Tissue Chip Modeling of Synovial Joint Pathologies: Effects of Inflammation and Adipose-Mediated Diabetic Complications

滑膜关节病理的组织芯片建模：炎症和脂肪介导的糖尿病并发症的影响

• 批准号: 10018947
• 负责人: Hang Lin
• 金额: $ 109.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-20 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018947
• 关键词: 3-Dimensional; Acute suppurative arthritis due to bacteria; Address; Adipose tissue; Affect; Aging; Animal Model; Animals; Anti-Inflammatory Agents; Arthritis; Biochemical; Biochemical Markers; Biological; Biological Markers; Bioreactors; Cell Culture Techniques; Cell Therapy; Cells; Clinical; Clinical Trials; Complex; Complications of Diabetes Mellitus; Data; Degenerative polyarthritis; Development; Diagnostic; Disease; Disease Progression; Disease model; Drug Screening; Drug Targeting; Drug toxicity; Economic Burden; Elements; Encapsulated; Engineering; Etiology; Exhibits; Exposure to; Failure; Future; Genetic; Health; Histologic; Histology; Human; Hydrogels; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Arthritis; Interleukin-4; Investigation; Joints; Mediating; Mesenchymal Stem Cells; Metalloproteases; Modeling; Molecular; Nature; Oligonucleotides; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Physiology; Plug-in; Prosthesis; Publishing; Quality of life; Replacement Arthroplasty; Stimulus; Structure; Synovial Membrane; Synovial joint; System; Testing; Therapeutic; Tissue Engineering; Tissue Microarray; Tissues; Toxic effect; Trauma; Treatment Efficacy; Validation; arthropathies; base; clinical efficacy; cost; design; design and construction; diabetic; drug discovery; drug sensitivity; efficacy testing; exosome; experience; high throughput screening; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; macrophage; molecular marker; musculoskeletal disorder therapy; osteochondral tissue; particle; personalized approach; personalized medicine; physically handicapped; potential biomarker; pre-clinical; response; scaffold; screening; specific biomarkers; stem cell therapy; stem cells; therapeutic candidate; therapy development; tissue degeneration; tool

Trauma, inflammation, infection, and aging can cause damages to joint tissues, ultimately leading to arthritic disorders, such as osteoarthritis (OA), septic arthritis, and inflammatory arthritis, resulting in physical disabilities that compromise quality of life; however, no efficacious therapies are currently available. The limited progress in the development of disease-modifying medications (DMMs) is principally because of: (1) insufficient mechanistic understanding of disease onset/progression; (2) inability to encompass the 3-dimensional (3D) and multi-tissue nature of the synovial joint in early phase in vitro drug discovery; and (3) limited utility of pre-clinical animal studies for early stage clinical efficacy and toxicity prediction (lacking “fail early/fail fast” capabilities), resulting in unanticipated and costly clinical trial failures. Also, patient-specific etiology, progression, and drug sensitivity profiles underscore the need for personalizable therapy development. To address these needs, we propose engineering a 3D human micro-joint chip (mJoint), physiologically analogous to the native joint and capable of modeling pathogenesis of joint diseases for DMM screening/development. UG3 - Aim 1: Engineering joint components The osteochondral complex, synovium, and adipose, will be engineered using primary cells, human mesenchymal stem cells (MSCs) or induced pluripotent stem cell (iPSC) derived MSCs encapsulated in a photocrosslinked hydrogel scaffold, with macrophages included to evaluate their critical function in mediating/regulating inflammation, and phenotype-characterized using molecular, biochemical and histological analyses. Aim 2: Generating normal and diseased mJoint A bioreactor will be designed to house all of the joint elements (mJoint), simulating the respective in vivo tissue conditions, and exposed to various pathogenic agents and conditions to model OA, inflammatory arthritis, and adipose-mediated diabetic joint complications, which will be assessed based on changes in histology and structure in each individual joint component as well as biomarkers. UH3 - Aim 3: Investigating tissue interactions and developing specific biomarkers using mJoint We will assess the contribution of and the interactions among the joint tissue components under normal and diseased conditions. Joint diseases with different etiologies (see Aim 2) will be simulated, tissue interactions analyzed, and potential biomarkers developed to predict joint health. Aim 4: Testing known drugs and screening candidate DMMs We will assess the efficacy of known and candidate DMMs using the mJoint disease models, including interleukin-4, NF-κB decoy oligonucleotides, statins, metalloproteinases inhibitors, and others, focusing also on the applicability of biomarkers identified in Aim 3. Aim 5: Testing potential of cell- based therapy The therapeutic efficacy of human MSCs and their products, such as exosomes and conditioned media, and other biologics, will be examined, in order to explore the scientific basis of the widely perceived utility of stem cell-based therapy for musculoskeletal disorders. In summary, the mJoint represents a high-utility in vitro platform to model synovial joint pathologies and to screen therapeutics for the treatment of joint diseases.

创伤、炎症、感染和衰老会对关节组织造成损害，最终导致关节炎 导致身体残疾的疾病，例如骨关节炎 (OA)、化脓性关节炎和炎性关节炎 损害生活质量；然而，目前尚无有效的治疗方法。 疾病缓解药物（DMM）的发展主要是因为：（1）机制不足 对疾病发作/进展的理解；(2) 无法涵盖 3 维 (3D) 和多组织 早期体外药物发现中滑膜关节的性质；以及（3）临床前动物的实用性有限； 早期临床疗效和毒性预测的研究（缺乏“早期失败/快速失败”能力），导致 此外，患者特定的病因、进展和药物敏感性也导致了意外且代价高昂的临床试验失败。 配置文件强调了个性化治疗开发的必要性，为了满足这些需求，我们建议。 设计 3D 人体微关节芯片 (mJoint)，在生理上类似于天然关节，并且能够 建模关节疾病的发病机制以进行 UG3 筛选/开发 - 目标 1：工程关节。 骨软骨复合体、滑膜和脂肪将使用原代细胞进行工程设计， 人间充质干细胞 (MSC) 或诱导多能干细胞 (iPSC) 衍生的 MSC 封装在 光交联水凝胶支架，其中包含巨噬细胞以评估其关键功能 介导/调节炎症，并使用分子、生化和组织学表征表型 目标 2：生成正常和患病的 mJoint 生物反应器将被设计为容纳所有的 mJoint。 关节元件（mJoint），模拟各自的体内组织状况，并暴露于各种致病菌 模拟 OA、炎性关节炎和脂肪介导的糖尿病关节并发症的药物和条件， 将根据每个关节部件的组织学和结构的变化以及 UH3 - 目标 3：使用研究组织相互作用并开发特定生物标记。 mJoint 我们将评估正常情况下关节组织成分的贡献和相互作用 将模拟不同病因的关节疾病（参见目标 2）、组织相互作用。 目标 4：测试已知的药物和药物。 筛选候选 DMM 我们将使用 mJoint 评估已知和候选 DMM 的功效 疾病模型，包括白细胞介素 4、NF-κB 诱饵寡核苷酸、他汀类药物、金属蛋白酶抑制剂和 其他，还重点关注目标 3 中确定的生物标志物的适用性。目标 5：测试细胞的潜力 基于疗法人类间充质干细胞及其产品的治疗效果，例如外泌体和条件治疗 将检查媒体和其他生物制品，以探索广泛认知的效用的科学基础 肌肉骨骼疾病的干细胞疗法的研究总而言之，mJoint 代表了一种高效的体外疗法。 模拟滑膜关节病理并筛选治疗关节疾病的疗法的平台。