“Surgeons perform thousands of tendon repair procedures annually. But repaired tendons often fail to return to normal function following injury and thus require continued efforts to improve patient outcomes,” said Dr. Hogan. “The ability to regenerate tendon tissue with properties equal to that of uninjured tendon could lead to improved treatment outcomes.”
Published 10/1/2013
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Mary Ann Porucznik
Early in his career, his interest in regenerating injured tendon tissue won MaCalus V. Hogan, MD, a Resident Clinician Scientist Training Grant from the Orthopaedic Research and Education Foundation. This year, a study that he and longtime collaborator Roshan James, PhD, developed on Achilles tendon regeneration in a rat model won them the J. Leonard Goldner Award from the American Orthopaedic Foot & Ankle Society (AOFAS). Dr. Hogan presented the results of his research at the 2013 AOFAS annual meeting.
Dr. Hogan noted that Achilles tendon injuries can be both acute and chronic in nature and are increasing in incidence. Management of these injuries is controversial, and recovery is not always guaranteed.
MaCalus V. Hogan, MD |
The aim of this study was to investigate, using a tendon-gap model, in vivo tendon regeneration. A biodegradable polymer was employed to deliver adipose-derived stromal cells (ADSCs) and a polypeptide—growth/differentiation factor-5 (GDF-5)—to the injury site. It’s an approach, said Dr. Hogan, that may be the future of bioengineered regenerative therapies.
Engineering tendon
“The problem is our current inability to truly regenerate native tendon,” said Dr. Hogan. “Our approach used a polylactide-co-glycolide (PLAGA) tubular scaffold, as well as ADSCs and GDF-5. The scaffold has been shown to be biocompatible and can support the structural delivery of growth factors and other drugs, as well as stem cell proliferation.”
The use of ADSCs, he noted, has been increasing. “They’re easy to harvest, readily available, and have a high differentiation capacity” said Dr. Hogan. GDF-5, which is also known as bone morphogenetic protein-14, has been shown to be involved in tendon development (increasing collagen organization) and repair (increasing tendon strength) and in stem cell differentiation.
Their experiment involved four groups of rats, all of which underwent unilateral Achilles tenotomies to create an 8 mm defect. Treatment for each group was as follows:
- Group 1 (control)—no treatment
- Group 2—PLAGA scaffold used to bridge the defect (Fig. 1)
- Group 3—PLAGA scaffold with ADSCs used to bridge the defect
- Group 4—PLAGA scaffold with GDF-5 used to bridge the defect
In all animals, the plantaris was left intact and the injured limbs were immobilized for 10 to 14 days, after which unrestricted activity was allowed. Half of each group was sacrificed at 4 weeks after surgery, the other half at 8 weeks after surgery. Tendons were assessed with histologic, biochemical, and mechanical analyses.
“Surgeons perform thousands of tendon repair procedures annually. But repaired tendons often fail to return to normal function following injury and thus require continued efforts to improve patient outcomes,” said Dr. Hogan. “The ability to regenerate tendon tissue with properties equal to that of uninjured tendon could lead to improved treatment outcomes.”
Fig. 1 In vivo application of PLAGA tubular scaffold to bridge an Achilles tendon defect and foster tendon regeneration in a rat. (Patent pending, University of Virginia).
Reprinted 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; 19:134–142.
Results
At 4 weeks, noted Dr. Hogan, the rats were functioning normally and the scaffold was still present. By 8 weeks, however, the scaffold had been absorbed. “All 3 groups with the scaffold showed increased collagen type 1 gene expression at both 4 and 8 weeks and improved tensile load strength compared to controls,” said Dr. Hogan. In addition, Groups 3 and 4 demonstrated increased expression of tenomodulin (a phenotype marker unique to tendon tissue) at 4 and 8 weeks.
“The increased tensile strength at 4 weeks may have been due to the presence of the scaffold,” said Dr. Hogan. “At 8 weeks, however, the scaffold had degraded but the improvement in tensile strength remained.”
Groups 2 and 3 also showed improved collagen deposition, as indicated by increased Collagen Area Fraction, which approached that of normal tendon at 8 weeks (P < 0.05). No adverse inflammatory reactions to the scaffold were noted. Compared to controls, the rat tendons in Group 3 (scaffold seeded with ADSCs) showed improved collagen organization and increased modulus of elasticity as well as properties approaching those of native tendon.
A successful conclusion
“These results demonstrate that a tubular bioresorbable scaffold can promote extracellular matrix synthesis and organization, and the formation of neotendinous tissue,” concluded Dr. Hogan, “as well as serve as a carrier of ADSCs and growth factors that are effective for tendon regeneration. We believe this is a report of successful tendon regeneration in an animal model.”
He noted, however, that this is just the beginning. “The translation to a larger animal model is something we must work toward. We must work to translate this safely into human clinical applications,” said Dr. Hogan. “With that in mind, in the future, through tissue engineering, we may truly be able to tell all of our patients that they will come back strong.”
The research study was carried out at the University of Virginia and University of Connecticut. Dr. Hogan recently completed his foot and ankle fellowship at the Hospital for Special Surgery and has joined the department of orthopaedic surgery at the University of Pittsburgh as an assistant professor.
Drs. Hogan and James believe that this award is a testament to the importance of collaboration between a surgeon-scientist and biomedical engineer toward the development of new regenerative strategies.
In addition to Dr. James, Dr. Hogan’s coauthors of “Successful Achilles Tendon Regeneration Using a Bioresorbable Nanofiber Scaffold, Stem Cells, and Growth Factor in a Rat Tendon Gap Defect Model” include Gary Balian, PhD; Cato T. Laurencin, MD, PhD; and A. Bobby Chhabra, MD.
Disclosure information: Dr. Hogan—AAOS Candidate, Resident, and Fellow Committee; J. Robert Gladden Society. Dr. James—no conflicts. Dr. Balian—Musculoskeletal Development Enterprise, LLC; Connective Tissue Research. Dr. Laurencin—Globus Medical; Zimmer; Pfizer; DePuy, A Johnson & Johnson Company; Soft Tissue Regeneration; Elsevier; Applied Biomaterials; Clinical Orthopaedics and Related Research; Asian Chitin Journal; Biologics: Targets & Therapy; Biomaterials; Emedicine Orthopaedics Journal; Expert Review of Medical Devices; International Journal of Nanomedicine; Journal of ASTM International; Journal of Biomedical Materials Research; Journal of Biomedical Nanotechnology; Journal of Biopharmaceutis and Biotechnology; Materials Science and Engineering; Recent Patents in Biomedical Engineering; Regenerative Medicine; The Journal of Trauma; Tissue Engineering; Nanomedicine and Nanobiotechnology; W. Montague Cobb/NMA Institute. Dr. Chhabra—MicroAire Surgical Instruments LLC; Auxillium; Saunders/Mosby-Elsevier.