Mechano-Instructive Material Inclusions to Direct Meniscus Repair

用于直接半月板修复的力学指导材料夹杂物

基本信息

批准号：
10534807
负责人：
RYAN C LOCKE
金额：
--
依托单位：
PHILADELPHIA VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534807
关键词：
3-Dimensional Acceleration Address Adhesives Adult Animal Model Apoptosis Area Behavior Biochemical Biocompatible Materials Biomechanics Biophysics Bioreactors Caring Cartilage Cell Adhesion Cell Culture Techniques Cell Density Cell Proliferation Cell physiology Cell-Matrix Junction Cells Chronic Cicatrix Clinic Clinical Collaborations Collagen Complex Cues Deposition Development Diffusion Disease Doctor of Philosophy Encapsulated Engineering Environment Formulation Fostering Gel Goals Health Hyaluronic Acid Hydrogels Image In Vitro Infiltration Injections Injury Intervention Knee Label Light Longevity Mechanics Mediating Medical center Meniscus structure of joint Mentors Mentorship Methods Microfluidic Microchips Miniature Swine Modeling Modulus Molecular Biology Techniques Multiscale Mechanics Nude Rats Orthopedics Pain Pathology Patients Pennsylvania Peptides Philadelphia Pilot Projects Predisposition Prevalence Production Proliferating Property Quality of life Research Scientist Site Stress Surface Time Tissue Engineering Tissues Training Translating Translations United States Department of Veterans Affairs Universities Weight-Bearing state Work attenuation career career development cell dimension cell motility clinical translation clinically relevant cost cost effective crosslink density design disability extracellular fabrication fortification healing improved in vivo joint destruction mechanical properties mechanical signal meniscal tear meniscus injury migration new technology novel novel strategies novel therapeutics particle professor recruit repaired research clinical testing senescence skills subcutaneous targeted treatment tissue regeneration wound wound healing

项目摘要

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.

职业发展和指导：我的长期目标是成为一名独立的人退伍军人事务医疗中心的科学家/教授，该中心靠近学术大学，可扩展科学合作并开发和转化新的疗法以改善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、多尺度生物力学和分子生物学技术（例如微阵列）。根据拟议的研究计划，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。另外，在我的大力支持下导师 Robert Mauck 博士，以及我的共同导师 Carla Scanzello 博士、医学博士、博士、Jason Burdick 博士、 Miltiadis Zgonis 博士（医学博士）、Lin Han 博士（博士）和 Daeyeon Lee 博士（博士），我将获得多样化的指导半月板病理学、大型动物模型和生物材料的职业发展、网络和研究合成。研究计划：半月板细胞的细胞外微环境决定其命运和健康。半月板损伤和疾病会破坏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。为了恢复半月板功能，本提案设计材料不仅可以恢复零时的天然微环境，还可以招募细胞并随后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策略来交付有益于调整半月板细胞力学生物学和行为的生物物理线索。具体来说，我们首先开发利用肽修饰渗透在伤口边缘建立硬度梯度的方法透明质酸水凝胶可增加 3 维细胞机械信号、运动性和收缩性（例如 3D 杜罗轴）。接下来，一旦细胞迁移到伤口边缘，我们就会通过呈现促进基质产生瞬态机械线索以及使用细胞粘合剂增加细胞附着的表面积 - 封装在本体水凝胶内的尺寸和硬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。完成这项工作的一部分将通过一系列机械疗法建立一种新的治疗方法，用于治疗其他无法修复的半月板损伤。重建细胞微环境的指导材料，具有高度的快速临床转化可行性以及对半月板力学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实现我的职业计划，成为一名成功的 VA 学生独立科学家。