On-Demand Stem Cell Delivery Systems for Tendon Healing Throughout Aging

用于整个衰老过程中肌腱愈合的按需干细胞输送系统

• 批准号: 9396569
• 负责人: Benjamin Ross Freedman
• 金额: $ 5.63万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396569
• 关键词: Acute; Adolescent; Adult; Affect; Age; Aging; Alginates; American; Animal Model; BMP-12; Biocompatible Materials; Cell Survival; Cell Transplantation; Cells; Chronic; Cicatrix; Clinical; Collagen; Contralateral; Cues; Development; Environment; Exhibits; Functional disorder; Future; Harvest; Homeostasis; Image; Incidence; Individual; Inferior; Injury; Learning; Ligaments; Magnetism; Mechanics; Methods; Modeling; Molecular Weight; Muscle; Musculoskeletal Diseases; Natural regeneration; Periodicity; Phenotype; Process; Property; Proteome; Rattus; Replacement Therapy; Research; Rodent; Rodent Model; Site; Sports; Stem cells; Structure; System; Technical Expertise; Technology; Tendon Injuries; Tendon structure; Testing; Therapeutic; Tissues; Training; Transplantation; Weight-Bearing state; Work; achilles tendon; age related; aged; aging population; cell behavior; clinically relevant; design; healing; implantation; improved; magnetic field; migration; musculoskeletal injury; novel strategies; programs; public health relevance; repaired; response; scaffold; self-renewal; senescence; spatiotemporal; stem; stemness; success; viscoelasticity

Project Summary Musculoskeletal injuries affect 28.6 million Americans of all ages per year, including injuries to tendon, ligament, and muscle. Following injury, tendons heal through scar formation, do not regain pre-injury material properties, and often display aberrant phenotypes that are further exacerbated with aging. The limited capacity of native tendon stem/progenitor cells (TSPCs) to aid in the repair process may contribute to this deficient healing response. Unlike normal tendon, degenerate and aged tendon contains TSPCs that exhibit deficits in clonogenicity, multipotency, and self-renewal capacity, as well as early maturation into senescence. TSPC replacement therapies have the potential to improve tendon healing following injury, but current strategies for delivery of TSPCs are limited in their ability to maintain cell viability and stemness. Such limitations may be overcome by developing biomaterials that maintain TSPC behavior, protect TSPCs immediately post- transplantation, and respond to force-sensitive triggers for on-demand delivery. Delivery of TSPCs using biphasic alginate ferrogels that provide responsive cell release in the presence of a magnetic field may greatly improve tendon healing throughout aging, but this has not yet been explored. Therefore, this study aims to develop and examine a new approach to on-demand TSPC delivery using implantable biphasic ferrogels. We hypothesize that a biomaterial system for delivery of TSPCs (using biphasic alginate ferrogels) will maintain TSPC clonogenicity, multipotency, and self-renewal prior to release, deliver TSPCs on-demand, and ultimately augment tendon following aging and injury. This hypothesis will be tested with the following aims: (1) develop and examine the ability of biphasic ferrogels to maintain TSPC behavior prior to release using cells derived from juvenile, adult, and aged tendons, (2) develop and examine the ability of biphasic ferrogels to deliver TSPCs derived from juvenile, adult, and aged tendons on-demand, and (3) investigate the ability of biphasic ferrogels to augment tendon throughout aging and healing in a clinically-relevant load-bearing rodent Achilles tendon injury model. Success in this effort 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 diseases. Overall, the project is designed to effectively train the applicant to develop the technical skills needed to establish a successful and independent research program in the future.

项目摘要 肌肉骨骼伤害每年影响2860万美国人，包括肌腱受伤， 韧带和肌肉。受伤后，肌腱通过疤痕形成愈合，不要恢复受伤前材料 特性，通常显示出异常的表型，这些表型会因衰老而进一步加剧。容量有限 天然肌腱茎/祖细胞（TSPC）以帮助维修过程 康复反应。与正常肌腱不同，退化和衰老的肌腱包含TSPC，表现出缺陷 克隆性，多能力和自我更新能力以及早期成熟到衰老。 TSPC 替代疗法受伤后有可能改善肌腱愈合，但目前的策略 TSPC的递送维持细胞活力和干性的能力受到限制。这样的限制可能是 通过开发维持TSPC行为的生物材料来克服，在 - 立即保护TSPC 移植，并响应对力敏感的触发器，以进行按需传递。使用TSPC的交付 在磁场存在下提供响应式细胞释放的双相藻酸盐凝胶凝胶可能会极大 改善整个衰老的肌腱愈合，但尚未探索。因此，本研究的目的是 使用可植入的双相效应开发并检查一种新的TSPC递送的方法。我们 假设用于递送TSPC的生物材料系统（使用双相藻酸盐的Ferrogels）将维持 释放前TSPC克隆性，多能力和自我更新，按需提供TSPC，并最终提供 衰老和受伤后增强肌腱。该假设将以以下目的进行检验：（1）发展 并检查双相二凝胶在使用得出的细胞释放之前释放之前保持TSPC行为的能力 从少年，成人和老年肌腱，（2）发展和检查双相绒毛的能力 源自少年，成人和年龄肌腱的TSPC，以及（3）研究双相的能力 在临床上与负载的啮齿动物致敬中，整个衰老和愈合整个衰老的肌腱 肌腱损伤模型。这项努力的成功将对患有肌腱的人产生巨大影响 受伤后功能障碍，可能有助于开发其他对其他的治疗剂 肌肉骨骼疾病。总体而言，该项目旨在有效地培训申请人以开发 未来建立成功且独立的研究计划所需的技术技能。