Microfluidic cell culture systems with integrated sensors for drug screening

Abstract

Cell-based testing is a key step in drug screening for cancer treatments. A microfluidic platform can permit more precise control of the cell culture microenvironment, such as gradients in soluble factors. These small-scale devices also permit tracking of low cell numbers. As a new screening paradigm, a microscale system for integrated cell culture and drug screening promises to provide a simple, scalable tool to apply standardized protocols used in cellular response assays. With the ability to dynamically control the microenvironment, we can create temporally varying drug profiles to mimic physiologically measured profiles. In addition, low levels of oxygen in cancerous tumors have been linked with drug resistance and decreased likelihood of successful treatment and patient survival. Our work also integrates a thin-film oxygen sensor with a microfluidic oxygen gradient generator which will in future allow us to create spatial oxygen gradients and study effects of hypoxia on cell response to drug treatment. In future, this technology promises to improve cell-based validation in the drug discovery process, decreasing the cost and increasing the speed in screening large numbers of compounds.

Spatial control of oxygen delivery to three‐dimensional cultures alters cancer cell growth and gene expression

“…GO: Gene Ontology; 3D: three-dimensional [Color figure can be viewed at wileyonlinelibrary.com] "organs," simulating entire or partial organism physiology (Marx et al, 2016;Pusch et al, 2011;Xiao et al, 2017;Zhang & Radisic, 2017;Zheng et al, 2012). The spatial and temporal delivery of biomolecules in these systems attempts to control the fate of cellular processes with many of these systems utilizing pre-equilibrated media or gas channels to achieve desired oxygenation (Beachley et al, 2015;Grist, Schmok, Liu, Chrostowski, & Cheung, 2015;Grist, Yu, Chrostowski, & Cheung, 2012;Samorezov & Alsberg, 2015). A standard of systematic oxygenation has not yet been established in these systems, so the implementation of a method of physiological oxygenation to 3D cultures that also allows for high-throughput scalability is therefore highly desirable (Brennan, Rexius-Hall, Elgass, & Eddington, 2014;Place, Domann, & Case, 2017;Sun, Haglund, Rogers, Ghanim, & Sethu, 2018).…”

Vacuum-driven power-free microfluidics utilizing the gas solubility or permeability of polydimethylsiloxane (PDMS)

“…64,83 The most straightforward approach for oxygen control in the devices is by diffusion from a pre-equilibrated liquid flowing through the device's control channels across a gas permeable PDMS membrane and into the cell culture region. 84 Another way is to flow gas directly though the control channels, eliminating the need for the pre-equilibration of liquid off-chip. 83,85 A variety of oxygen control methods, such as discrete control, 86 spatial control, 87,88 and temporal control, 87 has been demonstrated.…”

Spatial control of oxygen delivery to 3D cultures alters cancer cell growth and gene expression

“…Other models reconstitute multi-organ functions by linking devices together to facilitate metabolic and hormonal signaling between 'organs', simulating entire or partial organism physiology (Marx et al, 2016;Pusch et al, 2011;Xiao et al, 2017;Zhang and Radisic, 2017;Zheng et al, 2012). The spatial and temporal delivery of biomolecules in these systems attempts to control the fate of cellular processes with many of these systems utilizing pre-equilibrated media or gas channels to achieve desired oxygenation (Beachley et al, 2015;Grist et al, 2012;Grist et al, 2015;Samorezov and Alsberg, 2015). A standard of systematic oxygenation has not yet been established in these systems, so the implementation of a method of physiological oxygenation to 3D cultures that also allows for high-throughput scalability is therefore highly desirable (Brennan et al, 2014;Place et al, 2017;Sun et al, 2018).…”