Utilizing natural biological scaffold for enhancement of tendon healing

利用天然生物支架促进肌腱愈合

• 批准号: 9928219
• 负责人: NELLY Andarawis-Puri
• 金额: $ 1.3万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9928219
• 关键词: Adult; Biological; Biomechanics; Cells; Characteristics; Cicatrix; Committee Members; Data; Defect; Deposition; Development; Entrepreneurship; Environment; Exhibits; Extracellular Matrix; Failure; Fiber; Foundations; Future; Gel; Gelatinase B; Goals; Harvest; Human; Implant; Inbred Strains Mice; Incidence; Injury; Investigation; Lead; Mammals; Mechanics; Mediating; Mentors; Modeling; Mouse Strains; Mus; Operative Surgical Procedures; Organ; Organ Culture Techniques; Orthopedics; Outcome; Property; Proteins; Proteomics; Recovery; Research; Role; Science; Structural Protein; Structure; Techniques; Tendon structure; Therapeutic; Tissue Engineering; Tissues; Training; Translating; Translational Research; Translations; Transmission Electron Microscopy; Underrepresented Minority; United States National Institutes of Health; Work; career; career networking; design; experimental study; functional restoration; healing; health management; implantation; improved; in vivo; injured; innovation; insight; mechanical properties; musculoskeletal injury; novel; parent grant; patellar tendon; protein structure; regenerative; repaired; response; scaffold; soft tissue; surgery outcome; symposium; therapeutic development; therapy outcome; tool; webinar

Tendon tears are common musculoskeletal injuries that heal without restoration of the functional structure. Failure of healing tendons to restore the functional structure leads to progression of injury and high incidence of re-tear after surgical repair. Scarless tendon healing, with restored native tissue properties, could improve surgical outcome or eliminate the need for surgical repair altogether, but is not typically observed in post-natal mammals. The discovery that adult Murphy Roths Large (MRL/MpJ) mice exhibit a regenerative capacity has distinguished this mouse strain as an exciting model to investigate mechanisms that underlie adult regenerative healing. Investigation into the regenerative mechanisms of MRL/MpJ mice has generated hypotheses that implicate both, the systemic and local tissue level, but no conclusive data exists. The parent grant interrogates the contribution of the systemic environment of the MRL/MpJ mouse and the local environment of its tendon to scarless tendon healing. Novel microsurgical techniques and inbred mouse strains are utilized to uncouple the contribution of the systemic environment and the innate tendon to scarless tendon healing. Tendon organ culture is also employed to determine the role of the provisional extracellular matrix (ECM) from regenerative MRL/MpJ mice in modulating the cellular activity that leads to scarless tendon healing. Our findings show that the innate environment of the tendon is essential to the improved healing capacity of the MRL/MpJ tendon. This is evidenced by the fact that organ cultured midsubstance punched MRL/MpJ tendons, wherein the systemic environment is eliminated, exhibit superior recovery of the mechanical properties and the structure than B6 tendons. The parent grant also begins to explore the therapeutic potential of the provisional ECM derived from MRL/MpJ healing tendons to promote scarless tendon healing in scar-mediated B6 mice. More specifically, the provisional ECM from healing MRL/MpJ and B6 tendons will be harvested, decellularized, suspended in a delivery gel and placed in midsubstance punch injured patellar tendons (PT) of scar-mediated B6 mice. The supplement extends the studies proposed in the parent grant by determining the protein and structural composition that are associated with an improved therapeutic outcome. More specifically, the protein composition of the provisional ECM that is associated with the best and worst healing outcomes in B6 mice will be extensively evaluated using proteomics. Furthermore, the structure associated with the optimal composition will be determined from healing MRL/MpJ using Transmission Electron Microscopy (TEM), prior to pulverization. Future studies will use the tools developed in the parent grant (organ culture) and the data from supplement to identify the proteins or network of proteins that promote healing. In addition, the structural data will be used to inform structural design of future delivery scaffolds. In summary, data from the supplement will be instrumental in translating findings from the parent grant into therapeutics.

肌腱撕裂是一种常见的肌肉骨骼损伤，愈合后功能结构没有恢复。 肌腱愈合不能恢复功能性结构，导致损伤进展和高发病率。 手术修复后再次撕裂。无瘢痕肌腱愈合，恢复天然组织特性，可以改善 手术结果或完全消除手术修复的需要，但通常在出生后观察不到 哺乳动物成年墨菲罗斯大（MRL/MpJ）小鼠表现出再生能力的发现， 将这种小鼠品系作为一种令人兴奋的模型来研究成年再生的基础机制， 治愈对MRL/MpJ小鼠再生机制的研究产生了以下假设， 涉及全身和局部组织水平，但没有结论性数据。格兰特的父母询问 MRL/MpJ小鼠的全身环境及其肌腱的局部环境对 无瘢痕肌腱愈合。利用新的显微外科技术和近交系小鼠品系来解偶联 全身环境和先天肌腱对无瘢痕肌腱愈合的贡献。肌腱器官培养 还用于确定再生MRL/MpJ的临时细胞外基质（ECM）的作用 小鼠调节细胞活性，导致无瘢痕肌腱愈合。我们的发现表明， 肌腱的环境对于改善MRL/MpJ肌腱的愈合能力至关重要。这是 通过器官培养的中间物质刺穿MRL/MpJ肌腱的事实证明，其中全身 消除了环境，表现出比B6上级的力学性能和组织恢复能力 肌腱父母补助金也开始探索临时ECM的治疗潜力， MRL/MpJ愈合肌腱以促进瘢痕介导的B6小鼠中的无瘢痕肌腱愈合。更具体而言是 将来自愈合的MRL/MpJ和B6肌腱的临时ECM收获，脱细胞，悬浮在培养皿中， 递送凝胶中，并置于瘢痕介导的B6小鼠的中间物质穿孔损伤的髌腱（PT）中。的 补充扩展了父母补助金中提出的研究，通过确定蛋白质和结构 这些组合物与改善的治疗结果相关。更具体地说，蛋白质 与B6小鼠中最好和最差愈合结果相关的临时ECM的组成将 使用蛋白质组学进行广泛评估。此外，与最佳组成相关的结构 将在粉碎前使用透射电子显微镜（TEM）从愈合MRL/MpJ中确定。 未来的研究将使用在母基金（器官培养）中开发的工具和来自补充的数据， 识别促进愈合的蛋白质或蛋白质网络。此外，结构数据将用于 为未来交付脚手架的结构设计提供信息。总之，补编中的数据将是有用的 将研究成果转化为治疗方法。