Printable microscale interfaces for long-term peripheral nerve mapping and precision control

The nascent field of bioelectronic medicine seeks to decode and modulate peripheral nervous system signals to obtain therapeutic control of targeted end organs and effectors. Current approaches rely heavily on electrode-based devices, but size scalability, material and microfabrication challenges, limited surgical accessibility, and the biomechanically dynamic implantation environment are significant impediments to developing and deploying advanced peripheral interfacing technologies. Here, we present a microscale implantable device – the nanoclip – for chronic interfacing with fine peripheral nerves in small animal models that begins to meet these constraints. We demonstrate the capability to make stable, high-resolution recordings of behaviorally-linked nerve activity over multi-week timescales. In addition, we show that multi-channel, current-steering-based stimulation can achieve a high degree of functionally-relevant modulatory specificity within the small scale of the device. These results highlight the potential of new microscale design and fabrication techniques for the realization of viable implantable devices for long-term peripheral interfacing.https://www.biorxiv.org/node/801468.fullFirst author draf

Doctor of Philosophy

dissertationBiomedical implantable devices have been developed for both research and clinical applications, to stimulate and record physiological signals in vivo. Chronic use of biomedical devices with thin-film-based encapsulation in large scale is impeded by their lack of long-term functionality and stability. Biostable, biocompatible, conformal, and electrically insulating coatings that sustain chronic implantation are essential for chip-scale implantable electronic systems. Even though many materials have been studied to for this purpose, to date, no encapsulation method has been thoroughly characterized or qualified as a broadly applicable long-term hermetic encapsulation for biomedical implantable devices. In this work, atomic layer deposited Al2O3 and Parylene C bi-layer was investigated as encapsulation for biomedical devices. The combination of ALD Al2O3 and CVD Parylene C encapsulation extended the lifetime of coated interdigitated electrodes (IDEs) to up to 72 months (to date) with low leakage current of ~ 15 pA. The long lifetime was achieved by significantly reducing moisture permeation due to the ALD Al2O3 layer. Moreover, the bi-layer encapsulation separates the permeated moisture (mostly at the Al2O3 and Parylene interface) from the surface contaminants (mostly at the device and Al2O3 interface), preventing the formation of localized electrolyte through condensation. Al2O3 works as an inner moisture barrier and Parylene works as an external ion barrier, preventing contact of AI2O3 with liquid water, and slowing the kinetics of alumina corrosion. Selective removal of encapsulation materials is required to expose the active sites for interacting with physiological environment. A self-aligned mask process with three steps was developed to expose active sites, composed of laser ablation, oxygen plasma etching, and BOE etching. Al2O3 layer was found to prevent the formation of microcracks in the iridium oxide film during laser ablation. Bi-layer encapsulated iridium oxide had higher charge injection capacity and similar electrochemical impedance compared with Parylene C coated iridium oxide film after deinsulation. The Al2O3 and Parylene C bi-layer encapsulation was applied to Utah electrode array (UEA)-based neural interfaces to study its long-term performance. The median tip impedance of the bi-layer encapsulated wired Utah electrode array increased slowly during the 960 days of equivalent soak testing at 37 °C. Impedance for Parylene coated UEA dropped 50% to 75% within 6 months. In addition, bi-layer coated fully integrated Utah array-based wireless neural interfaces had stable power-up frequencies at ~910 MHz and constant RF signal strength of -50 dBm during the 1044 days of equivalent soaking time at 37 °C. This is much longer than lifetime achieved with Parylene C coating, which was about one year at room temperature

Doctor of Philosophy

dissertationImplantable microelectrode arrays are biomedical devices used in-vivo serving as neural interfaces between the nervous system and external systems such as neuroprosthetics. They are designed to be chronically implanted in the central or peripheral nervous system and record or stimulate neural signals. The Utah electrode array (UEA) is a representative example of silicon-based neural interfaces. They are typically encapsulated with the USP Class VI biocompatible material, Parylene-C, on the inactive areas to insulate and encapsulate the electrodes and minimize damage to the neural tissue. In order to record or stimulate neural signals, the active electrode sites must be deinsulated. Tip deinsulation of Parylene-coated UEAs is typically performed by a reactive ion etching (RIE) process using an O2 plasma, and an aluminum foil mask. This technique has limitations due to nonuniform tip exposure lengths contributing to large impedance variations (o > 0.5 MQ), and difficulty in controlling the magnitude of tip exposure, especially for tip exposures less than 40 ^m, which are needed to increase its selectivity in recording or stimulating single or multiple neurons. Moreover, foil masks cannot be used for more complex electrode geometries, such as variable height electrodes. In this work, excimer laser ablation of Parylene from a UEA using a tip metallization of iridium oxide (IrOx) was investigated as an alternative deinsulation technique. A hybrid method of etching Parylene-C using a combination of laser ablation and the O2 RIE was investigated in the efforts to minimize electrode damage and remove carbonaceous residues. The median impedance for fine tip ( 180 °C) temperatures in reducing ambients, resulting in dramatic changes to the structural and electrical properties of the tip metallization. The reduced IrOx material was found to tolerate significantly more laser irradiation than the fully oxidized material. The median impedance, cathodal charge storage capacity (CSCc), and charge injection capacity (CIC) for the reduced electrodes with 40 |im exposure were ~ 25 kQ, ~ 40 mC/cm2, and ~ 0.8 mC/cm2, respectively. These results suggest that a hybrid laser ablation using an excimer laser and RIE is promising for deinsulation of UEAs

Metallized printed microstructures for precision biomedical recording and stimulation

Implantable electrodes are the central tool for many techniques and treatments in biomedical research and medicine. There is a trend in these tools towards arrays of tissue-penetrating microelectrodes with low geometric surface areas for purposes of both increasing the specificity of recording/stimulation and reducing tissue damage due to insertion trauma and reactive immune responses. However, smaller electrode sizes present new constraints – both difficulty in fabrication as well as significant limitations on effective charge storage/injection capacities as well as higher impedances, making smaller electrodes less capable of easily passing charge safely and efficiently. Fabricating structures on the scale of tens of microns and below poses significant challenges compared to well established machining at larger sizes. Established sets of techniques such as classic MEMS processes are limited to relatively specific shapes, with significant limitations in their ability to produce curved surfaces and surfaces which are not composed of highly distinct stepped layers. We developed a method for improvement of impedance and charge storage capacity of flat electrodes without affecting geometric surface area (footprint) using Resonant Direct Laser Writing (rDLW) 3D printing to fabricate high surface area 3D structures, which were then rendered conductive. The ability to perform DLW printing at a range of laser powers on opaque reflective surfaces is demonstrated, previously a known limitation of direct laser writing. This is demonstrated through a variety of example prints. This capability opens the door to many new possibilities in micron resolution polymer printing which were previously inaccessible, with potentially far reaching ramifications for microfabrication

Doctor of Philosophy

dissertationBy enabling neuroprosthetic technologies, neural microelectrodes can greatly improve diagnostic and treatment options for millions of individuals living with limb loss, paralysis, and sensory and autonomic neural disorders. However, clinical use of these devices is restricted by the limited functional lifetimes of implanted electrodes, which are commonly less than a few years. One cause is the evolution of damage to dielectric encapsulation that insulates microelectrodes from the physiological environment. Fluid penetration and exposure to an aggressive immunological response over time may weaken encapsulating films and cause electrical shunting. This reduces electrode impedance, diverts electrical signal away from target tissue, and causes multi-channel crosstalk. To date, no neural microelectrode encapsulating material or design approach has reliably resolved this issue. We employ the parylene C-encapsulated Utah Electrode Array (UEA), a silicon-micromachined neural interface FDA-cleared for human use, to execute three aims that address this challenge through investigations of new materials, electrode designs, and testing methods. We first evaluate a novel bilayer encapsulating film comprised of atomic layer deposited Al2O3 and parylene C, testing this film using UEAs and devices with UEA-relevant topography. Contrasting with previous work employing simplified planar structures, the incorporation of neural electrode features on test structures revealed failure modes pointing to the dissolution of Al2O3 over time. Our results emphasize the need for dielectric coatings resistant to water degradation as well as test methods that take electrode features into account. In our second aim, we show through finite element modeling and aggressive in vitro testing that use of degenerately doped silicon as a conductive neural electrode material can mitigate the consequences of encapsulation damage, owing to the high electrochemical impedance of silicon. Our final aim compares oxidative in vitro aging to long-term in vivo material damages and finds clear evidence that such in vitro testbeds may help predict certain in vivo damage modes. By pairing this testing with absorption and emission spectroscopic characterization modalities, we identify contributors to material damage and future design solutions. Our results will inform future material and testing choices, to improve the resilience of neural electrode dielectric encapsulation and enhance the longevity of neuroprostheses

In vitro feasibility testing of floating light-activated minroelectrical stimulators

One of the major challenges of neural stimulation is the mechanical stress and resulting trauma induced on the implanted electrodes by the constant movement of the interconnects. A potential way of eliminating interconnects is to use floating micro-stimulators that can be activated through optical means. As a method of energy transfer to the micro-stimulator, we propose to use a laser beam at near infrared (NIR) wavelengths. There are two main objectives in this project to test the feasibility of the main approach; investigate the charge injection capacity of titanium nitride (TiN) and iridium oxide (IrOx) as potential contact materials, and measure the transmitted light power through the neural tissue for various implantation depths. The charge injection capacity of TiN electrodes for an extended range of cathodic voltages was also investigated. Because the microstimulator will be implanted into the neural tissue, the laser beam must penetrate a few millimeters before reaching the device. The transmitted light power was measured for various types of neural tissue. The transmitted light power through rat brain gray matter was much higher than that of the white matter and the sciatic nerve. Penetration depth and reflectance were calculated according to Lambert-Beer’s law from measurements of transmission for various tissue thicknesses. The results suggest that FLAMES approach is feasible for implantation depths of a few millimeters in the peripheral and central nervous system. Both IrOx and TiN allow sufficient charge injection for this application. TiN is preferred for future experimentation since TiN does not require a bias voltage to achieve useful charge injection rates, and thus is a good choice as an electrode material in this application

Metal Ir coatings on endocardial electrode tips, obtained by MOCVD

The present work demonstrates the application of the Metal-Organic Chemical Vapor Deposition technique to fabricate metal iridium coatings onto the pole tips of endocardial electrodes. Using iridium (III) acetylacetonate as volatile precursor, the target coatings were successfully applied to the working surface of cathodes and anodes of pacemaker electrodes in the flow type reactor in hydrogen atmosphere at deposition temperature of 550°C. The coating samples were characterized by means of XRD, SEM, Raman- and XPS-spectroscopies. The formation of non-textured coatings with fractal-like morphology and 7-24 nm crystallite size has been realized. The electrochemical properties of the coatings were investigated by cyclic voltammetry and electrochemical impedance spectroscopy. The charge storage capacity values of the electrochemically activated samples were 17.0-115 mC·cm–2 and 14.4-76.5 mC·cm–2 for measurements carried out in 0.1M sulfuric acid and in phosphate buffer saline solutions, respectively. A comparison of some characteristics of the samples obtained with commercially available cathode of pacemaker electrodes is also presented

Bringing sensation to prosthetic hands—chronic assessment of implanted thin-film electrodes in humans

Direct stimulation of peripheral nerves with implantable electrodes successfully provided sensory feedback to amputees while using hand prostheses. Longevity of the electrodes is key to success, which we have improved for the polyimide-based transverse intrafascicular multichannel electrode (TIME). The TIMEs were implanted in the median and ulnar nerves of three trans-radial amputees for up to six months. We present a comprehensive assessment of the electrical properties of the thin-film metallization as well as material status post explantationem. The TIMEs stayed within the electrochemical safe limits while enabling consistent and precise amplitude modulation. This lead to a reliable performance in terms of eliciting sensation. No signs of corrosion or morphological change to the thin-film metallization of the probes was observed by means of electrochemical and optical analysis. The presented longevity demonstrates that thin-film electrodes are applicable in permanent implant systems

Smartphone-Based pH Sensor for Home Monitoring of Pulmonary Exacerbations in Cystic Fibrosis.

Currently, Cystic Fibrosis (CF) patients lack the ability to track their lung health at home, relying instead on doctor checkups leading to delayed treatment and lung damage. By leveraging the ubiquity of the smartphone to lower costs and increase portability, a smartphone-based peripheral pH measurement device was designed to attach directly to the headphone port to harvest power and communicate with a smartphone application. This platform was tested using prepared pH buffers and sputum samples from CF patients. The system matches within ~0.03 pH of a benchtop pH meter while fully powering itself and communicating with a Samsung Galaxy S3 smartphone paired with either a glass or Iridium Oxide (IrOx) electrode. The IrOx electrodes were found to have 25% higher sensitivity than the glass probes at the expense of larger drift and matrix sensitivity that can be addressed with proper calibration. The smartphone-based platform has been demonstrated as a portable replacement for laboratory pH meters, and supports both highly robust glass probes and the sensitive and miniature IrOx electrodes with calibration. This tool can enable more frequent pH sputum tracking for CF patients to help detect the onset of pulmonary exacerbation to provide timely and appropriate treatment before serious damage occurs