Automated microfluidic platform for dynamic and combinatorial drug screening of tumor organoids

Brooke Schuster,Sara Saheb Kashaf,Michael Junkin,Savaş Tay,Kevin P White,Kori Kirby,Andrey Rzhetsky,Christopher R Weber,Isabel Romero-Calvo,Jonathan Matthews

doi:10.1038/s41467-020-19058-4

Brooke Schuster, Sara Saheb Kashaf + Show 8 more

Open Access

https://doi.org/10.1038/s41467-020-19058-4

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Abstract

Three-dimensional (3D) cell culture technologies, such as organoids, are physiologically relevant models for basic and clinical applications. Automated microfluidics offers advantages in high-throughput and precision analysis of cells but is not yet compatible with organoids. Here, we present an automated, high-throughput, microfluidic 3D organoid culture and analysis system to facilitate preclinical research and personalized therapies. Our system provides combinatorial and dynamic drug treatments to hundreds of cultures and enables real-time analysis of organoids. We validate our system by performing individual, combinatorial, and sequential drug screens on human-derived pancreatic tumor organoids. We observe significant differences in the response of individual patient-based organoids to drug treatments and find that temporally-modified drug treatments can be more effective than constant-dose monotherapy or combination therapy in vitro. This integrated platform advances organoids models to screen and mirror real patient treatment courses with potential to facilitate treatment decisions for personalized therapy.

Highlights

Three-dimensional (3D) cell culture technologies, such as organoids, are physiologically relevant models for basic and clinical applications
Patient-derived cancer tumor organoids can be established in a shorter period and are much more economical than costly patient-derived xenograft (PDX) models, which requires a large tissue sample, up to 6 months to establish tumor growth, and retains complications from infiltrating murine stromal cells[9,10]
We found that combination chemotherapy treatment resulted in significantly increased apoptosis in tumor organoids compared to monotherapy as expected

Summary

Introduction

Three-dimensional (3D) cell culture technologies, such as organoids, are physiologically relevant models for basic and clinical applications. We present an automated, high-throughput, microfluidic 3D organoid culture and analysis system to facilitate preclinical research and personalized therapies. We observe significant differences in the response of individual patient-based organoids to drug treatments and find that temporally-modified drug treatments can be more effective than constant-dose monotherapy or combination therapy in vitro This integrated platform advances organoids models to screen and mirror real patient treatment courses with potential to facilitate treatment decisions for personalized therapy. 3D culture and organoid based systems have been widely used for the study of different disease states, personalized drug screening, discovery drug safety and efficacy studies, and manipulations of cellular environment, providing more physiologically relevant information and more predictive data for in vivo tests than traditional methods[4,5]. Body-on-a-chip systems and other commercially available automatic and high-throughput methods often required complex or extremely expensive robotic based systems, have complications or incompatible with gel scaffolds, and not always suitable for real-time monitoring of cellular and molecular features[19,20]

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