A compartmentalized microfluidic chip with crisscross microgrooves and electrophysiological electrodes for modeling the blood–retinal barrier

Abstract

The interconnection of different tissue-tissue interfaces may extend organ-on-chips to a new generation of sophisticated models capable of recapitulating more complex organ-level functions. Single interfaces are largely recreated in organ-on-chips by culturing the cells on opposite sides of a porous membrane that splits a chamber in two or by connecting the cells of two adjacent compartments through microchannels. However, it is difficult to interconnect more than one interface using these approaches. To address this challenge, we present a novel microfluidic device where cells are arranged in parallel compartments and are highly interconnected through a grid of microgrooves, which facilitates paracrine signaling and heterotypic cell-cell contact between multiple tissues. In addition, the device includes electrodes on the substrate for the measurement of transepithelial electrical resistance (TEER). Unlike conventional methods for measuring the TEER where electrodes are on each side of the cell barrier, a method with only electrodes on the substrate has been validated. As a proof-of-concept, we have used the device to mimic the structure of the blood-retinal barrier by co-culturing primary human retinal endothelial cells (HREC), a human neuroblastoma cell line (SH-SY5Y), and a human retinal pigment epithelial cell line (ARPE-19). Cell barrier formations were assessed by a permeability assay, TEER measurements, and ZO-1 expression. These results validate the proposed microfluidic device with microgrooves as a promising in vitro tool for the compartmentalization and monitoring of barrier tissues.

A bilayer photoreceptor-retinal tissue model with gradient cell density design: A study of microvalve-based bioprinting

“…To use microvalve‐based bioprinting technology to prepare retinal tissue model has several advantages: (a) high throughput: the native tissue structure and cellular interactions can be rapidly reproduced to investigate cell functions, whereas manual cell seeding is time consuming with low accuracy (Hamilton, Foss, & Leach, ; Wisniewska‐Kruk et al, ); (b) accuracy and efficiency: the process is well controlled to maximally reduce manpower and exclude man‐vmade errors, and this method can be applied to produce retina on a chip device with improved producibility (Chung et al, ; Yeste et al, ); (c) alternatives to animal models: in vitro human tissue models may significantly improve accuracy, efficiency, reproducibility, and therapeutic translatability of animal‐free experiments, as well as resolve cruelty and ethical concerns of animal testing. Preparation of the blood–retinal barrier models using animal tissue is also challenging (Steuer, Jaworski, Stoll, & Schlosshauer, ).…”

Niosome-Based Approach for In Situ Gene Delivery to Retina and Brain Cortex as Immune-Privileged Tissues

“…Therefore, primarily cultures are normally used to evaluate the kind of cells that have been transfected by immunohistochemistry rather that the transfection efficiency in quantitative terms [9,51]. In the case of immune-privileged organs such as the brain and eye, in addition to culture cells, different and sophisticated in vitro models based on microfluidic chips of both the BBB and BRB can be used to better mimic the in vivo conditions and predict their behavior performance [117,118].…”

Ex Vivo Tumor‐on‐a‐Chip Platforms to Study Intercellular Interactions within the Tumor Microenvironment

“…In their simplest form, organ(s)‐on‐a‐chip consist of a single cell type lined along a microchannel or seeded in a single chamber while being perfused with media. More advanced models with multiple microchannels separated by membranes to mimic tissue interfaces and barriers such as air–liquid interface (ALI), blood–brain barrier (BBB), and blood–retinal barrier (BRB) have led to the development of lung‐on‐a‐chip, BBB‐on‐a‐chip, and BRB‐on‐a‐chip, respectively. Optical transparency of these devices allows real time visualization and imaging enabling easier in situ characterization.…”