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

• 批准号: 9038551
• 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
• 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/9038551
• 关键词: Adhesions; Animal Model; Area; Autologous; Binding; Cartilage; Cell Adhesion; 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; 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; Peripheral; Preventive; Procedures; Public Health; Publications; Publishing; Rattus; Research; Shapes; Site; Structure; Testing; Therapeutic; Therapeutic Effect; Tissues; Translating; Treatment Efficacy; Vascular Endothelial Cell; Vascularization; base; bone epiphysis; cartilage growth factor; cartilage regeneration; cartilage repair; design; disability; improved; in vivo; in vivo Model; injured; innovation; insight; matrilin 3; migration; minimally invasive; nano; novel; pre-clinical; prevent; public health relevance; scaffold

 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%至30%的儿童骨折是生长板骨折。由于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导致儿童严重的生长异常。在病理学上，生长异常是由受伤的生长板软骨中形成骨桥引起的。目前，生长板骨折的临床治疗包括手术切除骨桥和将自体脂肪或软骨组织插入到空的空间中以阻止骨桥再形成。这样的外科手术是侵入性的并且导致不令人满意的结果。此外，这种治疗方法只有在骨桥之后才有用 已经形成。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和促进生长板软骨再生，并开发第一种预防和治疗生长板骨折的方法。具体而言，该提案的主要目的是评估由matrilin-3（MATN 3）和玫瑰花状纳米管（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MATN 3/RNT纳米基质特异性地促进软骨细胞生长并增强间充质干细胞（MSC）的软骨形成，同时它还抑制骨折部位的血管化和成骨。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。我们将测试我们的中心假设，并通过追求两个具体目标来实现该提案的目标：1）确定MATN 3/RNT防止骨桥形成的能力; 2）确定MATN 3/RNT递送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。为实现这两个目标，我们的总体研究策略包括：1）优化MATN 3/RNT的比例和剂量，以及其体外负载生长因子的能力和生物活性; 2）测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。该研究具有创新性：1）生物学上，它同时促进软骨再生和抑制骨桥形成; 2）治疗上，MATN 3和RNT可以以微创方式作为液体注射，并在骨折部位形成纳米基质; 3）在结构上，纳米基质将生物活性MATN 3局部集中在骨折部位，并结合TGF-β1和IGF-1，以实现多功能递送。有了这两个具体目标的结果，我们期望1）实现一种协同策略，以特异性地促进软骨形成，同时抑制骨形成和血管形成; 2）开发一种用于局部递送软骨生长因子的注射方法。这些结果在开发新的，也许是第一个，生长板软骨修复的预防和治疗方法方面具有重要的积极影响。