In order to address material limitations of biologically interfacing electrodes, modified silica nanoparticles are utilized as dopants for conducting polymers. Silica precursors are selected to form a thiol modified particle (TNP), following which the particles are oxidized to sulfonate modified nanoparticles (SNPs). The selective inclusion of hexadecyl trimethylammonium bromide allows for synthesis of both porous and nonporous SNPs. Nonporous nanoparticle doped polyethylenedioxythiophene (PEDOT) films possess low interfacial impedance, high charge injection (4.8 mC cm−2), and improved stability under stimulation compared to PEDOT/poly(styrenesulfonate). Porous SNP dopants can serve as drug reservoirs and greatly enhance the capability of conducting polymer‐based, electrically controlled drug release technology. Using the SNP dopants, drug loading and release is increased up to 16.8 times, in addition to greatly expanding the range of drug candidates to include both cationic and electroactive compounds, all while maintaining their bioactivity. Finally, the PEDOT/SNP composite is capable of precisely modulating neural activity in vivo by timed release of a glutamate receptor antagonist from coated microelectrode sites. Together, this work demonstrates the feasibility and potential of doping conducting polymers with engineered nanoparticles, creating countless options to produce composite materials for enhanced electrical stimulation, neural recording, chemical sensing, and on demand drug delivery.

BackgroundOxidative stress acts as a trigger in the course of neurodegenerative diseases and neural injuries. An antioxidant-based therapy can be effective to ameliorate the deleterious effects of oxidative stress. Resveratrol (RSV) has been shown to be effective at removing excess reactive oxygen species (ROS) or reactive nitrogen species generation in the central nervous system (CNS), but the delivery of RSV into the brain through systemic administration is inefficient. Here, we have developed a RSV delivery vehicle based on polylactic acid (PLA)-coated mesoporous silica nanoparticles (MSNPs), conjugated with a ligand peptide of low-density lipoprotein receptor (LDLR) to enhance their transcytosis across the blood–brain barrier (BBB).ResultsResveratrol was loaded into MSNPs (average diameter 200 nm, pore size 4 nm) at 16 μg/mg (w/w). As a gatekeeper, the PLA coating prevented the RSV burst release, while ROS was shown to trigger the drug release by accelerating PLA degradation. An in vitro BBB model with a co-culture of rat brain microvascular endothelial cells (RBECs) and microglia cells using Transwell chambers was established to assess the RSV delivery across BBB. The conjugation of LDLR ligand peptides markedly enhanced the migration of MSNPs across the RBECs monolayer. RSV could be released and effectively reduce the activation of the microglia cells stimulated by phorbol-myristate-acetate or lipopolysaccharide.ConclusionsThese ROS responsive LDLR peptides conjugated PLA-coated MSNPs have great potential for oxidative stress therapy in CNS.Electronic supplementary materialThe online version of this article (10.1186/s12951-018-0340-7) contains supplementary material, which is available to authorized users.

Neurotechnology is facing an exponential growth in the recent decades. Neural electrode-tissue interface research has been well recognized as an instrumental component of neurotechnology development. While satisfactory long-term performance was demonstrated in some applications, such as cochlear implants and deep brain stimulators, more advanced neural electrode devices requiring higher resolution for single unit recording or microstimulation still face significant challenges in reliability and longevity. In this article, we review the most recent findings that contribute to our current understanding of the sources of poor reliability and longevity in neural recording or stimulation, including the material failure, biological tissue response and the interplay between the two. The newly developed characterization tools are introduced from electrophysiology models, molecular and biochemical analysis, material characterization to live imaging. The effective strategies that have been applied to improve the interface are also highlighted. Finally, we discuss the challenges and opportunities in improving the interface and achieving seamless integration between the implanted electrodes and neural tissue both anatomically and functionally.

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State‐of‐the‐art intraneural electrodes made from silicon or polyimide substrates have shown promise in selectively modulating efferent and afferent activity in the peripheral nervous system. However, when chronically implanted, these devices trigger a multiphase foreign body response ending in device encapsulation. The presence of encapsulation increases the distance between the electrode and the excitable tissue, which not only reduces the recordable signal amplitude but also requires increased current to activate nearby axons. Herein, this study reports a novel conducting polymer based intraneural electrode which has Young's moduli similar to that of nerve tissue. The study first describes material optimization of the soft wire conductive matrix and evaluates their mechanical and electrochemical properties. Second, the study demonstrates 3T3 cell survival when cultured with media eluted from the soft wires. Third, the study presents acute in vivo functionality for stimulation of peripheral nerves to evoke force and compound muscle action potential in a rat model. Furthermore, comprehensive histological analyses show that soft wires elicit significantly less scar tissue encapsulation, less changes to axon size, density and morphology, and reduced macrophage activation compared to polyimide implants in the sciatic nerves at 1 month postimplantation.

Optimized square wave voltammetry for electrochemical measurement of exogenously administered MT in vivo.

Surface modification is of significant interest in biomaterials, biosensors, and device biocompatibility. Immobilization of bioactive or biomimetic molecules is a common method of disguising a foreign body as host tissue to decrease the foreign body response (FBR) and/or increase device–tissue integration. For example, in neural interfacing devices, immobilization of L1, a neuron-specific adhesion molecule, has been shown to increase neuron adhesion and reduce inflammatory gliosis on and around the implants. However, the activity of modified surfaces is limited by the relatively low concentration of the immobilized component, in part due to the low surface area of flat surfaces available for modification. In this work, we demonstrate a novel method for increasing the device surface area by attaching a layer of thiolated silica nanoparticles (TNPs). This coating method results in an almost two-fold increase in the immobilized L1 protein. L1 immobilized nanotextured surfaces showed a 100% increase in neurite outgrowth than smooth L1 immobilized surfaces without increasing the adhesion of astrocytes in vitro. The increased bioactivity observed in the cell assay was determined to be mainly due to the higher protein surface density, not the increase in surface roughness. In addition, we tested immobilization of a superoxide dismutase mimic (SODm) on smooth and roughened substrates. The SODm immobilized rough surfaces demonstrated an increase of 145% in superoxide scavenging activity compared to chemically matched smooth surfaces. These results not only show promise in improving biomimetic coating for neural implants, but may also improve surface immobilization efficacy in other fields such as catalysts, protein purification, sensors, and tissue engineering devices.

Brain-computer interfaces are being developed to restore movement for people living with paralysis due to injury or disease. Although the therapeutic potential is great, long-term stability of the interface is critical for widespread clinical implementation. While many factors can affect recording and stimulation performance including electrode material stability and host tissue reaction, these factors have not been investigated in human implants. In this clinical study, we sought to characterize the material integrity and biological tissue encapsulation via explant analysis in an effort to identify factors that influence electrophysiological performance. We examined a total of six Utah arrays explanted from two human participants involved in intracortical BCI studies. Two platinum (Pt) arrays were implanted for 980 days in one participant (P1) and two Pt and two iridium oxide (IrOx) arrays were implanted for 182 days in the second participant (P2). We observed that the recording quality followed a similar trend in all six arrays with an initial increase in peak-to-peak voltage during the first 30–40 days and gradual decline thereafter in P1. Using optical and two-photon microscopy we observed a higher degree of tissue encapsulation on both arrays implanted for longer durations in participant P1. We then used scanning electron microscopy and energy dispersive X-ray spectroscopy to assess material degradation. All measures of material degradation for the Pt arrays were found to be more prominent in the participant with a longer implantation time. Two IrOx arrays were subjected to brief survey stimulations, and one of these arrays showed loss of iridium from most of the stimulated sites. Recording performance appeared to be unaffected by this loss of iridium, suggesting that the adhesion of IrOx coating may have been compromised by the stimulation, but the metal layer did not detach until or after array removal. In summary, both tissue encapsulation and material degradation were more pronounced in the arrays that were implanted for a longer duration. Additionally, these arrays also had lower signal amplitude and impedance. New biomaterial strategies that minimize fibrotic encapsulation and enhance material stability should be developed to achieve high quality recording and stimulation for longer implantation periods.