Microfluidic organoid-slice-on-a-chip system for studying anti-cholangiocarcinoma drug efficacy and hepatorenal toxicity

Organ-chip technology, in contrast to cell culture and animal models, offers a promising platform for accelerating drug development. However, current chip designs simulate human organ functions and there is a lack of multi-organ chip designs that can simultaneously study drug efficacy and hepatorenal toxicity. Here, we developed a novel microfluidic multi-organ chip that integrated cholangiocarcinoma organoids (CCOs) with recellularized liver slices (RLS) and recellularized kidney slices (RKS), to simultaneously assess anti-cholangiocarcinoma drug efficacy and hepatorenal toxicity. Co-culture of patient-derived CCOs with RLS and RKS was successfully achieved for 7 days under flow conditions with enhanced liver and renal cell functions. Furthermore, an <i>in vitro</i> biomimetic model showed IC₅₀ values of trastuzumab emtansine (T-DM1) of around 6.42 ± 7.34 μg mL^-1 in four clinical cases, with one outlier of 77.77 μg mL^-1 due to patient variability. Post-treatment, RLS and RKS cell viability remained high at 75.67% and 81.03%, respectively, suggesting low hepatorenal toxicity of T-DM1 for treating cholangiocarcinoma. Our study demonstrates the use of an organoid-slice-on-a-chip (OSOC) platform for personalized drug efficacy and toxicity assessment, particularly aiming at leveraging anticancer drugs for off-label use to save patient lives.