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 退伍军人事务医学中心的科学家/教授，位于学术大学附近，以扩大 科学合作，开发和翻译新的治疗方法，以改善对有问题的治疗 骨科损伤。在我的博士培训中，我微调了我在小动物模型中的技能，多尺度 生物力学和分子生物学技术(例如，微阵列)。从建议的研究计划中，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 使用大型动物模型在体外和体内的相互作用。此外，在我的大力支持下， 导师罗伯特·莫克博士和我的共同导师卡拉·斯坎泽洛博士，医学博士，博士，杰森·伯迪克博士， 米尔蒂亚迪斯·佐戈尼斯博士、林翰博士和李大仁博士，我将为我的 在半月板病理学、大型动物模型和生物材料方面的职业发展、网络和研究 综合。 研究计划：半月板细胞的细胞外微环境决定其命运和健康。 半月板损伤和疾病破坏了微环境的固有结构和机械性能， 导致组织功能丧失和慢性病理改变。为恢复半月板功能，本方案设计 这种材料不仅在时间零点恢复自然微环境，而且还能招募细胞并随后 促进半月板损伤后基质的生成。为此，我们使用以材料为导向的策略来交付 有利于半月板细胞机械生物学和行为的生物物理线索。具体来说，我们首先 开发利用多肽修饰的渗入在伤口边缘建立硬度梯度的方法 透明质酸水凝胶，可增加三维细胞机械信号、运动性和收缩能力(例如，3D 多药趋向性)。接下来，一旦细胞迁移到伤口边缘，我们就会通过呈现来促进基质的产生 瞬时机械提示以及使用细胞粘合剂增加细胞附着的表面积，以及- 块状水凝胶中包裹着大小和硬度可调的可降解微包裹体。最后，我们 开展试验性研究，以确定这些新技术在大型动物模型中的有效性。完成 这项工作将建立一个新的治疗方法，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性材料，可用于快速临床翻译 以及对半月板机械生物学和修复的广泛影响。总而言之，我提出的研究计划， 指导计划，以及费城退伍军人医疗中心出色的环境和设施 宾夕法尼亚大学将帮助我完成我的职业计划，成为一名成功的退伍军人 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.