Research Summary Research topic: Investigating methods for improved healing, repair, and regeneration of tendons following tendon injury.
Research results: Showed that using a bioresorbable polymer scaffold seeded with adipose-derived mesenchymal stromal cells (ADSCs) and a tendon development supporting growth factor can result in regeneration of a tendon defect with tissue similar to that of native tendon.
Patient care application of results: Development of tissue engineering therapies to heal, repair and regenerate acute or chronically injured tendons.
OREF grant recipient seeks a new normal for patients
By Mark Crawford
When he was a senior in high school, lying on the football field with a severely fractured ankle, little did MaCalus V. Hogan realize his injury would be a defining moment for his future medical career.
The orthopaedic surgeon from the opposing team, Aaron E. Joiner Jr., MD, reduced his fracture on the field and surgically repaired it four days later.
“Dr. Joiner told me I should think about orthopaedics,” said Dr. Hogan. “I was already planning on being a premed major. He said he’d return my ankle to the same activity and functional level as before the injury and I could take it from there. I followed his advice and mentorship and happy to have reached the point I am at today.”
While an Academic Orthopaedic Training Program (AOTP) resident in the Department of Orthopaedic Surgery at the University of Virginia, Dr. Hogan began his work on tendon regeneration therapies that could help a broad range of patients. With support from an OREF Resident Clinician Scientist Training Grant, Dr. Hogan was able to apply results from an earlier in-vitro study in which growth and differentiation factor 5 (GDF5) showed promise as a tendon healing and regenerative agent.
The OREF-funded study, “Tendon Regeneration Model Using Cell-based Augmentation and a Biodegradable Polymer Scaffold,” provided Dr. Hogan the funding necessary to expand his research aimed at developing new ways to repair and regenerate tendons.
“We hoped to show that a differentiation-supporting scaffold carrying GDF5-treated adipose-derived mesenchymal stromal cells is an ideal conduit for tendon regeneration,” stated Dr. Hogan.
Improving the healing process
Dr. Hogan explained that in almost all acute and chronic tendon injuries, the injury site eventually heals with scar tissue, which can severely limit function. “Surgeons perform a number of tendon repair and reconstructive procedures every year and despite our best efforts suboptimal results can still occur: such as re-rupture and restrictive adhesions. We hope to change that,” he said. Currently there is no surgical treatment that returns a tendon to its normal condition after injury.
“We wanted to find a way to regenerate tendon with tissue of similar quality to that of native tendon tissue,” said Dr. Hogan. “We hypothesized that the combination of stem cells, growth factors and polymers can provide the optimal environment for the repair and regenerative process"
Step by step
A prerequisite for investigating this therapeutic strategy was the successful isolation and selection of adipose-derived mesenchymal stem cells (ADSCs), a source of multi-potent cells that can differentiate into different phenotypes under the influence of the appropriate environmental cues. It is generally accepted that fibroblasts present at tendon healing sites arise from undifferentiated MSCs.
Next the team bioengineered a tubular DL-lactide-co-glycolide (PLAGA) scaffold through electrospinning. This scaffold was used alone, and to deliver ADSCs and/or GDF-5 during the repair of Achilles tendon defects in rats.
Dr. Hogan and his team demonstrated promising results that he hopes to take forward in future research.
“Histologically, we were able to show improved collagen alignment and increased collagen type-one expression, which is synonymous with native tendon.” Likewise, molecular results indicated an increased expression of Tenomodulin and Scleraxis—two markers that are specific to tendon development. This increased expression in regenerate tissue indicated it was becoming more like native tendon. Biomechanically, too, treated tissue showed improved strength compared to controls.
“Regeneration of enhanced tendon tissue, with properties equal to that of pre-injured tendon tissue, is our ultimate goal and our early results give us promise that this is possible” concluded Dr. Hogan. “We hope to translate our work into a larger animal model." The OREF funding was essential to our efforts to gather pilot data for future investigation.
Relationships and research
Dr. Hogan, now a foot ankle fellow at the Hospital for Special Surgery, is quick to recognize the importance of mentors for him and other aspiring clinician scientists. He credits Cato T. Laurencin, MD, PhD, Abhinar Bobby Chhabra, MD, and Shepard R. Hurwitz, MD who provided ongoing guidance and encouragement to be active academically early in his career and that support has been invaluable along his journey.
“OREF fosters the development of the essential relationships between surgeons and scientists,” he said, such as that he has developed with Roshan James, PhD, a longtime collaborator and co-investigator on this study. As someone planning a career in academics as a clinician scientist, Dr. Hogan recognizes that such collaborations will be of utmost importance as researchers continue to work toward sound and efficient translation of science from the laboratory to clinical application.