Multi-organ culture and pumping systems for ex vivo models of immunity in hybrid tissue-chips

用于混合组织芯片中免疫离体模型的多器官培养和泵系统

• 批准号: 10578463
• 负责人: Rebecca R Pompano
• 金额: $ 50.73万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578463
• 关键词: 3D Print; Address; Adjuvant; Adopted; Adoption; Air; Antigen Presentation; Antigen-Antibody Complex; Antigens; Arthritis; Autoimmunity; Bathing; Biological Models; Biology; Biomedical Research; Brain; Cancer Vaccines; Cell Culture Techniques; Cell Survival; Cells; Chronic Disease; Circulation; Coculture Techniques; Communication; Communities; Complex; Disease; Drainage procedure; Electronics; Engineering; Ensure; Environment; Event; Force of Gravity; Gel; Hybrids; Image; Immune; Immune response; Immunity; Immunologist; Immunology; Immunosuppression; Immunotherapy; In Vitro; Incubators; Infection; Inflammation; Inflammatory; Injections; Joints; Laboratories; Lateral; Leukocytes; Liquid substance; Lymph; Lymph Node Tissue; Lymphocyte; Magnetism; Methods; Microfluidics; Modeling; Molecular; Monitor; Motion; Movement; Organ; Organ Culture Techniques; Organ Model; Particulate; Pattern; Perfusion; Peripheral; Proteins; Public Health; Pump; Reporting; Reproducibility; Research Personnel; Sampling; Series; Site; Skin; Slice; Stimulus; Stromal Cells; System; Testing; Time; Tissue Microarray; Tissues; Tumor Immunity; Vaccination; Vaccine Design; Vaccines; Viscosity; Work; biomaterial compatibility; cancer immunotherapy; cooking; design; draining lymph node; effector T cell; experimental study; fighting; fluid flow; immune function; improved; in vivo; innovation; interstitial; lymph node microenvironment; lymph nodes; lymphoid organ; microdevice; miniaturize; organ on a chip; predicting response; preservation; prototype; recruit; response; scale up; simulation; technology development; therapeutic evaluation; tumor; usability; user-friendly

Multi-organ culture and pumping systems for ex vivo models of immunity in hybrid tissue-chips A better understanding of cellular and molecular communication between the lymph node (LN) and the organs it drains is imperative for public health. These events determine how well we fight infections and respond to vaccines, whether a nascent tumor is recognized and destroyed, and whether our own tissues remain safe from autoimmunity. However, the dynamic interactions of the lymph node with peripheral organs have been difficult to study in vivo or in vitro, making it difficult to predict immune responses, understand disease mechanisms, or design vaccines and immunotherapies. Here, we will develop a microfluidic culture and pumping system specifically designed to model communication between the lymph node and surrounding organs, to model multi- tissue immunity. This model will build on our prior establishment of a microfluidic system for co-culture of two slices under a recirculating loop of media, which showed promise in capturing tumor-induced immunosuppression of the lymph node (Shim, Lab Chip 2019). We will build on this concept to create the first tissue slice co-culture system that is specifically designed for use by immunologists and other biomedical researchers in terms of ease of use for precise flow control and circulation of white blood cells between tissues. First, we will develop a series of 3D printed multi-organ microdevices for culture of intact tissue slices under transverse or lateral perfusion, with or without an air/liquid interface (e.g. for brain and skin slices), and supporting recirculation of white blood cells through multiple tissues. In parallel, we will refine the fluidic control system for robust and user-friendly multi-slice co-cocultures and lymphocyte recirculation, with scale up to dozens of slice cultures. We will start from our recent prototype on-chip magnetic impeller-based pump, which is compatible with cell culture incubators and cell recirculation (Cook, Lab Chip 2022). Combining advanced fluid dynamic simulations with experimental tests, we will miniaturize the pump to reduce dead volume, ensure consistency of flow control, and preserve viability of circulating white blood cells. User tests in other laboratories will further refine the design. Making use of the available flow control, we will test the hypothesis that lymph node tissue function is sensitive to fluid flow rate, and determine the optimal flow mode for multi-organ lymph node culture. Finally, we will build on our strong team’s expertise in vaccine immunology to generate a simple model of vaccine drainage and response of the lymph node to vaccination, as a proof-of-principle for the system. Ultimately, the user-friendly platform developed here to model multi-organ immune function will enable the biomedical research community to better predict the response to vaccination and immunotherapy, onset of tumor immunity, and engagement of brain, gut, or arthritic joints with the lymph node during autoimmunity.

多器官培养和抽水系统，用于杂交组织芯片中免疫学模型的离体模型 更好地理解淋巴结（LN）与器官之间的细胞和分子通信 排水对于公共卫生至关重要。这些事件决定了我们对感染的斗争程度和回应 疫苗，是否识别和破坏了新生的肿瘤，以及我们自己的组织是否可以保护 自身免疫性。但是，淋巴结与周围器官的动态相互作用很困难 在体内或体外研究，使得难以预测免疫反应，了解疾病机制或 设计疫苗和免疫疗法。在这里，我们将开发微流体培养和抽水系统 专门设计用于建模淋巴结和周围器官之间的通信，以建模 组织免疫。该模型将建立在我们先前建立的微流体系统以共同文化的基础上 在循环循环下的切片，这表明了捕获肿瘤诱导的有望 淋巴结的免疫抑制（Shim，Lab Chip 2019）。我们将基于这个概念来创建第一个 组织切片共培养系统，专门设计用于免疫学家和其他生物医学 研究人员在易于使用方面可以控制整个组织之间的白细胞流动和循环。 首先，我们将开发一系列3D打印的多器官微论述，以培养完整的组织切片 横向或横向灌注，有或没有空气/液体界面（例如，用于大脑和皮肤切片），并支撑 通过多个时机再循环白细胞。同时，我们将完善用于的流体控制系统 稳健且用户友好的多片共培养和淋巴细胞再循环，缩放多达数十个切片 文化。我们将从我们最近的原型芯片磁性叶轮泵开始，该泵与 细胞培养孵化器和细胞再循环（Cook，Lab Chip 2022）。结合高级流体动态 通过实验测试的模拟，我们将小型化泵以减少死亡的体积，确保一致性 流动控制，并保留循环白细胞的生存能力。其他实验室的用户测试将进一步 完善设计。利用可用的流量控制，我们将测试淋巴结组织的假设 功能对流体流速敏感，并确定多器官淋巴结培养的最佳流动模式。 最后，我们将基于强大的团队在疫苗免疫学方面的专业知识，以生成一种简单的疫苗模型 淋巴结对疫苗接种的排水和反应，作为系统的原则证明。最终， 用户友好的平台在此开发为建模多器官免疫功能将使生物医学研究 社区更好地预测对疫苗接种和免疫疗法的反应，肿瘤免疫史发作以及 自身免疫期间，大脑，肠道或关节关节与淋巴结的接合。