Growth Plate Cartilage Repair via Novel Matrilin3/Rosette Nanotube Hybrid Matrix

通过新型 Matrilin3/Rosette 纳米管混合基质修复生长板软骨

基本信息

批准号：
9338126
负责人：
Yupeng Chen
金额：
$ 8.05万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9338126
关键词：
Adhesions Animal Model Area Autologous Binding Biological Cartilage Cell Adhesion Cell Proliferation Child Childhood Chondrocytes Chondrogenesis Clinical Treatment Clinical Trials Deformity Dose Drug Delivery Systems Epiphysial cartilage Event Excision Fatty acid glycerol esters Fracture Future Goals Growth Growth Factor Health Human Hybrids Hypertrophy In Vitro Injectable Injury Insulin-Like Growth Factor I Length Lesion Liquid substance Mature Bone Mesenchymal Stem Cells Metaphysis Mission Modeling Molecular Nanotubes Operative Surgical Procedures Osteoblasts Osteogenesis Outcome Pathologic Peripheral Preventive Procedures Public Health Publications Publishing Rattus Research Shapes Site Structure Testing Therapeutic Therapeutic Effect Tissues Translating Treatment Efficacy United States National Institutes of Health Vascular Endothelial Cell Vascularization Yang base cartilage growth factor cartilage regeneration cartilage repair design disability improved in vivo Model in vivo regeneration injured innovation insight matrilin 3 migration minimally invasive nano novel pre-clinical prevent public health relevance scaffold

项目摘要

DESCRIPTION (provided by applicant): Approximately 15% to 30% of all childhood fractures are growth plate fractures. Because the growth plate determines the length and shape of a mature bone, this type of fracture may result in severe growth abnormalities in children. Pathologically, the growth abnormality is caused by the formation of a bony bridge in the injured growth plate cartilage. Currently, the clinical treatment of growth plate fractures includes the surgical removal of the bony bridge and insertion of autologous fat or cartilage tissue into the empty space to discourage bony bridge reformation. Such surgical procedures are invasive and result in unsatisfactory outcomes. In addition, this treatment is only useful after the bony bridge has formed. Our long-term goal is to understand how to prevent bony bridge formation and improve growth plate cartilage regeneration at cellular and molecular levels and develop the first preventive and therapeutic approach for growth plate fracture. Specifically, the primary objective of this proposal is to evaluate the therapeutic effects of a nano-matrix assembled from matrilin-3 (MATN3) and rosette nanotube (RNT) in a preclinical growth plate fracture model. Our central hypothesis is that the MATN3/RNT nano-matrix specifically promotes chondrocyte growth and enhances chondrogenesis of mesenchymal stem cells (MSCs), while it also inhibits vascularization and osteogenesis at the fracture site. This is the cellular basis for such nano-matrix to improve growth plate cartilage regeneration and prevent bony bridge formation. We will test our central hypothesis and achieve the objective of the proposal by pursuing two specific aims: 1) to determine the ability of MATN3/RNT to prevent bony bridge formation; and 2) to determine the ability of MATN3/RNT to deliver growth factors for further improvement of chondrogenesis and growth plate cartilage regeneration. To achieve the two aims, our overall research strategy includes: 1) optimization of the ratio and dose of MATN3/RNT and its ability and bioactivity for loading growth factors in vitro; and 2) determination of the therapeutic efficay of the nano-matrix in our established growth plate fracture model in rats in long term. The proposed research is innovative: 1) biologically, it simultaneously promotes cartilage regeneration and inhibits bony bridge formation; 2) therapeutically, MATN3 and RNT can be injected as a liquid in a minimally invasive manner, and form a nano- matrix at the fracture site; 3) structurally, the nano-matrix concentrates bioactive MATN3 locally at the fracture site as well as binds TGF-β1 and IGF-1 to achieve multi-functional delivery. With the results of the two specific aims, we expect to 1) realize a synergistic strategy to specifically promote chondrogenesis while inhibiting osteogenesis and vascularization; and 2) develop an injectable approach for the localized delivery of cartilage growth factors. These outcomes have an important positive impact in developing novel, perhaps the first, preventive and therapeutic approach for growth plate cartilage repair.

描述（由申请人提供）：大约 15% 到 30% 的儿童骨折是生长板骨折，因为生长板决定了成熟骨骼的长度和形状，这种类型的骨折可能会导致儿童严重的病理生长异常。生长异常是由于受伤的生长板软骨形成骨桥造成的，目前临床上生长板骨折的治疗方法包括手术切除骨桥和植入骨桥。将自体脂肪或软骨组织植入空腔以阻止骨桥重建，这种手术过程是侵入性的，并且会导致不令人满意的结果。此外，这种治疗仅在骨桥之后才有用。我们的长期目标是了解如何在细胞和分子水平上预防骨桥形成并改善生长板软骨再生，并开发第一个预防和治疗生长板骨折的方法。具体来说，该提案的主要目标是。评估由 matrilin-3 (MATN3) 和玫瑰花纳米管 (RNT) 组装的纳米基质在临床前生长板骨折模型中的治疗效果，我们的中心假设是 MATN3/RNT 纳米基质特别。促进软骨细胞生长并增强间充质干细胞（MSC）的软骨形成，同时还抑制骨折部位的血管形成和成骨，这是这种纳米基质改善生长板软骨再生和防止骨桥形成的细胞基础。通过追求两个具体目标来测试我们的中心假设并实现该提案的目标：1）确定 MATN3/RNT 防止骨桥形成的能力；2）确定MATN3/RNT 传递生长因子以进一步改善软骨形成和生长板软骨再生的能力为了实现这两个目标，我们的总体研究策略包括：1）优化 MATN3/RNT 的比例和剂量及其能力和生物活性。体外加载生长因子；2）确定纳米基质在我们建立的大鼠生长板骨折模型中的长期治疗效果。本研究具有创新性：1）在生物学上，它同时促进。软骨再生并抑制骨桥形成；2）在治疗上，MATN3和RNT可以以微创方式以液体形式注射，并在骨折部位形成纳米基质；3）在结构上，纳米基质局部浓缩了生物活性MATN3。结合 TGF-β1 和 IGF-1 以实现多功能递送通过这两个特定目标的结果，我们期望 1) 实现协同作用。特异性促进软骨生成同时抑制成骨和血管形成的策略；2）开发一种可局部输送软骨生长因子的注射方法，这些结果对开发新颖的、也许是第一种生长板软骨的预防和治疗方法具有重要的积极影响。维修。