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INSULIN-LIKE GROWTH FACTOR-1 SIGNALING IN ENGINEERED ARTICULAR CARTILAGE

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ABSTRACT Title of Document: INSULIN-LIKE GROWTH FACTOR-1 SIGNALING IN ENGINEERED ARTICULAR CARTILAGE Diana Meeae Yoon, Ph.D., 2008 Directed By: Associate Professor John P. Fisher, Fischell Department of Bioengineering Articular cartilage can easily become damaged or diseased and it does not have the ability to heal itself. A tissue engineering approach to regenerate cartilage is to integrate chondrocytes, the primary cell in cartilage, with biomaterials and biomolecules. Currently, there is limited knowledge on how all these factors influence the expression of upstream insulin-like growth factor-1 (IGF-1) signaling molecules. In an effort to better understand how IGF-1 and phenotypic, type II collagen, expression can be modified by altering construct properties, chondrocytes were embedded in alginate hydrogels. Increasing alginate concentration resulted in an upregulation of IGF-1 expression and by increasing cell density further enhanced IGF-1 expression. Additional changes in chondrocyte signaling were observed when exogenously delivering IGF-1 to the constructs. IGF-1 expression decreased while the receptor for IGF-1 (IGF-1R) expression as well as type II collagen increased in the presence of excess IGF-1 indicating that it has a key role in IGF-1 andchondrocyte interaction. An extracellular matrix molecule, such as hyaluronic acid (HA), provides anchorage sites for chondrocytes and therefore the influence of HA on IGF-1 signaling was also investigated. The incorporation of HA created a dual affect by entrapping exogenously delivered IGF-1 as well as directly interacting with chondrocytes. As a result, the IGF-1 expression levels varied depending on HA concentration and there was also a lack of correlation with IGF-1R expression. The upregulated expression of type I collagen, a fibroblastic marker, by chondrocytes indicated that HA can overcome the beneficial affects of IGF-1. These in vitro works were also compared to an in vivo study. Alginate/HA constructs with embedded chondrocytes were pre-cultured with IGF-1 and then subcutaneously implanted into mice. Similar levels of type II collagen were observed for the constructs. However, by increasing the HA content a decrease in IGF-1 synthesis occurred with an increase in type I collagen staining. Pre-incubating the samples with IGF-1 led to a further decrease in IGF-1 production but was able to reverse the affects of HA on type I collagen expression. This research demonstrates that construct properties can alter endogenous IGF-1 signaling and overall shows the importance of understanding these details when engineering an articular cartilage construct.INSULIN-LIKE GROWTH FACTOR-1 SIGNALING IN ENGINEERED ARTICULAR CARTILAGE By Diana Meeae Yoon Dissertation submitted to the Faculty of the Graduate School of the University of Maryland, College Park, in partial fulfillment of the requirements for the degree of Doctor of Philosophy 2008 Advisory Committee: Associate Professor John P. Fisher, Chair Assistant Professor Jose Helim Aranda-Espinoza Professor William E. Bentley Professor Peter Kofinas Professor David M. Mosser© Copyright by Diana Meeae Yoon 2008ii Dedication I dedicate this work to my Appa and Umma.iii Acknowledgements I would like to thank my advisor, Dr. John P. Fisher, for giving me the opportunity to work in his lab. I really appreciate your guidance during my graduate career and also providing a tremendous amount of new research experiences that I will forever remember. Also, I would like to thank my committee members for their advice and support in the completion of this work. I am very greatful to Dr. Sabine Francke-Carroll, John J. Murone, and Emily C. Hawkins for their endless help in teaching me histology. Thanks to Dr. Srinivasa R. Raghavan for allowing me to use your lyophilization equipment. To Dr. A. Hari Reddi and Shane Curtiss at the University of California Davis Medical Center (UCDMC) – Center for Tissue Regeneration and Repair, I appreciate all of your help and guidance during the in vivo study. Additionally, thank you to the Orthopaedic Laboratory at UCDMC for being so welcoming and friendly during my stay in California. To all the members in the Tissue Engineering and Biomaterials Laboratory, thank you for all your helpful criticisms and suggestions especially during the late night lab sessions. A special thanks to the Fischell Department of Bioengineering for awarding me the Fischell Fellowship in Biomedical Engineering to help fund my graduate career. To all the friends that I have met along the way, I would not have been able to complete this journey without all the fun and laughter that you all have brought into my life. Finally to my parents and sister, thank you for your love and continuous support throughout all of my endeavors.iv Table of Contents Dedication..................................................................................................................... ii Acknowledgements...................................................................................................... iii Table of Contents......................................................................................................... iv List of Tables .............................................................................................................. vii List of Figures............................................................................................................ viii 1 Introduction ............................................................................................................1 2 Background – Engineering Articular Cartilage......................................................4 2.1 Articular Cartilage and Chondrocyte Signaling*...........................................4 2.1.1 Introduction........................................................................................... 4 2.1.2 Biology of Articular Cartilage .............................................................. 6 2.1.3 Basic Principles of Cellular Signaling .................................................. 8 2.1.4 Native Effectors on Chondrocyte Signaling ......................................... 9 2.1.4.1 Extracellular Matrix...........................................................................9 2.1.5 Signaling Molecules of Chondrocytes ................................................ 11 2.1.5.1 Growth


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