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: 10664877
• 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/10664877
• 关键词: 3D Print; Acceleration; Affect; Age; Animal Model; Architecture; Award; BMP2 gene; Back; Biological; Biology; Biomechanics; Biomimetics; Cartilage; Cellular Morphology; 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; Institution; 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; 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; graduate school; 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; transmission process

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，追求临床医生科学家的职业生涯 专注于软组织骨愈合的生物学。全面的培训计划 该提案中描述的内容将使我成为一名外科医生科学家，以独特地定位我）调查 软组织到骨愈合的生物学，ii) 描述生长因子的新方法 递送和支架设计，iii) 对潜在疗法进行临床前评估，并且， 最终，iv) 设计和运行适当动力的临床试验，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% 涉及肌肉骨骼损伤 肌腱或韧带。肌腱和韧带完全分离损伤不会愈合 他们的骨附着无需手术干预，因此通常通过手术治疗 手术包括肩袖肌腱修复和前十字韧带重建。 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。另外，还有超过20万条ACL 美国每年的伤害情况；这些伤害在军人中的发生率是军人的十倍 高于平民。正常的肌腱和韧带插入骨是 由复杂的组织结构组成，可以有效地传递之间的相互作用 动态肌肉组​​织和刚性骨骼。不幸的是，通过手术修复了肌腱撕裂 韧带重建手术的特点是“治愈”异常组织 导致生物力学性能较差的架构，从而导致高故障率。在这个 建议我们的目标是通过一种新方法刺激局部祖细胞修复附着点 将双磷酸盐靶向生长因子递送至断裂附着点的骨部位 再加上嵌入了独特设计的仿生支架的插入 因素。 CDA 奖项将为我提供将潜力转化为成果的机会。为了 为了实现该提案的目标，我们组建了一个国际公认的组织 指导团队为我提供这项研究所需的技术培训。并联 在我指导的技术培训、职业发展、药物发现、数据方面的指导 与我的研究目标相关的分析和转化方面将通过加州大学洛杉矶分校提供 CTSA 赞助的转化科学模块和补充培训计划 研究生院课程作业。有保障的保护时间、机构财政支持 从我的部门和 500 平方英尺的独立实验室空间以及 我的导师委员会、我的科学团队提供的跨学科、跨专业指导 顾问小组和我的合作者团队协助我发展成为独立的 转化科学家，最终目标是让我成功 i) 竞争额外的 VA、NIH 和 DoD 提供资金，ii) 管理实验室，iii) 同时开展职业生涯 它在工作台和床边都蓬勃发展。

项目成果

In Vitro Cellular Strain Models of Tendon Biology and Tenogenic Differentiation.

• DOI: 10.3389/fbioe.2022.826748
• 发表时间: 2022
• 期刊: Frontiers in bioengineering and biotechnology
• 影响因子: 5.7
• 作者: Wu SY;Kim W;Kremen TJ Jr
• 通讯作者: Kremen TJ Jr

Biologically-coupled bisphosphonate chaperones effectively deliver molecules to the site of soft tissue-bone healing.

生物耦合的双膦酸盐分子伴侣可有效地将分子递送至软组织-骨愈合部位。

• DOI: 10.1002/jor.25579
• 发表时间: 2023
• 期刊: Journal of orthopaedic research : official publication of the Orthopaedic Research Society
• 作者: KremenJr,ThomasJ;Shi,BrendanY;Wu,ShannonY;Sundberg,Oskar;Sriram,Varun;Kim,Won;Sheyn,Dmitriy;Lyons,KarenM;Wang,Weiguang;McKenna,CharlesE;Nishimura,Ichiro
• 通讯作者: Nishimura,Ichiro