Organic electrode coatings for next-generation neural interfaces

Traditional neuronal interfaces utilize metallic electrodes which in recent years have reached a plateau in terms of the ability to provide safe stimulation at high resolution or rather with high densities of microelectrodes with improved spatial selectivity. To achieve higher resolution it has become clear that reducing the size of electrodes is required to enable higher electrode counts from the implant device. The limitations of interfacing electrodes including low charge injection limits, mechanical mismatch and foreign body response can be addressed through the use of organic electrode coatings which typically provide a softer, more roughened surface to enable both improved charge transfer and lower mechanical mismatch with neural tissue. Coating electrodes with conductive polymers or carbon nanotubes offers a substantial increase in charge transfer area compared to conventional platinum electrodes. These organic conductors provide safe electrical stimulation of tissue while avoiding undesirable chemical reactions and cell damage. However, the mechanical properties of conductive polymers are not ideal, as they are quite brittle. Hydrogel polymers present a versatile coating option for electrodes as they can be chemically modified to provide a soft and conductive scaffold. However, the in vivo chronic inflammatory response of these conductive hydrogels remains unknown. A more recent approach proposes tissue engineering the electrode interface through the use of encapsulated neurons within hydrogel coatings. This approach may provide a method for activating tissue at the cellular scale, however, several technological challenges must be addressed to demonstrate feasibility of this innovative idea. The review focuses on the various organic coatings which have been investigated to improve neural interface electrodes

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Conducting polymer-hydrogels for medical electrode applications

Conducting polymers hold significant promise as electrode coatings; however, they are characterized by inherently poor mechanical properties. Blending or producing layered conducting polymers with other polymer forms, such as hydrogels, has been proposed as an approach to improving these properties. There are many challenges to producing hybrid polymers incorporating conducting polymers and hydrogels, including the fabrication of structures based on two such dissimilar materials and evaluation of the properties of the resulting structures. Although both fabrication and evaluation of structure–property relationships remain challenges, materials comprised of conducting polymers and hydrogels are promising for the next generation of bioactive electrode coatings

Mechanical characteristics of swollen gellan gum hydrogels

The behavior of swollen gellan gum hydrogels in terms of mechanical properties, weight loss, and cell growth inhibition of leachates is presented. Low-acyl gellan gum (LAGG), high-acyl gellan gum (HAGG), and a HAGG–LAGG blend were soaked in phosphate-buffered saline (PBS) at pH 7.4 and 37°C for up to 168 days. The gels exhibited their maximum mass loss and swelling after 28 days of immersion in PBS. LAGG gels exhibited lower value for mass loss and the chain-release diffusion coefficient than gels consisting of HAGG and the HAGG–LAGG blend. The change in mechanical and rheological characteristics during soaking of the three hydrogels was attributed to mass loss, while LAGG hydrogels also showed evidence of effects because of cation exchange with the surrounding medium. The mechanical characteristics of the LAGG, HAGG, and blend hydrogels relative to each other did not change during swelling (although the magnitude changed). L929 fibroblasts growth inhibition tests showed that the leachate products of the three gels can be considered noncytotoxic, which is important for their future application in tissue engineering

Effect of poly(vinyl alcohol) macromer chemistry and chain interactions on hydrogel mechanical properties

Poly (vinyl alcohol) (PVA) is a versatile polymer that when modified with functional groups can be polymerized to produce hydrogels with a range of mechanical properties. In this study, PVA was modified with pendent acrylamide groups and crosslinked via photopolymerisation. The swelling behavior and tensile properties of the resulting hydrogels were studied as a function of percent macromer at the time of polymerization, functional group density, backbone molecular weight, and percent hydrolysis of the PVA. Percent macromer had the strongest influence, with tensile modulus increasing in direct proportion to increasing percent macromer. Changing the functional group density of the macromers as well as changing the molecular weight of the PVA backbone significantly impacted the swelling and mechanical behavior. Although percent hydrolysis of the PVA backbone resulted only in slight variations in the network, it did prove to be a significant variable. However, it was also found that the tensile modulus was directly related to the amount of polymer in the hydrogel. Rheological studies demonstrated that by increasing the number of chain interactions in solution (i.e., increasing the percent macromer, etc.) the resulting network produced was more interconnected and thus stronger. Overall, it was found that hydrogels produced from PVA macromers that had larger molecular weights and more functional groups per PVA chain and were less hydrophilic and formulated into higher percent macromer solutions were stronger, stiffer materials

A critical review of cell culture strategies for modelling intracortical brain implant material reactions

The capacity to predict in vivo responses to medical devices in humans currently relies greatly on implantation in animal models. Researchers have been striving to develop in vitro techniques that can overcome the limitations associated with in vivo approaches. This review focuses on a critical analysis of the major in vitro strategies being utilized in laboratories around the world to improve understanding of the biological performance of intracortical, brain-implanted microdevices. Of particular interest to the current review are in vitro models for studying cell responses to penetrating intracortical devices and their materials, such as electrode arrays used for brain computer interface (BCI) and deep brain stimulation electrode probes implanted through the cortex. A background on the neural interface challenge is presented, followed by discussion of relevant in vitro culture strategies and their advantages and disadvantages. Future development of 2D culture models that exhibit developmental changes capable of mimicking normal, postnatal development will form the basis for more complex accurate predictive models in the future. Although not within the scope of this review, innovations in 3D scaffold technologies and microfluidic constructs will further improve the utility of in vitro approaches

New methods for the assessment of in vitro and in vivo stress cracking in biomedical polyurethanes

This article describes a new test method for the assessment of the severity of environmental stress cracking of biomedical polyurethanes in a manner that minimizes the degree of subjectivity involved. The effect of applied strain and acetone pre-treatment on degradation of Pellethane 2363 80A and Pellethane 2363 55D polyurethanes under in vitro and in vivo conditions is studied. The results are presented using a magnification-weighted image rating system that allows the semi-quantitative rating of degradation based on distribution and severity of surface damage. Devices for applying controlled strain to both flat sheet and tubing samples are described. The new rating system consistently discriminated between. the effects of acetone pre-treatments, strain and exposure times in both in vitro and in vivo experiments. As expected, P80A underwent considerable stress cracking compared with P55D. P80A produced similar stress crack ratings in both in vivo and in vitro experiments, however P55D performed worse under in vitro conditions compared with in vivo. This result indicated that care must be taken when interpreting in vitro results in the absence of in vivo data. (C) 2001 Elsevier Science Ltd. All rights reserved

NMR measurement of small-molecule diffusionin PVA hydrogels: a comparison of CONVEX and standard PGSE methods

Hydrogels are biocompatible polymeric materials that are becoming increasingly\ud important in biomedical applications, such as drug delivery and tissue engineering.\ud Understanding of small-molecule diffusion in these systems is important in the contexts\ud of controlled drug release; transport of nutrients (e.g., O2 and growth factors) into the\ud gel; and transport of cellular waste out of the gel. In this work, the diffusion coefficient of the aromatic amino acid phenylalanine (Phe) in non-crosslinked and crosslinked poly(vinyl alcohol) (PVA) hydrogels was measured using two NMR diffusion methods, CONVEX and the standard pulsed-gradient spin-echo (PGSE). Pulsed field-gradient\ud (PFG) NMR measurements provide the advantage of measuring the molecular selfdiffusion\ud coefficient directly and without having to rely on the physical release of the\ud solute, but are often difficult to perform in tissues and hydrated polymers due to a large water signal. CONVEX is a recently proposed diffusion method that alleviates this\ud problem by means of NMR excitation-sculpting water suppression. In the measurements\ud presented here, CONVEX results were superior to those from PGSE measurements with\ud respect to every test applied, and enabled a reliable comparison of the diffusion\ud coefficients of Phe in crosslinked and non-crosslinked hydrogels. The value of D(Phe)\ud was smaller in the non-crosslinked hydrogel than in the crosslinked gel; this finding is\ud discussed in the paper

Emerging trends in the development of flexible optrode arrays for electrophysiology

Optical-electrode (optrode) arrays use light to modulate excitable biological tissues and/or transduce bioelectrical signals into the optical domain. Light offers several advantages over electrical wiring, including the ability to encode multiple data channels within a single beam. This approach is at the forefront of innovation aimed at increasing spatial resolution and channel count in multichannel electrophysiology systems. This review presents an overview of devices and material systems that utilize light for electrophysiology recording and stimulation. The work focuses on the current and emerging methods and their applications, and provides a detailed discussion of the design and fabrication of flexible arrayed devices. Optrode arrays feature components non-existent in conventional multi-electrode arrays, such as waveguides, optical circuitry, light-emitting diodes, and optoelectronic and light-sensitive functional materials, packaged in planar, penetrating, or endoscopic forms. Often these are combined with dielectric and conductive structures and, less frequently, with multi-functional sensors. While creating flexible optrode arrays is feasible and necessary to minimize tissue–device mechanical mismatch, key factors must be considered for regulatory approval and clinical use. These include the biocompatibility of optical and photonic components. Additionally, material selection should match the operating wavelength of the specific electrophysiology application, minimizing light scattering and optical losses under physiologically induced stresses and strains. Flexible and soft variants of traditionally rigid photonic circuitry for passive optical multiplexing should be developed to advance the field. We evaluate fabrication techniques against these requirements. We foresee a future whereby established telecommunications techniques are engineered into flexible optrode arrays to enable unprecedented large-scale high-resolution electrophysiology systems