Enhancing the Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes with an n-Type Organic Semiconductor Coating.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are a promising cell source for cardiac regenerative medicine and in vitro modeling. However, hPSC-CMs exhibit immature structural and functional properties compared with adult cardiomyocytes. Various electrical, mechanical, and biochemical cues have been applied to enhance hPSC-CM maturation but with limited success. In this work, we investigated the potential application of the semiconducting polymer poly{[N,N'-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5'-(2,2'-bithiophene)} (P(NDI2OD-T2)) as a light-sensitive material to stimulate hPSC-CMs optically. Our results indicated that P(NDI2OD-T2)-mediated photostimulation caused cell damage at irradiances applied long-term above 36 µW/mm2 and did not regulate cardiac monolayer beating (after maturation) at higher intensities applied in a transient fashion. However, we discovered that the cells grown on P(NDI2OD-T2)-coated substrates showed significantly enhanced expression of cardiomyocyte maturation markers in the absence of a light exposure stimulus. A combination of techniques, such as atomic force microscopy, scanning electron microscopy, and quartz crystal microbalance with dissipation monitoring, which we applied to investigate the interface of the cell with the n-type coating, revealed that P(NDI2OD-T2) impacted the nanostructure, adsorption, and viscoelasticity of the Matrigel coating used as a cell adhesion promoter matrix. This modified cellular microenvironment promoted the expression of cardiomyocyte maturation markers related to contraction, calcium handling, metabolism, and conduction. Overall, our findings demonstrate that conjugated polymers such as P(NDI2OD-T2) can be used as passive coatings to direct stem cell fate through interfacial engineering of cell growth substrates.

N-Type polymeric mixed conductors for all-in-one aqueous electrolyte gated photoelectrochemical transistors.

An organic photoelectrochemical transistor (OPECT) is an organic electrochemical transistor (OECT) that utilizes light to toggle between ON and OFF states. The current response to light and voltage fluxes in aqueous media renders the OPECT ideal for the development of next-generation bioelectronic devices, including light-assisted biosensors, light-controlled logic gates, and artificial photoreceptors. However, existing OPECT architectures are complex, often requiring photoactive nanostructures prepared through labor-intensive synthetic methods, and despite this complexity, their performance remains limited. In this study, we develop aqueous electrolyte-compatible optoelectronic transistors using a single n-type semiconducting polymer. The n-type film performs multiple tasks: (1) gating the channel, (2) generating a photovoltage in response to light, and (3) coupling and transporting cations and electrons in the channel. We systematically investigate the photoelectrochemical properties of a range of n-type polymeric mixed conductors to understand the material requirements for maximizing phototransistor performance. Our findings contribute to the identification of crucial material and device properties necessary for constructing high-performance OPECTs with simplified design features and a direct interface with biological systems.

Eutectogels as a Semisolid Electrolyte for Organic Electrochemical Transistors.

Organic electrochemical transistors (OECTs) are signal transducers offering high amplification, which makes them particularly advantageous for detecting weak biological signals. While OECTs typically operate with aqueous electrolytes, those employing solid-like gels as the dielectric layer can be excellent candidates for constructing wearable electrophysiology probes. Despite their potential, the impact of the gel electrolyte type and composition on the operation of the OECT and the associated device design considerations for optimal performance with a chosen electrolyte have remained ambiguous. In this work, we investigate the influence of three types of gel electrolytes-hydrogels, eutectogels, and iongels, each with varying compositions on the performance of OECTs. Our findings highlight the superiority of the eutectogel electrolyte, which comprises poly(glycerol 1,3-diglycerolate diacrylate) as the polymer matrix and choline chloride in combination with 1,3-propanediol deep eutectic solvent as the ionic component. This eutectogel electrolyte outperforms hydrogel and iongel counterparts of equivalent dimensions, yielding the most favorable transient and steady-state performance for both p-type depletion and p-type/n-type enhancement mode transistors gated with silver/silver chloride (Ag/AgCl). Furthermore, the eutectogel-integrated enhancement mode OECTs exhibit exceptional operational stability, reflected in the absence of signal-to-noise ratio (SNR) variation in the simulated electrocardiogram (ECG) recordings conducted continuously over a period of 5 h, as well as daily measurements spanning 30 days. Eutectogel-based OECTs also exhibit higher ECG signal amplitudes and SNR than their counterparts, utilizing the commercially available hydrogel, which is the most common electrolyte for cutaneous electrodes. These findings underscore the potential of eutectogels as a semisolid electrolyte for OECTs, particularly in applications demanding robust and prolonged physiological signal monitoring.

The Role of Side Chains and Hydration on Mixed Charge Transport in n-Type Polymer Films.

Introducing ethylene glycol (EG) side chains to a conjugated polymer backbone is a well-established synthetic strategy for designing organic mixed ion-electron conductors (OMIECs). However, the impact that film swelling has on mixed conduction properties has yet to be scoped, particularly for electron-transporting (n-type) OMIECs. Here, the authors investigate the effect of the length of branched EG chains on mixed charge transport of n-type OMIECs based on a naphthalene-1,4,5,8-tetracarboxylic-diimide-bithiophene backbone. Atomic force microscopy (AFM), grazing-incidence wide-angle X-ray scattering (GIWAXS), and scanning tunneling microscopy (STM) are used to establish the similarities between the common-backbone films in dry conditions. Electrochemical quartz crystal microbalance with dissipation monitoring (EQCM-D) and in situ GIWAXS measurements reveal stark changes in film swelling properties and microstructure during electrochemical doping, depending on the side chain length. It is found that even in the loss of the crystallite content upon contact with the aqueous electrolyte, the films can effectively transport charges and that it is rather the high water content that harms the electronic interconnectivity within the OMIEC films. These results highlight the importance of controlling water uptake in the films to impede charge transport in n-type electrochemical devices.

Complementary integration of organic electrochemical transistors for front-end amplifier circuits of flexible neural implants.

The ability to amplify, translate, and process small ionic potential fluctuations of neural processes directly at the recording site is essential to improve the performance of neural implants. Organic front-end analog electronics are ideal for this application, allowing for minimally invasive amplifiers owing to their tissue-like mechanical properties. Here, we demonstrate fully organic complementary circuits by pairing depletion- and enhancement-mode p- and n-type organic electrochemical transistors (OECTs). With precise geometry tuning and a vertical device architecture, we achieve overlapping output characteristics and integrate them into amplifiers with single neuronal dimensions (20 micrometers). Amplifiers with combined p- and n-OECTs result in voltage-to-voltage amplification with a gain of >30 decibels. We also leverage depletion and enhancement-mode p-OECTs with matching characteristics to demonstrate a differential recording capability with high common mode rejection rate (>60 decibels). Integrating OECT-based front-end amplifiers into a flexible shank form factor enables single-neuron recording in the mouse cortex with on-site filtering and amplification.

Single-Component Electroactive Polymer Architectures for Non-Enzymatic Glucose Sensing.

Organic mixed ionic-electronic conductors (OMIECs) have emerged as promising materials for biological sensing, owing to their electrochemical activity, stability in an aqueous environment, and biocompatibility. Yet, OMIEC-based sensors rely predominantly on the use of composite matrices to enable stimuli-responsive functionality, which can exhibit issues with intercomponent interfacing. In this study, an approach is presented for non-enzymatic glucose detection by harnessing a newly synthesized functionalized monomer, EDOT-PBA. This monomer integrates electrically conducting and receptor moieties within a single organic component, obviating the need for complex composite preparation. By engineering the conditions for electrodeposition, two distinct polymer film architectures are developed: pristine PEDOT-PBA and molecularly imprinted PEDOT-PBA. Both architectures demonstrated proficient glucose binding and signal transduction capabilities. Notably, the molecularly imprinted polymer (MIP) architecture demonstrated faster stabilization upon glucose uptake while it also enabled a lower limit of detection, lower standard deviation, and a broader linear range in the sensor output signal compared to its non-imprinted counterpart. This material design not only provides a robust and efficient platform for glucose detection but also offers a blueprint for developing selective sensors for a diverse array of target molecules, by tuning the receptor units correspondingly.

Flexible switch matrix addressable electrode arrays with organic electrochemical transistor and pn diode technology.

Due to their effective ionic-to-electronic signal conversion and mechanical flexibility, organic neural implants hold considerable promise for biocompatible neural interfaces. Current approaches are, however, primarily limited to passive electrodes due to a lack of circuit components to realize complex active circuits at the front-end. Here, we introduce a p-n organic electrochemical diode using complementary p- and n-type conducting polymer films embedded in a 15-µm -diameter vertical stack. Leveraging the efficient motion of encapsulated cations inside this polymer stack and the opposite doping mechanisms of the constituent polymers, we demonstrate high current rectification ratios ([Formula: see text]) and fast switching speeds (230 µs). We integrate p-n organic electrochemical diodes with organic electrochemical transistors in the front-end pixel of a recording array. This configuration facilitates the access of organic electrochemical transistor output currents within a large network operating in the same electrolyte, while minimizing crosstalk from neighboring elements due to minimized reverse-biased leakage. Furthermore, we use these devices to fabricate time-division-multiplexed amplifier arrays. Lastly, we show that, when fabricated in a shank format, this technology enables the multiplexing of amplified local field potentials directly in the active recording pixel (26-µm diameter) in a minimally invasive form factor with shank cross-sectional dimensions of only 50×8 [Formula: see text].

Electrochemical Performance of Biocompatible TiC Films Deposited through Nonreactive RF Magnetron Sputtering for Neural Interfacing.

The efficacy of neural electrode stimulation and recording hinges significantly on the choice of a neural electrode interface material. Transition metal carbides (TMCs), particularly titanium carbide (TiC), have demonstrated exceptional chemical stability and high electrical conductivity. Yet, the fabrication of TiC thin films and their potential application as neural electrode interfaces remains relatively unexplored. Herein, we present a systematic examination of TiC thin films synthesized through nonreactive radio frequency (RF) magnetron sputtering. TiC films were optimized toward high areal capacitance, low impedance, and stable electrochemical cyclability. We varied the RF power and deposition pressure to pinpoint the optimal properties, focusing on the deposition rate, surface roughness, crystallinity, and elemental composition to achieve high areal capacitance and low impedance. The best-performing TiC film showed an areal capacitance of 475 µF/cm2 with a capacitance retention of 93% after 5000 cycles. In addition, the electrochemical performance of the optimum film under varying scanning rates demonstrated a stable electrochemical performance even under dynamic and fast-changing stimulation conditions. Furthermore, the in vitro cell culture for 3 weeks revealed excellent biocompatibility, promoting cell growth compared with a control substrate. This work presents a novel contribution, highlighting the potential of sputtered TiC thin films as robust neural electrode interface materials.

Salts as Additives: A Route to Improve Performance and Stability of n-Type Organic Electrochemical Transistors.

Organic electrochemical transistors (OECTs) are becoming increasingly ubiquitous in various applications at the interface with biological systems. However, their widespread use is hampered by the scarcity of electron-conducting (n-type) backbones and the poor performance and stability of the existing n-OECTs. Here, we introduce organic salts as a solution additive to improve the transduction capability, shelf life, and operational stability of n-OECTs. We demonstrate that the salt-cast devices present a 10-fold increase in transconductance and achieve at least one year-long stability, while the pristine devices degrade within four months of storage. The salt-added films show improved backbone planarity and greater charge delocalization, leading to higher electronic charge carrier mobility. These films show a distinctly porous morphology where the interconnectivity is affected by the salt type, responsible for OECT speed. The salt-based films display limited changes in morphology and show lower water uptake upon electrochemical doping, a possible reason for the improved device cycling stability. Our work provides a new and easy route to improve n-type OECT performance and stability, which can be adapted for other electrochemical devices with n-type films operating at the aqueous electrolyte interface.

SpyDirect: A Novel Biofunctionalization Method for High Stability and Longevity of Electronic Biosensors.

Electronic immunosensors are indispensable tools for diagnostics, particularly in scenarios demanding immediate results. Conventionally, these sensors rely on the chemical immobilization of antibodies onto electrodes. However, globular proteins tend to adsorb and unfold on these surfaces. Therefore, self-assembled monolayers (SAMs) of thiolated alkyl molecules are commonly used for indirect gold-antibody coupling. Here, a limitation associated with SAMs is revealed, wherein they curtail the longevity of protein sensors, particularly when integrated into the state-of-the-art transducer of organic bioelectronics-the organic electrochemical transistor. The SpyDirect method is introduced, generating an ultrahigh-density array of oriented nanobody receptors stably linked to the gold electrode without any SAMs. It is accomplished by directly coupling cysteine-terminated and orientation-optimized spyTag peptides, onto which nanobody-spyCatcher fusion proteins are autocatalytically attached, yielding a dense and uniform biorecognition layer. The structure-guided design optimizes the conformation and packing of flexibly tethered nanobodies. This biolayer enhances shelf-life and reduces background noise in various complex media. SpyDirect functionalization is faster and easier than SAM-based methods and does not necessitate organic solvents, rendering the sensors eco-friendly, accessible, and amenable to scalability. SpyDirect represents a broadly applicable biofunctionalization method for enhancing the cost-effectiveness, sustainability, and longevity of electronic biosensors, all without compromising sensitivity.

Ionic Liquid Gated Organic Electrochemical Transistors with Broadened Bandwidth.

The organic electrochemical transistor (OECT) is a biosignal transducer known for its high amplification but relatively slow operation. Here, we demonstrate that the use of an ionic liquid as the dielectric medium significantly improves the switching speed of a p-type enhancement-mode OECT, regardless of the gate electrode used. The OECT response time with the ionic liquid improves up to ca. 41-fold and 46-fold for the silver/silver chloride (Ag/AgCl) and gold (Au) gates, respectively, compared with devices gated with the phosphate buffered saline (PBS) solution. Notably, the transistor gain remains uncompromised, and its maximum is reached at lower voltages compared to those of PBS-gated devices with Ag/AgCl as the gate electrode. Through ultraviolet-visible spectroscopy and etching X-ray photoelectron spectroscopy characterizations, we reveal that the enhanced bandwidth is associated with the prediffused ionic liquid inside the polymer, leading to a higher doping level compared to PBS. Using the ionic liquid-gated OECTs, we successfully detect electrocardiography (ECG) signals, which exhibit a complete waveform with well-distinguished features and a stable signal baseline. By integrating nonaqueous electrolytes that enhance the device bandwidth, we unlock the potential of enhancement-mode OECTs for physiological signal acquisition and other real-time biosignal monitoring applications.

A single n-type semiconducting polymer-based photo-electrochemical transistor.

Conjugated polymer films, which can conduct both ionic and electronic charges, are central to building soft electronic sensors and actuators. Despite the possible interplay between light absorption and the mixed conductivity of these materials in aqueous biological media, no single polymer film has been utilized to create a solar-switchable organic bioelectronic circuit that relies on a fully reversible and redox reaction-free potentiometric photodetection and current modulation. Here we demonstrate that the absorption of light by an electron and cation-transporting polymer film reversibly modulates its electrochemical potential and conductivity in an aqueous electrolyte, which is harnessed to design an n-type photo-electrochemical transistor (n-OPECT). By controlling the intensity of light incident on the n-type polymeric gate electrode, we generate transistor output characteristics that mimic the modulation of the polymeric channel current achieved through gate voltage control. The micron-scale n-OPECT exhibits a high signal-to-noise ratio and an excellent sensitivity to low light intensities. We demonstrate three direct applications of the n-OPECT, i.e., a photoplethysmogram recorder, a light-controlled inverter circuit, and a light-gated artificial synapse, underscoring the suitability of this platform for a myriad of biomedical applications that involve light intensity changes.

Photo-Chemical Stimulation of Neurons with Organic Semiconductors.

Recent advances in light-responsive materials enabled the development of devices that can wirelessly activate tissue with light. Here it is shown that solution-processed organic heterojunctions can stimulate the activity of primary neurons at low intensities of light via photochemical reactions. The p-type semiconducting polymer PDCBT and the n-type semiconducting small molecule ITIC (a non-fullerene acceptor) are coated on glass supports, forming a p-n junction with high photosensitivity. Patch clamp measurements show that low-intensity white light is converted into a cue that triggers action potentials in primary cortical neurons. The study shows that neat organic semiconducting p-n bilayers can exchange photogenerated charges with oxygen and other chemical compounds in cell culture conditions. Through several controlled experimental conditions, photo-capacitive, photo-thermal, and direct hydrogen peroxide effects on neural function are excluded, with photochemical delivery being the possible mechanism. The profound advantages of low-intensity photo-chemical intervention with neuron electrophysiology pave the way for developing wireless light-based therapy based on emerging organic semiconductors.

Organic Electronic Platform for Real-Time Phenotypic Screening of Extracellular-Vesicle-Driven Breast Cancer Metastasis.

Tumor-derived extracellular vesicles (TEVs) induce the epithelial-to-mesenchymal transition (EMT) in nonmalignant cells to promote invasion and cancer metastasis, representing a novel therapeutic target in a field severely lacking in efficacious antimetastasis treatments. However, scalable technologies that allow continuous, multiparametric monitoring for identifying metastasis inhibitors are absent. Here, the development of a functional phenotypic screening platform based on organic electrochemical transistors (OECTs) for real-time, noninvasive monitoring of TEV-induced EMT and screening of antimetastatic drugs is reported. TEVs derived from the triple-negative breast cancer cell line MDA-MB-231 induce EMT in nonmalignant breast epithelial cells (MCF10A) over a nine-day period, recapitulating a model of invasive ductal carcinoma metastasis. Immunoblot analysis and immunofluorescence imaging confirm the EMT status of TEV-treated cells, while dual optical and electrical readouts of cell phenotype are obtained using OECTs. Further, heparin, a competitive inhibitor of cell surface receptors, is identified as an effective blocker of TEV-induced EMT. Together, these results demonstrate the utility of the platform for TEV-targeted drug discovery, allowing for facile modeling of the transient drug response using electrical measurements, and provide proof of concept that inhibitors of TEV function have potential as antimetastatic drug candidates.

Turning tissues into conducting matter.

An electrically conducting soft polymer is synthesized within living tissue.

Interactions of Catalytic Enzymes with n-Type Polymers for High-Performance Metabolite Sensors.

The tight regulation of the glucose concentration in the body is crucial for balanced physiological function. We developed an electrochemical transistor comprising an n-type conjugated polymer film in contact with a catalytic enzyme for sensitive and selective glucose detection in bodily fluids. Despite the promise of these sensors, the property of the polymer that led to such high performance has remained unknown, with charge transport being the only characteristic under focus. Here, we studied the impact of the polymer chemical structure on film surface properties and enzyme adsorption behavior using a combination of physiochemical characterization methods and correlated our findings with the resulting sensor performance. We developed five n-type polymers bearing the same backbone with side chains differing in polarity and charge. We found that the nature of the side chains modulated the film surface properties, dictating the extent of interactions between the enzyme and the polymer film. Quartz crystal microbalance with dissipation monitoring studies showed that hydrophobic surfaces retained more enzymes in a densely packed arrangement, while hydrophilic surfaces captured fewer enzymes in a flattened conformation. X-ray photoelectron spectroscopy analysis of the surfaces revealed strong interactions of the enzyme with the glycolated side chains of the polymers, which improved for linear side chains compared to those for branched ones. We probed the alterations in the enzyme structure upon adsorption using circular dichroism, which suggested protein denaturation on hydrophobic surfaces. Our study concludes that a negatively charged, smooth, and hydrophilic film surface provides the best environment for enzyme adsorption with desired mass and conformation, maximizing the sensor performance. This knowledge will guide synthetic work aiming to establish close interactions between proteins and electronic materials, which is crucial for developing high-performance enzymatic metabolite biosensors and biocatalytic charge-conversion devices.

A guide for the characterization of organic electrochemical transistors and channel materials.

The organic electrochemical transistor (OECT) is one of the most versatile devices within the bioelectronics toolbox, with its compatibility with aqueous media and the ability to transduce and amplify ionic and biological signals into an electronic output. The OECT operation relies on the mixed (ionic and electronic charge) conduction properties of the material in its channel. With the increased popularity of OECTs in bioelectronics applications and to benchmark mixed conduction properties of channel materials, the characterization methods have broadened somewhat heterogeneously. We intend this review to be a guide for the characterization methods of the OECT and the channel materials used. Our review is composed of two main sections. First, we review techniques to fabricate the OECT, introduce different form factors and configurations, and describe the device operation principle. We then discuss the OECT performance figures of merit and detail the experimental procedures to obtain these characteristics. In the second section, we shed light on the characterization of mixed transport properties of channel materials and describe how to assess films' interactions with aqueous electrolytes. In particular, we introduce experimental methods to monitor ion motion and diffusion, charge carrier mobility, and water uptake in the films. We also discuss a few theoretical models describing ion-polymer interactions. We hope that the guidelines we bring together in this review will help researchers perform a more comprehensive and consistent comparison of new materials and device designs, and they will be used to identify advances and opportunities to improve the device performance, progressing the field of organic bioelectronics.

Enhancing the Backbone Coplanarity of n-Type Copolymers for Higher Electron Mobility and Stability in Organic Electrochemical Transistors.

Electron-transporting (n-type) conjugated polymers have recently been applied in numerous electrochemical applications, where both ion and electron transport are required. Despite continuous efforts to improve their performance and stability, n-type conjugated polymers with mixed conduction still lag behind their hole-transporting (p-type) counterparts, limiting the functions of electrochemical devices. In this work, we investigate the effect of enhanced backbone coplanarity on the electrochemical activity and mixed ionic-electronic conduction properties of n-type polymers during operation in aqueous media. Through substitution of the widely employed electron-deficient naphthalene diimide (NDI) unit for the core-extended naphthodithiophene diimide (NDTI) units, the resulting polymer shows a more planar backbone with closer packing, leading to an increase in the electron mobility in organic electrochemical transistors (OECTs) by more than two orders of magnitude. The NDTI-based polymer shows a deep-lying lowest unoccupied molecular orbital level, enabling operation of the OECT closer to 0 V vs Ag/AgCl, where fewer parasitic reactions with molecular oxygen occur. Enhancing the backbone coplanarity also leads to a lower affinity toward water uptake during cycling, resulting in improved stability during continuous electrochemical charging and ON-OFF switching relative to the NDI derivative. Furthermore, the NDTI-based polymer also demonstrates near-perfect shelf-life stability over a month-long test, exhibiting a negligible decrease in both the maximum on-current and transconductance. Our results highlight the importance of polymer backbone design for developing stable, high-performing n-type materials with mixed ionic-electronic conduction in aqueous media.

A Peculiar Binding Characterization of DNA (RNA) Nucleobases at MoOS-Based Janus Biosensor: Dissimilar Facets Role on Selectivity and Sensitivity.

Distinctive properties of Janus monolayer have drawn much interest in biotechnology applications. For this purpose, it has explored theoretically all sensing possibilities of nucleobases molecules (DNA/RNA) by Janus MoOS monolayer on both oxygen and sulfur terminations by means of rigorous first-principles calculation. Indeed, differences in interaction energy between nucleobases indicate that a monolayer can be used for DNA sequencing. Exothermic interaction energy range for DNA/RNA molecules with both oxygen and sulfur sides of the Janus MoOS surfaces have been found to range between (0.61-0.91 eV), and (0.63-0.88 eV), respectively, and the binding distances indicate that these molecules bind to both facets by physisorption. The exchange of weak electronic charges between the MoOS monolayer and the nucleobases molecules has been studied by means of Hirshfeld-I charge analysis. It has been observed that the introduction of DNA/RNA nucleobases molecules alters the electronic properties of both oxygen and sulfur atomic layers of the Janus MoOS complex systems as determined by plotting the 3D Kohn-Sham frontier orbitals. A good correlation has been found between the interaction energy, van der Waals energy, Hirshfeld-I, and d-band center as a function of the nucleobase's affinity, and the interaction energy, suggesting adsorption dominated by van der Waals interactions driven by molybdenum d-orbital. Moreover, the lowering in the adsorption energy leads to an active interaction of the DNA/RNA with the surfaces, accordingly its conduct to shorter the recovery time. The selectivity of the biosensor modulation device has illustrated a significant sensitivity for the nucleobases on both the oxygen and sulfur layer sides of the MoOS monolayer. This finding reveals that apart from graphene, dichalcogenides-Janus transition metal may also be adequate for identifying DNA/RNA bases in applied biotechnology.