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Research Aims at Regenerating Tendons

OREF grant recipient seeks a new normal for patients

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, MD, 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 4 days later.


MaCalus V. Hogan, MD

“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 as a mentor, and I’m happy to have reached the point I am at today.”

While an academic orthopaedic training program 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 a Resident Clinician Scientist Training Grant from the Orthopaedic Research and Education Foundation (OREF), Dr. Hogan was able to apply results from an earlier in vitro study in which growth 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,” enabled Dr. Hogan to expand his research on developing new ways to repair and regenerate tendons.

“We hoped to show that a differentiation-supporting scaffold carrying adipose-derived mesenchymal stromal cells (ADMSCs) treated with GDF5 would be 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, such as rerupture and restrictive adhesions, can still occur. We hope to change that,” he said. Currently, no surgical treatment can return a tendon to its normal condition after injury.

“We wanted to find a way to regenerate tendons so that the new tissue is of similar quality to the native tendon tissue,” said Dr. Hogan. “We hypothesized that the combination of stem cells, growth factors, and polymers could provide the optimal environment for the repair and regenerative process.”

(Left) Tissue-engineered nanofiber tubular poly(lactide-co-glycolide) (PLAGA) polymer scaffold. (Right) Confocal microscopy live/dead assay of adipose mesenchymal stem cells (MSCs) proliferating on PLAGA scaffold at 14 days (magnification, 10). Green = live, red = dead.
Reproduced from Hogan MV, Bagayoko N, James R, Starnes T, Katz A, Chhabra AB: Tissue Engineering Solutions for Tendon Repair.
J Am Acad Orthop Surg 2011 Mar;19(3):134-142.

But before the investigation could begin, the researchers had to isolate and select the ADMSCs. ADMSCs are a source of multipotent 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 scaffold through electrospinning, a process that uses an electrical charge to draw very fine nanofibers from a liquid. This scaffold was used alone and also to deliver ADMSCs and/or GDF-5 during the repair of Achilles tendon defects in rats.

Promising results
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 1 expression, which is synonymous with native tendon,” he said.

Likewise, molecular results indicated an increased expression of tenomodulin (a transmembrane glycoprotein) and scleraxis (a transcription factor)—both of which are specific to tendon development. This increased expression in the regenerated tissue indicated that 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 the tendon tissue before the injury, is our ultimate goal. Our early results give us promise that this is possible,” concluded Dr. Hogan. “We hope to translate our work into a larger animal model, and the OREF funding was essential to our efforts to gather pilot data for future investigation.”

Relationships and research
Dr. Hogan, now a foot and 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; Abhinav Bobby Chhabra, MD; and Shepard R. Hurwitz, MD, for their guidance and encouragement early in his career. That support, he says, has been invaluable along his journey.

He also says that the OREF grant helped him find the right collaborator for his study.

“OREF fosters the development of essential relationships between surgeons and scientists, such as the one I’ve developed with Roshan James, PhD, a longtime collaborator and co-investigator on this study,” he said. As someone planning a career in academics as a clinician scientist, Dr. Hogan says he 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.

Mark Crawford is a contributing writer for OREF. He can be reached at communications@oref.org

AAOS Now
November 2012 Issue
http://www.aaos.org/news/aaosnow/nov12/research2.asp