Cartilage Repair Using Self Assembling Peptide Scaffolds

描述（由申请人提供）：软骨的急性损伤是常见的，通常会导致身体先天愈合反应用纤维软骨修复的缺陷。这种修复组织缺乏天然关节软骨的结构和机械性能，并且最常随时间退化。组织工程策略面临着促进细胞迁移、增殖、软骨分化和细胞外基质的综合问题 (ECM)组装，以便形成新软骨并可以与伤口边缘现有的软骨整合。我们提出，在自组装肽水凝胶支架内为BMSC设计生物功能性3D微环境可以刺激体内软骨形成和软骨新组织整合。该肽支架将用ECM组分和IGF-1的新型肝素结合形式功能化，它们一起将被优化以刺激浸润祖细胞的软骨形成并增强软骨-新组织界面处的整合。将使用兔和马模型测试这些体外开发的功能化支架在体内有用的软骨修复的翻译。这些综合研究代表了马萨诸塞州理工学院生物医学工程中心的科学家和工程师与科罗拉多州立大学骨科研究中心的临床科学家之间的合作。我们的具体目标是：（1）通过用促软骨形成分子（包括ECM成分如VI/I型胶原和硫酸乙酰肝素）和促合成代谢分子肝素结合IGF-1（HB-IGF-1）功能化来开发第二代KLD肽支架。然后，我们将测试这些优化的脱细胞肽支架在兔体内模型中促进浸润祖细胞的软骨形成、软骨新组织生物合成和软骨缺损修复的能力。(2)为了测试构建体和软骨之间的体外整合可以通过酶预处理和肽支架掺入的HB-IGF-1 + VI/I型胶原蛋白来优化的假设;然后在兔模型中测试构建体和软骨之间的体内整合可以通过酶预处理和肽支架掺入的HB-IGF-1 + VI/I型胶原蛋白来优化的假设;和（3）在经受剧烈运动的马模型中测试优化的脱细胞肽支架吸引祖细胞和促进软骨形成、软骨新组织产生以及与周围组织整合的能力。

DESCRIPTION (provided by applicant): Acute injuries to cartilage are common and often result in defects that the body's innate healing response repairs with fibrocartilage. This repair tissue lacks the architecture and mechanical properties of native articular cartilage and most often degenerates over time. Tissue engineering strategies have faced the combined problems of encouraging cell migration, proliferation, chondrogenic differentiation and extracellular matrix (ECM) assembly such that neocartilage is formed and can integrate with the existing cartilage at the wound edges. We propose that engineering a biologically functional 3D-microenvironment for BMSCs within self- assembling peptide hydrogel scaffolds can stimulate chondrogenesis and cartilage neotissue integration in vivo. This peptide scaffold will be functionalized with ECM components and a novel heparin-binding form of IGF-1, which together will be optimized to stimulate chondrogenesis of infiltrating progenitor cells and to enhance integration at the cartilage-neotissue interface. Translation of these functionalized scaffolds developed in vitro to useful cartilage repair in vivo will be tested using both rabbit and equine models. These combined, integrated studies represent a collaboration between scientists and engineers at the Center for Biomedical Engineering, Massachusetts Institute of Technology, and clinical scientists at the Orthopaedic Research Center, Colorado State University. Our Specific Aims are: (1) To develop second-generation KLD peptide nanofiber scaffolds by functionalizing with pro-chondrogenic molecules, including ECM constituents such as collagen types VI/I and heparan sulfate, and a pro-anabolic molecule, heparin binding IGF-1 (HB-IGF-1). We will then test the ability of these optimized acellular peptide scaffolds to promote the chondrogenesis of infiltrating progenitor cells, cartilage neotissue biosynthesis, and cartilage defect repair in a rabbit model in vivo. (2) To test the hypothesis that integration between construct and cartilage in vitro can be optimized through enzyme pre-treatments and peptide scaffold-incorporated HB-IGF-1 + collagen types VI/I; and then to test the hypothesis that integration between construct and cartilage in vivo can be optimized through enzyme pre- treatments and peptide scaffold-incorporated HB-IGF-1 + collagen types VI/I in a rabbit model; and (3) To test the ability of optimized acellular peptide scaffolds to attract progenitor cells and promote chondrogenesis, cartilage neotissue production, and integration with surrounding tissue in an equine model subjected to strenuous exercise.