Electronic tissue technologies for seamless biointerfaces

Bioelectronic interfaces establish a communication channel between a living system and an electrical machine. The first examples emerged in the 18th century when batteries were used to “galvanize” muscles and nerves. Today bioelectronic interfaces underpin key medical technologies such as the cardiac pacemaker and emerging ones such as neuroprostheses and brain-machine interfaces. Despite compelling applications in living systems, bioelectronic interfaces employ materials from microelectronics that are rigid, impermeable to water and bioinert. In contrast, electrical phenomena in soft tissues such as muscle and nerve are mediated by ions and molecules solvated in water. This disparity leads to missed opportunities for achieving seamless interfaces and communication that extends beyond electrical stimulation and recording. In this perspective, I discuss opportunities presented by hydrogel materials for building bioelectronic interfaces. This will require new types of hydrogels that support both ionic and electronic conductivity combined with key functions of the extracellular matrix

Direct writing of elastic fibers with optical, electrical, and microfluidic functionality

Direct Ink Writing is an additive fabrication technology that allows the integration of a diverse range of functional materials into soft and bioinspired devices such as robots and human‐machine interfaces. Typically, a viscoelastic ink is extruded from a nozzle as a continuous filament of circular cross section. Here it is shown that a careful selection of printing parameters such as nozzle height and speed can produce filaments with a range of cross‐sectional geometries. Thus, elliptic cylinder‐, ribbon‐, or groove‐shaped filaments can be printed. By using the nozzle as a stylus for postprint filament modification, even filaments with an embedded microfluidic channel can be produced. This strategy is applied to directly write freeform and elastic optical fibers, electrical interconnects, and microfluidics. The integration of these components into simple sensor‐actuator systems is demonstrated. Prototypes of an optical fiber with steerable tip and a thermal actuation system for soft tissues are presented

Printed elastic membranes for multimodal pacing and recording of human stem-cell-derived cardiomyocytes

Bioelectronic interfaces employing arrays of sensors and bioactuators are promising tools for the study, repair and engineering of cardiac tissues. They are typically constructed from rigid and brittle materials processed in a cleanroom environment. An outstanding technological challenge is the integration of soft materials enabling a closer match to the mechanical properties of biological cells and tissues. Here we present an algorithm for direct writing of elastic membranes with embedded electrodes, optical waveguides and microfluidics using a commercial 3D printing system and a palette of silicone elastomers. As proof of principle, we demonstrate interfacing of cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs), which are engineered to express Channelrhodopsin-2. We demonstrate electrical recording of cardiomyocyte field potentials and their concomitant modulation by optical and pharmacological stimulation delivered via the membrane. Our work contributes a simple prototyping strategy with potential applications in organ-on-chip or implantable systems that are multi-modal and mechanically soft

Highly conductive, stretchable, and cell‐adhesive hydrogel by nanoclay doping

Electrically conductive materials that mimic physical and biological properties of tissues are urgently required for seamless brain–machine interfaces. Here, a multinetwork hydrogel combining electrical conductivity of 26 S m−1, stretchability of 800%, and tissue‐like elastic modulus of 15 kPa with mimicry of the extracellular matrix is reported. Engineering this unique set of properties is enabled by a novel in‐scaffold polymerization approach. Colloidal hydrogels of the nanoclay Laponite are employed as supports for the assembly of secondary polymer networks. Laponite dramatically increases the conductivity of in‐scaffold polymerized poly(ethylene‐3,4‐diethoxy thiophene) in the absence of other dopants, while preserving excellent stretchability. The scaffold is coated with a layer containing adhesive peptide and polysaccharide dextran sulfate supporting the attachment, proliferation, and neuronal differentiation of human induced pluripotent stem cells directly on the surface of conductive hydrogels. Due to its compatibility with simple extrusion printing, this material promises to enable tissue‐mimetic neurostimulating electrodes

Electrochemically driven assembly of chitosan hydrogels on PEDOT surfaces

Hydrogels are attracting interest in the field of bioelectronics due to their ability to serve as coatings on electrodes, improving the electrochemical interface, addressing the mechanical mismatch, and offering potential for localized drug or cell delivery. Challenges persist in integrating hydrogels with electrodes typically composed of metals and/or organic semiconductors. Here, an electrochemically driven method is introduced for direct growth of chitosan hydrogels onto poly(3,4-ethylenedioxythiophene) (PEDOT) surfaces. The growth of ionic gelation chitosan is triggered by electrical release of a specific dopant, tripolyphosphate (TPP), from PEDOT. As a result, chitosan hydrogels grow directly from the PEDOT surface and firmly attach to it. Although this process temporarily reduces PEDOT to the benzoid structure, its unique electroactivity allows for reversible conversion to the quinoid structure after chitosan hydrogel assembly. Once assembled, the chitosan hydrogel coating can be further functionalized. The introduction of covalent cross-links and incorporation of additional interpenetrating polymer networks (IPNs) are explored. Electrochemical characterization reveals that an interface with favorable properties is formed between PEDOT and ionic-covalent chitosan, functionalized with a PEDOT IPN. The electroactivity of the proposed method surpasses any other PEDOT/chitosan system reported in the literature. These results underscore the potential of this material for bioelectronics applications

A multimodal neuroprosthetic interface to record, modulate and classify electrophysiological correlates of cognitive function

Most mental disorders are characterised by impaired cognitive function and behaviour control. Their often chronic reoccurring nature and the lack of efficient therapies necessitate the development of new treatment strategies. Brain-computer interfaces, equipped with multiple sensing and stimulation abilities, offer a new toolbox, whose suitability for diagnosis and therapy of mental disorders has not yet been explored. Here, we developed a soft and multimodal neuroprosthesis to measure and modulate prefrontal neurophysiological features of neuropsychiatric symptoms. We implanted the device epidurally above the medial prefrontal cortex of rats and obtained auditory event-related brain potentials reflecting intact neural stimulus processing and alcohol-induced neural impairments. Moreover, implant-driven electrical and pharmacological stimulation enabled successful modulation of neural activity. Finally, we developed machine learning algorithms which can deal with sparsity in the data and distinguish effects with high accuracy. Our work underlines the potential of multimodal bioelectronic systems to enable a personalised and optimised therapy

Rapid prototyping of soft bioelectronic implants for use as neuromuscular interfaces

Neuromuscular interfaces are required to translate bioelectronic technologies for application in clinical medicine. Here, by leveraging the robotically controlled ink-jet deposition of low-viscosity conductive inks, extrusion of insulating silicone pastes and in situ activation of electrode surfaces via cold-air plasma, we show that soft biocompatible materials can be rapidly printed for the on-demand prototyping of customized electrode arrays well adjusted to specific anatomical environments, functions and experimental models. We also show, with the monitoring and activation of neuronal pathways in the brain, spinal cord and neuromuscular system of cats, rats and zebrafish, that the printed bioelectronic interfaces allow for long-term integration and functional stability. This technology might enable personalized bioelectronics for neuroprosthetic applications

Electro-assisted printing of soft hydrogels via controlled electrochemical reactions

Hydrogels underpin many applications in tissue engineering, cell encapsulation, drug delivery and bioelectronics. Methods improving control over gelation mechanisms and patterning are still needed. Here we explore a less-known gelation approach relying on sequential electrochemical–chemical–chemical (ECC) reactions. An ionic species and/or molecule in solution is oxidised over a conductive surface at a specific electric potential. The oxidation generates an intermediate species that reacts with a macromolecule, forming a hydrogel at the electrode–electrolyte interface. We introduce potentiostatic control over this process, allowing the selection of gelation reactions and control of hydrogel growth rate. In chitosan and alginate systems, we demonstrate precipitation, covalent and ionic gelation mechanisms. The method can be applied in the polymerisation of hybrid systems consisting of more than one polymer. We demonstrate concomitant deposition of the conductive polymer Poly(3,4-ethylenedioxythiophene) (PEDOT) and alginate. Deposition of the hydrogels occurs in small droplets held between a conductive plate (working electrode, WE), a printing nozzle (counter electrode, CE) and a pseudoreference electrode (reference electrode, RE). We install this setup on a commercial 3D printer to demonstrate patterning of adherent hydrogels on gold and flexible ITO foils. Electro-assisted printing may contribute to the integration of well-defined hydrogels on hybrid electronic-hydrogel devices for bioelectronics applications

Electrically controlled click‐chemistry for assembly of bioactive hydrogels on diverse micro‐ and flexible electrodes

The seamless integration of electronics with living matter requires advanced materials with programmable biological and engineering properties. Here electrochemical methods to assemble semi-synthetic hydrogels directly on electronically conductive surfaces are explored. Hydrogels consisting of poly (ethylene glycol) (PEG) and heparin building blocks are polymerized by spatially controlling the click reaction between their thiol and maleimide moieties. The gels are grown as conformal coatings or 2D patterns on ITO, gold, and PtIr. This study demonstrates that such coatings significantly influence the electrochemical properties of the metal-electrolyte interface, likely due to space charge effects in the gels. Further a promising route toward engineering and electrically addressable extracellular matrices by printing arrays of gels with binary cell adhesiveness on flexible conductive surfaces is highlighted

Cytocompatible, injectable, and electroconductive soft adhesives with hybrid covalent/noncovalent dynamic network

Synthetic conductive biopolymers have gained increasing interest in tissue engineering, as they can provide a chemically defined electroconductive and biomimetic microenvironment for cells. In addition to low cytotoxicity and high biocompatibility, injectability and adhesiveness are important for many biomedical applications but have proven to be very challenging. Recent results show that fascinating material properties can be realized with a bioinspired hybrid network, especially through the synergy between irreversible covalent crosslinking and reversible noncovalent self‐assembly. Herein, a polysaccharide‐based conductive hydrogel crosslinked through noncovalent and reversible covalent reactions is reported. The hybrid material exhibits rheological properties associated with dynamic networks such as self‐healing and stress relaxation. Moreover, through fine‐tuning the network dynamics by varying covalent/noncovalent crosslinking content and incorporating electroconductive polymers, the resulting materials exhibit electroconductivity and reliable adhesive strength, at a similar range to that of clinically used fibrin glue. The conductive soft adhesives exhibit high cytocompatibility in 2D/3D cell cultures and can promote myogenic differentiation of myoblast cells. The heparin‐containing electroconductive adhesive shows high biocompatibility in immunocompetent mice, both for topical application and as injectable materials. The materials could have utilities in many biomedical applications, especially in the area of cardiovascular diseases and wound dressing