Proximal-tubule-on-chip with physiologically relevant tubular feature and teer sensing integration potential

Abstract

Kidney-on-chip (KOC) is an emerging technology aiming to facilitate pharmaceutical development by providing more robust prediction on drug nephrotoxicity and efficacy during preclinical stage. Proximal tubule is the primary site of investigation in the kidney for its role in drug excretion and vulnerability against drug-induced toxicity. Exposed to shearing stress of fluid flow, renal proximal tubule epithelial cells cultured in the microfluidic-based KOC platform exhibit improved long-term viability and express morphological and functional characteristics similar to proximal tubule epithelium in vivo, such as apical-basolateral membrane polarization, enhanced reabsorption function and appropriate injury response, which are deficient in conventional cell culture model. However, many KOC platforms utilizing larger-sized channels yet to fully represent human proximal tubule structure, while topography resembling tubular curvature of human proximal tubule have shown similar morphological improvement as fluid-driven KOC platforms. Therefore, a potential direction for KOC platform is through merging of physiologically relevant tubular structure and flow rate. In this study, a microfluidic device containing microchannels with dimension analogous to human proximal tubules was designed and fabricated with photo-lithography, thermal reflow, and soft lithography techniques. The fluid dynamics, particularly the shear stress performance, was analyzed with COMSOL, ensuring fluid delivered to such a device could induce desired shear stress. In addition, preliminary study on electrode design was performed, demonstrating the capability to integrate trans-epithelial electrical resistance sensing mechanism for real time monitoring the tissue integrity cultured in such devices.