3-D Osteochondral Micro-tissue to Model Pathogenesis of Osteoarthritis

3-D 骨软骨微组织模拟骨关节炎的发病机制

• 批准号: 8415187
• 负责人: ROCKY S TUAN
• 金额: $ 34.98万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-24 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415187
• 关键词: 3-Dimensional; Adipose tissue; Adult; Affect; Age; Anatomy; Architecture; Arthritis; Biochemical; Biocompatible Materials; Biological; Biological Assay; Biological Availability; Biology; Bioreactors; Blood Circulation; Bone Marrow; Bone necrosis; Cartilage; Catabolism; Cells; Chondrocytes; Complex; Degenerative polyarthritis; Development; Dimensions; Disease; Effector Cell; Endothelium; Evaluation; Exposure to; Future; Health; Histocompatibility Testing; Histologic; Housing; Image; In Vitro; Individual; Inflammation; Inflammatory; Injury; Investigation; Joints; Lesion; Maintenance; Mechanics; Mesenchymal Stem Cells; Modality; Modeling; Molecular; Monitor; Osteolysis; Osteopenia; Outcome; Pathogenesis; Perfusion; Pharmaceutical Preparations; Phenotype; Physiological; Population; Printing; Readiness; Reporter; Role; Safety; Sampling; Simulate; Source; Structure; Synovial Membrane; System; Technology; Testing; Therapeutic; Tissues; Toxicology; adult stem cell; articular cartilage; base; bone; bone quality; culture plates; cytokine; design; design and construction; improved; in vitro Model; microsystems; osteochondral tissue; osteogenic; promoter; response; scaffold

DESCRIPTION (provided by applicant): Osteoarthritis (OA), the most prevalent form of arthritis, affects up to 15% of the adult population and is principally characterized by degeneration of the articular cartilage component of the joint, often with accompanying subchondral bone lesions. Understanding the mechanisms underlying the pathogenesis of OA is important for the rational development of disease modifying OA drugs (DMOADs). While most studies on OA have focused on the investigation of either the cartilage or the bone components of the articular joint, the osteochondral complex represents a more physiologically relevant target as the disease ultimately is a disorder of osteochondral integrity and function. In this application, we propose to construct an in vitro 3-dimensional microsystem that models the structure and biology of the osteochondral complex of the articular joint. Osteogenic and chondrogenic tissue components will be produced using adult human mesenchymal stem cells (MSCs) derived from bone marrow and adipose seeded within biomaterial scaffolds photostereolithographically fabricated with defined internal architecture. A 3D-printed, perfusion-ready container platform with dimensions to fit into a 96-well culture plate format is designed to house and maintain the osteochondral microsystem that has the following features: (1) an anatomic cartilage/bone biphasic structure with a functional interface; (2) all tissue components derived from a single adult mesenchymal stem cell source to eliminate possible age/tissue type incompatibility; (3) individual compartments to constitute separate microenvironment for the "synovial" and "osseous" components; (4) cell-seeded envelopes to represent "synovium" and "endothelium"; (5) accessible individual compartments that may be controlled and regulated via the introduction of bioactive agents or candidate effector cells, and tissue/medium sampling and compositional assays; (6) compatibility with the application of mechanical load and perturbation; and (7) imaging capability to allow for non-invasive functional monitoring. The robustness and physiological relevance of the osteochondral microsystem will be tested on the basis of: (1) structural integrity and potential connectivity of the separate "synovial" and "osseous" compartments; (2) maintenance of distinct cartilage and bone phenotypes and the development of a histologically distinct osteochondral junction or tidemark; (3) applicability and tissue responsiveness to mechanical loading; and (4) imaging and analytical capabilities. The consequences of mechanical injury, exposure to inflammatory cytokines, and compromised bone quality on degenerative changes in the cartilage component will be examined in the osteochondral microsystem as a first step towards its eventual application as an improved and high-throughput in vitro model for prediction of efficacy, safety, bioavailability, and toxicology outcomes for candidate DMOADs. PUBLIC HEALTH RELEVANCE: Osteoarthritis, a degenerative joint disease that affects up to 15% of adults, is initiated by degeneration of the articular cartilage that covers the joint surfac. Development of disease modifying drugs for osteoarthritis requires a clear understanding of the underlying mechanisms, responsible for the failed interaction between cartilage and bone. This proposal aims to establish an in vitro 3-dimensional microsystem based on adult stem cells to simulate this bone-cartilage interface, which may be used in the future to identify and test candidate therapeutics for osteoarthritis.

描述（由申请人提供）：骨关节炎 (OA) 是最常见的关节炎形式，影响高达 15% 的成年人群，其主要特征是关节的关节软骨成分退化，通常伴有软骨下骨病变。了解 OA 发病机制对于合理开发 OA 疾病缓解药物 (DMOAD) 非常重要。虽然大多数关于 OA 的研究都集中在研究关节的软骨或骨成分上，但骨软骨复合体代表了更具生理相关性的目标，因为该疾病最终是骨软骨完整性和功能的紊乱。在此应用中，我们建议构建一个体外 3 维微系统来模拟关节骨软骨复合体的结构和生物学。成骨和软骨组织成分将使用源自骨髓和脂肪的成人间充质干细胞（MSC）生产，这些干细胞接种在生物材料支架内，通过光立体光刻技术制造，具有明确的内部结构。 3D 打印、可灌注容器平台的尺寸适合 96 孔培养板格式，旨在容纳和维护骨软骨微系统，该系统具有以下特征：(1) 具有功能性的解剖软骨/骨双相结构界面; (2) 所有组织成分均源自单一成体间充质干细胞来源，以消除可能的年龄/组织类型不相容性； (3) 单独的隔室构成“滑液”和“骨”成分的独立微环境； (4) 细胞接种的包膜代表“滑膜”和“内皮”； (5) 可通过引入生物活性剂或候选效应细胞以及组织/介质采样和成分测定来控制和调节的可进入的单独隔室； (6) 与机械载荷和扰动应用的兼容性； (7) 成像能力，可进行非侵入性功能监测。骨软骨微系统的稳健性和生理相关性将根据以下方面进行测试：（1）单独的“滑膜”和“骨”室的结构完整性和潜在连通性； (2) 维持不同的软骨和骨表型以及形成组织学上不同的骨软骨连接或潮汐标记； (3) 适用性和组织对机械负荷的反应性； (4)成像和分析能力。将在骨软骨微系统中检查机械损伤、暴露于炎性细胞因子以及骨质量受损对软骨成分退行性变化的影响，作为其最终应用为改进的高通量体外模型来预测的第一步。候选 DMOAD 的功效、安全性、生物利用度和毒理学结果。 公众健康相关性：骨关节炎是一种退行性关节疾病，影响多达 15% 的成年人，是由覆盖关节表面的关节软骨退化引起的。开发治疗骨关节炎的疾病修饰药物需要清楚地了解导致软骨和骨骼之间相互作用失败的潜在机制。该提案旨在建立一个基于成体干细胞的体外3维微系统来模拟这种骨-软骨界面，该系统将来可能用于识别和测试骨关节炎的候选疗法。