Guiding pancreatic beta cells to target electrodes in a whole-cell biosensor for diabetes

Abstract

We are developing a cell-based bioelectronic glucose sensor that exploits the multi-parametric sensing ability of pancreatic islet cells for the treatment of diabetes. These cells sense changes in the concentration of glucose and physiological hormones and immediately react by generating electrical signals. In our sensor, signals from multiple cells are recorded as field potentials by a micro-electrode array (MEA). Thus, cell response to various factors can be assessed rapidly and with high throughput. However, signal quality and consequently overall sensor performance rely critically on close cell-electrode proximity. Therefore, we present here a non-invasive method of further exploiting the electrical properties of these cells to guide them towards multiple micro-electrodes via electrophoresis. Parameters were optimized by measuring the cell's zeta potential and modeling the electric field distribution. Clonal and primary mouse or human β-cells migrated directly to target electrodes during the application of a 1 V potential between MEA electrodes for 3 minutes. The morphology, insulin secretion, and electrophysiological characteristics were not altered compared to controls. Thus, cell manipulation on standard MEAs was achieved without introducing any external components and while maintaining the performance of the biosensor. Since the analysis of the cells' electrical activity was performed in real time via on-chip recording and processing, this work demonstrates that our biosensor is operational from the first step of electrically guiding cells to the final step of automatic recognition. Our favorable results with pancreatic islets, which are highly sensitive and fragile cells, are encouraging for the extension of this technique to other cell types and microarray devices.

Integrating Biosensors in Organs-on-Chip Devices: A Perspective on Current Strategies to Monitor Microphysiological Systems

“…According to the physiology of pancreatic islets, β-cells sense glucose, metabolize it to secrete insulin, and are nevertheless electrically excitable. In fact, during the multistep process of glucose metabolism, ATP is produced, which in turn controls the opening and closure of specific ion channels and triggers well-defined ion fluxes that generate an electrical current [ 145 , 146 ]. The electrical signals produced from pancreatic islets are of two types: short-lived high-frequency action potentials (AP) that reflect single cell depolarization and longer lived changes in field potentials, named “low frequency slow potentials” (SP) [ 147 ].…”

“…In particular, SPs consist of a summation of single cell activity and reflect intraislet coupling, which represents a major index of physiological quality in insulin secretion [ 148 , 149 , 150 , 151 ]. Moreover, SPs carry information about glucose concentration, with their frequency being directly correlated to the nutrient concentration: for instance, Pedraza et al proved that, in murine islets, SPs are almost absent at low glucose (3 mM) levels, while their frequency increases for higher glucose (15 mM) stimulation [ 145 ]. Furthermore, Lebreton et al found a positive correlation between SP frequencies and glucose concentration in murine islet cells, as well as in human islets [ 148 ].…”

The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds

“…Tools are available for optical imaging of voltage responses, which enables high-throughput analyses of thousands of cells and will therefore likely supplant traditional electrophysiology for the characterisation of in vitro derived cells. Highthroughput electrophysiology and lab-on-a-chip technologies will be particularly useful in both understanding the phenotypic range of human islet cells and assessing their in vitro differentiated counterparts side by side [58][59][60]. The islet biologists and mathematical modellers who are most familiar with these aspects of beta cell behaviour should be engaged in studies of in vitro differentiated cells to dissect the properties of all of the major ion currents, the shape of the action potentials and the distinctive bursting patterns that are normally seen in healthy beta cells (Fig.…”

Reusable, Non-Invasive, and Ultrafast Radio Frequency Biosensor Based on Optimized Integrated Passive Device Fabrication Process for Quantitative Detection of Glucose Levels

“…The glucose biosensing detection system composed of bio-sensing detection conversion and peripheral electronic systems can be applied to monitor the glucose concentration of diabetic patients in time. In particular, biosensing detection conversion plays a very important role in the sensing system, which determines several key factors, such as accuracy, detection time and system cost [7][8][9]. A biosensor can convert different concentrations of glucose into corresponding electrical signals for output, which has advantages of high accuracy, fast analysis, low cost, good repeatability, simple operation and high specificity by comparing with traditional detection methods [10][11][12][13][14][15][16].…”