RESOURCES

Abstract
Most mental disorders, such as addictive diseases or schizophrenia, are characterized by impaired cognitive function and behavior control originating from disturbances within prefrontal neural networks. 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. This study, therefore, aimed to develop a biocompatible and multimodal neuroprosthesis to measure and modulate prefrontal neurophysiological features of neuropsychiatric symptoms. We used a 3D-printing technology to rapidly prototype customized bioelectronic implants through robot-controlled deposition of soft silicones and a conductive platinum ink. We implanted the device epidurally above the medial prefrontal cortex of rats and obtained auditory event-related brain potentials in treatment-naïve animals, after alcohol administration and following neuromodulation through implant-driven electrical brain stimulation and cortical delivery of the anti-relapse medication naltrexone. Towards smart neuroprosthetic interfaces, we furthermore developed machine learning algorithms to autonomously classify treatment effects within the neural recordings. The neuroprosthesis successfully captured neural activity patterns reflecting intact stimulus processing and alcohol-induced neural depression. Moreover, implant-driven electrical and pharmacological stimulation enabled successful enhancement of neural activity. A machine learning approach based on stepwise linear discriminant analysis was able to deal with sparsity in the data and distinguished treatments with high accuracy. Our work demonstrates the feasibility of multimodal bioelectronic systems to monitor, modulate and identify healthy and affected brain states with potential use in a personalized and optimized therapy of neuropsychiatric disorders.

Abstract
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.

Abstract
Abstract 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.

Abstract
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.

Abstract
Development of inexpensive, disposable, use-at-home, personalised health wearables can revolutionise clinical trial design and clinical care. Recent approaches have focused on electronic skins, which are complex systems of sensors and wiring produced by integration of multiple materials and layers. The requirement for high-end clean room microfabrication techniques create challenges for the development of such devices. Drawing inspiration from the ancient art of henna tattoos, where an artist draws designs directly on the hand by extruding a decorative ink, we developed a simple strategy for direct writing (3D printing) of bioelectronic sensors on textile. The sensors are realised using a very limited set of low-cost inks composed only of graphite flakes and silicone. By adapting sensor architectures in two dimensions, we produced electromyography (EMG), strain and pressure sensors. The sensors are printed directly onto stretchable textile (cotton) gloves and function as an integrated multimodal monitoring system for hand function. Gloves demonstrated functionality and stability by recording simultaneous readings of pinch strength, thumb movement (flexion) and EMG of the abductor pollicis brevis muscle over 5 days of daily recordings. Our approach is targeted towards a home based monitoring of hand function, with potential applications across a range of neurological and musculoskeletal conditions.

Abstract
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.