Multifunctional tough adhesive hydrogels to recruit, expand, and deliver tendoncells during aging and injury

项目摘要 我的职业目标是成为一名研究结构-功能的独立调查员和教育家 肌腱老化和损伤的机制，以及如何使用生物材料来改善它们。我的研究训练 在生物工程中，开始研究愈合和疲劳负荷对多尺度肌腱特性的作用。我 认识到生物材料和治疗输送策略的知识对于开发 肌腱的治疗在我的F32博士后培训期间，我们开发和探索了 坚韧的粘性生物材料，灵感来自鼻涕虫分泌的粘液，可以牢固地粘附在肌腱表面。 这种坚韧的粘附性生物材料的目的是为肌腱提供机械支撑和模板 再生，用作局部递送试剂的仓库，支持细胞生长和浸润，并提供滑动 周围的组织。此K99/R 00应用程序研究了一种新的细胞交付策略， 细胞在体内，扩大他们，并释放他们的需求，以促进肌腱愈合使用这种生物材料 平台我的导师团队由大卫穆尼博士（主要导师）和其他七位著名的 科学家专门从事肌腱发育和衰老生物学，肌肉骨骼生物学，药物输送， 矫形生物工程、材料科学和矫形外科。他们为我提供了一个特殊的 环境，以调查这些问题，并发展必要的技能，以促进外地作为一个 独立调查员我们假设，这种生物材料系统可以调整，以招募，扩大， 输送肌腱细胞（使用坚韧的粘性水凝胶），并在老化和损伤过程中增强肌腱性能。 本论文的主要目的是：（1）开发和研究坚韧水凝胶的性能 含有趋化剂，以募集腱源性细胞，促进其增殖，并增加 在体外和体内老化和损伤过程中肌腱标记物的表达;（2）开发和检查 水凝胶降解和嵌入的纤维模板成熟肌腱，驱动肌腱标志物的表达， 并且在体外和体内，在整个老化和损伤过程中促进细胞从支架释放到损伤部位;以及 (3)研究坚韧粘合剂水凝胶系统恢复肌腱中与年龄相关的缺陷的能力 使用临床相关的跟腱啮齿类动物模型，观察体内平衡和愈合。成功将有一个 对受伤后遭受肌腱功能障碍的个体产生巨大影响，并可能导致 开发其他肌肉骨骼和结缔组织疾病的按需治疗药物。总体而言，这 全面的项目和培训计划将为我提供出色的培训，以发展技术和 建立一个成功的和独立的研究计划，研究和提供必要的专业技能 指导肌肉骨骼组织老化和生物材料。

Project Summary My career goal is to become an independent investigator and educator who studies structure-function mechanisms of tendon aging and injury and how they may be improved using biomaterials. My research training in bioengineering started by studying the role of healing and fatigue loading on multiscale tendon properties. I realized that knowledge of biomaterials and therapeutic delivery strategies would be essential to develop treatments for tendon. During my F32 postdoctoral training, we have developed and explored the capacity of tough adhesive biomaterials, inspired by the mucus secreted by slugs, to adhere strongly to tendon surfaces. The goal of this tough adhesive biomaterial is to provide mechanical support and a template for tendon regeneration, serve as a depot for local delivery of agents, support cell growth and infiltration, and provide gliding of surrounding tissues. This K99/R00 Application examines a new cell delivery strategy to dynamically recruit cells in vivo, expand them, and release them on-demand to promote tendon healing using this biomaterial platform. My mentoring team consists of Dr. David Mooney (primary mentor) and seven other renowned scientists specializing in tendon developmental and aging biology, musculoskeletal biology, drug delivery, orthopaedic bioengineering, materials science, and orthopaedic surgery. They provide me with an exceptional environment to investigate these questions and develop the necessary skills to contribute to the field as an independent investigator. We hypothesize that this biomaterial system can be tuned to recruit, expand, and deliver tendon cells (using tough adhesive hydrogels) and augment tendon properties during aging and injury. This hypothesis will be tested with the following aims: (1) develop and examine the ability of tough hydrogels containing chemotactic agents to recruit tendon-derived cells, promote their proliferation, and increase expression of tendon markers throughout aging and injury in vitro and in vivo; (2) develop and examine the ability of hydrogel degradation and embedded fibers to template mature tendon, drive expression of tendon markers, and promote cell release from the scaffold to the injury site throughout aging and injury, in vitro and in vivo; and (3) investigate the ability of the tough adhesive hydrogel system to restore age-related deficits in tendon homeostasis and healing using a clinically-relevant Achilles tendon rodent model. Success would have a dramatic impact on individuals suffering from tendon dysfunction following injury and could contribute to the development of on-demand therapeutics for other musculoskeletal and connective tissue diseases. Overall, this comprehensive project and training plan will provide me outstanding training to develop the technical and professional skills necessary to establish a successful and independent research program to study and provide mentoring in musculoskeletal tissue aging and biomaterials.