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

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The Therapeutic Potential of Indian Hedgehog (Ihh) for Tendon-To-Bone Repair The Therapeutic Potential of Indian Hedgehog (Ihh) for Tendon-to-Bone Repair A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY (Ph.D.) in the Biomedical Engineering Program of the College of Engineering and Applied Science 2015 by Steven David Gilday B.S., University of Virginia, Charlottesville, VA, 2007 Committee Chair: Jason T. Shearn, Ph.D. Abstract 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 ii 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. iii iv Acknowledgements I would like to express my deep appreciation and gratitude to the many individuals who have helped and encouraged me on my path to becoming a physician-scientist. To all my current and former teachers, mentors, collaborators, and fellow lab members, I give you my sincerest thanks. This dissertation would not have been possible without you. The following list of people deserve special acknowledgement for their contributions to my research, their mentorship during my physician-scientist training, and their constant support as I navigated the trials and tribulations of graduate school. First and foremost, I would like to thank my two primary research advisors, Dr. David Butler and Dr. Jason Shearn. Your willingness to take me into your tissue engineering and biomechanics laboratory as an MD/PhD student, introduce me to the field of musculoskeletal research, and jointly mentor me throughout the course of my dissertation has been critical to my development as a scientist. Although different in your mentoring style, together you have guided me through the scientific process and taught me many valuable lessons, ranging from how to best design an experiment to how to communicate more effectively. Most importantly, you have constantly challenged me to reach my full potential and encouraged me to persevere in the face of hardship. I enjoyed working with both of you and look forward to continued collaboration in the future. I would also like to thank Dr. Rulang Jiang and Dr. Keith Kenter for serving on my dissertation committee. As a developmental biologist and an orthopaedic surgeon, respectively, your diverse perspectives on the biological and clinical aspects of my research are greatly valued. Your expertise, input, and suggestions have improved the quality of my work and forced me to think about research questions from more than one angle. v During my time as a graduate student, I have been fortunate enough to work side-by-side in the lab with some of the kindest, smartest, and most helpful people I have ever met. Dr. Nathaniel Dyment, Dr. Andrew Breidenbach, Dr. Andrea Lalley, Dr. Rebecca Spatholt, and Cindi Gooch not only provided me with invaluable technical training and experimental assistance, but also made the lab a fun place to work. Our daily discussions and general camaraderie helped break up the drudgery and dissipate the stresses of graduate school. I not only consider you scientific colleagues, but also close friends. Thank you so much for all you have done for me. Many of the studies presented in this dissertation could not have been completed without the help of a multidisciplinary team of researchers. In addition to my fellow lab members mentioned above, I am indebted to the many collaborators that I have been privileged to work with and learn from over the past four years, including: Dr. Chris Wylie, Dr. Rulang Jiang, Dr. Chia-Feng Liu, Dr. Han Liu, and Lindsey Aschbacher-Smith from the Division of Developmental Biology at Cincinnati Children’s Hospital Medical Center; Dr. Keith Kenter and Dr. Chris Casstevens from the Department of Orthopaedic Surgery at the University of Cincinnati; Dr. Samer Hasan from the Cincinnati Sports Medicine and Orthopaedic Center; Dr. Heather Powell from the Department of Materials Science and Engineering at The Ohio State University; Dr. Marepalli Rao from the Division of Biostatistics and Bioinformatics at the University of Cincinnati; and Dr. Daria Narmoneva from the Biomedical Engineering Program at the University of Cincinnati. My research successes would not have been possible without the committed support of the University of Cincinnati Medical Scientist Training Program (MSTP). Thank you to Dr. Patrick Tso for recruiting me into the program and thereby allowing me to pursue my goal of vi becoming a physician-scientist. I would also like to thank Dr. Gurjit (Neeru) Khurana Hershey, Dr. Kathryn Wikenheiser-Brokamp, Dr. George Deepe, Dr. Andrew Herr, Dr. Timothy LeCras, Laurie Mayleben, Andrea DeSantis, and Amy Flanary for your dedication to the UC MSTP and for your tireless efforts to create a nurturing environment that fosters both scientific and professional development. I am also constantly motivated and inspired by my MSTP classmates Rahul D’Mello, Mike Horwath, Jed Kendall, Julie Lander, and Dr. Martine Lamy, all of whom have supported and encouraged me throughout my training. I want to extend a special thank you to my former teachers Lois Schultz, Linda Noble, Jon Corum, and Mary Rhein for instilling in me a lifelong love of learning and science. I also want to thank Dr. Jay Hove for hiring me as an undergraduate lab assistant and thus introducing me to the wonders of modern biomedical research many summers ago. The positive experience I had working in the Hove lab with Dr. Michael Craig, Kate Olukalns, Mitul Desai, Dr. Robert Littleton, and Dr. Mikah Coffindaffer-Wilson cemented my desire to pursue a graduate degree. Most importantly, thank you to my wonderful family and friends who have stood by my side throughout the ups and downs of my research and graduate education. My parents, Dave and Cheryl, my brothers, Dan and Scott, and my wife, Sarah, have provided limitless love and encouragement. Your unwavering support has given me the strength and motivation to work hard, pursue my passions, and “finish strong.” I love you all very much. vii Organization of Dissertation This dissertation is composed of seven chapters and includes an introduction to the clinical problem of tendon-to-bone repair and a review of the
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