Mechano-Instructive Material Inclusions to Direct Meniscus Repair

点击翻译按钮获取中文摘要

Career Development and Mentoring: My long-term goals are to become an independent scientist/professor at a Veterans Affairs Medical Center in proximity to academic universities for expanded scientific collaborations and to develop and translate novel therapeutics for improved treatment of problematic orthopaedic injuries. In my doctoral training, I fine-tuned my skillset in small animal models, multi-scale biomechanics, and molecular biology techniques (e.g., microarrays). From the proposed Research Plan, I will expand my research skillset by answering fundamental questions about meniscus repair and cell-material interactions both in vitro and in vivo using large animal models. Additionally, with strong support from my Mentor, Dr. Robert Mauck, PhD, and my Co-Mentors, Dr. Carla Scanzello, MD, PhD, Dr. Jason Burdick, PhD, Dr. Miltiadis Zgonis, MD, Dr. Lin Han, PhD, and Dr. Daeyeon Lee, PhD, I will gain diverse mentorship for my career development, networking, and research on meniscus pathology, large animal models, and biomaterial synthesis. Research Plan: The extracellular microenvironment of meniscus cells determines their fate and health. Meniscus injury and disease disrupt the native structural and mechanical properties of the microenvironment, leading to loss of tissue function and chronic pathology. To restore meniscus function, this proposal designs materials that not only restore the native microenvironment at time zero but also recruit cells and subsequently promote matrix production following meniscus injury. For this, we utilize material-directed strategies to deliver biophysical cues that beneficially tailor meniscus cell mechanobiology and behavior. Specifically, we first develop methods to establish stiffness gradients at the wound edge using infiltration of peptide-modified hyaluronic acid hydrogels to increase 3-dimensional cell mechano-signaling, motility, and contractility (e.g., 3D durotaxis). Next, once cells have migrated to the wound margin, we promote matrix production via presentation of transient mechanical cues as well as increased surface area for cell attachment using cell-adhesive and - degradable micro-inclusions of tunable size and stiffness encapsulated within the bulk hydrogel. Finally, we carry out pilot studies to establish the efficacy of these new technologies in a large animal model. Completion of this work will establish a novel treatment for otherwise irreparable meniscus injuries via a set of mechano- instructive materials to reestablish the cell microenvironment with high feasibility for rapid clinical translation and broad implications for meniscus mechanobiology and repair. In summary, my proposed research plan, mentoring plan, as wells as the outstanding environment and facilities at the Philadelphia VA Medical Center and the University of Pennsylvania will help me to accomplish my career plans to be a successful VA-based independent scientist.