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，感染，感染和衰老会对关节组织造成损害，最终导致artritic 骨关节炎（OA），败血性关节炎和炎性关节炎等疾病，导致身体疾病 这种折衷的生活质量；但是，目前尚无高效疗法。有限的进展 疾病改良药物（DMM）的开发主要是由于：（1）机械不足 了解疾病的发作/进展； （2）无法涵盖3维（3D）和多组织 滑膜关节在早期的体外药物发现的性质； （3）临床前动物的效用有限 研究早期临床效率和毒性预测（缺乏“早期/失败快速失败”功能）的研究，导致 意外且昂贵的临床试验失败。此外，患者特异性的病因，进展和药物敏感性 概况强调了对个性化疗法开发的需求。为了满足这些需求，我们提出了 工程3D人类微接头芯片（mjoint），实际上类似于天然关节 建模用于DMM筛查/发育的关节疾病的发病机理。 UG3-目标1：工程关节 组件骨软骨复合物，滑膜和脂肪将使用原代细胞进行设计， 人间充质干细胞（MSC）或诱导的多能干细胞（IPSC）衍生的MSC封装在A中 Photocropslinked水凝胶支架，其中包括巨噬细胞，以评估其关键功能 使用分子，生化和组织学进行介导/调节注射和表型。 分析。 AIM 2：生成正常和解散的Mjoint生物反应器将被设计为容纳所有 关节元素（MJOINT），模拟体内组织条件的相对，并暴露于各种致病性 对OA，炎性关节炎和脂肪介导的糖尿病关节并发症建模的药物和条件， 将根据每个单独的关节成分的组织学和结构的变化以及 生物标志物。 UH3- AIM 3：研究组织相互作用并使用特定的生物标志物使用 mjoint我们将评估正常的关节组织成分之间的贡献和相互作用 和病态。将模拟具有不同病因的关节疾病（请参见目标2），组织相互作用 经过分析，并开发了潜在的生物标志物来预测联合健康。 AIM 4：测试已知药物和 筛选候选DMMS我们将使用Mjont评估已知和候选DMM的效率 疾病模型，包括白介素4，NF-κB诱饵寡核苷酸，他汀类药物，金属蛋白酶抑制剂和 其他人也专注于AIM 3中确定的生物标志物的适用性。目标5：测试细胞的潜力 人类MSC及其产品的基于基于的治疗效率，例如外泌体和条件 媒体和其他生物制剂将进行检查，以探讨广泛感知的实用程序的科学基础 基于干细胞的肌肉骨骼疾病的治疗。总而言之，Mjoint代表体外高纯度 建模滑膜关节病理和筛查关节疾病治疗的平台。