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: 10014168
• 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/10014168
• 关键词: 3D Print; Affect; Age; Animal Model; Architecture; Award; 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; Mesenchymal Stem Cells; Military Personnel; Molecular Chaperones; Muscle; Musculoskeletal; Natural regeneration; Operative Surgical Procedures; Orthopedics; Osteoclasts; Outcome; Parents; Peptide Hydrolases; 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; bone morphogenetic protein 2; 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; progenitor; 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.

我是骨科运动专家，从事临床科学家的职业 专注于软组织愈合到骨骼的生物学。全面的培训计划 在本提案中描述的将唯一将我定位为i）调查 软组织到骨愈合的生物学，ii）表征生长因子的新方法 交付和脚手架设计，iii）对潜在疗法进行临床前评估，并 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。 美国年度有3200万肌肉骨骼损伤 肌腱或韧带。完全肌腱和韧带分离损伤不会恢复到 他们没有手术干预的骨附件，因此经常通过外科手术治疗 程序包括肩袖肌腱维修和前交叉韧带的重建。 仅在美国，就有超过570万的肩袖肌腱撕裂 随着人口年龄的增长，人数正在增加。此外，还有超过200,000 ACL 美国每年受伤；这些伤害在军人中的事件是十倍 高于平民。正常的肌腱和韧带插入骨头是 由复杂的组织结构组成，该结构有效地传播了 动态肌肉组​​织和刚性骨骼。不幸的是，手术修复的肌腱眼泪 韧带重建程序特征在于用异常组织“治愈” 导致劣质生物力学特性的结构导致较高的失败率。在这个 提案我们旨在刺激局部祖细胞通过新颖的方法来修复源 将双磷酸靶靶性生长因子传递到破裂的骨位点 再加上独特设计的仿生脚手架的插入 因素。 CDA奖将使我有机会将潜力变成结果。为了 完成该提案的目的，我们已经组装了国际认可的 指导团队为我提供这项研究所需的技术培训。并联 通过我的指导技术培训，职业发展的指导，药物发现，数据 分析和翻译与我的研究目标相关的方面将通过UCLA提供 CTSA赞助的转化科学模块和补充培训计划 研究生院课程工作。在保证的受保护时间，机构财政支持下 来自我的部门和500平方英尺的独立实验室空间以及 我的科学委员会提供的跨学科，跨专业指导 咨询小组和我的合作者团队，以帮助我发展成为独立的 翻译科学家，最终的目标是让我成功地竞争更多 VA，NIH和DOD Grant Funding，ii）管理实验室和III）同时导航职业 这在台式和床边都荧光。