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，希望成为一名临床医生兼科学家

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