Kidney-on-a-Chip: Mechanical Stimulation and Sensor Integration

Abstract

Bioengineered in vitro models of the kidney offer unprecedented opportunities to better mimic the in vivo microenvironment. Kidney-on-a-chip technology reproduces 2D or 3D features which can replicate features of the tissue architecture, composition, and dynamic mechanical forces experienced by cells in vivo. Kidney cells are exposed to mechanical stimuli such as substrate stiffness, shear stress, compression, and stretch, which regulate multiple cellular functions. Incorporating mechanical stimuli in kidney-on-a-chip is critically important for recapitulating the physiological or pathological microenvironment. This review will explore approaches to applying mechanical stimuli to different cell types using kidney-on-a-chip models and how these systems are used to study kidney physiology, model disease, and screen for drug toxicity. We further discuss sensor integration into kidney-on-a-chip for monitoring cellular responses to mechanical or other pathological stimuli. We discuss the advantages, limitations, and challenges associated with incorporating mechanical stimuli in kidney-on-a-chip models for a variety of applications. Overall, this review aims to highlight the importance of mechanical stimuli and sensor integration in the design and implementation of kidney-on-a-chip devices.

Keywords: glomerulus; kidney-on-a-chip; mechanical stimuli; microfluidic; proximal tubule; shear stress; substrate stiffness.

Figure 1

Kidney cell microenvironment and the mechanical stimuli applied to cells to mimic the physiological environment.

Figure 2

Passive mechanical stimuli applied to cells. (A) Healthy and diseased ECM. Healthy ECM with normal composition and elasticity. Disease-mediated changes modify the ECM composition and stiffness. Changes in ECM stiffness are mediated by enzymatic crosslinking, glycation, chemical reactions, or gene mutation. (B) In vitro models of passive mechanical stimulation include culture dishes coated with synthetic or ECM hydrogels with tunable stiffness, modified Transwell culture inserts, microfluidic devices, and 3D printed structures that allow for both passive and active mechanical stimuli. (C) ECM affects cell behavior when being cultured on soft, normal, or stiff substrate. (D) ECM active mechanotransduction pathways which alters the gene and protein expression. These modifications further affect cell function. Accumulation of these factors contributes to organ dysfunction.

Figure 3

Shear stress applied to kidney-on-a-chip. Schematic drawing of the design for single-channel, multi-channel, and 3D cell culture devices. (A) A single channel is coated with collagen or laminin ECM, gelatin, or PAA hydrogel for cell attachment. Renal tubule cells, podocytes, or endothelial cells cultured on a thin layer of ECM. Cells are supplied with culture media and reagents for drug screening, toxicity evaluation, or interrogation of different cell functions. (B) Multi-channel device is composed of apical and basal channels with continuous media supply. Shear stress can be applied to each channel. Cell monolayer or co-cultured cells are supported by a bioengineered, synthetic, or commercially available porous membrane. (C) 3D cell culture device is composed of hollow fibers, 3D printed gels, or PDMS.

Figure 4

Sensor integration into kidney-on-a-chip with schematics of TEER measurement using (A) EVOM2 instrument and (B) four terminal sensing techniques using a potentiostat. TEER sensor measures the resistance across the cell layer. (C) Multiple sensors, such as pH and oxygen sensors, are integrated into microfluidic device with TEER measurements. (D) Bioreactors with small chambers are integrated with TEER sensors.