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

多功能坚韧粘合水凝胶可在衰老和损伤期间募集、扩张和输送肌腱细胞

• 批准号: 10116248
• 负责人: Benjamin Ross Freedman
• 金额: $ 12.68万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116248
• 关键词: Acute; Adhesives; Adolescent; Adult; Affect; Age; Aging; American; Biocompatible Materials; Biology; Biology of Aging; Biomedical Engineering; Cell Proliferation; Cell Separation; Cell Therapy; Cells; Chronic; Cicatrix; Collagen; Connective Tissue Diseases; Consumption; Development; Disease; Doctor of Philosophy; Drug Delivery Systems; Environment; Enzymes; Exhibits; Faculty; Fatigue; Fiber; Functional disorder; Goals; Homeostasis; Human; Hydrogels; In Vitro; Incidence; Individual; Infiltration; Injury; Insulin-Like Growth Factor I; Knowledge; Learning; Ligaments; Ligands; Mechanics; Mediating; Mentors; Methods; Modeling; Mucous body substance; Muscle; Musculoskeletal; National Research Service Awards; Natural regeneration; Orthopedic Surgery; Orthopedics; Phase; Phenotype; Positioning Attribute; Process; Property; Proteome; Research; Research Personnel; Research Training; Rodent; Rodent Model; Rogaine; Role; Scientist; Site; Sports; Structure; Supporting Cell; Surface; System; Technical Expertise; Techniques; Tendon Injuries; Tendon structure; Testing; Therapeutic; Time; Tissues; Training; Work; achilles tendon; age related; aged; aging population; career; cell age; cell growth; cell motility; clinically relevant; cost; design; healing; implantation; improved; in vivo; materials science; migration; mouse model; musculoskeletal injury; novel; novel strategies; post-doctoral training; programs; recruit; repaired; response; scaffold; scleraxis; senescence; skills; slug; soft tissue; stem; stem cells; success; viscoelasticity

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.

项目摘要 我的职业目标是成为研究结构功能的独立调查员和教育者 肌腱衰老和损伤的机制以及如何使用生物材料改善它们。我的研究培训 在生物工程中，首先研究愈合和疲劳负荷在多尺度肌腱特性上的作用。我 意识到生物材料和治疗性交付策略的知识对于发展至关重要 肌腱的治疗。在我的F32博士后培训期间，我们已经开发并探索了 坚硬的粘合剂生物材料，灵感来自Slugs分泌的粘液，强烈粘附在肌腱表面上。 这种坚硬的粘合剂生物材料的目的是提供机械支撑和肌腱模板 再生，用作局部交付代理，支持细胞生长和浸润的仓库，并提供滑行 周围的组织。此K99/R00应用程序研究了一种新的单元输送策略，以动态招募 体内细胞，扩展它们并按需释放它们以使用这种生物材料促进肌腱愈合 平台。我的指导团队由David Mooney博士（主要导师）和另外七个知名 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， 骨科生物工程，材料科学和骨科手术。他们为我提供了特殊的 调查这些问题并发展必要技能的环境，以为该领域做出贡献 独立研究者。我们假设该生物材料系统可以调整以招募，扩展和 在衰老和损伤过程中，输送肌腱细胞（使用坚硬的粘合水凝胶）和增强肌腱特性。 该假设将以以下目的进行检验：（1）发展和检查坚硬水凝胶的能力 含有趋化剂以募集肌腱衍生的细胞，促进其增殖并增加 整个体外和体内衰老和损伤的肌腱标记的表达； （2）发展和检查能力 水凝胶降解和嵌入式纤维的成熟肌腱，肌腱标记的表达， 在整个衰老和损伤中，体外和体内促进细胞从支架到损伤部位的细胞释放；和 （3）研究坚硬的粘附水凝胶系统恢复肌腱中与年龄相关的缺陷的能力 使用临床上的跟腱啮齿动物模型使用稳态和愈合。成功将有一个 受伤后患有肌腱功能障碍的个体的巨大影响，可能有助于 开发用于其他肌肉骨骼和结缔组织疾病的按需治疗。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，以开发技术和 建立成功且独立的研究计划所需的专业技能，以研究和提供 在肌肉骨骼组织衰老和生物材料中进行指导。