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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

基本信息

批准号：
10208992
负责人：
Hang Lin
金额：
$ 110.95万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-20 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208992
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 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 efficacious treatment efficacy testing exosome experience high throughput screening hydrogel scaffold 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 screening specific biomarkers stem cell therapy stem cells therapeutic candidate therapy development tool

项目摘要

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、感染和衰老可导致关节组织损伤，最终导致关节炎。疾病，如骨关节炎（OA）、脓毒性关节炎和炎性关节炎，导致身体残疾这损害了生活质量;然而，目前没有有效的治疗方法。进展有限疾病缓解药物（DMMs）的发展主要是因为：（1）机制不足理解疾病发作/进展;（2）无法涵盖三维（3D）和多组织滑膜关节在体外药物发现早期阶段的性质;和（3）临床前动物的有限效用早期临床疗效和毒性预测研究（缺乏“早期失败/快速失败”能力），导致无法预料且代价高昂的临床试验失败此外，患者特异性病因、进展和药物敏感性概况强调了个性化治疗开发的需要。为了满足这些需求，我们建议设计3D人体微关节芯片（mJoint），其在生理上类似于天然关节并且能够用于DMM筛选/开发的关节疾病发病机制建模。UG 3-目标1：工程接头成分骨软骨复合体、滑膜和脂肪，将使用原代细胞进行工程化，将人间充质干细胞（MSC）或诱导的多能干细胞（iPSC）衍生的MSC包封在光交联的水凝胶支架，包括巨噬细胞，以评估它们在介导/调节炎症，并使用分子、生物化学和组织学表征表型分析。目的2：产生正常和患病的mJoint A生物反应器将被设计成容纳所有的mJoint A。关节元件（mJoint），模拟相应的体内组织条件，并暴露于各种致病性用于模拟OA、炎性关节炎和脂肪介导的糖尿病关节并发症的试剂和条件，将根据每个单独关节组件的组织学和结构变化以及生物标志物。UH 3-目标3：使用生物标记物研究组织相互作用并开发特异性生物标记物我们将评估正常情况下关节组织成分的贡献和相互作用。和疾病状况。将模拟具有不同病因的关节疾病（见目标2），组织相互作用分析，并开发潜在的生物标志物来预测关节健康。目标4：测试已知药物和筛选候选DMM我们将使用mJoint评估已知和候选DMM的有效性疾病模型，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，也侧重于目标3中确定的生物标志物的适用性。目的5：测试细胞的潜力- 人MSC及其产物，如外来体和条件的MSC的治疗功效媒体，和其他生物制品，将被审查，以探讨广泛认为的效用的科学基础，以干细胞为基础的肌肉骨骼疾病治疗。总之，mJoint代表了一种高效用的体外该平台用于模拟滑膜关节病理并筛选治疗关节疾病的疗法。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Osteogenic ability of rat bone marrow concentrate is at least as efficacious as mesenchymal stem cells in vitro.

在体外，大鼠骨髓浓缩物的成骨能力至少与间充质干细胞一样有效。

DOI：
10.1002/jbm.b.34340
发表时间：
2019
期刊：
Journal of biomedical materials research. Part B, Applied biomaterials
影响因子：
0
作者：
Kohno,Yusuke;Lin,Tzuhua;Pajarinen,Jukka;Romero-Lopez,Monica;Maruyama,Masahiro;Huang,Jhih-Fong;Nathan,Karthik;Yao,Zhenyu;Goodman,StuartB
通讯作者：
Goodman,StuartB

Engineering in-vitro stem cell-based vascularized bone models for drug screening and predictive toxicology.

DOI：
10.1186/s13287-018-0847-8
发表时间：
2018-04-20
期刊：
Stem cell research & therapy
影响因子：
7.5
作者：
Pirosa A;Gottardi R;Alexander PG;Tuan RS
通讯作者：
Tuan RS

Design and validation of an osteochondral bioreactor for the screening of treatments for osteoarthritis.

DOI：
10.1007/s10544-018-0264-x
发表时间：
2018-02-14
期刊：
Biomedical microdevices
影响因子：
2.8
作者：
Nichols DA;Sondh IS;Little SR;Zunino P;Gottardi R
通讯作者：
Gottardi R

Clinical Applications of Bone Tissue Engineering in Orthopedic Trauma.

DOI：
10.1007/s40139-018-0166-x
发表时间：
2018-06
期刊：
CURRENT PATHOBIOLOGY REPORTS
影响因子：
0
作者：
Mittwede, Peter N;Gottardi, Riccardo;Alexander, Peter G;Tarkin, Ivan S;Tuan, Rocky S
通讯作者：
Tuan, Rocky S

Correction to: Design and validation of an osteochondral bioreactor for the screening of treatments for osteoarthritis.

更正：用于骨关节炎治疗筛选的骨软骨生物反应器的设计和验证。

DOI：
10.1007/s10544-018-0283-7
发表时间：
2018
期刊：
Biomedical microdevices
影响因子：
2.8
作者：
Nichols,DerekA;Sondh,InderbirS;Little,StevenR;Zunino,Paolo;Gottardi,Riccardo
通讯作者：
Gottardi,Riccardo