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（由适用提供）：骨折是小儿骨科的重要问题。童年骨折的三分之一涉及生长板，这是长骨的脆弱的软骨区域，为儿童持续生长提供了信号。从高影响和低冲击事件发生生长板损伤，从车祸到简单的跌倒。这种损伤会导致形成“骨棒”，其中键组织替代了正常的生长板软骨。这可能导致角度畸形或受影响的骨骼的完全停止。不幸的是，当前的生长板损伤治疗是侵入性的，容易感染，成功率低。没有可用的治疗方法可以充分再生生长板并确保正常的纵向骨生长。该项目的长期目标是开发一种用于生长板再生的临床有用的生物学疗法。当前应用的目的是防止束缚棒的形成，而是用软骨组织代替它，该组织更像天然生长板，并可能恢复正常的纵向骨生长。最近的进步已经阐明了影响束缚棒形成的机制以及可以促进再生的途径。已经表明，血管内皮生长因子（VEGF）及其在损伤生长板中相关的血管生成可以触发束缚棒的形成。同样，据报道，间充质干细胞（MSC）渗入损伤部位，表达成骨标记并参与键杆的形成。在该项目中，我们建议通过阻断血管生成和相关的骨形成（AIM 1），以防止或替换受伤的生长板中的债券杆形成（AIM 1），通过递送干细胞迁移因子（AIM 2）招募更多的内源性MSC到受伤的区域（AIM 2），并促进MSC软骨发生，而不是通过将它们释放到软骨生成因子（AIL 3）。这将通过大鼠模型的生长板损伤模型进行测试 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.总体而言，这些研究的数据将为生长板修复的基本生物学贡献新信息，还将提供有关拟议治疗方法的翻译潜力的信息。这将为进一步开发一种新型治疗铺平道路，该治疗不仅可以防止粘结杆的形成，还促进了功能性组织工程生长板的形成，该板可以防止与生长板损伤相关的生长问题。