On-microparticle construction of endothelialized liver microtissues for drug testing

Abstract

With the advantage of uniformity and customizability, hydrogel microparticles are widely used to establish in vitro organoid modeling for drug testing. However, the practical values of current strategies are limited by the lack of near-physiological structures and functions. In this work, microparticle-based liver models with biomimetic endothelial barriers are engineered using a simple, biocompatible, and high-throughput method for the application of drug testing. The hepatocyte-laden hydrogel microparticles with a rough surface are prepared using a microfluidic spraying technique, and their surfaces allow for customized protein modifications. Under the action of topological texture and matrigel modifications, the microparticle surface can induce endothelial cell adhesion, extension, and junction, thus generating a continuous, tight monolayer endothelial barrier. Semi-permeability of endothelial barrier and enhanced liver function was demonstrated in the constructed microparticle tissue models. Finally, these models were utilized to reproduce a sensitive inhibitory action of the endothelial barrier on the biotransformation of prodrugs (i.e., tegafur). Overall, microparticle-based endothelialized liver models achieved not only heterotypic cell co-culture but also tissue morphogenesis, which is anticipated to accelerate comprehensive evaluations of the drug biotransformation and improve the translatability of drug testing results from in vitro to in vivo.