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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The speed of high-resolution optical imaging has been a rate-limiting factor for meso-scale mapping of brain structures and functional circuits, which is of fundamental importance for neuroscience research. Here, we describe a new microscopy method of Volumetric Imaging with Synchronized on-the-fly-scan and Readout (VISoR) for high-throughput, high-quality brain mapping. Combining synchronized scanning beam illumination and oblique imaging over cleared tissue sections in smooth motion, the VISoR system effectively eliminates motion blur to obtain undistorted images. By continuously imaging moving samples without stopping, the system achieves high-speed 3D image acquisition of an entire mouse brain within 1.5 hours, at a resolution capable of visualizing synaptic spines. A pipeline is developed for sample preparation, imaging, 3D image reconstruction and quantification. Our approach is compatible with immunofluorescence methods, enabling flexible cell-type specific brain mapping and is readily scalable for large biological samples such as primate brains. Using this system, we examined behaviorally relevant whole-brain neuronal activation in 16 c-Fos-shEGFP mice under resting or forced swimming conditions. Our results indicate the involvement of multiple subcortical areas in stress response. Intriguingly, neuronal activation in these areas exhibits striking individual variability among different animals, suggesting the necessity of sufficient cohort size for such studies.

For brain computer interfaces (BCI), the immune response to implanted electrodes is a major biological cause of device failure. Bioactive coatings such as neural adhesion molecule L1 have been shown to improve the biocompatibility, but are difficult to handle or produce in batches. Here, a synthetic zwitterionic polymer coating, poly(sulfobetaine methacrylate) (PSBMA) is developed for neural implants with the goal of reducing the inflammatory host response. In tests in vitro, the zwitterionic coating inhibits protein adsorption and the attachment of fibroblasts and microglia, and remains stable for at least 4 weeks. In vivo two‐photon microscopy on CX3CR1‐GFP mice shows that the zwitterionic coating significantly suppresses the microglial encapsulation of neural microelectrodes over a 6 h observation period. Furthermore, the lower microglial encapsulation on zwitterionic polymer‐coated microelectrodes is revealed to originate from a reduction in the size but not the number of microglial end feet. This work provides a facile method for coating neural implants with zwitterionic polymers and illustrates the initial interaction between microglia and coated surface at high temporal and spatial resolution.