Cartilage Repair Using Self Assembling Peptide Scaffolds

描述(申请人提供)：软骨的急性损伤是常见的，通常会导致身体固有的修复反应与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，通常会随着时间的推移而退化。组织工程策略面临着鼓励细胞迁移、增殖、软骨分化和细胞外基质的综合问题。 (ECM)组装，以形成新的软骨，并能在伤口边缘与现有软骨结合。我们认为，在自组装多肽水凝胶支架内为BMSCs构建具有生物功能的三维微环境，可以促进体内软骨生成和软骨新生组织的整合。这种多肽支架将使用细胞外基质成分和一种新的肝素结合形式的IGF-1进行功能化，这两种成分一起将被优化，以刺激浸润性前体细胞的软骨生成，并加强软骨-肿瘤组织界面的整合。将在体外开发的这些功能化支架转化为体内有用的软骨修复将使用兔和马的模型进行测试。这些综合研究代表了麻省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整形外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)通过将促软骨分子和促合成分子HB-IGF-1(HB-IGF-1)功能化，开发第二代KLD多肽纳米纤维支架，包括VI型胶原和硫酸肝素等ECM成分。然后，我们将在兔体内模型中测试这些优化的脱细胞多肽支架促进浸润性祖细胞的软骨生成、软骨新组织生物合成和软骨缺损修复的能力。(2)通过酶预处理和HB-IGF-1多肽支架包裹的VI/I型胶原蛋白在体外验证构建物与软骨整合的优化假设；然后在兔模型中验证通过酶预处理和多肽支架整合HB-IGF-1胶原VI/I型可以优化构建物与软骨的整合；以及(3)在马剧烈运动模型中测试优化的无细胞多肽支架吸引祖细胞并促进软骨形成、软骨新组织生成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.