The integration of metabolic competence in developmental toxicity assays in vitro is of fundamental importance to better predict adverse drug effects. Here, a microfluidic hanging‐drop platform is presented that seamlessly integrates liver metabolism into the embryonic stem cell test (EST). Primary human liver microtissues (hLiMTs) and embryoid bodies (EBs) are combined in the same fluidic network, so that hLiMT‐generated metabolites are directly transported to the EBs. Gravity‐driven flow through the network enables continuous intertissue communication, constant medium turnover, and, most importantly, immediate exchange of metabolites. As a proof of concept, the prodrug cyclophosphamide is investigated and a fourfold lower ID50 concentration (50% inhibition of EB differentiation) is found after biotransformation, which demonstrates the potentially adverse effects of metabolites on embryotoxicity. The metaEST platform provides a promising tool to increase the predictive power of the current EST assay by more comprehensively including and better reflecting physiological processes in in vitro tests.
Safety assessment of the effects of developmental toxicants on pregnant women is challenging, and systemic effects in embryo–maternal interactions are largely unknown. However, most developmental toxicity studies rely on animal trials, while in vitro platforms that recapitulate the maternal–placental–embryonic axis are missing. Here, the development of a dedicated microfluidic device for co‐cultivation of a placental barrier and 3D embryoid bodies to enable systemic toxicity testing at the embryo–maternal interface is reported. The microfluidic platform features simple handling and recuperation of both tissue models, which facilitates post‐hoc in‐depth analysis at the tissue and single‐cell level. Gravity‐driven flow enables inter‐tissue communication through the liquid phase as well as simple and robust operation and renders the platform parallelizable. As a proof of concept and to demonstrate platform use for systemic embryotoxicity testing in vitro, maternal exposure to plastic microparticles is emulated, and microparticle effects on the embryo–placental co‐culture are investigated.
A monolithic multi-functional CMOS microelectrode array system was developed that enables label-free electrochemical impedance spectroscopy of cells in-vitro at high spatiotemporal resolution. The electrode array includes 59,760 platinum microelectrodes, densely packed within a 4.5 mm×2.5 mm sensing region at a pitch of 13.5 μm. 32 on-chip lock-in amplifiers can be used to measure the impedance of any arbitrarily chosen subset of electrodes in the array. A sinusoidal voltage, generated by an on-chip waveform generator with a frequency range from 1 Hz to 1 MHz, was applied to the reference electrode. The sensing currents through the selected recording electrodes were amplified, demodulated, filtered and digitized to obtain the magnitude and phase information of the respective impedances. The circuitry consumes only 412 μW at 3.3 V supply voltage and occupies only 0.1 mm2, for each channel. The system also included 2048 extracellular action-potential recording channels on the same chip. Proof of concept measurements of electrical impedance imaging and electrophysiology recording of cardiac cells and brain slices are demonstrated in this paper. Optical and impedance images showed a strong correlation.
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