Bioelectronic Interface Research Articles

Toughening hydrogels through a multiscale hydrogen bonding network enabled by saccharides for a bio-machine interface.

Hydrogels have considerably emerged in a variety of fields, but their weak mechanical properties severely restrict the wide range of implementation. Herein, we propose a multiscale hydrogen bonding toughening strategy using saccharide-based materials to optimize the hydrogel network. The monosaccharide (glucose) at the molecular scale and polysaccharide (cellulose nanofibrils) at the nano/micro scale can effectively form hydrogen bonds across varied scales within the hydrogel network, leading to significantly enhanced mechanical properties. Besides, the toughened hydrogels present excellent environmental resilience and bad solvent resistance, allowing them to retain their performance in various severe environments. Notably, after being exchanged with a bad solvent such as ethanol, the alcogel exhibits strain-depended vivid interference color, allowing it to function as a mechano-optical sensor. Finally, this strategy has been shown to be adaptable across multiple material systems, and the resulting hydrogels have potential as a bioelectronic interface for long-term stable recording of physiological signals, highlighting the potential of sustainable biomaterials in designing high-quality hydrogels for advanced applications.

A Mg Battery-Integrated Bioelectronic Patch Provides Efficient Electrochemical Stimulations for Wound Healing.

Bioelectronic patches hold promise for patient-comfort wound healing providing simplified clinical operation. Currently, they face paramount challenges in establishing long-term effective electronic interfaces with targeted cells and tissues due to the inconsistent energy output and high bio interface impedance. Here a new electrochemical stimulation technology is reported, using a simple wound patch, which integrates the efficient generation and delivery of stimulation. This is realized by employing a hydrogel bioelectronic interface as an active component in an integrated power source (i.e., Mg battery). The Mg battery enhances fibroblast functions (proliferation, migration, and growth factor secretion) and regulates macrophage phenotype (promoting regenerative polarization and down-regulating pro-inflammatory cytokines), by providing an electric field and the ability to control the cellular microenvironment through chemical release. This bioelectronic patch shows an effective and accelerated wound closure by guiding epithelial migration, mediating immune response, and promoting vasculogenesis. This new electrochemical-mediated therapy may provide a new avenue for user-friendly wound management as well as a platform for fundamental insights into cell stimulation.

A selective frequency damping and Janus adhesive hydrogel as bioelectronic interfaces for clinical trials

Maintaining stillness is essential for accurate bioelectrical signal acquisition, but dynamic noise from breathing remains unavoidable. Isotropic adhesives are often used as bioelectronic interfaces to ensure signal fidelity, but they can leave irreversible residues, compromising device accuracy. We propose a hydrogel with selective frequency damping and asymmetric adhesion as a bioelectronic interface. This hydrogel mitigates dynamic noise from breathing, with a damping effect in the breathing frequency range 60 times greater than at other frequencies. It also exhibits an asymmetric adhesion difference of up to 537 times, preventing residues. By homogenizing ion distribution, extending Debye length, and densifying the electric field, the hydrogel ensures stable signal transmission over 10,000 cycles. Additionally, it can non-invasively diagnose otitis media with higher sensitivity than invasive probes and has been effective in clinical polysomnography monitoring, aiding in the diagnosis of obstructive sleep apnea.

Poly(3-Hexylthiophene) Based Bioelectronic Interface Using Conducting Nanofibers (CNFs) for the Sensitive Determination of Folate Receptor Cancer Biomarkers in Human Plasma

Folate receptors (FRs) are important biomarkers that can indicate the presence of various cancers. Sensitive and accurate detection of FRs is crucial for early cancer diagnosis and treatment. The current methods of FRs detection have high cost, potential cytotoxicity, and complex production by relying on metallic nanomaterials, or have low electrical conductivity and sensitivity such as biopolymers. To address these challenges, a new approach using conducting nanofibers (CNFs) as bioelectronic surface was developed. A composite of sodium alginate (SA), a bio-friendly polymer, poly-ethylene oxide (PEO), an antifouling polymer, and poly(3-hexylthiophene) (P3HT), a semi-conducting organic polymer nanofiber was synthesized, with folic acid conjugated to the CNFs as a biorecognition element to target (FRs). The electrochemical and electrical properties were evaluated through cyclic voltammetry and electrochemical impedance spectroscopy in a solution containing both a redox marker and free redox species. The CNFs exhibit electroactivity in buffer solution without a redox marker, owing to the electronic properties of the P3HT of EIS readout. The obtained biosensor significantly improved sensitivity, enabling the detection of FRs with a limit of detection (LOD) of 0.12 pM in human plasma, the high sensitivity compared to all previous approaches and a 25-fold improvement compared to the sensor described in our previous study, with improved selectivity. Additionally, the results showed a good biocompatibility toward MCF-7 breast cancer cells, which opens the way for their use as theragnostic nanoprobes for cancer cells diagnosis and therapy. This study provided a simple, low cost and sensitive analytical approach for folate receptor detection.

Wireless Power and Data Transfer Technologies for Flexible Bionic and Bioelectronic Interfaces: Materials and Applications

Wireless Power and Data Transfer Technologies for Flexible Bionic and Bioelectronic Interfaces: Materials and Applications

Congeneric and Robust Adhesive Epidermal Patch for Anti‐Interference Physiological Signal Recognition

AbstractEpidermal patches utilized for the transduction of biopotentials and biomechanical signals are pivotal in wearable health monitoring. However, the shortcomings, such as inferior conformal ability, deficient adhesion, and motion artifacts, severely impede the bioelectrodes from perceiving stable and superior‐quality physiological signals. Herein, a polymer epidermal patch possessing a spontaneous Janus structure is facilely prepared through itaconic acylhydrazine (IAH) induced gradient polymerization. The solubility discrepancy of the monomers in IAH authorized the Janus structure with distinct adhesion properties on each side. Moreover, the hydrogen bond network constructed by IAH confers the polymer with a high degree of skin compliance, enabling dynamic and stable mechanical properties to withstand complex monitoring environments. By integrating skin‐like softness (Young's modulus ≈0.16 MPa), robust adhesion (35 kPa), and high signal‐to‐noise ratio (32 dB), this epidermal patch displays exceptional elasticity within the physiological activity spectrum, provides swift electrical and mechanical self‐recovery capabilities, and resists interference in dynamic signal monitoring (deformation, compression, humidity, etc.). By demonstrating multifaceted applications for Electrocardiogram recording under diverse disturbances, the epidermal patch profiles a promising noninvasive, enduring wearable bioelectronic interface with immunity to interference.

Electrochemically actuated microelectrodes for minimally invasive peripheral nerve interfaces.

Electrode arrays that interface with peripheral nerves are used in the diagnosis and treatment of neurological disorders; however, they require complex placement surgeries that carry a high risk of nerve injury. Here we leverage recent advances in soft robotic actuators and flexible electronics to develop highly conformable nerve cuffs that combine electrochemically driven conducting-polymer-based soft actuators with low-impedance microelectrodes. Driven with applied voltages as small as a few hundreds of millivolts, these cuffs allow active grasping or wrapping around delicate nerves. We validate this technology using in vivo rat models, showing that the cuffs form and maintain a self-closing and reliable bioelectronic interface with the sciatic nerve of rats without the use of surgical sutures or glues. This seamless integration of soft electrochemical actuators with neurotechnology offers a path towards minimally invasive intraoperative monitoring of nerve activity and high-quality bioelectronic interfaces.

Nanoparticles of Push-Pull Triphenylamine-Based Molecules for Light-Controlled Stimulation of Neuronal Activity.

Organic semiconductor materials with a unique set of properties are very attractive for interfacing biological objects and can be used for noninvasive therapy or detection of biological signals. Here, we describe the synthesis and investigation of a novel series of organic push-pull conjugated molecules with the star-shaped architecture, consisting of triphenylamine as a branching electron donor core linked through the thiophene π-spacer to electron-withdrawing alkyl-dicyanovinyl groups. The molecules could form stable aqueous dispersions of nanoparticles (NPs) without the addition of any surfactants or amphiphilic polymer matrixes with the average size distribution varying from 40 to 120 nm and absorption spectra very similar to those of human eye retina pigments such as rods and green cones. Variation of the terminal alkyl chain length of the molecules forming NPs from 1 to 12 carbon atoms was found to be an efficient tool to modulate their lipophilic and biological properties. Possibilities of using the NPs as light nanoactuators in biological systems or as artificial pigments for therapy of degenerative retinal diseases were studied both on the model planar bilayer lipid membranes and on the rat cortical neurons. In the planar bilayer system, the photodynamic activity of these NPs led to photoinactivation of ion channels formed by pentadecapeptide gramicidin A. Treatment of rat cortical neurons with the NPs caused depolarization of cell membranes upon light irradiation, which could also be due to the photodynamic activity of the NPs. The results of the work gave more insight into the mechanisms of light-controlled stimulation of neuronal activity and for the first time showed that fine-tuning of the lipophilic affinity of NPs based on organic conjugated molecules is of high importance for creating a bioelectronic interface for biomedical applications.

3D Printable Hydrogel Bioelectronic Interfaces for Healthcare Monitoring and Disease Diagnosis: Materials, Design Strategies, and Applications

AbstractIn recent years, additive manufacturing tools, such as 3D printing, has gained enormous attention in biomedical engineering for developing ionotropic devices, flexible electronics, skin‐electronic interfaces, and wearable sensors with extremely high precision and sensing accuracy. Such printed bioelectronics are innovative and can be used as multi‐stimuli response platforms for human health monitoring and disease diagnosis. This review systematically discusses the past, present, and future of the various printable and stretchable soft bioelectronics for precision medicine. The potential of various naturally and chemically derived conductive biopolymer inks and their nanocomposites with tunable physico‐chemical properties is also highlighted, which is crucial for bioelectronics fabrication. Then, the design strategies of various printable sensors for human body sensing are summarized. In conclusion, the perspectives on the future advanced bioelectronics are described, which will be helpful, particularly in the field of nano/biomedicine. An in‐depth knowledge of materials design to functional aspects of printable bioelectronics is demonstrated, with an aim to accelerate the development of next‐generation wearables.

A Cyto-silicon Hybrid System with On-chip Closed-loop Modulation.

We introduce a bioelectronic interface between biological electrogenic cells and a mixed-signal CMOS integrated circuit with an array of surface electrodes, where not only is the CMOS electrode array capable of electrophysiological recording and stimulation of the cells with 1,024 recording and stimulation channels, but it can also provide low-latency artificial signal pathways from cells it records to cells it stimulates. This on-chip closed-loop modulation has an intrinsic latency less than 5 μs. To demonstrate the utility of the on-chip closed loop modulation as an artificial feedback pathway between biological cells, we develop a silicon-cardiomyocyte self-sustained oscillator with a tunable frequency to which both the relevant part of the CMOS chip and cells are locked, and also a silicon-neuron interface with a silicon inhibitory connection between neuronal cells. This line of cyto-silicon hybrid system, where the boundary between biological and semiconductor systems is blurred, may find applications in prosthesis, brain-machine interface, and fundamental biology research.

An Antidehydration Hydrogel Based on Zwitterionic Oligomers for Bioelectronic Interfacing.

Hydrogels are ideal interfacing materials for on-skin healthcare devices, yet their susceptibility to dehydration hinders their practical use. While incorporating hygroscopic metal salts can prevent dehydration and maintain ionic conductivity, concerns arise regarding metal toxicity due to the passage of small ions through the skin barrier. Herein, an antidehydration hydrogel enabled by the incorporation of zwitterionic oligomers into its network is reported. This hydrogel exhibits exceptional water retention properties, maintaining ≈88% of its weight at 40% relative humidity, 25°C for 50 days and about 84% after being heated at 50°C for 3 h. Crucially, the molecular weight design of the embedded oligomers prevents their penetration into the epidermis, as evidenced by experimental and molecular simulation results. The hydrogel allows stable signal acquisition in electrophysiological monitoring of humans and plants under low-humidity conditions. This research provides a promising strategy for the development of epidermis-safe and biocompatible antidehydration hydrogel interfaces for on-skin devices.

In Situ Nanomechanical Characterization Techniques for Soft Bioelectronic Interfaces and Their Building Blocks

AbstractSoft bioelectronic interfaces constitute a paradigm shift for biomedical devices. High‐resolution monitoring and stimulation of physiological processes in vivo are becoming possible with minimally invasive devices operated without inflicting tissue damage or discomfort over prolonged timescales. However, the development and commercialization of such interfaces still must address significant challenges. Biological tissue is subjected to continuous motion and the related device deformations can easily trigger fracture or delamination of the device components, putting long‐term durability of soft implants at risk. In this review, an overview of experimental techniques for testing mechanical properties and failure mechanisms of soft bioelectronic devices at the nanoscale while the deformation takes place (in situ) is provided. Through the tensile test, bending test, nanoindentation, and micropillar compression test, precise measurements of the mechanical properties of individual building blocks and the interfaces themselves can be obtained. Such parameters are crucial to design, model, and optimize the device's performance. Then, recent examples of how this information guides design and optimization of soft bioelectronic interfaces and devices for healthcare, robotics, and human–machine interfaces is provided. Last of all, future research that is needed to fully achieve long‐term soft bioelectronic interfaces for integration with the human body is discussed.

Mechanically‐Compliant Bioelectronic Interfaces through Fatigue‐Resistant Conducting Polymer Hydrogel Coating (Adv. Mater. 40/2023)

Mechanically‐Compliant Bioelectronic Interfaces through Fatigue‐Resistant Conducting Polymer Hydrogel Coating (Adv. Mater. 40/2023)

Mechanically-Compliant Bioelectronic Interfaces through Fatigue-Resistant Conducting Polymer Hydrogel Coating.

Because of their distinct electrochemical and mechanical properties, conducting polymer hydrogels have been widely exploited as soft, wet, and conducting coatings for conventional metallic electrodes, providing mechanically compliant interfaces and mitigating foreign body responses. However, the long-term viability of these hydrogel coatings is hindered by concerns regarding fatigue crack propagation and/or delamination caused by repetitive volumetric expansion/shrinkage during long-term electrical interfacing. This study reports a general yet reliable approach to achieving a fatigue-resistant conducting polymer hydrogel coating on conventional metallic bioelectrodes by engineering nanocrystalline domains at the interface between the hydrogel and metallic substrates. It demonstrates the efficacy of this robust, biocompatible, and fatigue-resistant conducting hydrogel coating in cardiac pacing, showcasing its ability to effectively reduce the pacing threshold voltage and enhance the long-term reliability of electric stimulation. This study findings highlight the potential of its approach as a promising design and fabrication strategy for the next generation of seamless bioelectronicinterfaces.

3D printable high-performance conducting polymer hydrogel for all-hydrogel bioelectronic interfaces.

Owing to the unique combination of electrical conductivity and tissue-like mechanical properties, conducting polymer hydrogels have emerged as a promising candidate for bioelectronic interfacing with biological systems. However, despite the recent advances, the development of hydrogels with both excellent electrical and mechanical properties in physiological environments is still challenging. Here we report a bi-continuous conducting polymer hydrogel that simultaneously achieves high electrical conductivity (over 11 S cm-1), stretchability (over 400%) and fracture toughness (over 3,300 J m-2) in physiological environments and is readily applicable to advanced fabrication methods including 3D printing. Enabled by these properties, we further demonstrate multi-material 3D printing of monolithic all-hydrogel bioelectronic interfaces for long-term electrophysiological recording and stimulation of various organs in rat models.

A versatile bioelectronic interface programmed for hormone sensing

Precision medicine requires smart, ultrasensitive, real-time profiling of bio-analytes using interconnected miniaturized devices to achieve individually optimized healthcare. Here, we report a versatile bioelectronic interface (VIBE) that senses signaling-cascade-guided receptor-ligand interactions via an electronic interface. We show that VIBE offers a low detection limit down to sub-nanomolar range characterised by an output current that decreases significantly, leading to precise profiling of these peptide hormones throughout the physiologically relevant concentration ranges. In a proof-of-concept application, we demonstrate that the VIBE platform differentiates insulin and GLP-1 levels in serum samples of wild-type mice from type-1 and type-2 diabetic mice. Evaluation of human serum samples shows that the bioelectronic device can differentiate between samples from different individuals and report differences in their metabolic states. As the target analyte can be changed simply by introducing engineered cells overexpressing the appropriate receptor, the VIBE interface has many potential applications for point-of-care diagnostics and personalized medicine via the internet of things.

A viologen-based conductive hydrogel enables iontophoresis devices powered by Mg biobattery

Conductive hydrogels with both electrical responsiveness and drug loading capability are emerging as promising platforms for on-demand drug delivery systems to incorporate electron signals as biorelevant physical cues. However, conventional conductive hydrogels based on conducting polymers and carbon-based nanomaterials suffer from low conductivity and insufficient responsiveness to electrical stimuli, thus requiring high voltages to induce drug delivery. Herein, we develop a viologen-based conductive hydrogel via multiple dynamic interactions, including hydrogen bonds and boronate ester bonds. The cytocompatible and antibacterial hydrogel forms an intimate bioelectronic interface with skin tissue, including high ionic conductivity, low contact impedance, high toughness, and seamless adhesion. It offers a fast response to electrical signals and high release efficiency (65.8%) at a low voltage (-1.0 V). Further, a Mg biobattery powered-iontophoresis using the hydrogel as an integrated drug-carrying electrode demonstrates a stable and effective drug release, enabling high-dosage administration for long-period operation. This iontophoresis device provides new therapeutic approaches for chronic skin diseases requiring daily or precise drug delivery in a non-invasive way.

Recent Progress on Poly(3,4‐Ethylenedioxythiophene):Poly(Styrenesulfonate) Bioelectrodes

Sensing bioelectrical signals is of great significance to understand human disease. Reliable bioelectronic interface is the guarantee of high‐quality bioelectrical signals. The unique electrochemical property and the mixed ionic and electrical conductivity of poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) make it an ideal material for the skin/tissue–electronic interface. However, pristine PEDOT:PSS‐based devices cannot meet the requirements for practical use. Toward this end, herein, the development of PEDOT:PSS‐based electrodes and their most recent advances in sensing bioelectrical signals are summarized. First, the generation mechanism of bioelectrical signals is introduced in detail. Then, according to the characteristics of bioelectrical signals, the requirements of bioelectrodes are discussed. Next, representative achievements for improving conductivity, stretchability, and stability of PEDOT:PSS are introduced. Bioelectrical signals such as electromyogram (EMG), electrocardiogram (ECG), electrooculogram (EOG), and electroencephalogram (EEG) are successfully recorded by these PEDOT:PSS‐based electrodes. Finally, a brief summary is provided, and the opportunities and challenges are also discussed.

Hybrid neural interfacing devices based on Au wires with nanogranular Au shell and hydrogel layer for anti-inflammatory and bi-directional neural communications

Realizing a long-duration stable electrical contact with peripheral nerves in vivo is challenging due to the fragility and tubular shapes of peripheral nerves and the foreign body response caused by implanted devices at the nerve-device interface. Herein, we report the development of a hybrid neural interfacing device (HNID) based on Au wires with a nanogranular Au shell and hydrogel layer used to achieve a non-inflammatory, stable, and bi-directional bioelectronic interface with peripheral nerves. A natural hydrogel made up of genipin-crosslinked gelatin is developed to produce a three-dimensional network structure displaying excellent biocompatibility, sufficient ionic conductivity, and durable mechanical property. Neural electrodes based on Au wires with a nanogranular Au shell enable effective ionic/electrical coupling and neural communication with the nerve through the hydrogel layer. In in vivo studies involving rats, an implanted HNID suppresses the inflammatory response and fibrosis and causes negligible damage to the sciatic nerve, enabling stable stimulation of the nerve and recording of the neural signal of the sciatic nerve for 15 days after implantation. Our approach could extend the applicability of various inorganic electrode materials for the development of nerve-interfacing bioelectronics displaying high performance and long-term stability.

An integrated Mg battery-powered iontophoresis patch for efficient and controllable transdermal drug delivery

Wearable transdermal iontophoresis eliminating the need for external power sources offers advantages for patient-comfort when deploying epidermal diseases treatments. However, current self-powered iontophoresis based on energy harvesters is limited to support efficient therapeutic administration over the long-term operation, owing to the low and inconsistent energy supply. Here we propose a simplified wearable iontophoresis patch with a built-in Mg battery for efficient and controllable transdermal delivery. This system decreases the system complexity and form factors by using viologen-based hydrogels as an integrated drug reservoir and cathode material, eliminating the conventional interface impedance between the electrode and drug reservoir. The redox-active polyelectrolyte hydrogel offers a high energy density of 3.57 mWh cm−2, and an optimal bioelectronic interface with ultra-soft nature and low tissue-interface impedance. The delivery dosage can be readily manipulated by tuning the viologen hydrogel and the iontophoresis stimulation mode. This iontophoresis patch demonstrates an effective treatment of an imiquimod-induced psoriasis mouse. Considering the advantages of being a reliable and efficient energy supply, simplified configuration, and optimal electrical skin-device interface, this battery-powered iontophoresis may provide a new non-invasive treatment for chronic epidermal diseases.