Multianalyte Physiological Microanalytical Devices

Abstract

Advances in scientific instrumentation have allowed experimentalists to evaluate well-known systems in new ways and to gain insight into previously unexplored or poorly understood phenomena. Within the growing field of multianalyte physiometry (MAP), microphysiometers are being developed that are capable of electrochemically measuring changes in the concentration of various metabolites in real time. By simultaneously quantifying multiple analytes, these devices have begun to unravel the complex pathways that govern biological responses to ischemia and oxidative stress while contributing to basic scientific discoveries in bioenergetics and neurology. Patients and clinicians have also benefited from the highly translational nature of MAP, and the continued expansion of the repertoire of analytes that can be measured with multianalyte microphysiometers will undoubtedly play a role in the automation and personalization of medicine. This is perhaps most evident with the recent advent of fully integrated noninvasive sensor arrays that can continuously monitor changes in analytes linked to specific disease states and deliver a therapeutic agent as required without the need for patient action.

Keywords: biosensor; electroanalytical; microclinical analyzer; multianalyte physiometry; multielectrode arrays; multiplex.

Figure 1.

Schematic of a cell showing cellular bioenergetics pathways. Metabolites commonly detected with multianalyte physiometry (lactate, glucose, oxygen, and acid) are highlighted. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; G6P, glucose 6-phosphate; NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide hydrate; TCA, tricarboxylic acid. Adapted with permission from Reference . Copyright 2006, Elsevier.

Figure 2.

Multianalyte physiometers. (a) Side cross section and (b) bottom view of a CytosensorTM modified into a multianalyte microphysiometer by electrode addition. The four added platinum electrodes include three working electrodes and one counter electrode. The working electrodes detect glucose, lactate, and oxygen. Panels a and b adapted with permission from Reference . Copyright 2004, American Chemical Society. (c) Samples are stop-flowed into the device, and pH is measured through light-emitting diode (LED)-illuminated light-addressable potentiometric sensors (LAPS). Panel adapted with permission from Reference. Copyright 2006, Elsevier. (d) Schematic of a multianalyte physiometer based on a glass chip that combines a cell cultivation chamber, microfluidics, and metabolic monitoring. Oxygen and pH 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. Panel adapted with permission from Reference . Copyright 2014, Royal Society of Chemistry.

Figure 3.

Photograph of a microclinical analyzer inset with a schematic of a screen-printed electrode. The pump and valve work together to flow 26μL of buffer, calibrants, and/or sample into the sample chamber containing the electrodes. From left to right, electrodes are modified to detect pH (blue), glucose (yellow), oxygen(middle), and lactate (pink). The far right electrode is an Ag/AgCl quasi-reference. Photograph courtesy of Dmitry Markov.

Figure 4.

Clinical and wearable devices. (a) i-STAT handheld device. Adapted with permission from Reference . Copyright 1998, American Chemical Society. (b) Photograph and schematic of the selective multianalyte detection in complex media using the finger-powered OECT array. Photograph shows a red-colored solution that was pressure driven from the inlet through the sensing areas, as indicated by the vertical arrow. Adapted with permission from Reference . Copyright 2016, John Wiley & Sons. (c) A fully integrated wearable multiplexed sensing system on a subject’s arm. Adapted with permission from Reference . Copyright 2013, Royal Society of Chemistry. Abbreviations: BSA, bovine serum albumin; OECT, organic electrochemical transistor