 10 to 15 minutes and offers compressive strength that is five to six times greater than human cancellous bone. He adds that the carbonated apatite agent readily facilitates screw thread purchase. It subsequently degrades by osteoclasis and is replaced by new bone via creeping substitution over many months, according to Dr. Malay. Dr. Malay adds that he has only used Norian in joint depression calcaneal fractures. He notes that Norian is similar to coralline HA in that it remains visible on radiographs for between eight to 14 months. When determining whether incorporation has occurred, Dr. Malay says he generally uses a combination of clinical and radiographic inspection. In his experience using bioceramic agents, Dr. Malay has found that calcium phosphate is replaced most rapidly by new bone. This is followed by calcium sulfate and HA, according to Dr. Malay. However, he emphasizes that “none of the bioceramics are suitable replacements for cortical bone’s structural role.” Accordingly, Dr. Malay says he still resorts to autogenous or allogenic (freeze-dried) corticocancellous grafts whenever a cortical strut is required. Otherwise, Dr. Malay will employ callus distraction techniques. In regard to assessing incorporation, Dr. Zgonis utilizes serial radiographs according to the bone graft substitute’s resorption rate and may also obtain a computerized tomogram (CT) at a later time. Doing so allows the surgeon to assess the bone graft’s resorption and trabeculation pattern, according to Dr. Zgonis. In regard to plain radiographs, Dr. Weinraub cautions that is often difficult to assess full incorporation of calcium phosphate products “since they do such a good job of mimicking native bone.” Dr. Weinraub says it is easier to assess incorporation for calcium sulfates and HA materials as calcium sulfates appear more opaque on plain radiographs, and the HA materials stay opaque and visible for a prolonged period of time during incorporation. However, Dr. Mahan counters that the slow absorption rate of HA may obscure radiographic details in certain situations. Whenever Dr. Weinraub has serious questions about healing or complete incorporation, he concurs with Dr. Zgonis that a CT scan be useful and adds that a radionucleotide study may also be helpful. Dr. Zgonis adds that bone scintigraphy may be useful in assessing any concerns of a delayed union or nonunion. Question Dr. Dollard: Since synthetic bioceramic materials mainly act as osteoconductive scaffolds, how important is it for a surgeon to add osteogenic or osteoinductive agents to these products in order to enhance graft incorporation? Do the anticipated outcomes justify their combined costs? Answer Dr. Weinraub says a general checklist for bone healing would include good vascularity, nutritional capability, stable fixation, osteoinduction, osteoconduction and osteogenic capability. While he may utilize osteogenic or osteoinductive materials by themselves (with local bone interface acting as the conductive element), Dr. Weinraub maintains he would never use an osteoconductive agent without the addition of genic or inductive material. Dr. Zgonis says incorporating an osteoinductive growth factor and/or osteogenic cells to the osteoconductive scaffold is important in trying to achieve an ideal composite bone graft substitute. “These growth factors help in the overall production and resorption of bone,” explains Dr. Zgonis. “When they are incorporated into the bony defect, they are comparable to the functionality of autograft or allograft.” While it is important to add agents, Dr. Leal says they do not necessarily have to be inductive agents, such as DBM or BMP, unless there is a significant risk of non-healing (i.e. large gaps where cell source is limited). He also points out that inductive agents increase the costs of the procedure and since they do not act as scaffolds themselves, osteoconductive scaffolds would still be required. Some of these products are “very expensive” according to Dr. Mahan, who says this is a key consideration at many facilities. “More hospitals are exerting cost controls, limiting the number of vendors in a given product line and performing one or more forms of economic credentialing,” points out Dr. Mahan. Dr. Mahan says some combination of these materials is ideal. Dr. Leal suggests mixing bone marrow or local bone with ceramic graft, noting that they act as sources of cells and growth factors. Dr. Mahan concurs, adding that one may obtain harvested bone marrow very easily. He also points out that surgeons can harvest autogenous bone from the calcaneus with just a stab incision and a trephine. Graft properties should allow for stable packing and controlled resorption, maintains Dr. Leal. He says this ensures the graft does not disappear before its function is complete. While a combination of materials is not necessary for packing of defects, Dr. Mahan says having some osteogenic material is “critical” when it comes to treating nonunions, for joint fusions and when performing revision surgery. “Osteoinduction is an important property but it does not replace osteogenesis,” emphasizes Dr. Mahan. In order to enhance bone healing in adult patients, Dr. Malay says he combines conductors and inductors with osteogenic cells whenever he can. In the past 10 years, Dr. Malay emphasizes that the medical literature has been full of relatively good quality, randomized, controlled trials and systematic reviews that show bone healing using bioceramics and DBM is equivalent to bone healing with autogenous bone graft, and even better when donor site morbidity is considered.3-13 However, he concedes that most of this literature focuses on the spine and mandible. To the best of his knowledge, Dr. Malay says there are no quality investigations exploring the cost-effectiveness of orthobiological materials for the treatment of fractures, fusions and nonunions in the foot and ankle. However, Drs. Malay and Zgonis believe combinations of these materials can facilitate promising and cost-effective outcomes. Dr. Malay says judicious use of these agents is less expensive than dealing with a nonunion when one considers all the variables including: material costs; surgical, anesthesia and hospital fees; bone growth stimulators; lost productivity; doctor and patient time and energy; and the patient’s pain and suffering. Taking it a step further, Dr. Weinraub cites a 2003 study by St. John, et. al., who showed that the mean overall cost of autogenous iliac crest harvesting was $4,200.14 Dr. Weinraub points out that one application of pure BMP — which he says is the most expensive orthobiologic available — is approximately $4,900. When you compare these modalities, “it becomes clear that cost is really not an issue,” maintains Dr. Weinraub. Question Dr. Dollard: What other concerns do you have regarding the present or future status of orthobiologic materials as replacements for the autograft “gold standard” or allograft enhancers? Answer Dr. Mahan says the three most important issues are efficacy, cost and safety. Dr. Leal concurs. He notes that many manufacturers claim their grafts are as good as autograft. In order to minimize confusion, Dr. Leal emphasizes that such claims of efficacy must be backed up by controlled, clinical data. Future studies should also resolve “exactly how much each of these products adds to various indications,” emphasizes Dr. Mahan. Dr. Zgonis notes that a combination of osteoconductive scaffolds and osteoinductive biologic growth factors, such as recombinant human growth factors, and/or osteogenic cells has shown promise in many clinical outcomes. The biggest challenge, according to Dr. Malay, is obtaining a substitute that conveys the structural properties — namely resistance to three-point bending, compression, tension and shearing — that are provided by human cortical bone. Currently, Dr. Malay says surgeons can combine osteoconductive bioceramics or hydroxyapatites with osteoinductive DBM proteins, and add osteogenic cells and potentially osteogenic stem cells to formulate a bone graft substitute. However, he feels the combination lacks the structural integrity of cortical bone. While spine and maxillofacial surgeons frequently use metallic or polymer cages to secure unstable bone graft substitutes, Dr. Malay says podiatric surgeons do not have readily available metallic or polymeric cages in which one could secure bone graft substitutes until creeping substitution replaces the construct with new bone in the foot and ankle. “Until this obstacle to bone graft substitution is overcome, autogenous corticocancellous bone grafts will probably remain the gold standard,” maintains Dr. Malay. Dr. Weinraub prefers to call the autograft a “historical standard.” In the future, he would like to see lower costs for pure BMPs as well as the development of better BMP carriers to contain this bone material to the specific osteogenesis site. “The ultimate biologic material would utilize a plasmid to deliver the genetic coding instructions for bone formation directly to a fusion or fracture site,” notes Dr. Weinraub. “I just hope to see this level of biologic technology take place in my lifetime.” Drs. Leal and Mahan maintain that the cost of orthobiologic materials is a critical issue as they note that hospitals are increasingly looking to cut costs and reduce the number of vendors. Dr. Mahan says it is important to ensure that the right products get on the shelves. Drs. Mahan and Zgonis add that it is important for podiatric surgeons to have a strong awareness of all the advantages and disadvantages of orthobiologic materials. Dr. Mahan also emphasizes having a familiarity with the bone bank your hospital uses. “Ultimately, we need to be responsible for our patient’s safety to the best of our ability,” concludes Dr. Mahan. “The best way to do that is to be as familiar as possible with all of these products and the safety issues with each.” Dr. Dollard is a Fellow of the American College of Foot and Ankle Surgeons, and the American Academy of Podiatric Sports Medicine. He is in private practice at the Loudon Foot and Ankle Center in Sterling, Va., and the Falls Church Medical Center in Falls Church, Va. Dr. Dollard is a Member of the American Society of Bone and Mineral Research. Dr. Leal is a Fellow of the American College of Foot and Ankle Surgeons. He is in practice at the Reconstructive Foot and Ankle Center within the Palisades Medical Center in Edgewater, N.J. Dr. Mahan is a Professor in the Department of Surgery at the Temple University School of Podiatric Medicine. He is a Diplomate of the American Board of Podiatric Surgery, a Fellow of the American College of Foot and Ankle Surgeons, and a member of the faculty of the Podiatry Institute. Dr. Malay is a Fellow of the American College of Foot and Ankle Surgeons, and is in private practice at the Ankle and Foot Medical Centers of the Delaware Valley. He is the Director of Podiatric Research at Penn Presbyterian Medical Center and is a Postdoctoral Research Fellow of the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania. Dr. Malay is also a faculty member of the Podiatry Institute. Dr. Weinraub is a Fellow of the American College of Foot and Ankle Surgeons. He is a Clinical Assistant Professor of Medicine at the University of Virginia and a Clinical Assistant Professor of Orthopaedic and Podiatric Surgery at the Virginia College of Osteopathic Medicine. Dr. Weinraub can be contacted at firstname.lastname@example.org. Dr. Zgonis is an Assistant Professor within the Department of Orthopaedics/Podiatry Division at the University of Texas Health Science Center in San Antonio. He is also the Director of Fellowship Training Programs at the aforementioned institution. Dr. Zgonis is a Fellow of the American College of Foot and Ankle Surgeons, and is a Diplomate of the American Board of Podiatric Surgery. He can be reached via e-mail at: email@example.com.
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