Research topic: Investigating ways to employ tissue engineering to prompt mesenchymal cell growth that will result in bone formation, remodeling and integration, replicating the patient’s own tissue
Research results: Development of allografts that integrate fully and function biomechanically as the patient’s own tissue, and effectively act as autographs
Patient care application of results: Through tissue engineering, development of allografts that are as effective as autografts, substantially increasing grafting success rates and reducing the need for revision surgeries.
Simplified patient care application: Patients receive treatments that will replace lost or defective bone tissue with new tissue that will last a lifetime
Engineering Periosteum to Promote Bone Graft Healing
OREF grant recipient aims to reverse the failures of allografts
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%.1. Moreover, 75% of non-fatal war wounds are injuries of the extremities that involve infected critical-size defects.2.
The search for improved allografts is the focus of an Orthopaedic Research and Education Foundation (OREF) grant awarded to Danielle S. W. Benoit, PhD, an assistant professor of biomedical engineering and researcher at the Center for Musculoskeletal Research at the University of Rochester in Rochester, New York. She and her team received an OREF/Musculoskeletal Transplant Foundation Research Grant in 2011 for their project “Tissue Engineered Periosteum to Promote Allograft Integration and Healing.”
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 who suffer massive bone defects. Dr. Benoit hopes they will eliminate the need for revisions so that five 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% of their own tissue that works for the rest of their life.”
Success in two and three dimensions
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. “There’s really no alternative to allografts for treating critical-size defects for which there usually isn’t enough of the patient’s own tissue available to perform an autograft. 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 a provisional matrix for cell delivery, a scaffold will be designed to promote proliferation of transplanted cells and osteogenic differentiation to 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 over a period of six to nine weeks how healing is improved.”
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—and encouragement—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.”
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 three to five years, this could be an actual therapy. We can potentially help a lot of people all over the world. And beyond the autograft and allograft work, 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.”
She believes that OREF is picking up some of the slack in government funding to enable researchers like her and her colleagues, and therefore deserves support from orthopaedic surgeons to help patients and to keep orthopaedics moving in the right direction. “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.”
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1. Muscolo, D. L.; Ayerza, M. A.; Aponte-Tinao, L. A. Long-term results of allograft replacement after total calcanectomy. A report of two cases J Bone Joint Surg Am 2000, 82, 109. Mankin, H. J.; Gebhardt, M. C.; Jennings, L. C.; Springfield, D. S.; Tomford, W. W. Long-term results of allograft replacement in the management of bone tumors Clin Orthop Relat Res 1996, 86.
2. Zeljko, B., Lovrc, Z., Amc, E., Busic, V., Lovrc, L. and Markovc, I. War injuries of the extremities: twelve-year follow-up data. Mil Med 171 (2006), pp. 55-7.