Experts discuss current data, clinical experience with biologics and other cutting-edge technologies

Malunions, delayed unions, and wounds that are difficult to heal pose challenges to physicians who treat patients with foot and ankle conditions. But panelists at the American Orthopaedic Foot & Ankle Society (AOFAS) 2009 Specialty Day noted that biologics and cell-based therapies offer exciting new possibilities for promoting healing.

During a session moderated by Sheldon Lin, MD, experts Christopher W. DiGiovanni, MD; Bryan J. Hawkins, MD; and Michael S. Pinzur, MD, discussed gene therapy, cellular therapy, protein therapy, and much more—and shared their experiences with using these new treatments in the clinical setting.

Solving a ‘multi-billion dollar problem’
According to Dr. DiGiovanni, the number of foot and ankle fusions being performed in the United States is estimated to be increasing about 7 percent annually. Because the outcome for some of these patients will be complicated by delayed union or nonunion, he said, such challenges to healing represent a “multi-billion dollar problem.”

“I’m not certain a definitive solution to this problem is known yet; however, I am convinced that autologous bone graft, which is currently our gold standard for foot and ankle fusion enhancement, will soon be supplanted by something else—be it locally delivered, percutaneously injected, systemically administered, or externally applied,” said Dr. DiGiovanni.

He noted that today’s orthobiologics fit into three main categories: gene therapy, cellular therapy, and protein therapy.

“Gene therapy,” explained Dr. DiGiovanni, “involves delivering osteogenic genes to a specific site. In cellular therapy, on the other hand, scaffolds are loaded with mesenchymal stem cells (MSCs). Finally, protein therapy involves applying proteins to a targeted site or introducing them through systemic administration.”

Although little Level I data related to the use of biologics in foot and ankle conditions exist, some notable studies have been conducted.

“Platelet-derived growth factor (PDGF) is the most researched growth factor we have in the foot and ankle world,” said Dr. DiGiovanni. He noted that two multicenter, prospective trials have been performed in North America with the recombinant human protein recently, including an open label study conducted in Canada of patients treated with a combination of PDGF and tricalcium phosphate (TCP) for ankle, hindfoot, or midfoot fusion procedures.

“The study, which was recently submitted to the Journal of Bone and Joint Surgery—British, found an approximate 90 percent union rate in the absence of bone graft,” said Dr. DiGiovanni.

Dr. DiGiovanni is also leading a study on PDGF.

“Our initial pilot data has been reviewed by the U.S. Food and Drug Administration (FDA),” he said. “It was subsequently approved for a pivotal trial of similar design that includes more than 436 patients from approximately 36 sites. This Level I, randomized, prospective, controlled, multicenter study is one of the largest—if not the very largest—investigations that has ever been performed related to use of growth factors in the foot and ankle.”

Although some data exist related to the use of bone morphogenetic proteins (BMPs) in orthopaedics, little of it focuses on foot and ankle conditions.

“Most data on BMPs come from research related to its use in healing long bone fractures and spinal conditions,” said Dr. DiGiovanni. “Dr. Lin and his group have performed studies regarding the ability of BMP to overcome the effects of diabetes in a rat femoral fracture model. His work has greatly increased our understanding of orthobiologics.

“Growth factor researchers are now exploring the coating of implants and sutures, and are searching for better carriers and easier ways to introduce these factors,” he continued. He was also quick to point out that MSCs likely hold great potential for fusion enhancement.

“MSCs are the hottest thing beyond growth factors right now with regard to fusion,” he said. “More and more data suggest there are ways we can incorporate MSCs with scaffolds to help with healing.

“Gene transfer,” he continued, “is another biologic mechanism that holds promise, as do adeno-associated viral vectors, platelet-rich plasma, and bone marrow aspirate.” He added, however, that it’s difficult to recommend one biologic over another.

“Most of our current data is based on case studies or series and thus may not stand up to today’s more stringent expectations for data,” he said. “We orthopaedists who specialize in the foot and ankle must stop extrapolating data from studies pertaining to other anatomical regions, and continue working on obtaining data from high quality prospective studies or randomized trials that apply to foot and ankle conditions.”

“Orthobiologics hold great promise for enhancing bone healing and improving outcomes in the orthopaedic patient,” he concluded.

Using biologic augment in fractures
Dr. Hawkins noted that approximately 6.2 million fractures occur every year; an estimated 10 per-cent involve delayed unions or nonunions. Autografts and allografts, the traditional treatment for these problems, have potential drawbacks.

“Autograft supply is limited, complications are reported in 10 percent to 30 percent of cases, and costs are estimated at approximately $1,500 per case.

“The supply of allograft is much greater and does not involve donor site morbidity; however, it can spread infection and has a significant cost.

“The question is,” continued Dr. Hawkins, “do we have better alternatives?”

BMP-2, a type of BMP that is essential for osteoblast differentiation and is required for bone healing, has been approved by the FDA for very specific indications. Dr. Hawkins’ first experience with off-label use of BMP-2 yielded surprising results.

“The first case was an 84-year-old female with a femoral nonunion who had failed multiple treatments and could not undergo a long surgery due to her age. After multiple discussions, we elected to use BMP-2 in treating the fracture. We were amazed with the results, so we began to consider using BMP more often.”

Another case involved a 50-year-old male patient who had undergone multiple unsuccessful surgeries to repair a distal tibial fracture (Fig. 1).

“Sixteen months after his original injury, we did a revision fixation with BMP and TCP,” said Dr. Hawkins. “At 11 months post revision, his radiographs showed that the bone was very nicely consolidated.

“BMP-2 is a great adjunct osteoinductor,” he stated. “We use TCP if graft is not available, and we’ve begun using stem cells occasionally.”

Dr. Hawkins noted that healing sometimes cannot be achieved, even with the use of biologic augment.

“BMP-2 and TCP have been used in a midfoot fusion that did not heal, as well as in subtrochanteric and atrophic humeral nonunions that did not heal,” he added. “But overall, we’re very encouraged.”

Treating wounds
Biologics and other agents can be used in the treatment of wounds, said Dr. Pinzur, but it’s crucial to create a clean wound and optimize the patient’s metabolic status first.

“If we let the superficial cells desiccate and die, the wound can’t heal,” he explained. “We have to optimize the environment by keeping it moist and clean.”

He noted that strong Level 1 evidence supports the use of vacuum-assisted wound healing. This technology allows the orthopaedist, after débriding the wound, to use sponges to create a seal.

Another option, according to Dr. Pinzur, is treating the wound with recombinant PDGF administered via a gel.

“Very good Level 1 studies have found PDGF speeds up the healing process by 30 percent in wounds that would otherwise heal,” he said. “It will not cause wounds to heal that would not otherwise heal.

“The old rules haven’t changed,” summarized Dr. Pinzur, “but we have a few new tools to help us.”

Participants reported the following disclosures: Dr. Lin—Tornier; Dr. Pinzur—Small Bone Innovations, Smith & Nephew; Dr. DiGiovanni—Biomimetic Therapeutics, Inc., Extremity Medical, and Synthes; Dr. Hawkins—no conflicts.

Jennie McKee is a staff writer for AAOS Now. She can be reached at mckee@aaos.org