Multianalyte microphysiometry as a tool in metabolomics and systems biology

Eklund, Sven E.; Snider, Rachel M.; Wikswo, John P.; Baudenbacher, Franz; Prokop, Andreas; Cliffel, David E.

doi:10.1016/j.jelechem.2005.11.024

Cited by 61 publications

(53 citation statements)

References 21 publications

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“…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.…”

Section: Significancementioning

confidence: 99%

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

Zhang

Aleman

Shin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

623

571

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Organ-on-a-chip systems are miniaturized microfluidic 3D human tissue and organ models designed to recapitulate the important biological and physiological parameters of their in vivo counterparts. They have recently emerged as a viable platform for personalized medicine and drug screening. These in vitro models, featuring biomimetic compositions, architectures, and functions, are expected to replace the conventional planar, static cell cultures and bridge the gap between the currently used preclinical animal models and the human body. Multiple organoid models may be further connected together through the microfluidics in a similar manner in which they are arranged in vivo, providing the capability to analyze multiorgan interactions. Although a wide variety of human organ-on-a-chip models have been created, there are limited efforts on the integration of multisensor systems. However, in situ continual measuring is critical in precise assessment of the microenvironment parameters and the dynamic responses of the organs to pharmaceutical compounds over extended periods of time. In addition, automated and noninvasive capability is strongly desired for long-term monitoring. Here, we report a fully integrated modular physical, biochemical, and optical sensing platform through a fluidics-routing breadboard, which operates organ-on-a-chip units in a continual, dynamic, and automated manner. We believe that this platform technology has paved a potential avenue to promote the performance of current organ-on-a-chip models in drug screening by integrating a multitude of real-time sensors to achieve automated in situ monitoring of biophysical and biochemical parameters.organ-on-a-chip | microbioreactor | electrochemical biosensor | physical sensor | drug screening D rug discovery is a lengthy process associated with tremendous cost and high failure rate (1). On average, less than 1 in 10 drug candidates are eventually approved by the Food and Drug Administration (2), during which successful transition ratios to next phases are roughly 65, 32, and 60% for phase I, phase II, and phase III, respectively (3). Among the primary causes of failure, nonclinical/ clinical safety (>50%) and efficacy (>10%) stand out in the front, more than all other factors (e.g., strategic, commercial, operational) combined (3, 4). These two major causes not only contribute to the low success rates during the drug development but also lead to the withdrawal of approved drugs from the market. Among all of the drug attritions, it is estimated that safety liabilities related to the cardiovascular system account for 45%, whereas 32% are due to hepatotoxicity (5, 6). These high failure/attrition ratios of drugs SignificanceMonitoring human organ-on-a-chip systems presents a significant challenge, where the capability of in situ continual monitoring of organ behaviors and their responses to pharmaceutical compounds over extended periods of time is critical in understanding the dynamics of drug effects and therefore accurate prediction of human organ reacti...

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Section: Significancementioning

confidence: 99%

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

Zhang

Aleman

Shin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

623

571

View full text Add to dashboard Cite

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“…25 Microfluidic detection methods are highly suited for integration with organ-on-chip devices due to their potential for the analysis of low-volume liquids and high degree of automation. 29 A variety of microfluidic optical and electrochemical techniques have been developed to measure oxygen 22,[30][31][32][33][34][35][36][37][38] and pH 31,34,37,[39][40][41][42][43][44] for cell-based studies. Moreover, in some instances, the optical methods are preferred over electrical methods since they do not require electrical connections and electrodes which may be prone to biofouling and corrosion.…”

Section: Introductionmentioning

confidence: 99%

A microfluidic optical platform for real-time monitoring of pH and oxygen in microfluidic bioreactors and organ-on-chip devices

et al. 2016

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There is a growing interest to develop microfluidic bioreactors and organ-on-chip platforms with integrated sensors to monitor their physicochemical properties and to maintain a well-controlled microenvironment for cultured organoids. Conventional sensing devices cannot be easily integrated with microfluidic organ-on-chip systems with low-volume bioreactors for continual monitoring. This paper reports on the development of a multi-analyte optical sensing module for dynamic measurements of pH and dissolved oxygen levels in the culture medium. The sensing system was constructed using low-cost electro-optics including light-emitting diodes and silicon photodiodes. The sensing module includes an optically transparent window for measuring light intensity, and the module could be connected directly to a perfusion bioreactor without any specific modifications to the microfluidic device design. A compact, user-friendly, and low-cost electronic interface was developed to control the optical transducer and signal acquisition from photodiodes. The platform enabled convenient integration of the optical sensing module with a microfluidic bioreactor. Human dermal fibroblasts were cultivated in the bioreactor, and the values of pH and dissolved oxygen levels in the flowing culture medium were measured continuously for up to 3 days. Our integrated microfluidic system provides a new analytical platform with ease of fabrication and operation, which can be adapted for applications in various microfluidic cell culture and organ-on-chip devices.

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“…[13][14][15][16] Our laboratory has modified the Cytosensor ™ microphysiometer (originally developed by Molecular Devices for the measurement of acidification rates) into the MAMP to allow for simultaneously recording four analytes: glucose and oxygen uptake, lactate production and extracellular acidification rates for large numbers (> 10 5 ) of cells. The MAMP proves a useful tool in studies such as the response of various cell types to chemical agents and toxins with ramifications in biodefense studies; 15 cancer cellular metabolism relating genetic mutations to different metabolic phenotypes, with implications in mathematical modeling of cancer. 17,18 The MAMP yields metabolic rates (e.g., lactate production rate) for large number of cells, but has no ability to assess cell to cell variability.…”

Section: Introductionmentioning

confidence: 99%

Glucose and Lactate Biosensors for Scanning Electrochemical Microscopy Imaging of Single Live Cells

et al. 2008

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We have developed glucose and lactate ultramicroelectrode (UME) biosensors based on glucose oxidase and lactate oxidase (with enzymes immobilized onto Pt UMEs by either electropolymerization or casting) for scanning electrochemical microscopy (SECM), and have determined their sensitivity to glucose and lactate, respectively. The results of our evaluations reveal different advantages for sensors constructed by each method: improved sensitivity and shorter manufacturing time for hand-casting, and increased reproducibility for electropolymerization. We have acquired amperometric approach curves (ACs) for each type of manufactured biosensor UME, and these ACs can be used as a means of positioning the UME above a substrate at a known distance. We have used the glucose biosensor UMEs to record profiles of glucose uptake above individual fibroblasts. Likewise, we have employed the lactate biosensor UMEs for recording the lactate production above single cancer cells with the SECM. We also show that oxygen respiration profiles for single cancer cells do not mimic cell topography, but are rather more convoluted, with a higher respiration activity observed at the points where the cell touches the Petri dish. These UME biosensors, along with the application of others already described in the literature, could prove to be powerful tools for mapping metabolic analytes, such as glucose, lactate and oxygen, in single cancer cells.

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Multianalyte microphysiometry as a tool in metabolomics and systems biology

Cited by 61 publications

References 21 publications

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

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

A microfluidic optical platform for real-time monitoring of pH and oxygen in microfluidic bioreactors and organ-on-chip devices

Glucose and Lactate Biosensors for Scanning Electrochemical Microscopy Imaging of Single Live Cells

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