Glomerulus-on-a-Chip: Current Insights and Future Potential Towards Recapitulating Selectively Permeable Filtration Systems

Abstract

Glomerulopathy, characterized by a dysfunctional glomerular capillary wall, results in proteinuria, leading to end-stage renal failure and poor clinical outcomes, including renal death and increased overall mortality. Conventional glomerulopathy research, including drug discovery, has mostly relied on animal experiments because in-vitro glomerulus models, capable of evaluating functional selective permeability, was unavailable in conventional in-vitro cell culture systems. However, animal experiments have limitations, including time- and cost-consuming, multi-organ effects, unstable reproducibility, inter-species reliability, and the social situation in the EU and US, where animal experiments have been discouraged. Glomerulus-on-a-chip, a new in-vitro organ model, has recently been developed in the field of organ-on-a-chip research based on microfluidic device technology. In the glomerulus-on-a-chip, the podocytes and endothelial cells are co-cultured in a microfluidic device with physical stimuli that mimic the physiological environment to enhance cell function to construct a functional filtration barrier, which can be assessed by permeability assays using fluorescently labeled molecules including inulin and albumin. A combination of this glomerulus-on-a chip technology with the culture technology to induce podocytes and endothelial cells from the human pluripotent stem cells could provide an alternative organ model and solve the issue of animal experiments. Additionally, previous experiments have verified the difference in the leakage of albumin using differentiated podocytes derived from patients with Alport syndrome, such that it could be applied to intractable hereditary glomerulopathy models. In this review, we provide an overview of the features of the existing glomerulus-on-a-chip systems, focusing on how they can address selective permeability verification tests, and the challenges they involved. We finally discuss the future approaches that should be developed for solving those challenges and allow further improvement of glomerulus-on-a-chip technologies.

Characterizing Glomerular Barrier Dysfunction with Patient-Derived Serum in Glomerulus-on-a-Chip Models: Unveiling New Insights into Glomerulonephritis

“…All of them showed higher levels of albumin leakage than those in normal controls. Our results also revealed that serum exposure led to enhanced intercellular albumin diffusion in some IgAN and MN patients, similar to results of previous studies [15,38]. However, there was no statistically significant difference in the permeability of albumin in MCD and LN groups compared to the control group.…”

Development of Drug Efficacy Testing Platform for Glomerulonephritis

“…The glomerulus chip model can be divided into the following mechanisms [ 12 ]. The first is a chip with a porous membrane, made from a polydimethylsiloxane plate with the porous membrane serving as the boundary for growing endothelium and podocytes.…”

Enhanced podocyte differentiation and changing drug toxicity sensitivity through pressure-controlled mechanical filtration stress on a glomerulus-on-a-chip

“…Shear stress alone 34 , a combination of shear stress and cyclic straining cell adherent substrate 23 , and topographical micro-convex scaffold 25,35 have been reported to promote the podocyte maturation through maturation marker expression and/or cellular process elongation of podocytes compared to conventional static culture. 36 Meanwhile, glomerular filtration flow is generated upon hemofiltration and is considered a vertical shear stress acting on the podocyte. It is distinct from the horizontal shear stress because it is a force pulling away from basal to apical side for the cell.…”