Cell culture monitoring for drug screening and cancer research: a transparent, microfluidic, multi-sensor microsystem

Abstract

We present a novel, multiparametric microphysiometry system for the dynamic online monitoring of human cancer cell metabolism. The optically transparent, modular, hybrid microsystem is based on a glass chip and combines a cell cultivation chamber, microfluidics and metabolic monitoring with fully integrated chemo- and biosensors. pH and oxygen are measured in the cell culture area, and biosensors for lactate and glucose are connected downstream by microfluidics. The wafer-level fabrication features thin-film platinum and iridium oxide microelectrodes on a glass chip, microfluidics in an epoxy resist, a hybrid assembly and an on-chip reference electrode. The reliable analytical performance of the sensors in cell culture medium was demonstrated. The pH sensors exhibit a long-term stable, linear response. The oxygen sensors show a linear behaviour, which is also observed for low oxygen concentrations. Glucose and lactate measurements show a linear, long-term stable, selective and reversible behaviour in the desired range. T98G human brain cancer cells were cultivated and cell culture metabolism was measured on-chip. Stop/flow cycles were applied and extracellular acidification, respiration, glucose consumption and lactate production were quantified. Long-term metabolic rates were determined and all parameters could be measured in the outlet channel. A placement downstream of the cell cultivation area for biosensors was realised. A highly effective medium exchange and undiluted sampling from the cell culture chamber with low flow rates (2 μl min(-1)) and low volumes (15 μl per cycle) were achieved. The drug screening application was demonstrated by detecting alteration and recovery effects of cellular metabolism induced by the addition of substances to the medium.

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

“…Several efforts have been initiated toward the accomplishment of this ambitious goal. For example, prototype microphysiometers have been developed for on-line measurement of glucose and lactate (19,35), oxygen (35), transepithelial electrical resistance (24,36,37), ions (38), extracellular acidification rate (pH), and protein biomarkers (39) in organ-on-a-chip systems (40)(41)(42)(43)(44)(45)(46). However, these sensing units were either built upon a single chip and limited in system-level integration and full automation (19), or were designed for measurements over relatively short periods of time in the range of minutes to hours.…”

Highly sensitive electrodic materials based on Pt nanoflowers grown on Pt nanospheres for biosensor development

“…Glucose oxidase was utilized as a model of oxidases and was immobilized onto the nanostructured surface by cross-linking with glutaraldehyde [13]. The monitoring of different metabolites such as glucose produced from cell culture is very important in biomedical field [14]. For this reason, we performed chronoamperometric experiments also in a cell media.…”

Multi-analyte biosensor interface for real-time monitoring of 3D microtissue spheroids in hanging-drop networks

“…Flow-through-type sensor systems have been devised to analyze cell culture conditions and metabolites in liquid samples downstream of cell cultures [44][45][46][47][48][49][50][51] . Silicon-based sensor chips for multi-parameter online monitoring have been mounted in a perfused cell culture unit 52 , and multiple sensing electrodes have been directly incorporated into transparent microfluidic systems to measure the glucose consumption of single cardiac cells 53 or the lactate production of cells of various types 54 and, combined with optical read-out, for monitoring cancer cell metabolism 55 . The combination and integration of microfluidics and microsensors with cell culturing units poses challenges.…”