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Tissue Engineering Strategies to Improve Tendon Healing and Insertion Site Integration

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Tissue Engineering Strategies to Improve Tendon Healing and Insertion Site Integration Tissue Engineering Strategies to Improve Tendon Healing and Insertion Site Integration A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the of the requirements for the degree of DOCTOR OF PHILOSOPHY (Ph.D.) in the Department of Biomedical Engineering of the College of Engineering and Applied Science 2011 by Kirsten Rose Carol Kinneberg B.S., University of Minnesota, Twin Cities, MN, 2006 Committee Chair: Jason T. Shearn Abstract Tendon and ligament tears and ruptures remain common and significant musculoskeletal injuries. Repairing these injuries continues to be a prominent challenge in orthopaedics and sports medicine. Despite advances in surgical techniques and procedures, traditional repair techniques maintain a high incidence of re-rupture. This has led some researchers to consider using tissue engineered constructs (TECs). Previous studies in our laboratory have demonstrated that TEC stiffness at the time of surgery is positively correlated with repair tissue stiffness 12 weeks post-surgery. This correlation provided the rationale for implanting a soft tissue patellar tendon autograft (PTA) to repair a central-third defect in the rabbit patellar tendon (PT). The PTA was significantly stiffer than previous TECs and matched the stiffness of the normal central-third PT. Accordingly, we expected a significant improvement in repair tissue biomechanics relative to both natural healing (NH) and TEC repair. At 12 weeks, treatment with PTA improved repair tissue stiffness relative to NH. However, PTA and NH tissues did not differ in maximum force, modulus or maximum stress. Additionally, neither repair group regenerated normal zonal insertion sites. To enhance integration at the tendon-to-bone insertion site, PTA repairs were 1) given up to 26 weeks to recover and 2) augmented at the patellar and tibial insertions with mesenchymal stem cell (MSC)-collagen gel biologic augmentations (BAs). The role of the native cell population in PTA healing was also tested by de-cellularizing the PTA at surgery. We found that osteotendinous integration improved with recovery time for both de-cellularized PTA (dcPTA) and PTA repairs. However, biomechanical properties were only affected by recovery time for dcPTA repairs. Despite the changes in biomechanical properties demonstrated by dcPTA repairs, biomechanical properties did not vary between dcPTA and PTA repairs at any time point. We ii also found that MSC-collagen gel BAs did not enhance osteotendinous integration or repair tissue biomechanical properties relative to PTA repairs at 12 weeks post-surgery. Overall, the repair tissue biomechanics of our mechanically pre-conditioned MSC- collagen sponge TECs were approximately twice the biomechanical properties for both PTA repairs and NH. This result warranted additional experiments to further improve in vitro TEC stiffness and mRNA expression with the objective to enhance tendon healing. We investigated the effects of pore size, scaffold composition and mechanical pre-conditioning in vitro on MSC- collagen sponge TEC stiffness and mRNA expression levels for genes of interest. Our initial results indicated that for collagen sponge TECs, pore size did not affect linear stiffness and mechanical stimulation only enhanced stiffness when chondroitin-6-sulfate was incorporated into the collagen sponge. The goals of my research were to 1) understand the effects of the resident cell population and healing time on PTA integration into bone, 2) develop a biologic augmentation that would improve tendon insertion site development, and 3) improve TEC-mediated PT healing. Future studies need to investigate the effects of combining biological and mechanical factors at the insertion site on PTA integration and also validate our in vitro-to-in vivo predictors for MSC- collagen sponge TEC repair using updated sponge materials. iii iv Acknowledgements1 First and foremost, I would like to thank my advisor, Dr. Jason Shearn. I could not have asked for a better advisor. I would like to specifically thank Dr. Shearn for trusting me to work independently but always being there when I had questions or needed advice on how to move a project forward. Dr. Shearn pushed me to my limits and helped me realize my full potential and capability as a researcher. I would also like to extend a very special thank you to Dr. David Butler. His methodologies have forever shaped the way I approach research. I feel privileged to have learned research design from Dr. Butler and also thank him for helping me better communicate my research. With the help of both Drs. Shearn and Butler I have learned to appreciate the idea of “keep it simple.” I am also grateful to Dr. Keith Kenter for serving as a member of my dissertation committee. He has brought a unique aspect to my research and helped me to think critically in terms of the clinical problem. His comments and advice will help ensure our continued projects have clinical impact and move the field of tissue engineering in a positive direction. I would also like to acknowledge the significant contributions of Dr. Marc Galloway (Cincinnati Sportsmedicine). His research ideas have had a great impact on this dissertation and I thank both him and Dr. Shearn for the opportunity to work on these projects. Dr. Galloway, along with Dr. Kenter, has helped ensure that our laboratory maintains a focus on clinically relevant problems. I would also like to thank Dr. Galloway for always creating a positive and fun atmosphere. Completing the projects described in this dissertation would not have been possible without the significant contributions of Mrs. Cindi Gooch. She has taught me the invaluable skills of cell culture technique and animal care for surgery. Cindi has not only taught me the „tricks of the trade‟ for cell culture but she has also been a good friend and a good source of advice during my time at the University of Cincinnati. _______________________________ 1 This work was supported by two grants from the National Institutes of Health (NIH AR46574-10 and NIH AR56943-02) and also by a grant from the National Science Foundation (NSF 0333377) awarded to the University of Cincinnati. v A note of gratitude is also due to my colleagues. Specifically, I would like to thank Dr. William Ball, Dr. Natalia Juncosa-Melvin, Dr. Victor Nirmalanandhan, Dr. Kumar Chokalingam, Nathaniel Dyment, Andrea Lalley, Jennifer Hurley and Abdul Sheikh for helping to conduct experiments, understand data or discuss ideas for future studies. Their contributions and ideas were invaluable in completing this dissertation. Sincere thanks also to Lori Beth Derenski, Linda Moeller, Shelly Smith, Kathryn Siefert, and Michelle Montoya. They have come to my rescue on more than one occasion and I am very grateful for their efforts. Finally, I would like to thank my family and Patrick Mihalik. They now know more than they ever wanted to know about mesenchymal stem cells, collagen sponges, and patellar tendon autografts. I appreciate their kindness in being there for me and helping me though the difficulties of research. My mom, dad, sister, grandma and Patrick have always supported and encouraged me even when I doubted myself. I would like to also thank Patrick, especially, for his patience while I completed this dissertation. vi Life is a succession of lessons which must be done to be understood. - Ralph Waldo Emerson vii Table of Contents Abstract ii Acknowledgements v Table of Contents List of Tables 2 List of Figures 3 Chapter 1 Literature Review 4 Chapter 2 Research Objectives and Hypotheses 23 Chapter 3 Effects of Implanting a Soft Tissue Autograft in a Central-Third Patellar Tendon Defect: Biomechanical and Histological Comparisons 38 Chapter 4 Effects of Recovery Time and the Role of the Native Cell Population on Insertion Site Formation and Repair Tissue Biomechanics of the Patellar Tendon Autograft 53 Chapter 5 MSC-Collagen Gel Augmentation to Enhance Osteotendinous Integration of a Patellar Tendon Autograft 70 Chapter 6 Chondroitin-6-Sulfate Incorporation and Mechanical Stimulation Increase MSC-Collagen Sponge Construct Stiffness 95 Chapter 7 Discussion 113 Chapter 8 Recommendations for Future Studies 120 Bibliography 124 1 List of Tables Table 1 Repair Tissue Dimensions [mean (SEM)] for Whole and Central-Third PT 43 Table 2 Biomechanical Properties (Mean ± SEM) of Natural Healing, Patellar Tendon Autograft, Tissue Engineered Construct and Normal Central-Third PT 45 Table 3 Repair Tissue Dimensions (Mean ± SD) for Whole and Central-Third PT Repair Tissues 59 Table 4 Biomechanical Properties (Mean ± SD) of Patellar Tendon Autograft and De-Cellularized Patellar Tendon Autograft Repairs 61 Table 5 Gene Names*, TaqMan® Assay Identification (ID) Numbers, and Amplicon Length for All Tested Genes 79 Table 6 Biomechanical Properties (Mean ± SD) of Patellar Tendon Autograft and PTA+BA Repairs and Normal Central-Third PT 83 Table 7 Repair Tissue Dimensions (Mean ± SD) for Whole and Central-Third PT 87 Table 8 Experimental Design 99 Table 9 Biomechanics and Gene Expression Data for MSC-Collagen Sponge TECs [Mean (SEM)] Cultured for Two Weeks Statically and with Mechanical Stimulation 106 2 List of Figures Figure 1 Schematic of tendon hierarchical structure 6 Figure 2 Experimental design flow chart 25 Figure 3 SEM images of small (A), medium (B), and large (C) pore size scaffold materials 36 Figure 4 Force-displacement curves (mean ± SEM) 44 Figure 5 H&E staining and IHC staining for collagen
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