Enhanced Soft Tissue-to-Bone Healing via Treatment with Novel Growth Factor NELL-1: Targeted Delivery and Biomimetic Scaffolds

通过新型生长因子 NELL-1 治疗增强软组织到骨的愈合：靶向递送和仿生支架

• 批准号: 10456093
• 负责人: THOMAS John KREMEN
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456093
• 关键词: 3D Print; Affect; Age; Animal Model; Architecture; Award; BMP2 gene; Back; Biological; Biology; Biomechanics; Biomimetics; Cartilage; Cellular Morphology; Characteristics; Clinical; Clinical Trials; Complex; Coupled; Data Analyses; Development; Environment; Exhibits; Exposure to; Extracellular Matrix; Failure; Financial Support; Fluorochrome; Funding; Generations; Goals; Grant; Growth Factor; Implant; Incidence; Inferior; Injury; Instruction; International; Laboratories; Ligaments; Link; Measures; Mechanics; Mentors; Mentorship; Mesenchymal Stem Cells; Military Personnel; Molecular Chaperones; Muscle; Musculoskeletal; Natural regeneration; Operative Surgical Procedures; Orthopedics; Osteoclasts; Outcome; Parents; Peptide Hydrolases; Persons; Physiologic Ossification; Population; Positioning Attribute; Procedures; Process; Property; Proteins; Research; Role; Rotator Cuff; Rupture; Savings; Schools; Scientist; Site; Skeleton; Societies; Soft Tissue Injuries; Specialist; Sports Medicine; Structure; Surgeon; Technology; Tendon structure; Time; Tissues; Training; Training Programs; Translational Research; United States; United States National Institutes of Health; Use Effectiveness; Work; anterior cruciate ligament injury; anterior cruciate ligament reconstruction; anterior cruciate ligament rupture; bisphosphonate; bone; bone cell; bone healing; career; career development; cathepsin K; clinical efficacy; comparative efficacy; compare effectiveness; design; drug discovery; healing; implantation; improved; in vivo; innovation; insight; medical specialties; musculoskeletal injury; novel; novel strategies; osteochondral tissue; pre-clinical assessment; reconstitution; reconstruction; repaired; scaffold; soft tissue; square foot; stem cells; targeted delivery; translational scientist

I am an Orthopaedic Sports Medicine specialist pursuing a career as a clinician-scientist focusing on the biology of soft tissue healing to bone. The comprehensive training plan described in this proposal will uniquely position me as a surgeon-scientist to i) investigate the biology of soft-tissue-to-bone healing, ii) characterize novel approaches for growth factor delivery and scaffold design, iii) perform preclinical assessments of potential therapies and, ultimately, iv) design and operate appropriately powered clinical trials aimed at improving the treatment of soft tissue musculoskeletal injuries. There are 32 million musculoskeletal injuries in the United States annually of which 45% involve tendons or ligaments. Complete tendon and ligament separation injuries do not heal back to their bony attachments without surgical intervention and, thus, are often treated with surgical procedures including rotator cuff tendon repairs and anterior cruciate ligament reconstructions. There are more than 5.7 million people with a rotator cuff tendon tear in the US alone and this number is increasing as our population ages. In addition, there are more than 200,000 ACL injuries in the US each year; the incidence of these injuries in the military population is ten times higher than that of the civilian population. Normal tendon and ligament insertions to bone are comprised of a complex tissue structure that effectively transmits the interactions between dynamic muscle tissues and the rigid skeleton. Unfortunately, surgically repaired tendon tears and ligament reconstruction procedures characteristically “heal” with an abnormal tissue architecture that results in inferior biomechanical properties resulting in high failure rates. In this proposal we aim to stimulate local progenitor cells to repair the enthesis via a novel approach by delivering bisphosphonate-targeted growth factors to the bony site of the ruptured enthesis coupled with the insertion of a uniquely-designed biomimetic scaffold embedded with those factors. The CDA award would provide me the opportunity to turn potential into results. In order to accomplish the aims of this proposal we have assembled an internationally-recognized mentoring team to provide me with the technical training required for this research. In parallel with my mentored technical training, instruction in career development, drug discovery, data analysis and translational aspects relevant to my research goals will be provided via the UCLA CTSA-sponsored Training Program in Translational Science modules and supplemental graduate school course work. With guaranteed protected time, institutional financial support from my Department and 500 square feet of independent laboratory space and with transdisciplinary, cross-specialty guidance provided by my mentorship committee, my scientific advisory panel and my team of collaborators to assist in my development into an independent translational scientist, The ultimate goal is to allow me to successfully i) compete for additional VA, NIH and DoD grant funding, ii) manage a laboratory and iii) concurrently navigate a career that flourishes at both the benchtop and the bedside.

我是一名骨科运动医学专家，追求临床科学家的职业生涯 专注于软组织愈合的生物学。综合培训计划 本提案中所描述的将使我成为一名外科医生-科学家， 软组织-骨愈合的生物学，ii）表征生长因子的新方法 递送和支架设计，iii）进行潜在疗法的临床前评估，以及， 最终，iv）设计和操作适当的临床试验，旨在改善 治疗软组织肌肉骨骼损伤。 美国每年有3200万例肌肉骨骼损伤，其中45%涉及 肌腱或韧带。完全的肌腱和韧带分离损伤不会愈合， 它们的骨性附着体无需外科手术干预，因此， 手术包括肩袖肌腱修复和前交叉韧带重建。 仅在美国就有超过570万人患有肩袖肌腱撕裂， 随着人口老龄化，这一数字正在增加。此外，还有20多万个ACL 在美国每年的受伤;这些伤害的发生率在军事人口的十倍 高于平民人口。正常的肌腱和韧带附着于骨 由一个复杂的组织结构组成， 动态的肌肉组织和僵硬的骨骼。不幸的是手术修复的肌腱撕裂 和韧带重建手术的特征是用异常组织“愈合” 这种结构导致较差的生物力学性能，从而导致高故障率。在这 我们的目标是通过一种新的方法刺激局部祖细胞来修复附着点， 将双膦酸盐靶向生长因子递送至断裂的附着点的骨部位 再加上一个精心设计的仿生支架， 因素 CDA奖将为我提供将潜力转化为成果的机会。为了 为了实现这一建议的目标，我们召集了一个国际公认的 指导团队为我提供这项研究所需的技术培训。并行 通过我的指导技术培训，职业发展指导，药物发现，数据 与我的研究目标相关的分析和翻译方面将通过加州大学洛杉矶分校提供 CTSA赞助的翻译科学模块和补充培训计划 研究生院课程作业。有保障的保护时间，机构的财政支持 和500平方英尺的独立实验室空间， 我的导师委员会提供的跨学科，跨专业的指导，我的科学 顾问小组和我的合作者团队，以协助我发展成为一个独立的 翻译科学家，最终目标是让我成功地i）竞争额外的 VA，NIH和DoD赠款资金，ii）管理实验室，iii）同时导航职业生涯 在工作台和床边都能看到。