John P. Seymour

The insulation performance of reactive parylene films in implantable electronic devices

Parylene-C (poly-chloro-p-xylylene) is an appropriate material for use in an implantable, microfabricated device. It is hydrophobic, conformally deposited, has a low dielectric constant, and superb biocompatibility. Yet for many bioelectrical applications, its poor wet adhesion may be an impassable shortcoming. This research contrasts parylene-C and poly(p-xylylene) functionalized with reactive group X (PPX-X) layers using long-term electrical soak and adhesion tests. The reactive parylene was made of complementary derivatives having aldehyde and aminomethyl side groups (PPX-CHO and PPX-CH2NH2 respectively). These functional groups have previously been shown to covalently react together after heating. Electrical testing was conducted in saline at 37 degrees C on interdigitated electrodes with either parylene-C or reactive parylene as the metal layer interface. Results showed that reactive parylene devices maintained the highest impedance. Heat-treated PPX-X device impedance was 800% greater at 10kHz and 70% greater at 1Hz relative to heated parylene-C controls after 60 days. Heat treatment proved to be critical for maintaining high impedance of both parylene-C and the reactive parylene. Adhesion measurements showed improved wet metal adhesion for PPX-X, which corresponds well with its excellent high frequency performance.

Chronic In Vivo Evaluation of PEDOT/CNT for Stable Neural Recordings

Objective: Subcellular-sized chronically implanted recording electrodes have demonstrated significant improvement in single unit (SU) yield over larger recording probes. Additional work expands on this initial success by combining the subcellular fiber-like lattice structures with the design space versatility of silicon microfabrication to further improve the signal-to-noise ratio, density of electrodes, and stability of recorded units over months to years. However, ultrasmall microelectrodes present very high impedance, which must be lowered for SU recordings. While poly(3,4-ethylenedioxythiophene) (PEDOT) doped with polystyrene sulfonate (PSS) coating have demonstrated great success in acute to early-chronic studies for lowering the electrode impedance, concern exists over long-term stability. Here, we demonstrate a new blend of PEDOT doped with carboxyl functionalized multiwalled carbon nanotubes (CNTs), which shows dramatic improvement over the traditional PEDOT/PSS formula. Methods: Lattice style subcellular electrode arrays were fabricated using previously established method. PEDOT was polymerized with carboxylic acid functionalized carbon nanotubes onto high-impedance (8.0 ± 0.1 MΩ: M ± S.E.) 250-μm2 gold recording sites. Results: PEDOT/CNT-coated subcellular electrodes demonstrated significant improvement in chronic spike recording stability over four months compared to PEDOT/PSS recording sites. Conclusion: These results demonstrate great promise for subcellular-sized recording and stimulation electrodes and long-term stability. Significance: This project uses leading-edge biomaterials to develop chronic neural probes that are small (subcellular) with excellent electrical properties for stable long-term recordings. High-density ultrasmall electrodes combined with advanced electrode surface modification are likely to make significant contributions to the development of long-term (permanent), high quality, and selective neural interfaces.

In vivo evaluation of a neural stem cell-seeded prosthesis

Neural prosthetics capable of recording or stimulating neuronal activity may restore function for patients with motor and sensory deficits resulting from injury or degenerative disease. However, overcoming inconsistent recording quality and stability in chronic applications remains a significant challenge. A likely reason for this is the reactive tissue response to the devices following implantation into the brain, which is characterized by neuronal loss and glial encapsulation. We have developed a neural stem cell-seeded probe to facilitate integration of a synthetic prosthesis with the surrounding brain tissue. We fabricated parylene devices that include an open well seeded with neural stem cells encapsulated in an alginate hydrogel scaffold. Quantitative and qualitative data describing the distribution of neuronal, glial, and progenitor cells surrounding seeded and control devices are reported over four time points spanning 3 months. Neuronal loss and glial encapsulation associated with cell-seeded probes were mitigated during the initial week of implantation and exacerbated by 6 weeks post-insertion compared to control conditions. We hypothesize that graft cells secrete neuroprotective and neurotrophic factors that effect the desired healing response early in the study, with subsequent cell death and scaffold degradation accounting for a reversal of these results later. Applications of this biohybrid technology include future long-term neural recording and sensing studies.

A Materials Roadmap to Functional Neural Interface Design

Advancement in neurotechnologies for electrophysiology, neurochemical sensing, neuromodulation, and optogenetics are revolutionizing scientific understanding of the brain while enabling treatments, cures, and preventative measures for a variety of neurological disorders. The grand challenge in neural interface engineering is to seamlessly integrate the interface between neurobiology and engineered technology, to record from and modulate neurons over chronic timescales. However, the biological inflammatory response to implants, neural degeneration, and long-term material stability diminish the quality of interface overtime. Recent advances in functional materials have been aimed at engineering solutions for chronic neural interfaces. Yet, the development and deployment of neural interfaces designed from novel materials have introduced new challenges that have largely avoided being addressed. Many engineering efforts that solely focus on optimizing individual probe design parameters, such as softness or flexibility, downplay critical multi-dimensional interactions between different physical properties of the device that contribute to overall performance and biocompatibility. Moreover, the use of these new materials present substantial new difficulties that must be addressed before regulatory approval for use in human patients will be achievable. In this review, the interdependence of different electrode components are highlighted to demonstrate the current materials-based challenges facing the field of neural interface engineering.

State-of-the-art MEMS and microsystem tools for brain research

Mapping brain activity has received growing worldwide interest because it is expected to improve disease treatment and allow for the development of important neuromorphic computational methods. MEMS and microsystems are expected to continue to offer new and exciting solutions to meet the need for high-density, high-fidelity neural interfaces. Herein, the state-of-the-art in recording and stimulation tools for brain research is reviewed, and some of the most significant technology trends shaping the field of neurotechnology are discussed.

Fiberless multicolor neural optoelectrode for in vivo circuit analysis

Maximizing the potential of optogenetic approaches in deep brain structures of intact animals requires optical manipulation of neurons at high spatial and temporal resolutions, while simultaneously recording electrical data from those neurons. Here, we present the first fiber-less optoelectrode with a monolithically integrated optical waveguide mixer that can deliver multicolor light at a common waveguide port to achieve multicolor modulation of the same neuronal population in vivo. We demonstrate successful device implementation by achieving efficient coupling between a side-emitting injection laser diode (ILD) and a dielectric optical waveguide mixer via a gradient-index (GRIN) lens. The use of GRIN lenses attains several design features, including high optical coupling and thermal isolation between ILDs and waveguides. We validated the packaged devices in the intact brain of anesthetized mice co-expressing Channelrhodopsin-2 and Archaerhodopsin in pyramidal cells in the hippocampal CA1 region, achieving high quality recording, activation and silencing of the exact same neurons in a given local region. This fully-integrated approach demonstrates the spatial precision and scalability needed to enable independent activation and silencing of the same or different groups of neurons in dense brain regions while simultaneously recording from them, thus considerably advancing the capabilities of currently available optogenetic toolsets.

Fabrication of polymer neural probes with sub-cellular features for reduced tissue encapsulation.

Intracortical microelectrodes currently have great potential as a neural prosthesis in patients with neurodegenerative disease or spinal cord injury. In an effort to improve the consistency of neural probe performance, many modifications to probe design are focused on reducing the tissue encapsulation. Since researchers have shown that small polymer fibers (less than 7-mum diameter) induce a small to non-existent encapsulation layer in the rat subcutis, we have proposed a neural probe design with similarly small diameter structures. This paper discusses the fabrication and design parameters of a microscale neural probe with a sub-cellular lattice structure. We developed a microfabrication process using SU-8 and parylene-C to create the relatively thick probe shank and thin lateral arms. The stiff penetrating shank (70-mum by 42-mum) had an SU-8 core that allowed control over stiffness and simplified the process. Parylene-only structures lateral to the shank could be defined with a 4-mum feature-size to meet our sub-cellular criterion. We fabricated four varying geometries for implantation into the neocortex of seven Sprague-Dawley rats. Our in vivo testing verifies that despite the flexible substrate and small dimensions (4-mumtimes5-mum), these devices are mechanically robust and practical as neural probes. These devices provide an important tool for neural engineers to investigate the tissue response around sub-cellular structures and potentially improve device efficacy

Investigation of the photoelectrochemical effect in optoelectrodes and potential uses for implantable electrode characterization

The combination of optical stimulation and electrical recording is commonly employed in neuroscience research. Researchers using optogenetics are familiar with the photo-induced “artifacts” that arise from illumination of an electrode array. We sought to characterize this photoelectrochemical (PEC) effect to understand the underlying mechanism seen on NeuroNexus optoelectrodes. In doing so, we discovered that the phenomenon is inversely proportional to electrode site area in the same manner as electrical impedance measurements. We have applied the PEC effect as a method of electrode evaluation and show that a PEC measurement system can be both faster and more effective than impedance at sensing defects in high-throughput biomedical device testing.

Fiberless multicolor optoelectrodes using Injection Laser Diodes and Gradient-index lens coupled optical waveguides

We present an integrated optoelectrode that can deliver multicolor light from a waveguide coupled to an optical mixer. Such a device can provide spatial precision and scalability needed to enable independent activation and silencing of local neural circuits, allowing study of brain activities such as memory consolidation networks in the hippocampus. We have demonstrated successful implementation of fiber-less optoelectrodes in a highly compact form by achieving efficient end-fire coupling between a side-emitting injection laser diode (ILD) and a dielectric channel waveguide via a Gradient-index (GRIN) lens. Total optical efficiency achieved for 405nm and 635nm wavelengths through an optical mixer was 12.2% and 5.4%, respectively. This approach also provides robust thermal packaging by efficiently managing thermal power loss of ILDs.

GaN-on-Si μLED optoelectrodes for high-spatiotemporal-accuracy optogenetics in freely behaving animals

We present the micromachined GaN-on-Si μLED optoelectrodes with neuron-sized LEDs monolithically integrated on a thin narrow silicon shank for optical stimulation and electrical recording in a behaving animal. The fabricated μLEDs show an optical power of 1.9 μW at 4 V from a small size of 15 μm × 10 μm with a peak plug efficiency of 0.6 %. This allows high spatial and temporal resolution optogenetic studies from the μLED array in a small pitch of 60 μm along with the integrated recording electrodes in 20-μm pitch. Stimulation artifacts were significantly mitigated by two-metal-layer shielding topology. In vivo validation of the fabricated optoelectrode confirmed the successful light-induced modulation of neuronal activities in hippocampus with square optical pulses of 100-ms duration.