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The Therapeutic Potential of Indian Hedgehog (Ihh) for Tendon-to-Bone Repair

Gilday, Steven
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460731518

Abstract Details

2016, PhD, University of Cincinnati, Engineering and Applied Science: Biomedical Engineering.
Tendon injuries are common, debilitating, and often difficult to treat. Reattaching ruptured tendons to their bony insertions has been a fundamental challenge in orthopaedics for decades, yet effective solutions that restore normal fibrocartilaginous enthesis architecture and mechanical function are still lacking. In our tissue engineering laboratory, we believe that the developmental signals governing tendon differentiation and patterning can be strategically reintroduced and/or manipulated during adult tendon repair in order to achieve better functional outcomes. In recent years, Indian hedgehog (Ihh) signaling has emerged as a key regulator of enthesis differentiation, growth, and mineralization. Given Ihh’s importance during development, the overall objective of this dissertation was to examine the role of hedgehog signaling in mature tendons and evaluate the potential therapeutic effects of recombinant Ihh during enthesis healing. In aim 1, we developed and biomechanically characterized a new murine model of patellar tendon (PT) enthesis injury. Unlike the larger animal models that have been traditionally used for studies of tendon-to-bone healing, the murine model provides us the opportunity to conduct both basic and translational tissue engineering studies in transgenic strains relatively quickly and at low cost. In aim 2, we defined the natural patterns of endogenous hedgehog signaling in the mature murine PT. We found that hedgehog signaling remained active in the unmineralized entheseal fibrocartilage even in 46 week old mice, thereby suggesting a role for Ihh in enthesis homeostasis throughout life. Prominent hedgehog signaling activity was also seen in regions of tendon undergoing fibrocartilaginous metaplasia. This observation, coupled with our finding that direct stimulation of cultured tenocytes with Ihh caused the cells to adopt a more chondrocytic phenotype, suggests that hedgehog signaling may regulate fibrocartilage formation in tendons. In aim 3, we attempted to translate these discoveries into a clinically relevant biologic therapy that would promote regeneration of a zonal fibrocartilaginous enthesis during tendon-to-bone healing. In collaboration with materials scientists, we designed and fabricated Ihh-infused polymeric drug delivery scaffolds and tested their ability to improve repair outcomes in our murine injury model. To our knowledge, this represents the first ever study to evaluate the effects of Ihh on tendon-to-bone healing in vivo. Although Ihh-infused scaffolds appeared to increase fibrocartilaginous cellular morphology at the healing enthesis, this unfortunately did not translate into improved biomechanical properties at 5 weeks post-surgery. Further work is needed in order to fully characterize the effects of Ihh on enthesis healing, but efficacious therapies for tendon-to-bone repair will likely remain elusive unless more precise methods for controlling the spatiotemporal delivery of biologic factors to the site of injury are developed. As our knowledge of tendon biology continues to expand, the ongoing challenge for clinicians and bioengineers will be to translate this growing knowledge into effective treatments for tendon disorders. This dissertation paves the way for future tissue engineering studies in which the Ihh signaling pathway is targeted during tendon repair. Ultimately, we hope the continuation of our work by others will eventually lead to new therapeutic strategies for tendon disorders via modulation of hedgehog signaling.
Jason Shearn, Ph.D. (Committee Chair)
Keith Kenter, M.D. (Committee Member)
David Butler, Ph.D. (Committee Member)
Rulang Jiang, Ph.D. (Committee Member)
193 p.
Biomedical Research
patellar tendon; enthesis; tendon healing; Indian hedgehog; functional tissue engineering; tendon-to-bone repair

Recommended Citations

Citations

  • Gilday, S. (2016). The Therapeutic Potential of Indian Hedgehog (Ihh) for Tendon-to-Bone Repair [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460731518

    APA Style (7th edition)

  • Gilday, Steven. The Therapeutic Potential of Indian Hedgehog (Ihh) for Tendon-to-Bone Repair. 2016. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460731518.

    MLA Style (8th edition)

  • Gilday, Steven. "The Therapeutic Potential of Indian Hedgehog (Ihh) for Tendon-to-Bone Repair." Doctoral dissertation, University of Cincinnati, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460731518

    Chicago Manual of Style (17th edition)

ucin1460731518
535
© 2016, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.