Implantable Bioelectronics Research Articles

Wafer-patterned, permeable, and stretchable liquid metal microelectrodes for implantable bioelectronics with chronic biocompatibility.

Implantable bioelectronics provide unprecedented opportunities for real-time and continuous monitoring of physiological signals of living bodies. Most bioelectronics adopt thin-film substrates such as polyimide and polydimethylsiloxane that exhibit high levels of flexibility and stretchability. However, the low permeability and relatively high modulus of these thin films hamper the long-term biocompatibility. In contrast, devices fabricated on porous substrates show the advantages of high permeability but suffer from low patterning density. Here, we report a wafer-scale patternable strategy for the high-resolution fabrication of supersoft, stretchable, and permeable liquid metal microelectrodes (μLMEs). We demonstrate 2-μm patterning capability, or an ultrahigh density of ~75,500 electrodes/cm2, of μLME arrays on a wafer-size (diameter, 100 mm) elastic fiber mat by photolithography. We implant the μLME array as a neural interface for high spatiotemporal mapping and intervention of electrocorticography signals of living rats. The implanted μLMEs have chronic biocompatibility over a period of eight months.

Recent advances in enzymatic biofuel cells enabled by innovative materials and techniques.

The past few decades have seen increasingly rapid advances in the field of sustainable energy technologies. As a new bio- and eco-friendly energy source, enzymatic biofuel cells (EBFCs) have garnered significant research interest due to their capacity to power implantable bioelectronics, portable devices, and biosensors by utilizing biomass as fuel under mild circumstances. Nonetheless, numerous obstacles impeded the commercialization of EBFCs, including their relatively modest power output and poor long-term stability of enzymes. To depict the current progress of EBFC and address the challenges it faces, this review traces back the evolution of EBFC and focuses on contemporary advances such as newly emerged multi or single enzyme systems, various porous framework-enzyme composites techniques, and innovative applications. Besides emphasizing current achievements in this field, from our perspective part we also introduced novel electrode and cell design for highly effective EBFC fabrication. We believe this review will assist readers in comprehending the basic research and applications of EBFCs as well as potentially spark interdisciplinary collaboration for addressing the pressing issues in this field.

Emerging Design Strategies Toward Developing Next‐Generation Implantable Batteries and Supercapacitors

AbstractIn recent years, the development of implantable bioelectronics has garnered significant attention. With the continuous advancement of IoT and information technology, implantable bioelectronics can be utilized more effectively for health monitoring to enhance treatment outcomes, reduce healthcare costs, and improve quality of life. Implantable energy storage devices have been widely studied as critical components for energy supply. Conventional power sources are bulky, inflexible, and potentially contain materials that are dangerous to the body. Meanwhile, human tissues are soft, flexible, dynamic, and closed, which puts new requirements on energy storage devices to improve the safety, stability, and matching of implantable batteries or supercapacitors. Herein, recent advances in state‐of‐the‐art nonconventional power options for implantable electronics, specifically biocompatible, miniaturized, stretchable/deformable, biodegradable/bioresorbable, edible, and injectable energy storage devices, are reviewed in this paper. The material strategy and architectural design of the next‐generation implantable energy storage device are discussed, including the selection principle of electrolytes, the all‐in‐one structure design strategy, and the way to realize self‐charging. Finally, the challenges and prospects of emerging design strategies toward developing next‐generation implantable batteries and supercapacitors for the future are put forward.

Tissue‐Adhesive Piezoelectric Soft Sensor for In Vivo Blood Pressure Monitoring During Surgical Operation

AbstractThe reliable function in vivo of self‐powered implantable bioelectric devices (iBEDs) requires biocompatible, seamless, effective interactions with biological tissues. Herein, an implantable tissue‐adhesive piezoelectric soft sensor (TPSS), in which the piezoelectric sensor converts biomechanical signals into electrical signals, and the adhesive hydrogel (AH) strengthens this conversion by seamlessly adhering the sensor on the wet and curvilinear surface, is proposed. The optimized AH exhibits strong adhesion to various organic or inorganic surfaces, including six commonly used engineering materials and three biological tissues. As a pressure sensor, TPSS proves good in vitro electrical performance with a high output of 8.3 V, long‐term stability of over 6000 cycles, and high energy power density of 186.9 µW m−2. In a large animal experiment, TPSS seamlessly adheres to the right‐side internal carotid artery of a Yorkshire pig to monitor blood pressure during a surgical operation. Compared to commercial sensors that work by inserting into tissues, TPSS does not cause any damage and can be peeled off after service. The integration of adhesive hydrogel and self‐powered pressure sensors enables biocompatible, seamless, and more efficient interactions between the biological system and iBEDs, which also contributes to next‐generation implantable bioelectronics with features of battery‐free, intelligent, and accurate.

3D Printing of Multifunctional Conductive Polymer Composite Hydrogels

AbstractFunctional conductive hydrogels are widely used in various application scenarios, such as artificial skin, cell scaffolds, and implantable bioelectronics. However, their novel designs and technological innovations are severely hampered by traditional manufacturing approaches. Direct ink writing (DIW) is considered a viable industrial‐production 3D‐printing technology for the custom production of hydrogels according to the intended applications. Unfortunately, creating functional conductive hydrogels by DIW has long been plagued by complicated ink formulation and printing processes. In this study, a highly 3D printable poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)‐based ink made from fully commercially accessible raw materials is demonstrated. It is shown that complex structures can be directly printed with this ink and then precisely converted into high‐performance hydrogels via a post‐printing freeze–thawing treatment. The 3D‐printed hydrogel exhibits high electrical conductivity of ≈2000 S m−1, outstanding elasticity, high stability and durability in water, electromagnetic interference shielding, and sensing capabilities. Moreover, the hydrogel is biocompatible, showing great potential for implantable and tissue engineering applications. With significant advantages, the fabrication strategy is expected to open up a new route to create multifunctional hydrogels with custom features, and can bring new opportunities to broaden the applications of hydrogel materials.

Magnetoeletric Backscatter Communication for Millimeter-Sized Wireless Biomedical Implants

Magnetoelectric power transfer has shown remarkable promise for the development of wireless millimetric bioelectronic implants with its low tissue absorption, high efficiency, and low misalignment sensitivity. Utilizing the same physical mechanism for power and communication is critical for implant miniaturization. For the first time, we designed and demonstrated near-zero power magnetoelectric backscatter from mm-sized implants by exploiting the converse magnetostriction effects. The prototype system consists of an 8.2-mm3 wireless implant integrating an application-specific integrated circuit (ASIC) that achieves frequency-shift-keying backscattering via capacitive load modulation and a custom transceiver demodulating data through frequency-to-digital conversion. The magnetoelectric backscatter archives > 1 kbps data rate at the 335-kHz carrier frequency, with a communication distance greater than 2 cm and a bit error rate (BER) less than 1E-3.

Novel highly stable conductive polymer composite PEDOT:DBSA for bioelectronic applications

In this work, a novel conductive polymer composite consisting of poly(3,4-ethylenedioxythiophene) doped with dodecylbenzenesulfonic acid (PEDOT:DBSA) for bioelectronic applications was prepared and optimized. The novel PEDOT:DBSA composite possesses superior biocompatibility toward cell culture and electrical characteristics comparable to the widely used PEDOT:PSS. The cross-linking processes induced by the cross-linker glycidoxypropyltrimethoxysilane (GOPS), which was investigated in detail using Fourier transform Raman spectroscopy and XPS analysis, lead to the excellent long-term stability of PEDOT:DBSA thin films in aqueous solutions, even without treatment at high temperature. The electrical characteristics of PEDOT:DBSA thin films with respect to the level of cross-linking were studied in detail. The conductivity of thin films was significantly improved using sulfuric acid posttreatment. A model transistor device based on PEDOT:DBSA shows typical transistor behavior and suitable electrical properties comparable or superior to those of available conductive polymers in bioelectronics, such as PEDOT:PSS. Based on these properties, the newly developed material is well suited for bioelectronic applications that require long-term contact with living organisms, such as wearable or implantable bioelectronics.

Wearable and implantable bioelectronics as eco‐friendly and patient‐friendly integrated nanoarchitectonics for next‐generation smart healthcare technology

AbstractSince the beginning of human history, the demand for effective healthcare systems for diagnosis and treatment of health problems has grown steadily. However, traditional centralized healthcare requires hospital visits, making in‐time and long‐term healthcare challenging. Bioelectronics has shown potential in patient‐friendly healthcare owing to the rapid advances in diverse fields of biology and electronics. In particular, wearable and implantable bioelectronics have emerged as an alternative or adjunct to conventional healthcare. To develop into next‐generation healthcare systems, however, custom designs for biological targets with a deepened understanding of the intrinsic features of the target are essential. In addition, bioelectronic systems must be designed eco‐friendly for sustainable healthcare. In this review, bioelectronics as eco‐friendly and patient‐friendly integrated nanoarchitectonics as next‐generation smart healthcare technology are described. For an in‐depth understanding of biological targets and guidelines for target‐tailored design, we discuss target‐specific considerations and relevant key parameters of bioelectronic systems with the representative examples.image

Silk‐based conductive materials for smart biointerfaces (2/2023)

Silk-based conductive materials are widely used in bio interface applications, such as artificial epidermal sensors, soft and implantable bioelectronics, and tissue/cell scaffolds. In this article, Fu and coworkers reviewed the advanced paradigms of these conductive silk materials, with perspectives on the application challenges.

Integrated opposite charge grafting induced ionic-junction fiber

The emergence of ionic-junction devices has attracted growing interests due to the potential of serving as signal transmission and translation media between electronic devices and biological systems using ions. Among them, fiber-shaped iontronics possesses a great advantage in implantable applications owing to the unique one-dimensional geometry. However, fabricating stable ionic-junction on curved surfaces remains a challenge. Here, we developed a polyelectrolyte based ionic-junction fiber via an integrated opposite charge grafting method capable of large-scale continuous fabrication. The ionic-junction fibers can be integrated into functions such as ionic diodes and ionic bipolar junction transistors, where rectification and switching of input signals are implemented. Moreover, synaptic functionality has also been demonstrated by utilizing the fiber memory capacitance. The connection between the ionic-junction fiber and sciatic nerves of the mouse simulating end-to-side anastomosis is further performed to realize effective nerve signal conduction, verifying the capability for next-generation artificial neural pathways in implantable bioelectronics.

Silk-based conductive materials for smart biointerfaces.

Silk-based conductive materials are widely used in biointerface applications, such as artificial epidermal sensors, soft and implantable bioelectronics, and tissue/cell scaffolds. Such biointerface materials require coordinated physicochemical, biological, and mechanical properties to meet current practical needs and future sophisticated demands. However, it remains a challenge to formulate silk-based advanced materials with high electrical conductivity, good biocompatibility, mechanical robustness, and in some cases, tissue adhesion ability without compromising other physicochemical properties. In this review, we highlight recent progress in the development of functional conductive silk-based advanced materials with different morphologies. Then, we reviewed the advanced paradigms of these silk materials applied as wearable flexible sensors, implantable electronics, and tissue/cell engineering with perspectives on the application challenges. Silk-based conductive materials can serve as promising building blocks for biomedical devices in personalized healthcare and other fields of bioengineering.

Stretchable Low-Impedance Conductor with Ag-Au-Pt Core-Shell-Shell Nanowires and in Situ Formed Pt Nanoparticles for Wearable and Implantable Device.

Mechanically soft metallic nanocomposites have gained much attention as a key material for intrinsically stretchable biointegrated devices. However, it has been challenging to develop a stretchable conductive nanocomposite with all the desired material characteristics including high conductivity, high stretchability, low cytotoxicity, and low impedance. Here, we present a material strategy for the stretchable conductive nanocomposite, particularly emphasizing low impedance, by combining silver-gold-platinum core-shell-shell nanowires and homogeneously dispersed in situ synthesized platinum nanoparticles (Pt NPs). The highly embossed structure of the outermost Pt shell, together with the intrinsic electrical property of Pt, contributes to minimizing the impedance. The gold-platinum double-layer sheath prevents leaching of cytotoxic Ag ions, thus improving biocompatibility. Homogeneously dispersed Pt NPs, synthesized in situ during fabrication of the nanocomposite, simultaneously enhance conductivity, reduce impedance, and improve stretchability by supporting the percolation network formation. This intrinsically stretchable nanocomposite conductor can be applied to wearable and implantable bioelectronics for recording biosignals and delivering electrical stimulations in vivo.

Blood-Glucose-Powered Metabolic Fuel Cell for Self-Sufficient Bioelectronics.

Currently available bioelectronic devices consume too much power to be continuously operated on rechargeable batteries, and are often powered wirelessly, with attendant issues regarding reliability, convenience, and mobility. Thus, the availability of a robust, self-sufficient, implantable electrical power generator that works under physiological conditions would be transformative for many applications, from driving bioelectronic implants and prostheses to programing cellular behavior and patients' metabolism. Here, capitalizing on a new copper-containing, conductively tuned 3D carbon nanotube composite, an implantable blood-glucose-powered metabolic fuel cell is designed that continuously monitors blood-glucose levels, converts excess glucose into electrical power during hyperglycemia, and produces sufficient energy (0.7mW cm-2 , 0.9V, 50mm glucose) to drive opto- and electro-genetic regulation of vesicular insulin release from engineered beta cells. It is shown that this integration of blood-glucose monitoring with elimination of excessive blood glucose by combined electro-metabolic conversion and insulin-release-mediated cellular consumption enables the metabolic fuel cell to restore blood-glucose homeostasis in an automatic, self-sufficient, and closed-loop manner in an experimental model of type-1 diabetes.

Zinc hybrid sintering for printed transient sensors and wireless electronics

Transient electronics offer a promising solution for reducing electronic waste and for use in implantable bioelectronics, yet their fabrication remains challenging. We report on a scalable method that synergistically combines chemical and photonic mechanisms to sinter printed Zn microparticles. Following reduction of the oxide layer using an acidic solution, zinc particles are agglomerated into a continuous layer using a flash lamp annealing treatment. The resulting sintered Zn patterns exhibit electrical conductivity values as high as 5.62 × 106 S m−1. The electrical conductivity and durability of the printed zinc traces enable the fabrication of biodegradable sensors and LC circuits: temperature, strain, and chipless wireless force sensors, and radio-frequency inductive coils for remote powering. The process allows for reduced photonic energy to be delivered to the substrate and is compatible with temperature-sensitive polymeric and cellulosic substrates, enabling new avenues for the additive manufacturing of biodegradable electronics and transient implants.

Hybrid assembly of polymeric nanofiber network for robust and electronically conductive hydrogels

Electroconductive hydrogels have been applied in implantable bioelectronics, tissue engineering platforms, soft actuators, and other emerging technologies. However, achieving high conductivity and mechanical robustness remains challenging. Here we report an approach to fabricating electroconductive hydrogels based on the hybrid assembly of polymeric nanofiber networks. In these hydrogels, conducting polymers self-organize into highly connected three dimensional nanostructures with an ultralow threshold (~1 wt%) for electrical percolation, assisted by templating effects from aramid nanofibers, to achieve high electronic conductivity and structural robustness without sacrificing porosity or water content. We show that a hydrogel composed of polypyrrole, aramid nanofibers and polyvinyl alcohol achieves conductivity of ~80 S cm−1, mechanical strength of ~9.4 MPa and stretchability of ~36%. We show that patterned conductive nanofiber hydrogels can be used as electrodes and interconnects with favorable electrochemical impedance and charge injection capacity for electrophysiological applications. In addition, we demonstrate that cardiomyocytes cultured on soft and conductive nanofiber hydrogel substrates exhibit spontaneous and synchronous beating, suggesting opportunities for the development of advanced implantable devices and tissue engineering technologies.

Capacitive stimulation-sensing system for instrumented bone implants: Finite element model to predict the electric stimuli delivered to the interface

BackgroundPrevalence of orthopaedic replacements are increasing around the world. The main cause of revision remains associated to the interface loosening. In this work, a computational study using the Finite element method was developed to predict the electric field stimuli delivered to trabecular bone structures, as well as to predict the sensing ability to detect different bone-implant interface scenarios. MethodsThree finite element models were developed: two simplified models, including a Gyroid TMP structure, and a realistic model based on microCT scan of a trabecular bone from sheep vertebra. Simulations were performed using a co-surface capacitive technology for stimulating and sensing bone-implant interfaces. Different fixation scenarios were considered, namely by establishing bone-stimulator gap sizes up to 1 mm (from fixation to massive loosening scenario). Electrodes were excited with sinusoidal and square electric signals up to 10V voltage and 64kHz frequency. ResultsSimplification of bone geometry resulted in significant electric stimuli differences compared to the realistic bone geometry. Realistic modelling allowed to observe that, in the fixation scenario, the electric field stimuli decreased 85% from the sensor interface to a parallel plane 2 mm apart from such interface. A significant influence of the bone-stimulator distance on the electric stimuli was found: the electric stimuli magnitudes varied in the range between 0.38 V/mm (fixation scenario) and 4.8 mV/mm (massive loosening scenario) for voltages up to 10V. Strong frequency-dependent behaviours were also observed in the electric stimuli: their magnitudes can reach 106-fold decreases when the excitation frequency is decreased from 32 kHz to 14 Hz ConclusionThis study points out the inability of our two simplified models to predict the electric stimulation provided to different bone-implant interface scenarios. Results highlight that co-surface stimulators can deliver osteogenic electric stimuli along trabecular bone structures, ensuring low electric power excitations. Moreover, realistic models strongly enhance the sensing predictability of the bone-implant fixation states. These new and significant evidences provide a strong support to integrate co-surface capacitive into bioelectronic implants for both therapeutic and sensing operations.

Advances in Triboelectric Nanogenerators for Self‐powered Neuromodulation

AbstractAdvances in implantable bioelectronics for the nervous system are reinventing the stimulation, inhibition, and sensing of neuronal activity. These efforts promise not just breakthrough treatments of several neurological and psychiatric conditions but also signal the beginning of a new era of computer‐controlled human therapeutics. Batteries remain the major power source for all implanted electrical neuromodulation devices, which impairs miniaturization and necessitates replacement surgery when the battery is drained. Triboelectric nanogenerators (TENGs) have recently emerged as an innovative power solution for self‐powered, closed loop electrical neurostimulation devices. TENGs can leverage the biomechanical activities of different body organs to sustainably generate electricity for electrical neurostimulation. This review features advances in TENGs as they pave the way for self‐sustainable closed loop neurostimulation. A comprehensive review of TENG research for the neurostimulation of brain, autonomic, and somatic nervous systems is provided. The direction of growth of this field, publication trends, and modes of TENG in implantable bioelectronics are also discussed. Finally, an insightful outlook into challenges facing self‐sustainable neuromodulators to reach clinical practice is provided, and solutions for neurological maladies are proposed.

Smart nanoengineered electronic-scaffolds based on triboelectric nanogenerators as tissue batteries for integrated cartilage therapy

At present, cartilage defect therapy requires a long-term repair period and does not permit real-time detection of the cartilage repair state named “black box”. Inspired by the electroactive nature of living organisms, next-generation tissue trauma therapy with integrated bioelectronics promises to achieve the desired therapeutic effects. Here, a tissue battery for integrated cartilage therapy was nanoengineered through the on-demand integration of intelligent scaffolds with a porous three-dimensional structure and multi-convex triboelectric nanogenerator (TENG)-based sensor. The proposed cartilage tissue battery is repair-induced, self-powered, highly sensitive, implantable, intelligently degradable, and anti-interference. The sensor based on the contact separation TENG mechanism has a high sensitivity (52.5 V MPa–1) within the pressure range of joint movement (0–1.8 MPa), enabling the tissue battery to in-situ detect the real-time status of cartilage repair in the “black box”. Additionally, in vitro and in vivo experiments demonstrated that the tissue battery converts mechanical energy into electricity to stimulate chondrocyte proliferation in the scaffold, thereby shortening the cartilage repair period. The proposed tissue battery for tissue repair under electrical stimulation is beneficial for reducing pain and treatment costs for patients with cartilage defects and is a promising strategy for bioelectronic implants.

Self-Healing Bimodal Sensors Based on Bioderived Polymerizable Deep Eutectic Solvent Ionic Elastomers

Despite the remarkable progress in electronic skins (e-skins), it remains a great challenge to achieve high biocompatibility, multimodal response, and self-healing abilities simultaneously. Here, a fully biobased self-healing bimodal sensor based on the polymerizable deep eutectic solvent (PDES) ionic elastomer is elaborately constructed for skin-contact multifunctional e-skin applications. Utilizing the synergistic regulation of physical and hydrogen bonding networks constructed by the polydopamine-coated cellulose nanocrystal, the bioderived PDES breaks the limitations of general biobased materials in strength and toughness while possessing excellent self-healing properties. The resulting ionic elastomer exhibits outstanding biocompatibility (cell viability over 87%), excellent autonomous self-healing efficiency (>90%), and superior mechanical properties (2.95 and 69.57 times higher tensile strength and toughness than pure bioderived PDES). Furthermore, intrinsic ionic migration within the PDES and the pH-responsive property of the anthocyanin coating enable the sensor to bimodally detect human motion and sweat physiological information visualization, with a stable electrical output signal and a wide sweat visualization range (pH 3–12) both before and after self-healing. This work provides new perspectives for the future skin-contact and implantable bioelectronics in medical diagnostics and healthcare.

Open thoracic surgical implantation of cardiac pacemakers in rats.

Genetic engineering and implantable bioelectronics have transformed investigations of cardiovascular physiology and disease. However, the two approaches have been difficult to combine in the same species: genetic engineering is applied primarily in rodents, and implantable devices generally require larger animal models. We recently developed several miniature cardiac bioelectronic devices suitable for mice and rats to enable the advantages of molecular tools and implantable devices to be combined. Successful implementation of these device-enabled studies requires microsurgery approaches that reliably interface bioelectronics to the beating heart with minimal disruption to native physiology. Here we describe how to perform an open thoracic surgical technique for epicardial implantation of wireless cardiac pacemakers in adult rats that has lower mortality than transvenous implantation approaches. In addition, we provide the methodology for a full biocompatibility assessment of the physiological response to the implanted device. The surgical implantation procedure takes ~40 min for operators experienced in microsurgery to complete, and six to eight surgeries can be completed in 1 d. Implanted pacemakers provide programmed electrical stimulation for over 1 month. This protocol has broad applications to harness implantable bioelectronics to enable fully conscious in vivo studies of cardiovascular physiology in transgenic rodent disease models.