Abstract
The interaction of immune cells with drugs and/or with other cell types should be mechanistically investigated in order to reduce attrition of new drug development. However, they are currently only limited technologies that address this need. In our work, we developed initial but significant building blocks that enable such immune-drug studies. We developed a novel microfluidic platform replicating the Lymph Node (LN) microenvironment called LN-on-a-chip, starting from design all the way to microfabrication, characterization and validation in terms of architectural features, fluidics, cytocompatibility, and usability. To prove the biomimetics of this microenvironment, we inserted different immune cell types in a microfluidic device, which showed an in-vivo-like spatial distribution. We demonstrated that the developed LN-on-a-chip incorporates key features of the native human LN, namely, (i) similarity in extracellular matrix composition, morphology, porosity, stiffness, and permeability, (ii) compartmentalization of immune cells within distinct structural domains, (iii) replication of the lymphatic fluid flow pattern, (iv) viability of encapsulated cells in collagen over the typical timeframe of immunotoxicity experiments, and (v) interaction among different cell types across chamber boundaries. Further studies with this platform may assess the immune cell function as a step forward to disclose the effects of pharmaceutics to downstream immunology in more physiologically relevant microenvironments.
Highlights
Every year, new drug candidates, which previously underwent in vitro and in silico investigations, are proposed to enter preclinical and clinical studies [1,2,3]
The microfluidic device is designed to mimic the in vivo Lymph Node (LN) architecture as each region within the device corresponds to an LN component as follows: region 1 corresponds to the subcapsular sinus region, region 2 corresponds to the reticular conduit network which mediates the transport of antigens from the peripheral SCS into the interior of the LN, region 3A corresponds to the follicle where B lymphocytes reside, and region 3B corresponds to the paracortex where T lymphocytes reside
We showed that the developed LN-on-a-chip maintains cell viability for a duration of more than 72 h, which is sufficient for drug toxicity testing, and that it replicates the key features of the native LN, namely, the confinement of different cellular communities within distinct anatomical locations and the sustainment of a unique flow pattern
Summary
New drug candidates, which previously underwent in vitro and in silico investigations, are proposed to enter preclinical and clinical studies [1,2,3]. The effect of a drug candidate on the immune system, known as immunotoxicity, is often underestimated along the drug development process. The techniques currently available to evaluate the immunotoxicity of drug candidates during preclinical stages often lack reliability and sensitivity, resulting in many drugs, which have initially passed the preclinical phase of drug approval, to fail in the clinical phase. This represents a significant waste of time, resources, and money [4,5,6,7]
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