A High-Throughput and Logarithm-Serial-Dilution Microfluidic Chip for Combinational Drug Screening on Tumor Organoids.

Abstract

Tumor organoids are biological models for studying precision medicine. Microfluidic technology offers significant benefits for high throughput drug screening using tumor organoids. However, the range of concentrations achievable with traditional linear gradient generators in microfluidics is restricted, generating logarithmic drug concentration gradients by adjusting the channel ratio in the chip is confined to single-drug dilution chips, significantly restricting the application of microfluidics in drug screening. Here, we presented a microfluidic chip featuring continuous dilution capabilities, which generates logarithmic stepwise drug concentration gradients. We have devised a "mathematical-circuit-chip" model for designing such chips, and based on this model, we have developed and fabricated a device capable of providing 36 distinct drug concentration conditions for two types of drugs. The chip is composed of two structurally identical yet orthogonally arranged layers, each containing a dilution network capable of forming a 5-fold gradient and a tumor organoid culture module. Drug and culture medium delivery to the open culture chamber array is driven by syringe pumps. We have conducted drug screening experiments on patient-derived tumor organoids. This device facilitates high-throughput drug screening for patient-derived organoids, representing a significant stride toward the realization of precision medicine.