A bistable, multiport valve enables microformulators creating microclinical analyzers that reveal aberrant glutamate metabolism in astrocytes derived from a tuberous sclerosis patient

Miller, Dusty R.; Schaffer, David K.; Neely, M. Diana; McClain, Ethan S.; Travis, Adam R.; Block, Frank E.; McKenzie, Jennifer R.; Werner, Erik M.; Armstrong, Laura; Markov, Dmitry A.; Bowman, Aaron B.; Ess, Kevin C.; Cliffel, David E.; Wikswo, John P.

doi:10.1016/j.snb.2021.129972

Cited by 8 publications

(10 citation statements)

References 51 publications

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“…The use of valves is critical in the calibration of these biosensors. 125 In this paper, an automated multipumps system was used for in situ calibration of an electrochemical glutamate sensor. The sensor was calibrated every four hours during the 76-hour experiment.…”

Section: Biochemical Parametersmentioning

confidence: 99%

“…Some recently developed on-chip valves are easier to use. 125,149,150 The on-chip valves are actuated by rolling the roller and pressing the PC bar with through hole. These technologies offer the possibility of developing fully automated, integrated, and miniaturized MPSs, which could provide a better understanding of disease mechanisms and accelerate the development of drugs in the future.…”

Section: Easy To Usementioning

confidence: 99%

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Integrated biosensors for monitoring microphysiological systems

et al. 2022

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Section: Biochemical Parametersmentioning

confidence: 99%

Section: Easy To Usementioning

confidence: 99%

Integrated biosensors for monitoring microphysiological systems

et al. 2022

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“…A replicate set of valves and pumps aspirates fluid out of the wells; coordinating the aspiration and dispensing enables changing the drug concentration in each well. A controller is programmed to generate a defined drug exposure profile over a set time interval (24-hour) cycle using predefined intervals of drug/media refresh to achieve the desired time-dependent change in drug concentrations [ 19 ]. Each well is individually addressable, and 1 or 2 compounds can be administered simultaneously, each with its own PK profile.…”

Section: Resultsmentioning

confidence: 99%

“…The design, fabrication, and performance validation of the rotary planar valves and rotary planar peristaltic micropumps that comprise the Microformulator have been previously described [ 19 ] and were built using technologies developed at the VIIBRE. Other embodiments of the Microformulator and its pumps and valves have been described elsewhere [ 37 , 38 ].…”

Section: Methodsmentioning

confidence: 99%

“…Stepper motors were controlled by a 4-channel USB microcontroller (MCU) (Arduino Uno R3, Arduino, USA), which was connected to a laptop and operated using Automated Multipump Experiment Running Environment software (AMPERE, VIIBRE) ( S2 Fig ). Controlling the speed and duration of operation of the pumps, the angular positioning of valves and the oscillations between sample inputs (media and drug stock solutions), AMPERE enabled controlled removal of media from wells and delivery of the desired drug concentrations into individual wells (flow rate = 2.4 +/− 1.7 to 890 +/− 77 μL/min) [ 19 ]. Flow rates of 400 to 750 μL/min were used in the experiments in Figs 3 – 5 .…”

Section: Methodsmentioning

confidence: 99%

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A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models

et al. 2022

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Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compounds over multiweek experiments, both as monotherapy and drug combinations, comparing the effects on tumour cell efficacy in vitro with efficacy seen in in vivo xenograft models. In the first example, an ERK1/2 inhibitor was tested using fixed bolus dosing and Microformulator-replicated PK profiles, in 2 cell lines with different in vivo sensitivities. The Microformulator-replicated PK profiles were able to discriminate between cell line sensitivities, unlike the conventional fixed bolus dosing. In a second study, murine in vivo PK profiles of multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) and DNA-dependent protein kinase (DNA-PK) inhibitor combinations were replicated in a FaDu cell line resulting in a reduction in cell growth in vitro with similar rank ordering to the in vivo xenograft model. Additional PK/efficacy insight into theoretical changes to drug exposure profiles was gained by using the Microformulator to expose FaDu cells to the DNA-PK inhibitor for different target coverage levels and periods of time. We demonstrate that the Microformulator enables incorporating PK exposures into cellular assays to improve in vitro–in vivo translation understanding for early therapeutic insight.

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