Endogenous repair of growth plate injuries by local and sequential delivery of factors that inhibit osteogenesis and promote chondrogenesis

通过局部和顺序递送抑制成骨和促进软骨形成的因子来内源性修复生长板损伤

• 批准号: 9038665
• 负责人: Karin A Payne
• 金额: $ 9.02万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038665
• 关键词: Accounting; Affect; Antibodies; Area; Biocompatible Materials; Biological Factors; Biological Response Modifier Therapy; Biology; Biopolymers; Blood Vessels; Bone Growth; Bone Lengthening; Bone Tissue; CCL25 gene; Cartilage; Cell Count; Child; Childhood; Childhood Injury; Chondrogenesis; Clinical Management; Data; Defect; Deformity; Deposition; Development; Engineering; Ensure; Epiphysial cartilage; Event; Fracture; Goals; Growth; Growth Factor Inhibition; Hydrogels; Individual; Infection; Injectable; Injury; Lead; Length; Limb structure; Measurement; Mesenchymal; Mesenchymal Stem Cells; Modeling; Natural regeneration; Operative Surgical Procedures; Orthopedics; Osteogenesis; Pathway interactions; Quality of life; Rattus; Recruitment Activity; Reporting; Side; Signal Transduction; Site; Stem cells; Stromal Cell-Derived Factor 1; System; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Vascular Endothelial Growth Factors; Work; angiogenesis; bone; cell motility; chemokine; controlled release; design; falls; injured; innovation; long bone; multipotent cell; novel; osteogenic; patient subsets; prevent; public health relevance; receptor; receptor expression; repaired; response; spatiotemporal; stem cell differentiation; success; tissue repair; vehicular accident

 DESCRIPTION (provided by applicant): Fractures are a significant problem in pediatric orthopedics. One third of childhood fractures involve the growth plate, a fragile, cartilaginous region in long bones that provides signaling for continued growth in children. Growth plate injuries occur from both high and low impact events, ranging from vehicular accidents to simple falls. Such injuries can result in the formation of a "bony bar" in which bony tissue replaces normal growth plate cartilage. This can result in angular deformities or complete growth cessation in the affected bone. Unfortunately, current growth plate injury treatments are invasive, prone to infections, and have low success rates. There is no treatment available that can fully regenerate the growth plate and ensure normal longitudinal bone growth. The long-term goal of this project is to develop a clinically useful biological therapy for growth plate regeneration. The objective of the current application is to prevent bony bar formation, replacing it instead with a cartilaginous tissue that more closely resembles the native growth plate and may restore normal longitudinal bone growth. Recent advances have elucidated mechanisms that affect bony bar formation as well as pathways that can promote regeneration. It has been shown that vascular endothelial growth factor (VEGF) and its associated angiogenesis in the injured growth plate can trigger bony bar formation. As well, it has been reported that mesenchymal stem cells (MSCs) infiltrate the injury site, express osteogenic markers, and participate in bony bar formation. In this project, we propose to prevent or replace bony bar formation in the injured growth plate by blocking angiogenesis and associated bone formation (Aim 1), recruiting more endogenous MSCs to the injured area by delivery of stem cell migratory factors (Aim 2), and promoting MSC chondrogenesis rather than osteogenesis by exposing them to a chondrogenic factor (Aim 3). This will be tested in a rat model of growth plate injury by using an injectable biomaterial delivery system that will sequentially release three therapeutic factors locally: (1) anti-VEGF antibody to block angiogenesis and bone formation, (2) a stem cell attracting factor such as SDF-1 or CCL25 to recruit endogenous MSCs to the injured area, and (3) TGF-β1 to direct the recruited stem cells down the cartilage lineage instead of the bone lineage. Overall, data from these studies will contribute new information to the basic biology of growth plate repair, and will also provide information on the translational potential of the proposed therapeutic approach. This will pave the way for further development of a novel treatment that not only prevents bony bar formation but also promotes formation of a functional tissue engineered growth plate that can prevent growth problems associated with growth plate injuries.

 描述（由申请人提供）：骨折是儿童骨科的一个重要问题，三分之一的儿童骨折涉及生长板，这是长骨中的一个脆弱的软骨区域，为儿童的持续生长提供信号。低冲击事件，从交通事故到简单的跌倒，都会导致“骨条”的形成，其中骨组织取代了正常的生长板软骨，这可能导致成角。不幸的是，目前的生长板损伤治疗是侵入性的，容易发生感染，并且成功率很低，没有可以完全再生生长板并确保正常的纵向骨生长的治疗方法。该项目的长期目标是开发一种临床上有用的生长板再生生物疗法，当前应用的目的是防止骨棒形成，用更接近天然生长板并可能恢复的软骨组织代替。正常纵骨最近的进展阐明了影响骨棒形成的机制以及促进再生的途径，研究表明血管内皮生长因子（VEGF）及其在受损生长板中的相关血管生成也可以触发骨棒形成。据报道，间充质干细胞（MSC）浸润损伤部位，表达成骨标志物，并参与骨棒形成。在这个项目中，我们建议预防或替代受伤生长中的骨棒形成。通过阻断血管生成和相关骨形成（目标 1）、通过输送干细胞迁移因子将更多内源性 MSC 募集到损伤区域（目标 2）以及通过将 MSC 暴露于软骨形成因子来促进 MSC 软骨形成而不是成骨（目标 3）这将在生长板损伤的大鼠模型中进行测试。 使用可注射的生物材料输送系统，该系统将在局部顺序释放三种治疗因子：(1) 抗 VEGF 抗体，以阻断血管生成和骨形成，(2) 干细胞吸引因子，如 SDF-1 或 CCL25，以将内源性 MSC 招募到(3) TGF-β1 引导招募的干细胞沿着软骨谱系而不是骨谱系流动。总体而言，这些研究的数据将为生长板修复的基础生物学提供新的信息。还将提供有关所提出的治疗方法的转化潜力的信息，这将为进一步开发新型治疗方法铺平道路，该治疗方法不仅可以防止骨棒形成，还可以促进功能性组织工程生长板的形成，从而防止相关的生长问题。生长板损伤。