Cartilage Repair Using Self Assembling Peptide Scaffolds

使用自组装肽支架修复软骨

• 批准号: 8371394
• 负责人: ALAN J. GRODZINSKY
• 金额: $ 34.27万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371394
• 关键词: Acute; Anabolism; Animals; Architecture; Binding; Biochemical; Biomechanics; Biomedical Engineering; Bone Marrow; Cartilage; Cells; Chondrogenesis; Clinical; Collaborations; Collagen Type VI; Colorado; Data Analyses; Defect; Engineering; Enzymes; Equus caballus; Extracellular Matrix; Fibrocartilages; Generations; Goals; Growth Factor; Healed; Heparin Binding; Heparitin Sulfate; Histocompatibility Testing; Hydrogels; In Vitro; Injury; Institutes; Insulin-Like Growth Factor I; Massachusetts; Measures; Mechanics; Microfluidics; Modeling; Orthopedics; Oryctolagus cuniculus; Outcome Measure; Peptides; Production; Property; Research; Scientist; Stem cells; Strenuous Exercise; Stromal Cells; Technology; Testing; Time; TimeLine; Tissue Engineering; Tissues; Translations; Universities; animal tissue; articular cartilage; cartilage repair; cell motility; design; healing; in vivo; in vivo Model; joint function; nanofiber; nanomechanical; novel; programs; repaired; response; scaffold; tissue repair; wound

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. PUBLIC HEALTH RELEVANCE: Acute injuries to cartilage are common and often result in defects that the body's innate healing response repairs with fibrocartilage. We propose that engineering a biologically functional 3D-microenvironment for bone marrow stromal cells within self-assembling peptide hydrogel scaffolds can stimulate chondrogenesis and cartilage neotissue integration in vivo. Translation of these functionalized scaffolds developed in vitro to useful cartilage repair in vivo will be tested using both rabbit and equine studies.

描述（由申请人提供）：软骨急性损伤很常见，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特性，并且通常会随着时间的推移而退化。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，使得新软骨形成并可以与伤口边缘处的现有软骨整合。我们建议在自组装肽水凝胶支架内为 BMSC 设计一个具有生物功能的 3D 微环境可以刺激体内软骨形成和软骨新组织整合。这种肽支架将通过 ECM 成分和新型肝素结合形式的 IGF-1 进行功能化，它们将一起进行优化，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转化为体内有用的软骨修复。这些综合、综合的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）通过促软骨形成分子功能化来开发第二代 KLD 肽纳米纤维支架，包括 ECM 成分，如 VI/I 型胶原蛋白和硫酸乙酰肝素，以及促合成代谢分子，肝素结合 IGF-1 (HB-IGF-1)。然后，我们将在体内兔模型中测试这些优化的无细胞肽支架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) 检验通过酶预处理和掺入肽支架的 HB-IGF-1 + VI/I 型胶原蛋白可以在体外优化构建体与软骨之间的整合的假设；然后在兔模型中测试以下假设：通过酶预处理和肽支架掺入HB-IGF-1 + VI/I型胶原蛋白可以优化体内构建体与软骨之间的整合； (3) 在剧烈运动的马模型中测试优化的无细胞肽支架吸引祖细胞并促进软骨形成、软骨新组织产生以及与周围组织整合的能力。 公众健康相关性：软骨急性损伤很常见，通常会导致身体先天愈合反应通过纤维软骨修复缺陷。我们提出，在自组装肽水凝胶支架内为骨髓基质细胞设计一个具有生物功能的3D微环境可以刺激体内软骨形成和软骨新组织整合。将使用兔子和马的研究来测试这些体外开发的功能化支架转化为体内有用的软骨修复。