Abstract:International audienceBiomonitoring is a research topic that has largely relied on cell culture systems. Recently, the development of “Organ-on-a-Chip” (OC) platforms and the need for a continuous monitoring of these systems has increased its interest. However, the biomonitorization in these systems is still at its infancy due to the difficulty to adapt the sensors to microfluidic OC systems. In this work we have fabricated a modular, versatile, scalable, multi-analyte sensing platform, which integrates dissol… Show more
“…24 However, in the last few years, various strategies have been proposed for real-time monitoring without compromising the operation of the OOC. Some works have focussed on the monitoring of the physical parameters external to the cell culture area of the OOC, using modular sensing platforms 23,[25][26][27] in-line with the microfluidic system to measure the inlets and outlets without disturbing the cell culture area. Recently, Zhang et al 23 presented a fully integrated multi-sensing platform to achieve automated in-situ monitoring of biophysical (pH, oxygen, temperature) and biochemical parameters of a liver-and heart-on-a-chip model systems.…”
The demand for real-time monitoring of cell functions and cell conditions has dramatically increased with the emergence of organ-on-a-chip (OOC) systems. However, the incorporation of co-cultures and microfluidic channels in OOC systems increases their biological complexity and therefore makes the analysis and monitoring of analytical parameters inside the device more difficult. In this work, we present an approach to integrate multiple sensors in an extremely thin, porous and delicate membrane inside a liver-on-a-chip device. Specifically, three electrochemical dissolved oxygen (DO) sensors were inkjet-printed along the microfluidic channel allowing local online monitoring of oxygen concentrations. This approach demonstrates the existence of an oxygen gradient up to 17.5% for rat hepatocytes and 32.5% for human hepatocytes along the bottom channel. Such gradients are considered crucial for the appearance of zonation of the liver. Inkjet printing (IJP) was the selected technology as it allows drop on demand material deposition compatible with delicate substrates, as used in this study, which cannot withstand temperatures higher than 130 °C. For the deposition of uniform gold and silver conductive inks on the porous membrane, a primer layer using SU-8 dielectric material was used to seal the porosity of the membrane at defined areas, with the aim of building a uniform sensor device. As a proof-of-concept, experiments with cell cultures of primary human and rat hepatocytes were performed, and oxygen consumption rate was stimulated with carbonyl-cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP), accelerating the basal respiration of 0.23 ± 0.07 nmol s-1/106 cells up to 5.95 ± 0.67 nmol s-1/106 cells s for rat cells and the basal respiration of 0.17 ± 0.10 nmol s-1/106 cells by up to 10.62 ± 1.15 nmol s-1/106 cells for human cells, with higher oxygen consumption of the cells seeded at the outflow zone. These results demonstrate that the approach of printing sensors inside an OOC has tremendous potential because IJP is a feasible technique for the integration of different sensors for evaluating metabolic activity of cells, and overcomes one of the major challenges still remaining on how to tap the full potential of OOC systems.
“…24 However, in the last few years, various strategies have been proposed for real-time monitoring without compromising the operation of the OOC. Some works have focussed on the monitoring of the physical parameters external to the cell culture area of the OOC, using modular sensing platforms 23,[25][26][27] in-line with the microfluidic system to measure the inlets and outlets without disturbing the cell culture area. Recently, Zhang et al 23 presented a fully integrated multi-sensing platform to achieve automated in-situ monitoring of biophysical (pH, oxygen, temperature) and biochemical parameters of a liver-and heart-on-a-chip model systems.…”
The demand for real-time monitoring of cell functions and cell conditions has dramatically increased with the emergence of organ-on-a-chip (OOC) systems. However, the incorporation of co-cultures and microfluidic channels in OOC systems increases their biological complexity and therefore makes the analysis and monitoring of analytical parameters inside the device more difficult. In this work, we present an approach to integrate multiple sensors in an extremely thin, porous and delicate membrane inside a liver-on-a-chip device. Specifically, three electrochemical dissolved oxygen (DO) sensors were inkjet-printed along the microfluidic channel allowing local online monitoring of oxygen concentrations. This approach demonstrates the existence of an oxygen gradient up to 17.5% for rat hepatocytes and 32.5% for human hepatocytes along the bottom channel. Such gradients are considered crucial for the appearance of zonation of the liver. Inkjet printing (IJP) was the selected technology as it allows drop on demand material deposition compatible with delicate substrates, as used in this study, which cannot withstand temperatures higher than 130 °C. For the deposition of uniform gold and silver conductive inks on the porous membrane, a primer layer using SU-8 dielectric material was used to seal the porosity of the membrane at defined areas, with the aim of building a uniform sensor device. As a proof-of-concept, experiments with cell cultures of primary human and rat hepatocytes were performed, and oxygen consumption rate was stimulated with carbonyl-cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP), accelerating the basal respiration of 0.23 ± 0.07 nmol s-1/106 cells up to 5.95 ± 0.67 nmol s-1/106 cells s for rat cells and the basal respiration of 0.17 ± 0.10 nmol s-1/106 cells by up to 10.62 ± 1.15 nmol s-1/106 cells for human cells, with higher oxygen consumption of the cells seeded at the outflow zone. These results demonstrate that the approach of printing sensors inside an OOC has tremendous potential because IJP is a feasible technique for the integration of different sensors for evaluating metabolic activity of cells, and overcomes one of the major challenges still remaining on how to tap the full potential of OOC systems.
“…To achieve good accuracy, it was essential to choose an appropriate anionic site, as it affected selectivity as well as sensitivity [32,40,41]. We selected two different salts, namely, NaTFPB and KTClPB, widely used in recent works [42][43][44][45][46]. Considering that the extensive conditioning protocol is often disregarded in flexible film electrodes and wearable platforms, we provide the experiment results on using both salts after the same period of conditioning.…”
Wireless, flexible, ion-selective electrodes (ISEs) are of great interest in the development of wearable health monitors and clinical systems. Existing film-based electrochemical sensors, however, still have practical limitations due to poor electrical contact and material–interfacial leakage. Here, we introduce a wireless, flexible film-based system with a highly selective, stable, and reliable sodium sensor. A flexible and hydrophobic composite with carbon black and soft elastomer serves as an ion-to-electron transducer offering cost efficiency, design simplicity, and long-term stability. The sensor package demonstrates repeatable analysis of selective sodium detection in saliva with good sensitivity (56.1 mV/decade), stability (0.53 mV/h), and selectivity coefficient of sodium against potassium (−3.0). The film ISEs have an additional membrane coating that provides reinforced stability for the sensor upon mechanical bending. Collectively, the comprehensive study of materials, surface chemistry, and sensor design in this work shows the potential of the wireless flexible sensor system for low-profile wearable applications.
“…Discrete sensing channels enabled the flexibility to replenish and replace the beads as desired prior to saturation. In addition, the group was able to demonstrate a multiplexing capability with both TGF-β1 and hepatocyte growth factor simultaneously using multiple sets of beads with different fluorescent markers.Figure 9Examples of Instrumented Organ-on-chip Models of the Liver and Kidneys(A) Detection of TGF-β1 within a reconfigurable device to allow communication between injured hepatocytes and stellate cells via an aptamer-based electrochemical sensor.(B) On-chip detection of the hepatocyte growth factor and TGF-β1 secreted by primary hepatocytes via a fluorescent-bead-based optical sensor.(C) Transferrin and albumin production from human primary hepatocytes cultured in the bioreactor quantified via a bead-based electrochemical immunosensor.(D) Continuous real-time monitoring of hepatocyte metabolic function via a glucose/lactate enzyme-based electrochemical sensors and oxygen sensing phosphorescent microprobes.(E) Hepatocyte oxygen consumption rate assessed via inkjet-printed electrochemical dissolved oxygen sensors and commercial Clark-type sensors.(F) Permeability study of an MDCK-2 cell monolayer cultured on the membrane of a bilayer chip via TEER electrodes.(G) Assessment of renal epithelial cell growth and tight junction integrity quantified within a continuous fluid shear stress model via integrated TEER electrodes.(H) TEER measurements from a human renal epithelial cell monolayer cultured in a multi-use microfluidic device with integrated electrodes.(I) Electrical cell–substrate impedance monitoring of MDCK-2 cells to investigate wound healing and barrier integrity via an organic electrochemical transistor.(J) Electrochemical measurement of dissolved oxygen, Na + and K + ion concentration, and pH in kidney exactments via potentiometric and amperometric electrodes.Reprinted and adapted with permission from: A (Zhou et al., 2015); B (Son et al., 2017); C (Riahi et al., 2016); D (Bavli et al., 2016); E (Moya et al., 2018b); F (Douville et al., 2010); G (Ferrell et al., 2010); H (Brakeman et al., 2016); I (Curto et al., 2017); and J (Moya et al., 2018a). TGF-β1, transforming growth factor; MDCK-2, Madin Darby canine kidney-2; TEER, transepithelial electrical resistance.…”
Section: Liver-on-chipmentioning
confidence: 99%
“…Reprinted and adapted with permission from: A (Zhou et al., 2015); B (Son et al., 2017); C (Riahi et al., 2016); D (Bavli et al., 2016); E (Moya et al., 2018b); F (Douville et al., 2010); G (Ferrell et al., 2010); H (Brakeman et al., 2016); I (Curto et al., 2017); and J (Moya et al., 2018a). TGF-β1, transforming growth factor; MDCK-2, Madin Darby canine kidney-2; TEER, transepithelial electrical resistance.…”
Section: Liver-on-chipmentioning
confidence: 99%
“…Although not yet integrated into an organ-chip model, Moya et al. developed highly sensitive, low-volume electrochemical sensors for measuring the dissolved oxygen, Na + and K + ion concentration, and pH in kidney exactments (Figure 9J) (Moya et al., 2018a). Dissolved oxygen was measured amperometrically with three electrodes, ion concentrations were measured potentiometrically with ion-sensitive electrodes, and pH was measured potentiometrically with iridium oxide–coated electrodes.…”
Recent advancements in electronic materials and subsequent surface modifications have facilitated real-time measurements of cellular processes far beyond traditional passive recordings of neurons and muscle cells. Specifically, the functionalization of conductive materials with ligand-binding aptamers has permitted the utilization of traditional electronic materials for bioelectronic sensing. Further, microfabrication techniques have better allowed microfluidic devices to recapitulate the physiological and pathological conditions of complex tissues and organs in vitro or microphysiological systems (MPS). The convergence of these models with advances in biological/biomedical microelectromechanical systems (BioMEMS) instrumentation has rapidly bolstered a wide array of bioelectronic platforms for real-time cellular analytics. In this review, we provide an overview of the sensing techniques that are relevant to MPS development and highlight the different organ systems to integrate instrumentation for measurement and manipulation of cellular function. Special attention is given to how instrumented MPS can disrupt the drug development and fundamental mechanistic discovery processes.
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