Approximately 30 billion dollars are spent on musculoskeletal injuries in the United States each year. Tendon and ligament injuries represent almost half of these injuries. In the upper extremity, flexor tendon wounds to the hand often require surgical reconstruction and lead to prolonged disability. Poor clinical outcomes typically result from early repair-site failure and the formation of adhesions between the tendon and its surrounding synovial sheath. Our goal is to develop therapeutic solutions to prevent repair-site failure and to reduce adhesion formation following intrasynovial tendon repair. Early healing of flexor tendons relies on the migration of tendon surface cells and/or the extension of extrinsic cells from the synovial sheath to the repair site. The mechanical properties of the repair do not improve until migrating cells populate the site and synthesize extracellular matrix. The proliferation of cells on the tendon surface and the ingrowth of extrinsic vessels, however, can lead to adhesion formation between the tendon and its sheath, with associated loss of digital function. Prior studies have shown that the healing of dense connective tissues can be enhanced via growth factor- and cell-based therapies. Our previous studies demonstrated that sustained delivery of the growth factor PDGF-BB can improve range of motion after flexor tendon repair. Others have shown that adult stem cells can enhance healing in extrasynovial tendons, articular cartilage, and other tissues. However, few have applied this approach to repair pauci-cellular intrasynovial flexor tendons. The central hypothesis of this study is that a combined cell/growth factor therapy can improve gliding and strength of intrasynovial flexor tendons following repair. To test this hypothesis, we will examine the effects of autologous adipose derived mesenchymal stem cell therapy, with and without growth factor administration, on intrasynovial flexor tendon healing. A novel nanofiber scaffold capable of controlling the delivery of cells and growth factors will be used. In an effort to promote stem cell differentiatio during healing, a tenogenic growth factor will be combined with stem cells and delivered to the repair. In an effort to enhance range of motion during healing, an anti-adhesive growth factor will be combined with a tenogenic growth factor and stem cells and delivered to the repair. The effects of mesenchymal stem cell application will be determined and the impact of co-treatment using both mesenchymal stem cells and growth factors will be evaluated. Results will be directly translatable to clinical repair of flexor tendons and broadly applicable to tendon and ligament repair at other anatomic sites.

Public Health Relevance

Treatment of musculoskeletal injuries results in 30 billion dollars in healthcare costs in the United States each year. Approximately half of these injuries involve tendons and ligaments. Growth factor- and cell- based therapy has the potential to improve healing for a broad range of connective tissue injuries. Our long-term goal is to apply growth factor and cell therapy solutions in order to positively affect the clinical outcomes of tendon repair.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR062947-03
Application #
8720698
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Wang, Fei
Project Start
2012-09-15
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Li, Jianhua; Linderman, Stephen W; Zhu, Chunlei et al. (2016) Surgical Sutures with Porous Sheaths for the Sustained Release of Growth Factors. Adv Mater 28:4620-4
Kormpakis, Ioannis; Linderman, Stephen W; Thomopoulos, Stavros et al. (2016) Enhanced Zone II Flexor Tendon Repair through a New Half Hitch Loop Suture Configuration. PLoS One 11:e0153822
Shen, Hua; Kormpakis, Ioannis; Havlioglu, Necat et al. (2016) The effect of mesenchymal stromal cell sheets on the inflammatory stage of flexor tendon healing. Stem Cell Res Ther 7:144
Gelberman, Richard H; Shen, Hua; Kormpakis, Ioannis et al. (2016) Effect of adipose-derived stromal cells and BMP12 on intrasynovial tendon repair: A biomechanical, biochemical, and proteomics study. J Orthop Res 34:630-40
Yang, Guang; Lin, Hang; Rothrauff, Benjamin B et al. (2016) Multilayered polycaprolactone/gelatin fiber-hydrogel composite for tendon tissue engineering. Acta Biomater 35:68-76
Manning, Cionne N; Martel, Catherine; Sakiyama-Elbert, Shelly E et al. (2015) Adipose-derived mesenchymal stromal cells modulate tendon fibroblast responses to macrophage-induced inflammation in vitro. Stem Cell Res Ther 6:74
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Thomopoulos, Stavros; Parks, William C; Rifkin, Daniel B et al. (2015) Mechanisms of tendon injury and repair. J Orthop Res 33:832-9
Rothrauff, Benjamin B; Tuan, Rocky S (2014) Cellular therapy in bone-tendon interface regeneration. Organogenesis 10:13-28

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