Abstract
The properties of a semipermeable porous membrane, including pore size, pore density, and thickness, play a crucial role in creating a tissue interface in a microphysiological system (MPS) because it dictates multicellular interactions between different compartments. The small pore-sized membrane has been preferentially used in an MPS for stable cell adhesion and the formation of tissue barriers on the membrane. However, it limited the applicability of the MPS because of the hindered cell transmigration via sparse through-holes and the optical translucence caused by light scattering through pores. Thus, there remain unmet challenges to construct a compartmentalized MPS without those drawbacks. Here we report a submicrometer-thickness (∼500 nm) fibrous extracellular matrix (ECM) film selectively condensed on a large pore-sized track-etched (TE) membrane (10 µm-pores) in an MPS device, which enables the generation of functional tissue barriers simultaneously achieving optical transparency, intercellular interactions, and transmigration of cells across the membrane. The condensed ECM fibers uniformly covering the surface and 10 µm-pores of the TE membrane permitted sufficient surface areas where a monolayer of the human induced pluripotent stem cell-derived brain endothelial cells is formed in the MPS device. The functional maturation of the blood–brain barrier (BBB) was proficiently achieved due to astrocytic endfeet sheathing the brain endothelial cells through 10 µm pores of the condensed-ECM-coated TE (cECMTE) membrane. We also demonstrated the extravasation of human metastatic breast tumor cells through the human BBB on the cECMTE membrane. Thus, the cECMTE membrane integrated with an MPS can be used as a versatile platform for studying various intercellular communications and migration, mimicking the physiological barriers of an organ compartment.
Highlights
Microphysiological systems (MPS) mimicking various organ compartments in the human body attracted considerable interest due to their prodigious potential to predict drug toxicity and efficacy that was elusive with conventional studies based on animal models or 2D cell culture methods [1, 2]
Fabrication of the condensed-ECM-coated TE (cECMTE) membrane integrated with an MPS The extracellular matrix (ECM) hydrogel is a porous and biocompatible material consisting of a 3D hydrophilic network of cross-linked polymers [13]
Despite considerable efforts in recent years, no fabrication approach was developed, which could address these problems simultaneously. This is an important problem as it is necessary for the cells on both sides of the porous membranes to freely interact with their neighboring cells and transmigrate through the barriers without physical restriction because these confinements of the cells could potentially mislead experimental results obtained from the MPS platform
Summary
(UNIST), UNIST gil 50, Ulju-gun, Ulsan 44919, Republic of Korea 1 These authors contributed to this work . The small pore-sized membrane has been preferentially used in an MPS for stable cell adhesion and the formation of tissue barriers on the membrane. It limited the applicability of the MPS because of the hindered cell transmigration via sparse through-holes and the optical translucence caused by light scattering through pores. We report a submicrometer-thickness (∼500 nm) fibrous extracellular matrix (ECM) film selectively condensed on a large pore-sized track-etched (TE) membrane (10 μm-pores) in an MPS device, which enables the generation of functional tissue barriers simultaneously achieving optical transparency, intercellular interactions, and transmigration of cells across the membrane. The cECMTE membrane integrated with an MPS can be used as a versatile platform for studying various intercellular communications and migration, mimicking the physiological barriers of an organ compartment
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