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Identifying and Evaluating Novel Biological Targets to Improve Musculoskeletal Tissue Engineering Strategies

Lalley, Andrea L.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416231302

Abstract Details

2014, PhD, University of Cincinnati, Engineering and Applied Science: Biomedical Engineering.
Tendon and ligament injuries pose a significant socioeconomic burden to the United States. Tissue engineering seeks to design tissue substitutes that are better equipped to improve the healing process. Previous work shows a benefit to this approach; however, we have not produced native biological and mechanical properties. To design effective tissue substitutes, we need to investigate successful tendon tissue formation. This dissertation is focused on identifying and evaluating biological targets using regenerative models and normal development to guide tissue engineering strategies. We proposed a strategy for identifying, prioritizing, and evaluating potential biological success criteria for improving tendon healing and repair and determined that successful tendon formation and function relies on scleraxis-expressing cells, well-aligned collagen, and a tendon-bone insertion site. To expand our potential biological design criteria, we planned to investigate normal development and regenerative models, such as the MRL/MpJ. To validate the MRL/MpJ as a model of regenerative-like healing, we evaluated its response to a central patellar tendon injury and found improved mechanical outcomes at 8 weeks post surgery compared to wildtype. This response was not a result of a p21 deficiency. We then evaluated the RNA transcriptome at early post-surgical time points using RNA-Seq and found the MRL/MpJ decreases activation of immune-related pathways while expressing developmental transcription factors. While our laboratory focuses on tendon, we also acknowledge the importance of translating our findings to other tissue systems. We thus investigated the MRL/MpJ’s responses to a critical-size femoral osteotomy. While the MRL/MpJ did not show improved biomechanical outcomes, increased expression of bone remodeling markers was observed up to 5 weeks post injury, suggesting a prolonged healing response. To assess the role of mohawk homeobox in tendon maturation, we investigated tendon morphology and biomechanical properties using a mohawk homeobox knock-out strain. Mkx-/- tendons were significantly smaller than wildtype, displayed abnormal collagen color/vibrancy, and displayed a 33% and 31% reduction in linear stiffness and modulus, respectively. Finally, we investigated a mouse model of collagenase-induced tendon injury. This allows for comparison among multiple tendon injury models to understand mechanistic differences in the natural healing responses. Injecting 15000IU-20000IU collagenase into the patellar tendon resulted in decreased mechanical properties at 2 weeks, with a return to normal levels by 5 weeks. Future work should focus on connecting normal development and regenerative processes, identifying the role of the immune response in tendon healing, and evaluating additional models of regeneration to strengthen our tissue engineering approaches.
Jason Shearn, Ph.D. (Committee Chair)
Keith Kenter, M.D. (Committee Member)
Rulang Jiang, Ph.D. (Committee Member)
Jeffrey Johnson, Ph.D. (Committee Member)
226 p.
Biomedical Research
Tendon; Tissue Engineering; MRL MpJ; Tendon Healing; Tendon Mechanics; Normal Tendon Development

Recommended Citations

Citations

  • Lalley, A. L. (2014). Identifying and Evaluating Novel Biological Targets to Improve Musculoskeletal Tissue Engineering Strategies [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416231302

    APA Style (7th edition)

  • Lalley, Andrea. Identifying and Evaluating Novel Biological Targets to Improve Musculoskeletal Tissue Engineering Strategies. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416231302.

    MLA Style (8th edition)

  • Lalley, Andrea. "Identifying and Evaluating Novel Biological Targets to Improve Musculoskeletal Tissue Engineering Strategies." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416231302

    Chicago Manual of Style (17th edition)

ucin1416231302
822
© 2014, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.