Current approaches to detect analytes use biomolecules or single cells and thus do not harness the computational power of endogenous algorithms present in micro-organs. Consequently, current on-line detection of glucose does not allow an autonomous artificial pancreas. In contrast, monitoring a few electrogenic pancreatic islets may provide a more appropriate read-out. Indeed, upon stimulation islets react with so-called slow potentials (SP) and their amplitude reflects the degree of intercellular coupling. We have now developed a microfluidic microelectrode chip containing a few islets and linked to interstitial fluids in live rats by microdialysis. Blood and dialysate glucose were determined concomitantly with ex-vivo islet electrical activity during an intraperitoneal glucose or insulin challenge. Blood glucose was tightly correlated to islet SP frequency, and to a lesser degree to SP amplitudes. This demonstrates the feasibility and usefulness of microorgan-based biosensors which may also be of interest in the therapy of diabetes.

Pancreatic islets contain α, β, γ, and δ cells as sensors and actuators regulating glucose homeostasis. Despite the known importance of α cells, they are seemingly required for glucose tolerance only under metabolic stress. In an inducible model of α cell ablation in mice (GluDTR), glucose tolerance was considerably decreased by the addition of amino acids mimicking meals. Analysis of islet β cell secretion and electrical activities using microelectrode arrays (MEAs) detected only minor differences in GluDTR mice for glucose but revealed a major reduction upon addition of amino acids. Analysis of functional islet β cell networks by high-density MEA revealed leader regions in different locations, a high degree of synchrony, and the activation of large cell clusters. The characteristics of leading regions were preserved in GluDTR islets, but synchrony, cluster size, and signal propagation speed were largely reduced. Thus, even without metabolic stress, α cells are required for nutrient homeostasis by regulating the dynamics of β cell networks.

Bio-nanoelectronic islets are new tools for diabetes research and therapy.

ABSTRACT Chiral conducting polymers have gained considerable attention as specific environments for enantioselective recognition, separation and synthesis. In this work, we report the rational design of a specific class of conducting polymers with chiral features for the enantiodiscrimination of amino acids. This is achieved by introducing chiral features on the trimer unit bis[3,4‐ethylenedioxythiophene]‐thiophene via the functionalization of the β‐position of the thiophene with the enantiomers of two different amino acids, serine and cysteine. The electrochemical polymerization produces films showing reversible charging/discharging ( Q c / Q a ≈ 1), with electric properties characterized by a charge hopping mechanism. The electrochemical and electrical features of the corresponding enantiomers of the polymers nearly overlap, demonstrating that the charging/discharging processes of these materials are identical regardless of their chiral nature. Finally, the enantioselectivity of the films with respect to amino acids is revealed by significant differences of the current and charge. This type of soft materials allows envisioning their possible use for the design of flexible enantioselective organic transistors for biological applications.

Herein, we take advantage of the photoelectric effect produced on light-emitting diodes to induce a kinetically controlled electrocatalytic polymerization of 3,4-alkoxythiophenes. Wireless polymerization was achieved by fine-tuning the irradiation time, the power density and the molecular structure of the thiophenes. A smartphone based light-driven system is introduced as a simple and low cost polymerization approach to π-conjugated films.

Pancreatic islets play a major role in glucose homeostasis as well as in diabetes, and islets-on-chip devices have been mainly developed using optical means for on-line monitoring. In contrast, no well-characterized electrophysiological platform for on-line analysis with unrivalled temporal resolution has been reported. Extracellular electrophysiology monitors two crucial parameters, islet β-cell activity and β-to-β-cell coupling, does not require chemical or genetic probes with inherent potential bias, is non-invasive and permits repetitive long-term monitoring. We have now developed and characterized a microfluidic islets-on-chip for combined electrophysiology (on-line) and hormone monitoring (off-line) with two chambers for concomitant monitoring. Fabrication of the device, based on commercial or easily manufacturable components, is within the reach of non-specialized laboratories. The chip permits convenient loading as well as long-term culture with comparable glucose kinetics and low shear stress in both chambers. An optimized flow rate did not alter islet β-cell electrical activity or coupling in response to glucose. Culturing for up to 8 days did not change islet survival as well as glucose-induced electrical or secretory kinetics of islet β-cells. The addition of a physiological amino acid mix, in the presence of elevated glucose, made a considerable change in the functional organisation of islet β-cell activity in terms of frequency and coupling, which explains the ensuing strong increase in insulin secretion. This device thus allows reliable long-term multiparametric on-line monitoring in two islet populations. The ease of fabrication, assembly and handling should permit widespread long-term on-line monitoring of islet activity in native micro-organs (e.g. controls/mutants), pseudo-islets or stem-cell-derived islet-like organoids.

AbstractOrganic mixed ionic‐electronic conductors (OMIEC) have emerged as pivotal materials in organic bioelectronics, particularly when integrated into organic electrochemical transistors (OECTs). Conducting polymer‐based devices have indeed demonstrated their capability to transduce biological signals into amplified output signals, harnessing the high transconductance of OECTs. The OECT operating principle and sensing capability strongly depend on ion‐conjugated backbone coupling: the dual nature of OMIECs, i.e. ion‐conductor and electron/hole‐conductor, presents an intrinsic interface in the bulk of the thin film across which transduction of ionic signals into electronic signals and vice versa occurs. Recent works have shown how selective sodium and potassium detection can be achieved by direct chemical modification of the polymer. Such modifications introduce ligands with affinity for the cations of interest as substituents on the polymer chain. The present work explores the integration of specifically modified conducting polymers into OECT channels, offering selectivity for zinc cations. Zinc fluxes are crucial in various biological processes, and their reliable detection, especially at low concentrations, is an important challenge. By electropolymerizing a thiophene‐based trimer, modified with a dipicolylamine (DPA) substituent, a conducting polymer‐based OECT is obtained that can selectively detect Zn2+ in the 10−6 to 10−3 mol L−1 concentration range in physiological buffers.

ABSTRACTContinuous monitoring of glucose levels has improved diabetes therapy. Current approaches rely on enzyme-linked electrochemical probes but do not allow a fully autonomous artificial pancreas. In contrast, monitoring the activity of a few electrogenic pancreatic islets in a biosensor may harness the computational power of the different endocrine cell types in the micro-organ, shaped for nutrient detection during evolution, and provide a more appropriate read-out. Extracellular electrophysiology captures slow potentials (SPs), which reflect coupled islet β-cell activity and is thus a method of choice for long-term monitoring of native islet activityin vitro.We have now developed a microfluidic microelectrode chip containing a few islets and linked to interstitial fluids in live rats by subcutaneous microdialysis. The electrical activity in terms of slow potentials monitored by this biosensor reactsex vivoproportionally to glucose levels off-line in serum or dialysed interstitial fluid. On-line monitoringin vivoreveals an excellent correlation between islet slow potential frequency, and to a lesser degree to slow potential amplitudes, to glucose concentrations with little variation between animals. The microorgan-based biosensor harness multiple parametersin vivoand provides a read-out closer to physiology. This demonstrates the usefulness of such biosensors for sensor-based therapy of diabetes.

iPSC-derived human β-like cells (BLC) hold promise for both therapy and disease modelling, but their generation remains challenging and their functional analyses beyond transcriptomic and morphological assessments remain limited. Here, we validate an approach using multicellular and single cell electrophysiological tools to evaluate function of BLCs from pioneer protocols that can be easily adapted to more differentiated BLCs. The Multi-Electrode Arrays (MEAs) measuring the extracellular electrical activity revealed that BLCs are electrically coupled, produce slow potential (SP) signals like primary β-cells that are closely linked to insulin secretion. We also used high-resolution single-cell patch-clamp measurements to capture the exocytotic properties, and characterise voltage-gated sodium and calcium currents and found that they were comparable to those in primary β and EndoC-βH1 cells. The KATP channel conductance is greater than in human primary β-cells which may account for the limited glucose responsiveness observed with MEA. We used MEAs to study the impact of the type 2 diabetes protective SLC30A8 allele (p.Lys34Serfs*50) and found that BLCs with this allele have stronger electrical coupling activity. Our data suggest that BLCs can be used to evaluate the functional impact of genetic variants on β-cell function and coupling.

Continuous monitoring of glucose levels has improved diabetes therapy. Current approaches rely on enzyme-linked electrochemical probes but do not allow a fully autonomous artificial pancreas. In contrast, monitoring the activity of a few electrogenic pancreatic islets in a biosensor may harness the computational power of the different endocrine cell types in the micro-organ, shaped for nutrient detection during evolution, and provide a more appropriate read-out. Extracellular electrophysiology captures slow potentials (SPs), which reflect coupled islet β-cell activity and is thus a method of choice for long-term monitoring of native islet activity in vitro .We have now developed a microfluidic microelectrode chip containing a few islets and linked to interstitial fluids in live rats by subcutaneous microdialysis. The electrical activity in terms of slow potentials monitored by this biosensor reacts ex vivo proportionally to glucose levels off-line in serum or dialysed interstitial fluid. On-line monitoring in vivo reveals an excellent correlation between islet slow potential frequency, and to a lesser degree to slow potential amplitudes, to glucose concentrations with little variation between animals. The microorgan-based biosensor harness multiple parameters in vivo and provides a read-out closer to physiology. This demonstrates the usefulness of such biosensors for sensor-based therapy of diabetes.### Competing Interest StatementThe authors have declared no competing interest.

BackgroundPancreatic islets are important in nutrient homeostasis and improved cellular models of clonal origin may very useful especially in view of relatively scarce primary material. Close 3D contact and coupling between β-cells are a hallmark of physiological function improving signal/noise ratios. Extracellular electrophysiology using micro-electrode arrays (MEA) is technically far more accessible than single cell patch clamp, enables dynamic monitoring of electrical activity in 3D organoids and recorded multicellular slow potentials (SP) provide unbiased insight in cell-cell coupling.ObjectiveWe have therefore asked whether 3D spheroids enhance clonal β-cell function such as electrical activity and hormone secretion using human EndoC-βH1, EndoC-βH5 and rodent INS-1 832/13 cells.MethodsSpheroids were formed either by hanging drop or proprietary devices. Extracellular electrophysiology was conducted using multi-electrode arrays with appropriate signal extraction and hormone secretion measured by ELISA. ResultsEndoC-βH1 spheroids exhibited increased signals in terms of SP frequency and especially amplitude as compared to monolayers and even single cell action potentials (AP) were quantifiable. Enhanced electrical signature in spheroids was accompanied by an increase in the glucose stimulated insulin secretion index. EndoC-βH5 monolayers and spheroids gave electrophysiological profiles similar to EndoC-βH1, except for a higher electrical activity at 3 mM glucose, and exhibited moreover a biphasic profile. Again, physiological concentrations of GLP-1 increased AP frequency. Spheroids also exhibited a higher secretion index. INS-1 cells did not form stable spheroids, but overexpression of connexin 36, required for cell-cell coupling, increased glucose responsiveness, dampened basal activity and consequently augmented the stimulation indexConclusionIn conclusion, spheroid formation enhances physiological function of the human clonal β-cell lines and these models may provide surrogates for primary islets in extracellular electrophysiology.

: An electropolymerized ion selective PEDOT analog is presented in this communication. Poly-(2-phenyl-15crown-5-(3,4-ethylene-dioxythiophene)-amine) (PEDOT-Crown15) showed excellent electrochemical stability with a fast electron transfer ( Δ E p = 50 mV). In comparison

Islet transplantation improves metabolic control in patients with unstable type 1 diabetes. Clinical outcomes have been improving over the last decade, and the widely used beta-score allows the evaluation of transplantation results. However, predictive pre-transplantation criteria of islet quality for clinical outcomes are lacking. In this proof-of-concept study, we examined whether characterization of the electrical activity of donor islets could provide a criterion. Aliquots of 8 human donor islets from the STABILOT study, sampled from islet preparations before transplantation, were characterized for purity and split for glucose-induced insulin secretion and electrical activity using multi-electrode-arrays. The latter tests glucose concentration dependencies, biphasic activity, hormones, and drug effects (adrenalin, GLP-1, glibenclamide) and provides a ranking of CHIP-scores from 1 to 6 (best) based on electrical islet activity. The analysis was performed online in real time using a dedicated board or offline. Grouping of beta-scores and CHIP-scores with high, intermediate, and low values was observed. Further analysis indicated correlation between CHIP-score and beta-score, although significance was not attained (R = 0.51, p = 0.1). This novel approach is easily implantable in islet isolation units and might provide means for the prediction of clinical outcomes. We acknowledge the small cohort size as the limitation of this pilot study.