Creation of a Knee Joint-on-a-Chip for Modeling Joint Diseases and Testing Drugs.
Creation of a Knee Joint-on-a-Chip for Modeling Joint Diseases and Testing Drugs.
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创建用于建模关节疾病和测试药物的膝关节片。
DOI：
10.3791/64186
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发表时间：
2023-01-27
期刊：
影响因子：
--
通讯作者：
Lin H
中科院分区：
文献类型：
--
作者：
Makarcyzk MJ;Li ZA;Yu I;Yagi H;Zhang X;Yocum L;Li E;Fritch MR;Gao Q;Bunnell BA;Goodman SB;Tuan RS;Alexander PG;Lin H
骨关节炎（OA）等致残性关节疾病的高患病率造成了沉重的社会经济负担。目前，针对关节疾病的可用药物大多是姑息性的。对有效的疾病修饰性OA药物（dmoad）的需求未得到满足，主要是由于缺乏合适的模型来研究疾病机制和测试潜在的dmoad。在本文中，我们描述了一个微型滑膜关节模拟微生理系统（miniJoint）的建立，该系统包括来自人间充质干细胞（MSCs）的脂肪、纤维和骨软骨组织成分。为了获得三维显微组织，在分化之前或之后，将MSCs包被在光交联的甲基丙烯酸明胶中。然后，将装载细胞的组织结构整合到3d打印的生物反应器中，形成微型关节。分别引入成骨、纤维和脂肪培养基来维持各自的组织表型。通过软骨、滑膜和脂肪组织灌注共同共享的流，使组织相互作用。这种流动模式允许在一个或多个组织成分中诱导扰动以进行机械研究。此外，潜在的dmoad可以通过通过所有介质流的“全身给药”或通过仅将药物添加到共享的“滑液”模拟流的“关节内给药”来测试。因此，微型关节可以作为一个多功能的体外平台，有效地研究疾病机制和个性化医疗药物测试。我们提供了从人间充质干细胞生成四种组织的详细方法，这些组织用于再现人膝关节的软骨、骨、脂肪垫和滑膜。这四个组织被整合到一个定制的生物反应器中，并通过微流体连接起来，从而产生一个芯片上的膝关节。
The high prevalence of debilitating joint diseases like osteoarthritis (OA) poses a high socioeconomic burden. Currently, the available drugs that target joint disorders are mostly palliative. The unmet need for effective disease-modifying OA drugs (DMOADs) has been primarily caused by the absence of appropriate models for studying the disease mechanisms and testing potential DMOADs. Herein, we describe the establishment of a miniature synovial joint-mimicking microphysiological system (miniJoint) comprising adipose, fibrous, and osteochondral tissue components derived from human mesenchymal stem cells (MSCs). To obtain the three-dimensional (3D) microtissues, MSCs were encapsulated in photocrosslinkable methacrylated gelatin before or following differentiation. The cell-laden tissue constructs were then integrated into a 3D-printed bioreactor, forming the miniJoint. Separate flows of osteogenic, fibrogenic, and adipogenic media were introduced to maintain the respective tissue phenotypes. A commonly shared stream was perfused through the cartilage, synovial, and adipose tissues to enable tissue crosstalk. This flow pattern allows the induction of perturbations in one or more of the tissue components for mechanistic studies. Furthermore, potential DMOADs can be tested via either “systemic administration” through all the medium streams or “intraarticular administration” by adding the drugs to only the shared “synovial fluid”-simulating flow. Thus, the miniJoint can serve as a versatile in vitro platform for efficiently studying disease mechanisms and testing drugs in personalized medicine. We provide detailed methods for generating four types of tissues from human mesenchymal stem cells, which are used to recapitulate the cartilage, bone, fat pad, and synovium in the human knee joint. These four tissues are integrated into a customized bioreactor and connected through microfluidics, thus generating a knee joint-on-a-chip.
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影响因子：
23.9
作者：
Ronaldson-Bouchard K;Vunjak-Novakovic G
通讯作者：
Vunjak-Novakovic G
影响因子：
27.4
作者：
Atukorala I;Kwoh CK;Guermazi A;Roemer FW;Boudreau RM;Hannon MJ;Hunter DJ
通讯作者：
Hunter DJ
影响因子：
14
作者：
Lin H;Sohn J;Shen H;Langhans MT;Tuan RS
通讯作者：
Tuan RS
影响因子：
--
作者：
Lawrence, Reva C.;Felson, David T.;Wolfe, Frederick
通讯作者：
Wolfe, Frederick
影响因子：
28.1
作者：
Occhetta, Paola;Mainardi, Andrea;Rasponi, Marco
通讯作者：
Rasponi, Marco