Mechano-Instructive Material Inclusions to Direct Meniscus Repair

职业发展和指导：我的长期目标是成为一名独立的 科学家/教授在退伍军人事务医疗中心附近的学术大学扩大 科学合作，并开发和翻译新的治疗方法，以改善治疗问题 骨科损伤。在我的博士培训中，我微调了我在小动物模型，多尺度 生物力学和分子生物学技术（例如，微阵列）。根据研究计划，我将 通过回答有关半月板修复和细胞材料的基本问题来扩展我的研究技能 使用大型动物模型进行体外和体内相互作用。此外，在我的大力支持下， 导师Robert Mauck博士和我的共同导师Carla Scanzello博士、Jason Burdick博士、 博士Miltiadis Zavis，医学博士，Lin Han博士，博士和Daeyeon Lee博士，博士，我将获得不同的指导， 职业发展，网络和半月板病理学，大型动物模型和生物材料的研究 合成. 研究计划：半月板细胞的细胞外微环境决定了它们的命运和健康。 半月板损伤和疾病破坏了微环境的天然结构和机械特性， 导致组织功能丧失和慢性病理学。为了恢复半月板功能，本提案设计 材料不仅在零时恢复天然微环境，而且还招募细胞， 促进半月板损伤后基质的产生。为此，我们利用以材料为导向的战略， 生物物理线索，有益地定制半月板细胞机械生物学和行为。具体来说，我们首先 开发使用肽修饰的渗透在伤口边缘建立刚度梯度的方法， 透明质酸水凝胶以增加三维细胞机械信号传导、运动性和收缩性（例如，3D 硬旋转）。接下来，一旦细胞迁移到伤口边缘，我们通过呈递促进基质产生 短暂的机械线索，以及增加表面积的细胞附着使用细胞粘附和- 封装在本体水凝胶内的尺寸和刚度可调的可降解微内含物。最后我们 开展试点研究，以确定这些新技术在大型动物模型中的功效。完成 这项工作将建立一种新的治疗，否则无法修复的半月板损伤，通过一套机械， 重建细胞微环境的指导材料，具有快速临床翻译的高度可行性 以及对半月板机械生物学和修复的广泛影响。总之，我提出的研究计划， 指导计划，以及威尔斯优秀的环境和设施，在费城退伍军人医疗中心 宾夕法尼亚大学将帮助我完成我的职业计划，成为一个成功的VA为基础的 独立科学家

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.