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.
