Pixelated Microfluidics for Drug Screening on Tumour Spheroids and Ex Vivo Microdissected Tumour Explants

Abstract

Anticancer drugs have the lowest success rate of approval in drug development programs. Thus, preclinical assays that closely predict the clinical responses to drugs are of utmost importance in both clinical oncology and pharmaceutical research. 3D tumour models preserve the tumoral architecture and are cost- and time-efficient. However, the short-term longevity, limited throughput, and limitations of live imaging of these models have so far driven researchers towards less realistic tumour models such as monolayer cell cultures. Here, we present an open-space microfluidic drug screening platform that enables the formation, culture, and multiplexed delivery of several reagents to various 3D tumour models, namely cancer cell line spheroids and ex vivo primary tumour fragments. Our platform utilizes a microfluidic pixelated chemical display that creates isolated adjacent flow sub-units of reagents, which we refer to as fluidic ‘pixels’, over tumour models in a contact-free fashion. Up to nine different treatment conditions can be tested over 144 samples in a single experiment. We provide a proof-of-concept application by staining fixed and live tumour models with multiple cellular dyes. Furthermore, we demonstrate that the response of the tumour models to biological stimuli can be assessed using the platform. Upscaling the microfluidic platform to larger areas can lead to higher throughputs, and thus will have a significant impact on developing treatments for cancer.

Applications and Advances of Multicellular Tumor Spheroids: Challenges in Their Development and Analysis

“…Currently, many advanced approaches have been introduced to tissue research that allow for the combination of many of the aforementioned features. Many labs use microfluidic platforms that can mimic, to a great degree, the (patho)physiological functions of tissues and organs [ 166 , 167 , 168 , 169 ]. These chip-like devices consist of microfluidic channels connected to each other, such that cells from different compartments can communicate via their shared fluid.…”

Next-Generation Microfluidics for Biomedical Research and Healthcare Applications

“…Microfluidic probes, 13 on the other hand, further expand the boundaries of microfluidics through innovative “wall-free” control of fluid, which makes them suitable for multiplexing. For example, Dorrigiv et al 30 , 31 presented computer-controlled drug screening platform that utilizes pixelated MFPs to enable multiplexed delivery of multiple biochemical reagents—up to 9 distinct biochemical reagents—to 3D tumor models. This innovation significantly increased the throughput of traditional MFPs, enabling multiple testing scenarios in each experiment.…”

Drug testing of monodisperse arrays of live microdissected tumors using a valved multiwell microfluidic platform

“…Gervais' group loaded manually-punched μDTs by sedimentation into microfluidic traps located within serpentine channels 39 and into a custom microwell array for multiplexed reagent delivery via fluidic pixels. 43 However, the manual punching process is difficult to scale to hundreds or thousands of μDTs. Other groups have explored entrapment strategies beyond sedimentation.…”