Parallel microfluidic chemosensitivity testing on individual slice cultures

Abstract

There is a critical unmet need to tailor chemotherapies to individual patients. Personalized approaches could lower treatment toxicity, improve the patient’s quality of life, and ultimately reduce mortality. However, existing models of drug activity (based on tumor cells in culture or animal models) cannot accurately predict how drugs act in patients in time to inform the best possible treatment. Here we demonstrate a microfluidic device that integrates live slice cultures with an intuitive multi well platform that allows for exposing the slices to multiple compounds at once or in sequence. We demonstrate the response of live mouse brain slices to a range of drug doses in parallel. Drug response is measured by imaging of markers for cell apoptosis and for cell death. The platform has the potential to allow for identifying the subset of therapies of greatest potential value to individual patients, on a timescale rapid enough to guide therapeutic decision-making.

Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment

“…The embedded tumour sections retain the tumour vasculature, nearby stroma and the heterogeneity of the tumour cells. Microfluidic technology can be combined with an ex vivo tumour section culture system for parallel drug sensitivity testing while maintaining continuous control over culture conditions [35].…”

BaroFuse, a novel pressure-driven, adjustable-throughput perfusion system for tissue maintenance and assessment

“…For instance, a single tissue sample has been treated sequentially with many different drugs [30]. However, the goal of having a large number of tissue perifusion chambers each with its own perfusate supply to facilitate the testing of for instance 96 drugs on 96 separate tissue samples using lithography has not been previously developed.…”

Microfluidics in Malignant Glioma Research and Precision Medicine

“…The combination of cell separation technology with single-cell imaging and analysis techniques can tremendously improve screening and diagnosis of cancers. [73,74] Microfluidics present several advantages for these types of assays including minimal reagent usage, high-throughput screening, and single-cell analysis using lesser amounts of sample on the scale of 1–3000 cells alone. [68] Processing strategies such as microfluidic flow cytometry allows for single-cell measurements that confirm intratumoral heterogeneity of common tumor signaling pathways and can be validated by immunohistochemical processing of the same tissue samples.…”

“…[88] Other devices incorporating slice cultures into multiwell platforms can be used to develop personalized therapies and evaluate the effects of different drugs and treatment conditions on tumor progression. [73] Compartmentalized or multichannel microfluidic devices incorporating gradient generators, regulators of fluid flow, and other tunable parameters enable the detailed characterization of the migratory behavior of tumor cells, help study tumor recurrence and metastasis, and facilitate the efficacy testing of glioma-specific anticancer agents. [89] In another example, microenvironment-specific chemokine gradients were constructed within a microfluidic device to study the anticancer drug efficacy and penetration into the tumor bulk.…”