Commercializing the ?SIM: A Modular Platform for the Development and Analysis of Barrier Tissue Models - Abstract
In vitro models of tissue barriers such as the gut, lung, and vasculature are important for understanding
the basis of disease and for assessing the ability of drug formulations to reach target tissues. Despite the
growth of sophisticated 3D (also microphysiological and tissue chip) culture systems, the simplest and
most popular tools for the in vitro study of barrier tissues remains the Corning Transwell™ and its
competitors (collectively referred to here as “Transwells™”). These products suspend a thick (~ 10 µm )
polymer membrane in a culture well to create apical and basal compartments separated by a monolayer or
co-culture grown on the membrane. Despite their popularity, Transwells™ are notoriously bad for cell
imaging and do not provide the fluid flow needed to properly condition vascular barriers and to study
immune cell trafficking. Here, we propose to use SiMPore's ultrathin (< 300 nm), highly permeable, and
optically transparent membranes to create a cell culture platform that overcomes these limitations.
Our project will create a modular platform featuring a core unit called the µSiM (microphysiological
system enabled by a Silicon Membrane; developed in Aim 1) that readily converts into a flow cell
through the addition of a “plug-and-play” flow module (developed in Aim 2). The µSiM will enable live
cell and high resolution microscopy in an open-well format that is familiar to Transwells™ users. To suit
different applications, the µSiM will feature one of three SiMPore membranes: 1) nanoporous, 2) dual
nano and microporous; and 3) 0.5 µm pores. The µSiM will convert into a flow cell through the addition
of a flow module that aligns and seals via magnetic latches. In this way users can initiate culture in an
easy-to-use open-well device before initiating flow. Non-modular open well and flow cell devices
featuring SiMPore membranes are already produced for academic collaborators by PI McGrath
(University of Rochester) in a one-by-one manner that cannot support broader distribution. This STTR
will create a commercial alternative using high-throughput manufacturing to achieve unit costs in line
with those of Transwells™. In addition to high yields in manufacturing (> 90%), our success metrics will
ensure the µSiM platform achieves the basic functionality of the lab-crafted devices. Specifically we will
verify: 1) endothelial barrier maturation as indicated by tight junction formation and low permeability to
small molecule diffusion (<1.7 x 10-6 cm/sec for 4kDa FITC dextran); 2) barrier enhancement and
endothelial alignment in response to the application of physiological levels of shear (10 dynes/cm2); and
3) the ability to introduce leukocytes under flow and witness each stage of trafficking across a vascular
barrier (rolling, luminal and abluminal crawling, diapedesis). Results will be externally verified through
the McGrath lab collaborations. Phase I will produce both the µSiM and the µSiM flow module as
products. Phase II will introduce additional functional modules (TEER, ELISA) and multiplex formats.
