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.

混合组织芯片免疫体外模型的多器官培养和泵送系统 更好地了解淋巴结(LN)和器官之间的细胞和分子通讯 排水对公众健康是必不可少的。这些事件决定了我们如何更好地对抗感染和应对 疫苗，新生肿瘤是否被识别和摧毁，以及我们自己的组织是否保持安全 自身免疫力。然而，淋巴结与周围器官的动态相互作用一直是困难的。 在体内或体外进行研究，使预测免疫反应、了解疾病机制或 设计疫苗和免疫疗法。在这里，我们将开发一种微流控培养和泵送系统 专门设计用于模拟淋巴结和周围器官之间的通信，以模拟多个 组织免疫力。这个模型将建立在我们先前建立的微流控系统的基础上，用于两种细胞的共培养 在介质循环循环下的切片，这在捕获由肿瘤诱导的肿瘤方面显示出希望 淋巴结的免疫抑制(Shim，Lab Chip 2019)。我们将在这个概念的基础上创造第一个 专门为免疫学家和其他生物医学人员设计的组织切片共培养系统 研究人员在易用性方面为精确的流量控制和组织之间的白细胞循环提供了便利。 首先，我们将开发一系列3D打印多器官微型设备，用于在 横向或侧向灌注，有或没有空气/液体界面(例如，用于脑和皮肤切片)，并支持 白细胞在多个组织中的再循环。同时，我们将改进射流控制系统，以 强大且用户友好的多切片共培养和淋巴细胞再循环，可扩展到数十个切片 文化。我们将从我们最新的芯片上磁力叶轮泵的原型开始，它与 细胞培养孵化器和细胞再循环(库克，实验室芯片2022)。结合先进的流体力学 模拟结合实验测试，我们将泵小型化，以减少死体积，确保一致性 控制血液流动，并保持循环中白细胞的活性。其他实验室的用户测试将进一步 改进设计。利用可用的流量控制，我们将检验淋巴组织 功能对液体流速敏感，并决定多器官淋巴结培养的最佳流动方式。 最后，我们将利用我们强大的团队在疫苗免疫学方面的专业知识来产生一个简单的疫苗模型 淋巴引流和对接种疫苗的反应，作为该系统的原则证明。归根结底， 这里开发的用户友好的多器官免疫功能建模平台将使生物医学研究成为可能 社区以更好地预测接种疫苗和免疫治疗的反应、肿瘤免疫的开始，以及 自体免疫期间大脑、肠道或关节炎关节与淋巴结相接触。