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者和教育者 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，首先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传递策略的知识将是开发 肌腱的治疗。在我的F32博士后培训期间，我们开发和探索了 坚韧的粘附性生物材料，受到鼻涕虫分泌的粘液的启发，能够强烈地附着在肌腱表面。 这种坚韧粘附性生物材料的目标是为肌腱提供机械支撑和模板 再生，作为局部递送药剂的仓库，支持细胞生长和渗透，并提供滑动 周围的组织。这个K99/R00应用程序研究了一种新的细胞递送策略，以动态招募 体内的细胞，扩大它们，并按需释放它们，以使用这种生物材料促进肌腱愈合 站台。我的指导团队由大卫·穆尼博士(主要导师)和其他七位著名的 科学家专门研究肌腱发育和衰老生物学、肌肉骨骼生物学、药物输送、 整形外科生物工程、材料科学和整形外科。他们为我提供了一种非凡的 为研究这些问题创造环境，并培养必要的技能，为实地工作做出贡献 独立调查员。我们假设这个生物材料系统可以被调整来招募、扩大和 提供肌腱细胞(使用坚韧的粘性水凝胶)，并在老化和损伤期间增强肌腱性能。 这一假说将以以下目的进行检验：(1)开发和检验坚韧水凝胶的能力 含有趋化因子，以招募肌腱来源的细胞，促进其增殖，并增加 肌腱标志物在体外和体内衰老和损伤过程中的表达；(2)开发和检验能力 水凝胶降解和嵌入纤维到模板成熟肌腱，驱动肌腱标志物的表达， 在体外和体内老化和损伤过程中，促进细胞从支架释放到损伤部位；以及 (3)观察Tough粘附性水凝胶修复增龄性肌腱损伤的能力。 使用临床相关的跟腱啮齿动物模型的动态平衡和愈合。成功将会有一个 对受伤后肌腱功能障碍的个人产生巨大影响，并可能导致 其他肌肉骨骼和结缔组织疾病的按需疗法的发展。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 建立成功的独立研究计划所需的专业技能，以研究和提供 在肌肉骨骼组织老化和生物材料方面提供指导。

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.