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

项目摘要 肌肉骨骼损伤每年影响2860万各年龄段的美国人，包括肌腱损伤， 韧带和肌肉受伤后，肌腱通过瘢痕形成愈合，不会恢复受伤前的材料 性质，并经常显示出异常的表型，这些表型随着年龄的增长而进一步恶化。能力有限 天然肌腱干/祖细胞（TSPC），以帮助修复过程可能有助于这种缺陷 治愈反应与正常肌腱不同，退化和老化的肌腱含有TSPC，其表现出TSPC的缺陷。 克隆形成、多能性和自我更新能力，以及早熟进入衰老。TSPC 替代疗法有可能改善损伤后的肌腱愈合，但目前的策略 TSPC的递送在其维持细胞活力和干细胞性的能力方面受到限制。这种限制可能是 通过开发维持TSPC行为的生物材料来克服， 移植，并响应力敏触发器按需交付。使用TSPC交付 在磁场存在下提供响应性细胞释放的双相藻酸盐铁凝胶可大大 在整个老化过程中改善肌腱愈合，但这尚未被探索。因此，本研究旨在 开发和研究一种新的方法，按需TSPC交付使用植入式双相铁凝胶。我们 假设用于递送TSPC的生物材料系统（使用双相藻酸盐铁凝胶）将维持 TSPC在发布前具有克隆原性、多能性和自我更新能力，可按需提供TSPC， 增加老化和损伤后的肌腱。这一假设将通过以下目标进行检验：（1）发展 并检查双相铁凝胶在释放之前使用细胞衍生的TSPC行为的能力， 从青少年，成人和老年肌腱，（2）开发和检查双相铁凝胶递送的能力， TSPC来源于青少年，成人和老年肌腱的需求，和（3）调查双相的能力， 铁凝胶在临床相关承重啮齿动物跟腱老化和愈合过程中增强肌腱 肌腱损伤模型。这项工作的成功将对患有肌腱炎的人产生巨大的影响 损伤后的功能障碍，并可能有助于开发其他 肌肉骨骼疾病总的来说，该项目旨在有效地培训申请人开发 在未来建立一个成功的和独立的研究计划所需的技术技能。

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.