Failure rates are sure to weigh on the minds of patients in need of a bone graft. Studies have found that half of all allografts following tumor resection fail in the first 5 years. At 10 years, that statistic rises to 60 percent. Moreover, 75 percent of nonfatal war wounds are injuries of the extremities that involve infected critical-size defects.

Biological boosters
Dr. Benoit and her team hope to devise simple, biologically active coatings that can be applied to allografts to enhance healing and integration. These coatings would enable surgeons to salvage the injured limb and would significantly affect the rate of healing of bone defects. They also would improve substantially the quality of life for patients with massive bone defects. Dr. Benoit hopes they will eliminate the need for revisions so that 5 years after implantation, the graft will become, in effect, the patient’s own tissue.

“Patients won’t have to contend with revision surgery,” Dr. Benoit said. “That will be a one-shot deal, where they get 100 percent of their own tissue that works for the rest of their life.”

Stem cell engineering
Dr. Benoit has long been interested in the periosteum and its importance in bone remodeling and bone healing.

“My interest extends as well to the use of stem cells and adult stem cells,” she said. “If a patient has a critical-size defect and not enough tissue is available for an autograft, an allograft is the only alternative. But allografts typically fail within 10 years. I hope to help develop a tissue-engineered periosteum composed of stem cells and chemical cues to improve allograft healing and integration. In addition to developing a provisional matrix for cell delivery, we want to design a scaffold to promote both proliferation of transplanted cells and osteogenic differentiation. This will enhance therapeutic efficacy.”

Once these engineered cells are on the bone surface, they will undergo robust proliferation and aid in providing a cell population that can then contribute to osteogenic bone formation and eventual remodeling and healing. Dr. Benoit and her research team have recently succeeded in using small molecules to induce mesenchymal stem cell proliferation in two dimensions as well as within three-dimensional microenvironments of hydrogel networks.

“In our mouse models, we’re also examining autograft versus allograft control studies,” said Dr. Benoit. “We’re now encapsulating these cells within hydrogel microenvironments, putting them on the bone, and observing how healing improves over a 6- to 9-week period.”

In a typical study, the allograft acts as a negative control, the autograft as a positive control. The allograft won’t heal and integrate, while the autograft will. “We’re trying to enhance the vast amount of cadaveric tissue that’s available for allografts to bring it up to the gold standard of autografting,” Dr. Benoit explained.

Opportunity to advance
Because of her expertise in stem cell transplantation methods and biomaterials, some of Dr. Benoit’s colleagues and mentors recommended that she look into OREF’s funding opportunities. She considers the OREF grant hugely important to her allograft research.

“It’s tough for young investigators without a track record to get their research off the ground. Thanks to this grant, we’re working to understand how we can exploit mesenchymal stem cells and biomaterials to design and implement new regenerative therapies. It really jumpstarts not just this project but a whole series of creative hypotheses that we’re exploring,” she said.

Although Dr. Benoit describes the project as basic science research, she also is considering how to translate the team’s hypothesis to patient care. “In 3 to 5 years, this could be an actual therapy. We can potentially help a lot of people all over the world. Beyond our work with autografts and allografts, I can see how, down the road, some of the stem cell and biomaterial innovations could be highly valuable in many different regenerative medicine applications.”

Dr. Benoit believes that OREF is picking up some of the slack in government funding for researchers like herself and her colleagues and, therefore, deserves support from orthopaedic surgeons to help patients and to keep orthopaedics moving forward. “OREF is great about keeping the orthopaedic community informed of what grant recipients are working on in research and in translational medicine. OREF continues to bang the drum. We need to do our part to help,” she said.

Catherine Rategan is a contributing writer for OREF and can be reached at communications@oref.org

References

1. Muscolo DL, Ayerza MA, Aponte-Tinao LA: Long-term results of allograft replacement after total calcanectomy: A report of two cases. J Bone Joint Surg Am 2000 Jan;82(1):109–112.
2. Mankin HJ, Gebhardt MC, Jennings LC, Springfield DS, Tomford WW: Long-term results of allograft replacement in the management of bone tumors. Clin Orthop Relat Res 1996 Mar;(324):86–97.
3. Zeljko B, Lovrc Z, Amc E, Busic V, Lovrc L, Markovc, I: War injuries of the extremities: Twelve-year follow-up data. Mil Med 2006 Jan;171(1):55–57.