This review paper shows that tungsten should not generally be used as a chronically implanted material. The metal has a long implant history, from neuroscience, vascular medicine, radiography, orthopaedics, prosthodontics, and various other fields, primarily as a result of its high density, radiopacity, tensile strength, and yield point. However, a crucial material criterion for chronically implanted metals is their long-term resistance to corrosion in body fluids, either by inherently noble metallic surfaces, or by protective passivation layers of metal oxide. The latter is often assumed for elemental tungsten, with references to its 'inertness' and 'stability' common in the literature. This review argues that in the body, metallic tungsten fails this criterion, and will eventually dissolve into the soluble hexavalent form W6+, typically represented by the orthotungstate [Formula: see text] (monomeric tungstate) anion. This paper outlines the metal's unfavourable corrosion thermodynamics in the human physiological environment, the chemical pathways to either metallic or metal oxide dissolution, the rate-limiting steps, and the corrosion-accelerating effects of reactive oxidising species that the immune system produces post-implantation. Multiple examples of implant corrosion have been reported, with failure by dissolution to varying extents up to total loss, with associated emission of tungstate ions and elevated blood serum levels measured. The possible toxicity of these corrosion products has also been explored. As the field of medical implants grows and designers explore novel solutions to medical implant problems, the authors recommend the use of alternative materials.
Cardiac disease progression reflects the dynamic interaction between adversely remodeled neurohumoral control systems and an abnormal cardiac substrate. Vagal nerve stimulation (VNS) is an attractive neuromodulatory option to dampen this dynamic interaction; however, it is limited by off-target effects. Spatially-selective VNS (sVNS) offers a promising solution to induce cardioprotection while mitigating off-target effects by specifically targeting pre-ganglionic parasympathetic efferent cardiac fibers. This approach also has the potential to enhance therapeutic outcomes by eliminating time-consuming titration required for optimal VNS. Recent studies have demonstrated the independent modulation of breathing rate, heart rate, and laryngeal contraction through sVNS. However, the spatial organization of afferent and efferent cardiac-related fibers within the vagus nerve remains unexplored. By using trial-and-error sVNS
Abstract Electrical neurostimulation is effective in treating neurological disorders, but associated recording artefacts generally limit applications to ‘open-loop’ stimuli. Since light does not prevent concurrent electrical recordings, optogenetics enables real-time, continuous ‘closed-loop’ control of brain activity. Here we show that closed-loop optogenetic stimulation with excitatory opsins (CLOSe) affords precise manipulation of neural dynamics, both in vitro , in brain slices from transgenic mice, and in vivo , with anesthetised monkeys. We demonstrate the generation of oscillations in quiescent tissue, enhancement or suppression of endogenous patterns in active tissue, and modulation of seizure-like bursts elicited by 4-aminopyridine. New network properties, emergent under CLOSe, depended on the phase-shift imposed between neural activity and optical stimulation, and could be modelled with a nonlinear dynamical system. In particular, CLOSe could stabilise or destabilise limit cycles associated with seizure oscillations, evident from systematic changes in the variability and entropy of seizure trajectories that correlated with their altered duration and intensity. Furthermore, CLOSe was achieved using intracortical optrodes incorporating light-emitting diodes, paving the way for translation of closed-loop optogenetics towards therapeutic applications in humans.
Abstract Silicon integrated circuits (ICs) are central to the next-generation miniature active neural implants, whether packaged in soft polymers for flexible bioelectronics or implanted as bare die for neural probes. These emerging applications bring the IC closer to the corrosive body environment, raising reliability concerns, particularly for long-term clinical use. Here, we evaluated the long-term electrical and material stability of silicon-ICs from two foundries, after one-year accelerated in vitro and in vivo animal studies. The ICs featured various custom-designed test structures and were partially PDMS coated, creating two regions on each chip, uncoated “bare die” and “PDMS-coated”. During the accelerated in vitro study, ICs were electrically biased and periodically monitored. Results demonstrated stable electrical performance for at least a year, suggesting that bare die ICs can function in the body for months. Despite electrical stability, material analysis revealed chemical and electrically driven degradation of the IC passivation in the bare die regions. In contrast, PDMS-coated regions revealed no such degradation, making PDMS a highly suitable encapsulant for ICs intended for years-long implantation. Based on the new insights, guidelines are proposed that may enhance the longevity of implantable ICs, significantly broadening their applications in the biomedical field.
Abstract Spatially selective vagus nerve stimulation (sVNS) offers a promising approach for addressing heart disease with enhanced precision. Despite its therapeutic potential, VNS is limited by off‐target effects and the need for time‐consuming titration. Our research aimed to determine the spatial organization of cardiac afferent and efferent fibres within the vagus nerve of pigs to achieve targeted neuromodulation. Using trial‐and‐error sVNS in vivo and ex vivo micro‐computed tomography fascicle tracing, we found significant spatial separation between cardiac afferent and cardiac efferent fibres at the mid‐cervical level and they were localized on average on opposite sides of the nerve cross‐section. This was consistent between both in vivo and ex vivo methods. Specifically, cardiac afferent fibres were located near pulmonary fibres, consistent with findings of cardiopulmonary convergent circuits and, notably, cardiac efferent fascicles were exclusive. These cardiac efferent regions were located in close proximity to the recurrent laryngeal regions. This is consistent with the roughly equitable spread across the nerve of the afferent and efferent fibres. Our study demonstrated that targeted neuromodulation via sVNS could achieve scalable heart rate decreases without eliciting cardiac afferent‐related reflexes; this is desirable for reducing sympathetic overactivation associated with heart disease. These findings indicate that understanding the spatial organization of cardiac‐related fibres within the vagus nerve can lead to more precise and effective VNS therapy, minimizing off‐target effects and potentially mitigating the need for titration. image Key points Spatially selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. Our study reveals significant spatial separation between cardiac afferent and efferent fibres in the vagus nerve, particularly at the mid‐cervical level. Utilizing trial‐and‐error sVNS in vivo and micro‐computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects such as scalable heart rate decrease without stimulating cardiac afferent‐related reflexes. This spatial understanding opens avenues for more effective VNS therapy, minimizing off‐target effects and potentially eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions.
Objective. Neural interfaces and other implantable micro-devices that use polymer-encapsulated integrated circuits will only be allowed in medical devices when their lifetimes can be estimated from experimental data. An apparatus has been developed and tested that allows hundreds of insulated samples (interdigitated combs) to be aged under accelerated conditions of high temperature and voltage stress. Occasionally, aging is paused while the sample's impedance is measured; the impedance spectrogram may show degradation as it progresses before failure. Approach. The design was based on practical considerations which are reviewed. A Solartron Modulab provides the frequency response analyser and the femtoammeter. The apparatus can accommodate batches of samples at several temperatures and with different aging voltage waveforms. It is important to understand features of the spectra that are not due to comb–comb leakage, but come from other places (for example substrate-solution leakage); some have been observed and investigated using SPICE. Main results. The design is described in detail and test results show that it is capable of making measurements over long periods, at least up to 67 °C. Despite the size of the apparatus, background capacitance is about 1 pF and comb–comb capacitances of about 30 pF can be measured down to 10 mHz, an impedance of about 100 GΩ. An important discovery was the advantage of grounding the bathing solution, primarily in that it raises the measurement ceiling. Observation and SPICE simulation shows that leakage from the substrate to the bathing solution can give phase lags >90°, in contrast to comb–comb leakage which reduces phase lag to <90°. Significance. The value of this paper is that it will facilitate research into the endurance of small implanted devices because, given a description of a proven apparatus, researchers can start building their own apparatus relatively quickly and with confidence.
Background and Objectives: Spatially-selective vagus nerve stimulation (sVNS) offers a promising solution to mitigate the off-target effects associated with traditional VNS, potentially serving as a precise method for addressing chronic heart failure (HF) by specifically targeting efferent cardiac fibers. This approach holds the potential to enhance therapeutic outcomes by avoiding off-target effects and eliminating the current need for time-consuming titration required for optimal VNS. Recent studies have demonstrated the independent modulation of breathing rate, heart rate, and laryngeal contraction through sVNS. However, the spatial organization of afferent and efferent cardiac-related fibers within the vagus nerve remains unexplored. Methods and Results: By using trial-and-error sVNS in vivo in combination with ex vivo micro-computed tomography fascicle tracing, we show the significant spatial separation of cardiac afferent and efferent fibers (179{plus minus}55{degree sign} SD microCT, p<0.05 and 200{plus minus}137{degree sign} SD, p<0.05 sVNS - degrees of separation across a cross-section of nerve) at the mid-cervical level. Cardiac afferent fibers are located in proximity to pulmonary fibers consistent with recent findings of cardiopulmonary convergent neurons and circuits. We demonstrate the ability to selectively elicit therapeutic-related effect (heart rate decrease) without stimulating afferent-related reflexes. Conclusions: By investigating the spatial organization of cardiac-related fibers within the vagus nerve, our findings pave the way for more targeted neuromodulation, thereby reducing off-target effects and eliminating the need for titration. This, in turn, will enhance the precision and efficacy of VNS therapy in treating HF, myocardial infarction and other conditions, allowing for therapeutic effect to be achieved much sooner.
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