Developing technologies to assess vascular ageing: a roadmap from VascAgeNet.

Vascular ageing is the deterioration of arterial structure and function which occurs naturally with age, and which can be accelerated with disease. Measurements of vascular ageing are emerging as markers of cardiovascular risk, with potential applications in disease diagnosis and prognosis, and for guiding treatments. However, vascular ageing is not yet routinely assessed in clinical practice. A key step towards this is the development of technologies to assess vascular ageing. In this Roadmap, experts discuss several aspects of this process, including: measurement technologies; the development pipeline; clinical applications; and future research directions. The Roadmap summarises the state of the art, outlines the major challenges to overcome, and identifies potential future research directions to address these challenges.

Towards ultrasound wearable technology for cardiovascular monitoring: from device development to clinical validation.

The advent of flexible, compact, energy-efficient, robust, and user-friendly wearables has significantly impacted the market growth, with an estimated value of 61.30 billion USD in 2022. Wearable sensors have revolutionized in-home health monitoring by warranting continuous measurements of vital parameters. Ultrasound is used to non-invasively, safely, and continuously record vital parameters. The next generation of smart ultrasonic devices for healthcare integrates microelectronics with flexible, stretchable patches and body-conformable devices. They offer not only wearability, and user comfort, but also higher tracking accuracy of immediate changes of cardiovascular parameters. Moreover, due to the fixed adhesion to the skin, errors derived from probe placement or patient movement are mitigated, even though placement at the correct anatomical location is still critical and requires a user's skill and knowledge. In this review, the steps required to bring wearable ultrasonic systems into the medical market (technologies, device development, signal-processing, in-lab validation, and, finally, clinical validation) are discussed. The next generation of vascular ultrasound and its future research directions offer many possibilities for modernizing vascular health assessment and the quality of personalized care for home and clinical monitoring.

Fabrication and Characterization of PDMS Waveguides for Flexible Optrodes.

With the growth of optogenetic research, the demand for optical probes tailored to specific applications is ever rising. Specifically, for applications like the coiled cochlea of the inner ear, where planar, stiff, and nonconformable probes can hardly be used, transitioning from commonly used stiff glass fibers to flexible probes is required, especially for long-term use. Following this demand, polydimethylsiloxane (PDMS) with its lower Young's modulus compared to glass fibers can serve as material of choice. Hence, the long-term usability of PDMS as a waveguide material with respect to variations in transmission and refractive index over time is investigated. Different manufacturing methods for PDMS-based flexible waveguides are established and compared with the aim to minimize optical losses and thus maximize optical output power. Finally, the waveguides with lowest optical losses (-4.8 dB cm-1 ± 1.3 dB cm-1 at 472 nm) are successfully inserted into the optogenetically modified cochlea of a Mongolian gerbil (Meriones unguiculatus), where optical stimuli delivered by the waveguides evoked robust neuronal responses in the auditory pathway.

Colonic Electrical Stimulation for Chronic Constipation: A Perspective Review.

Chronic constipation affects around 20% of the population and there is no efficient solution. This perspective review explores the potential of colonic electric stimulation (CES) using neural implants and methods of bioelectronic medicine as a therapeutic way to treat chronic constipation. The review covers the neurophysiology of colonic peristaltic function, the pathophysiology of chronic constipation, the technical aspects of CES, including stimulation parameters, electrode placement, and neuromodulation target selection, as well as a comprehensive analysis of various animal models highlighting their advantages and limitations in elucidating the mechanistic insights and translational relevance for CES. Finally, the main challenges and trends in CES are discussed.

Recording Quality Is Systematically Related to Electrode Impedance.

Extracellular recordings with planar microelectrodes are the gold standard technique for recording the fast action potentials of neurons in the intact brain. The introduction of microfabrication techniques has revolutionized the in vivo recording of neuronal activity and introduced high-density, multi-electrode arrays that increase the spatial resolution of recordings and the number of neurons that can be simultaneously recorded. Despite these innovations, there is still debate about the ideal electrical transfer characteristics of extracellular electrodes. This uncertainty is partly due to the lack of systematic studies comparing electrodes with different characteristics, particularly for chronically implanted arrays over extended time periods. Here a high-density, flexible, and thin-film array is fabricated and tested, containing four distinct electrode types differing in surface material and surface topology and, thus, impedance. It is found that recording quality is strongly related to electrode impedance with signal amplitude and unit yield negatively correlated to impedance. Electrode impedances are stable for the duration of the experiment (up to 12 weeks) and recording quality does not deteriorate. The findings support the expectation from the theory that recording quality will increase as impedance decreases.

Biomimetic computer-to-brain communication enhancing naturalistic touch sensations via peripheral nerve stimulation.

Artificial communication with the brain through peripheral nerve stimulation shows promising results in individuals with sensorimotor deficits. However, these efforts lack an intuitive and natural sensory experience. In this study, we design and test a biomimetic neurostimulation framework inspired by nature, capable of "writing" physiologically plausible information back into the peripheral nervous system. Starting from an in-silico model of mechanoreceptors, we develop biomimetic stimulation policies. We then experimentally assess them alongside mechanical touch and common linear neuromodulations. Neural responses resulting from biomimetic neuromodulation are consistently transmitted towards dorsal root ganglion and spinal cord of cats, and their spatio-temporal neural dynamics resemble those naturally induced. We implement these paradigms within the bionic device and test it with patients (ClinicalTrials.gov identifier NCT03350061). He we report that biomimetic neurostimulation improves mobility (primary outcome) and reduces mental effort (secondary outcome) compared to traditional approaches. The outcomes of this neuroscience-driven technology, inspired by the human body, may serve as a model for advancing assistive neurotechnologies.

NeuroBus - Architecture for an Ultra-Flexible Neural Interface.

This article presents the system architecture for an implant concept called NeuroBus. Tiny distributed direct digitizing neural recorder ASICs on an ultra-flexible polyimide substrate are connected in a bus-like structure, allowing short connections between electrode and recording front-end with low wiring effort and high customizability. The small size (344 µm × 294 µm) of the ASICs and the ultraflexible substrate allow a low bending stiffness, enabling the implant to adapt to the curvature of the brain and achieving high structural biocompatibility. We introduce the architecture, the integrated building blocks, and the post-CMOS processes required to realize a NeuroBus, and we characterize the prototyped direct digitizing neural recorder front-end as well as polyimide-based ECoG brain interface. A rodent animal model is further used to validate the joint capability of the recording front-end and thin-film electrode array.

From Bioinspired Topographies toward Non-Wettable Neural Implants.

The present study investigates different design strategies to produce non-wettable micropatterned surfaces. In addition to the classical method of measuring the contact angle, the non-wettability is also discussed by means of the immersion test. Inspired by non-wettable structures found in nature, the effects of features such as reentrant cavities, micropillars, and overhanging layers are studied. We show that a densely populated array of small diameter cavities exhibits superior non-wettability, with 65% of the cavities remaining intact after 24 h of full immersion in water. In addition, it is suggested that the wetting transition time is influenced by the length of the overhanging layer as well as by the number of columns within the cavity. Our findings indicate a non-wetting performance that is three times longer than previously reported in the literature for a small, densely populated design with cavities as small as 10 µm in diameter. Such properties are particularly beneficial for neural implants as they may reduce the interface between the body fluid and the solid state, thereby minimiing the inflammatory response following implantation injury. In order to assess the effectiveness of this approach in reducing the immune response induced by neural implants, further in vitro and in vivo studies will be essential.

Neuromuscular adaptations after osseointegration of a bone-anchored prosthesis in a unilateral transfemoral amputee - a case study.

PURPOSE: Many individuals with a lower limb amputation experience problems with the fitting of the socket of their prosthesis, leading to dissatisfaction or device rejection. Osseointegration (OI)- the implantation of a shaft directly interfacing with the remaining bone- is an alternative for these patients. In this observational study, we investigated how bone anchoring influences neuromuscular parameters during balance control in a patient with a unilateral transfemoral amputation. MATERIAL AND METHODS: Center of pressure (CoP) and electromyography (EMG) signals from muscles controlling the hip and the ankle of the intact leg were recorded during quiet standing six months before and one and a half years after this patient underwent an OI surgery. Results were compared to a control group of nine able-bodied individuals. RESULTS: Muscle co-activation and EMG intensity decreased after bone anchoring, approaching the levels of able-bodied individuals. Muscle co-activation controlling the ankle decreased in the high-frequency range, and the EMG intensity spectrum decreased in the lower-frequency range for all muscles when vision was allowed. With eyes closed, the ankle extensor muscle showed an increased EMG intensity in the high-frequency range post-surgery. CoP length increased in the mediolateral direction of the amputated leg. CONCLUSIONS: These findings point to shifts in the patient's neuromuscular profile towards the one of able-bodied individuals.

Highly conformable chip-in-foil implants for neural applications.

Demands for neural interfaces around functionality, high spatial resolution, and longevity have recently increased. These requirements can be met with sophisticated silicon-based integrated circuits. Embedding miniaturized dice in flexible polymer substrates significantly improves their adaptation to the mechanical environment in the body, thus improving the systems' structural biocompatibility and ability to cover larger areas of the brain. This work addresses the main challenges in developing a hybrid chip-in-foil neural implant. Assessments considered (1) the mechanical compliance to the recipient tissue that allows a long-term application and (2) the suitable design that allows the implant's scaling and modular adaptation of chip arrangement. Finite element model studies were performed to identify design rules regarding die geometry, interconnect routing, and positions for contact pads on dice. Providing edge fillets in the die base shape proved an effective measure to improve die-substrate integrity and increase the area available for contact pads. Furthermore, routing of interconnects in the immediate vicinity of die corners should be avoided, as the substrate in these areas is prone to mechanical stress concentration. Contact pads on dice should be placed with a clearance from the die rim to avoid delamination when the implant conforms to a curvilinear body. A microfabrication process was developed to transfer, align, and electrically interconnect multiple dice into conformable polyimide-based substrates. The process enabled arbitrary die shape and size over independent target positions on the conformable substrate based on the die position on the fabrication wafer.

Multilayer Arrays for Neurotechnology Applications (MANTA): Chronically Stable Thin-Film Intracortical Implants.

Flexible implantable neurointerfaces show great promise in addressing one of the major challenges of implantable neurotechnology, namely the loss of signal connected to unfavorable probe tissue interaction. The authors here show how multilayer polyimide probes allow high-density intracortical recordings to be combined with a reliable long-term stable tissue interface, thereby progressing toward chronic stability of implantable neurotechnology. The probes could record 10-60 single units over 5 months with a consistent peak-to-peak voltage at dimensions that ensure robust handling and insulation longevity. Probes that remain in intimate contact with the signaling tissue over months to years are a game changer for neuroscience and, importantly, open up for broader clinical translation of systems relying on neurotechnology to interface the human brain.

Flexible Ultrathin Chip-Film Patch for Electronic Component Integration and Encapsulation using Atomic Layer-Deposited Al2O3-TiO2 Nanolaminates.

Plasma-enhanced atomic layer deposition (PEALD) is utilized to improve the barrier properties of an organic chip-film patch (CFP) when it is used as an implant to prevent moisture and ions from migrating into the embedded electronic circuits. For this purpose, surface condition and material properties of eight modifications of Al2O3-TiO2 nanolaminates sequentially deposited on polyimide PI-2611 films are evaluated in detail. The effect of stress-induced warpage of the deposited Al2O3-TiO2 on the wafer level is calculated with the Stoney equation and reveals higher tensile stress values while increasing the thickness of Al2O3-TiO2 nanolaminates from 20 up to 80 nm. Contact angle measurement and atomic force microscopy are used to investigate the surface energy and wettability, as well as the surface morphology of polyimide-Al2O3-TiO2 interfaces. We show that plasma treatment of pristine polyimide leads to an enhanced adhesion force of the PEAL-deposited layer by a factor of 1.3. The water vapor transmission rate (WVTR) is determined by exposing the coated polyimide films to 85% humidity and 23 °C and yields down to 1.58 × 10-3 g(H2O)/(m2 d). The data obtained are compared with alternative coating processes using the polymers parylene-C and benzocyclobutene (BCB). The latter shows higher WVTR values of 1.2 × 10-1 and 1.7 × 10-1 g(H2O)/(m2 d) compared to the PEALD-PI-2611 systems, indicating lower barrier properties. Two Al2O3-TiO2 modifications with low WVTR values have been chosen for encapsulating the CFP substrates and exposing them in a long-time experiment to chemical and mechanical loads in a chamber filled with phosphate-buffered saline at 37 °C, pH 7.3, and a cyclically applied pressure of 160 mbar (∼120 mm Hg). The electrical leakage behavior of the CFP systems is measured and reveals reliable electrical long-term stability far beyond 11 months, highlighting the great potential of PEALD-encapsulated CFPs.

Toward higher-performance bionic limbs for wider clinical use.

Most prosthetic limbs can autonomously move with dexterity, yet they are not perceived by the user as belonging to their own body. Robotic limbs can convey information about the environment with higher precision than biological limbs, but their actual performance is substantially limited by current technologies for the interfacing of the robotic devices with the body and for transferring motor and sensory information bidirectionally between the prosthesis and the user. In this Perspective, we argue that direct skeletal attachment of bionic devices via osseointegration, the amplification of neural signals by targeted muscle innervation, improved prosthesis control via implanted muscle sensors and advanced algorithms, and the provision of sensory feedback by means of electrodes implanted in peripheral nerves, should all be leveraged towards the creation of a new generation of high-performance bionic limbs. These technologies have been clinically tested in humans, and alongside mechanical redesigns and adequate rehabilitation training should facilitate the wider clinical use of bionic limbs.

A flexible protruding microelectrode array for neural interfacing in bioelectronic medicine.

Recording neural signals from delicate autonomic nerves is a challenging task that requires the development of a low-invasive neural interface with highly selective, micrometer-sized electrodes. This paper reports on the development of a three-dimensional (3D) protruding thin-film microelectrode array (MEA), which is intended to be used for recording low-amplitude neural signals from pelvic nervous structures by penetrating the nerves transversely to reduce the distance to the axons. Cylindrical gold pillars (Ø 20 or 50 µm, ~60 µm height) were fabricated on a micromachined polyimide substrate in an electroplating process. Their sidewalls were insulated with parylene C, and their tips were optionally modified by wet etching and/or the application of a titanium nitride (TiN) coating. The microelectrodes modified by these combined techniques exhibited low impedances (~7 kΩ at 1 kHz for Ø 50 µm microelectrode with the exposed surface area of ~5000 µm²) and low intrinsic noise levels. Their functionalities were evaluated in an ex vivo pilot study with mouse retinae, in which spontaneous neuronal spikes were recorded with amplitudes of up to 66 µV. This novel process strategy for fabricating flexible, 3D neural interfaces with low-impedance microelectrodes has the potential to selectively record neural signals from not only delicate structures such as retinal cells but also autonomic nerves with improved signal quality to study neural circuits and develop stimulation strategies in bioelectronic medicine, e.g., for the control of vital digestive functions.

Multifaceted understanding of human nerve implants to design optimized electrodes for bioelectronics.

Bioelectronic medicine is a promising venue for treatment of disabilities using implantable neural interfaces. Peripheral neurostimulation of residual nerves recently enabled multiple functional benefits in amputees. Despite the preliminary promising impact on patients' life, the over-time stability of implants and the related nerve reactions are unclear. To unveil the mechanisms and inform the design of better nerve-electrode interfaces, we engaged a multifaceted approach, merging functional responses from patients, their histological data, and corresponding computational modelling. Neurostimulation evoked different selective sensation locations and qualities over-time, with respective perceptual thresholds, that showed different degree of time stabilities dependent from the stimulating active sites. The histological analysis after explant showed mild tissue reactions, while electromechanically active sites and substrates remained conserved. Computational models, based on patients' histology, revealed the direct influence of the simulated tissue reaction to change of thresholds and type of perceived sensations. Novel insights of electrode biocompatibility was observed compared to animals and the increase of thresholds could be predicted computationally. This multifaced framework suggest that future intraneural implants should have easier implantation and higher biocompatibility counteracting the sensations changes through AI-based stimulations and electrode coatings.

Towards non-wettable neural electrodes for a minimized foreign body reaction.

Functionality of neural implants can be seriously impaired by scarring during the foreign body reaction (FBR). Tailoring of the material-tissue interface is supposed to modulate part of the FBR. Surface structures might physically modulate the foreign body reaction in the acute phase directly after implantation. This work focuses on fabrication and characterization of bioinspired microtextures comprising reentrant cavities with non-wettable surface characteristics. The Selected microstructure patterns were fabricated using direct laser writing and were characterized by means of contact angle measurements and immersion tests. Clinical Relevance-Suggested by the outcome of this study, the proposed surface characteristics in neural interface can impact the wetting properties of the interface, hence, influence the interaction between the body fluid with the surface of the neural implant. Future studies should address the impact of the suggested design criterion and their applicability in improving the long-term stability of neural implants.

New Insights into In Vivo Dopamine Physiology and Neurostimulation: A Fiber Photometry Study Highlighting the Impact of Medial Forebrain Bundle Deep Brain Stimulation on the Nucleus Accumbens.

New technologies, such as fiber photometry, can overcome long-standing methodological limitations and promote a better understanding of neuronal mechanisms. This study, for the first time, aimed at employing the newly available dopamine indicator (GRABDA2m) in combination with this novel imaging technique. Here, we present a detailed methodological roadmap leading to longitudinal repetitive transmitter release monitoring in in vivo freely moving animals and provide proof-of-concept data. This novel approach enables a fresh look at dopamine release patterns in the nucleus accumbens, following the medial forebrain bundle (mfb) DBS in a rodent model. Our results suggest reliable readouts of dopamine levels over at least 14 days of DBS-induced photometric measurements. We show that mfb-DBS can elicit an increased dopamine response during stimulation (5 s and 20 s DBS) compared to its baseline dopamine activity state, reaching its maximum peak amplitude in about 1 s and then recovering back after stimulation. The effect of different DBS pulse widths (PWs) also suggests a potential differential effect on this neurotransmitter response, but future studies would need to verify this. Using the described approach, we aim to gain insights into the differences between pathological and healthy models and to elucidate more exhaustively the mechanisms under which DBS exerts its therapeutic action.

An optoelectronic neural interface approach for precise superposition of optical and electrical stimulation in flexible array structures.

Optical stimulation of genetically modified nerve cells has become one of the state-of-the-art methods in neuroscience. This so-called optogenetic approach allows cell-type specific activation in comparison to more generalized electrical stimulation. Combinations of both stimulation modalities would be desirable to investigate effects in detail and specify differences. This work presents the design of a miniaturized optoelectronic device that allows optical and electrical activation at the same spot. Indium tin oxide (ITO), which is transparent to visible light, has been chosen as electrode material. Light emitting diodes were assembled on a polyimide substrate with integrated interconnection lines, directly behind the electrodes to compare optical with electrical stimulation. The optical transparency of the ITO-polyimide layer stack was investigated and showed sufficient transmission in the required wavelength range. ITO electrodes with diameters up to 1000 µm were electrochemically characterized using electrical impedance spectroscopy (EIS). Several diameters did show comparable results to platinum, a commonly used electrode material. Fully assembled devices were used in combination an ex vivo setting with genetically modified retina to demonstrate the functionality of this approach. Retinal ganglion cells were excited by both, optical and electrical stimulation at the same spot and signals were recorded via standard microelectrode arrays (MEA) as reference. The simultaneous stimulation and recording of directly evoked action potentials indicates a similar mode of action of the two stimulation modalities. Further engineering work is needed to transfer the presented and proven concept into devices for chronic implantation, might it be in animal or first-in-human studies.

Corrigendum: A Psychometric Platform to Collect Somatosensory Sensations for Neuroprosthetic Use.

[This corrects the article DOI: 10.3389/fmedt.2021.619280.].