Establishment of organoid models based on a nested array chip for fast and reproducible drug testing in colorectal cancer therapy

Abstract

The conventional microwell-based platform for construction of organoid models exhibits limitations in precision oncology applications because of low-speed growth and high variability. Here, we established organoid models on a nested array chip for fast and reproducible drug testing using 50% matrigel. First, we constructed mouse small intestinal and colonic organoid models. Compared with the conventional microwell-based platform, the mouse organoids on the chip showed accelerated growth and improved reproducibility due to the nested design of the chip. The design of the chip provides miniaturized and uniform shaping of the matrigel that allows the organoid to grow in a concentrated and controlled manner. Next, a patient-derived organoid (PDO) model from colorectal cancer tissues was successfully generated and characterized on the chip. Finally, the PDO models on the chip, from three patients, were implemented for high-throughput drug screening using nine treatment regimens. The drug sensitivity testing on the PDO models showed good quality control with a coefficient of variation under 10% and a Z' factor of more than 0.7. More importantly, the drug responses on the chip recapitulate the heterogeneous response of individual patients, as well as showing a potential correlation with clinical outcomes. Therefore, the organoid model coupled with the nested array chip platform provides a fast and reproducible means for predicting drug responses to accelerate precise oncology.

Establishment and large-scale validation of a three-dimensional tumor model on an array chip for anticancer drug evaluation

“…The traditional matrigel assay usually reduced matrigel concentration (5% vol/vol) for drug testing to improve reproducibility ( Driehuis et al, 2020 ). The different concentrations of the matrigel may alter the composition of secretion proteins, cellular phenotype, and drug response ( Cui et al, 2022 ). The high reproducibility of the 3D tumor model using the high concentration of matrigel (>65% vol/vol) is because of controlled shaping of the matrigel and medium exchange without disturbing the matrigel.…”

Patient‐Derived Microphysiological Systems for Precision Medicine

“…Furthermore, the nested array chip has effectively demonstrated the facilitation of a PDO model from CRC tissue obtained from three different patients, indicating its capability for high‐throughput drug screening (Figure 4B). [ 140 ] They assessed the drug sensitivity of organoids to nine different treatment regimens and confirmed the heterogeneous response among patients and a possible correlation with clinical outcomes based on enhanced computerized tomography and magnetic resonance imaging. Similarly, Ooft et al.…”

“…(Bio‐Design and Manufacturing 5 (2022); Copyright 2022 Springer). [ 140 ] D) A superhydrophobic microwell array chip for patient‐derived lung cancer organoid models that recapitulate the histological and genetic features of the parental tumors to produce clinically meaningful drug responses within a week. Reproduced with permission from Hu et al.…”

“…The head and neck squamous cell carcinoma organoids were subsequently used at MPS for chemotherapeutic screening in a semi‐automated manner. [ 140 ] Lung cancer organoids (LCOs) and normal bronchial organoids from patient tissues were compared in MPS, revealing distinct histological subtypes of lung cancer and non‐neoplastic bronchial mucosa. [ 159 ] Notably, LCO exhibited concordant responses to targeted drugs based on specific genomic alterations.…”

Establishment and evaluation of on-chip intestinal barrier biosystems based on microfluidic techniques

“…In follow-up studies, I believe that the connected gut-liver-vascular chip can simulate the ingestion process of oral drugs, and can better predict the biotransformation, bioavailability and metabolites of drugs. Ai et al developed an intestinal organoid chip to achieve fast and high-throughput drug screening for colorectal cancer therapy [ 157 ]. Chemotherapeutic drug-sensitivity testing on the organoid chip generalized the heterogeneous responses of individual patients and showed a high relevance to clinical findings [ 157 ].…”