Focused Epicranial Brain Stimulation by Spatial Sculpting of Pulsed Electric Fields Using High Density Electrode Arrays.

Transcranial electrical neuromodulation of the central nervous system is used as a non-invasive method to induce neural and behavioral responses, yet targeted non-invasive electrical stimulation of the brain with high spatial resolution remains elusive. This work demonstrates a focused, steerable, high-density epicranial current stimulation (HD-ECS) approach to evoke neural activity. Custom-designed high-density (HD) flexible surface electrode arrays are employed to apply high-resolution pulsed electric currents through skull to achieve localized stimulation of the intact mouse brain. The stimulation pattern is steered in real time without physical movement of the electrodes. Steerability and focality are validated at the behavioral, physiological, and cellular levels using motor evoked potentials (MEPs), intracortical recording, and c-fos immunostaining. Whisker movement is also demonstrated to further corroborate the selectivity and steerability. Safety characterization confirmed no significant tissue damage following repetitive stimulation. This method can be used to design novel therapeutics and implement next-generation brain interfaces.

Residual voltage as an ad-hoc indicator of electrode damage in biphasic electrical stimulation.

Objective.We derive and demonstrate how residual voltage (RV) from a biphasic electrical stimulation pulse can be used to recognize degradation at the electrode-tissue interface.Approach.Using a first order model of the electrode-tissue interface and a rectangular biphasic stimulation current waveform, we derive the equations for RV as well as RV growth over several stimulation pulses. To demonstrate the use of RV for damage detection, we simulate accelerated damage on sputtered iridium oxide film (SIROF) electrodes using potential cycling. RV measurements of the degraded electrodes are compared against standard characterization methods of cyclic voltammetry and electrochemical impedance spectroscopy.Main results.Our theoretical discussion illustrates how an intrinsic RV arises even from perfectly balanced biphasic pulses due to leakage via the charge-transfer resistance. Preliminary data inin-vivorat experiments follow the derived model of RV growth, thereby validating our hypothesis that RV is a characteristic of the electrode-tissue interface. RV can therefore be utilized for detecting damage at the electrode. Our experimental results for damage detection show that delamination of SIROF electrodes causes a reduction in charge storage capacity, which in turn reflects a measurable increase in RV.Significance.Chronically implanted electrical stimulation systems with multi-electrode arrays have been the focus of physiological engineering research for the last decade. Changes in RV over time can be a quick and effective method to identify and disconnect faulty electrodes in large arrays. Timely diagnoses of electrode status can ensure optimal long term operation, and prevent further damage to the tissue near these electrodes.

Hydrogel-based electrodes for selective cervical vagus nerve stimulation.

Objective.Electrical vagus nerve stimulation (VNS) has the potential to treat a wide variety of diseases by modulating afferent and efferent communication to the heart, lungs, esophagus, stomach, and intestines. Although distal vagal nerve branches, close to end organs, could provide a selective therapeutic approach, these locations are often surgically inaccessible. In contrast, the cervical vagus nerve has been targeted for decades using surgically implantable helix electrodes to treat epileptic seizures and depression; however, to date, clinical implementation of VNS has relied on an electrode with contacts that fully wrap around the nerve, producing non-selective activation of the entire nerve. Here we demonstrate selective cervical VNS using cuff electrodes with multiple contacts around the nerve circumference to target different functional pathways.Approach.These flexible probes were adjusted to the diameter of the nerve using an adhesive hydrogel wrap to create a robust electrode interface. Our approach was verified in a rat model by demonstrating that cervical VNS produces neural activity in the abdominal vagus nerve while limiting effects on the cardiovascular system (i.e. changes in heart rate or blood pressure).Main results.This study demonstrates the potential for selective cervical VNS as a therapeutic approach for modulating distal nerve branches while reducing off target effects.Significance.This methodology could potentially be refined to treat gastrointestinal, metabolic, inflammatory, cardiovascular, and respiratory diseases amenable to vagal neuromodulatory control.

Inkjet Printing of Curing Agent on Thin PDMS for Local Tailoring of Mechanical Properties.

Rapid prototyping of thin, stretchable substrates with engineered stiffness gradients at desired locations has potential impact in the robustness of skin-wearable electronics, as the gradients can inhibit cracking of interconnect and delamination of embedded electronic chips. Drop-on-demand inkjetting of thinned polydimethylsiloxane (PDMS) curing agent onto a spin-cast 80 µm-thick 20:1 (base: curing agent) PDMS substrate sets the elastic modulus of the subsequently cured film with sub-millimeter accuracy. The inkjet process creates digitally defined stiffness gradient spans as small as 100 µm for single droplets. Varying the drop density results in differences in elastic modulus of up to 80%. In jetting tests of curing agent into pure base PDMS, a continuous droplet spacing of 100 µm results in smooth lines with total widths of 1 mm and a curing agent gradient span of ≈300 µm. Release of freeform mesh elastomer microstructures by removing the uncured base after selective jetting of curing agent into pure base PDMS results in structural line width resolution down to 500 µm.

Parylene neural probe with embedded CMOS multiplexing amplifier.

We present a method for embedding integrated circuit chips in parylene neural probes where Anisotropic Conductive Film (ACF) electrically and physically connects the chip to the probe. Adequate insulation of the assembly is verified up to 150 h in vitro (testing ongoing). A custom-designed 8-to-1 multiplexing amplifier for neural application was fabricated in a 0.18 µm CMOS process. As a feasibility demonstration, the $830 \mu \mathrm {m}\times 1030 \mu \mathrm {m}$ die was connected to a parylene probe on a glass substrate. Preliminary results of the amplifier tests indicate similar performance in air and in phosphate buffered saline (PBS), and demonstrate around 200 V/V amplification of signals in saline.

Insulation of thin-film parylene-C/platinum probes in saline solution through encapsulation in multilayer ALD ceramic films.

The long-term electrical leakage performance of parylene-C/platinum/parylene-C (Px/Pt/Px) interconnect in saline is evaluated using electrochemical impedance spectroscopy (EIS). Three kinds of additional ceramic encapsulation layers between the metal and Px are characterized: 50 nm-thick alumina (Al2O3), 50 nm-thick titania (TiO2), and 80 nm-thick Al2O3-TiO2 nanolaminate (NL). The Al2O3 and TiO2 encapsulation layers worsen the overall insulation properties. The NL encapsulation layer improves the insulation when combined with a TiO2 outer layer to promote adhesion to the Px. Experiments are performed with various insulation promotion treatments: A-174 silane (A174) treatment before Px deposition (to promote adhesion); SF6 plasma treatment (F) after Px deposition (to increase hydrophobicity); and ion-milling descum (IM) after Px deposition (to prevent parylene oxidation). A174 and F treatments do not have a significant impact, while IM leads to worse insulation performance. A circuit model elucidates the insulation characteristics of Px-ceramic-Pt-ceramic-Px interconnect. These studies provide a foundation for processing ultra-compliant neural probes with long-term chronic utility.

The role of hierarchical design and morphology in the mechanical response of diatom-inspired structures via simulation.

Diatoms are microscopic algae with intricate shell morphologies and features ranging from the nanometer to the micrometer scale, which have been proposed as templates for drug delivery carriers, optical devices, and metamaterials design. Several studies have found that diatom shells show unique mechanical properties such as high specific strength and resilience. One hypothesis is that these properties stem from the structural arrangement of the material at the nanometer and micrometer length scales, challenging the concept between what constitutes a "material" versus a "structure". In this work, we have conducted a systematic simulation-prototyping study to shed light on the mechanics of diatom-inspired hierarchical microstructures. The Finite Element Method (FEM) was used to replicate three-dimensional diatom shells under compressive forces. The intricate hierarchical shell structure of the Coscinodiscus sp. diatom frustule observed in nature was reproduced in detail. Simulation parameters were selected to reproduce compression experiments, with a force distributed on the surface of the diatom shell. A frustule diameter of 50 µm was used with pore diameters ranging from 0.25 to 1.2 µm across different layers. A "unit cell" FEM model was also created to focus on the basic structural element of a diatom frustule. Both of these models were used to elucidate the relation between morphology and mechanical response. Additionally, select designs were prototyped using 3D Direct Laser Writing (DLW) lithography to evaluate the feasibility of manufacturing diatom-inspired devices at the micro-scale. Distinct correlations between pore size in each frustule layer, or pore shape in the basal layers, and the mechanical response of the diatom shell were established in this study. The 3D-DLW prototypes exhibit a similar level of intricate morphological traits observed in real diatoms, opening the possibility of a simulation-based process for the design and fabrication of diatom-inspired microdevices. This research helps explain how morphology features are central to the mechanical performance of hierarchically arranged structures and biomaterials in general, and it represents a step toward the manufacture of emerging metamaterials and microarchitectures.

Ultra-miniature ultra-compliant neural probes with dissolvable delivery needles: design, fabrication and characterization.

Stable chronic functionality of intracortical probes is of utmost importance toward realizing clinical application of brain-machine interfaces. Sustained immune response from the brain tissue to the neural probes is one of the major challenges that hinder stable chronic functionality. There is a growing body of evidence in the literature that highly compliant neural probes with sub-cellular dimensions may significantly reduce the foreign-body response, thereby enhancing long term stability of intracortical recordings. Since the prevailing commercial probes are considerably larger than neurons and of high stiffness, new approaches are needed for developing miniature probes with high compliance. In this paper, we present design, fabrication, and in vitro evaluation of ultra-miniature (2.7 µm x 10 µm cross section), ultra-compliant (1.4 × 10-2 µN/µm in the axial direction, and 2.6 × 10-5 µN/µm and 1.8 × 10-6 µN/µm in the lateral directions) neural probes and associated probe-encasing biodissolvable delivery needles toward addressing the aforementioned challenges. The high compliance of the probes is obtained by micron-scale cross-section and meandered shape of the parylene-C insulated platinum wiring. Finite-element analysis is performed to compare the strains within the tissue during micromotion when using the ultra-compliant meandered probes with that when using stiff silicon probes. The standard batch microfabrication techniques are used for creating the probes. A dissolvable delivery needle that encases the probe facilitates failure-free insertion and precise placement of the ultra-compliant probes. Upon completion of implantation, the needle gradually dissolves, leaving behind the ultra-compliant neural probe. A spin-casting based micromolding approach is used for the fabrication of the needle. To demonstrate the versatility of the process, needles from different biodissolvable materials, as well as two-dimensional needle arrays with different geometries and dimensions, are fabricated. Further, needles incorporating anti-inflammatory drugs are created to show the co-delivery potential of the needles. An automated insertion device is developed for repeatable and precise implantation of needle-encased probes into brain tissue. Insertion of the needles without mechanical failure, and their subsequent dissolution are demonstrated. It is concluded that ultra-miniature, ultra-compliant probes and associated biodissolvable delivery needles can be successfully fabricated, and the use of the ultra-compliant meandered probes results in drastic reduction in strains imposed in the tissue as compared to stiff probes, thereby showing promise toward chronic applications.

Material Gradients in Stretchable Substrates toward Integrated Electronic Functionality.

The approach toward a stretchable electronic substrate employs multiple soft polymer layers patterned around silicon chips, which act as surrogates for conventional electronics chips, to create a controllable stiffness gradient. Adding just one intermediate polymer layer results in a six-fold increase in the strain failure threshold enabling the substrate to be stretched to over twice its length before delamination occurs.

In vitro electrochemical characterization of polydopamine melanin as a tissue stimulating electrode material.

The properties of redox active polydopamine melanin (PDM) films as a coating material for neural electrodes were evaluated. PDM films with nanometer-scale thicknesses exhibit dc bias dependent charge injection capacities (CIC) with maximum values of 110 ± 23 µC cm-2 at 0.2V (vs Ag/AgCl) and reduce the interfacial impedance compared to inorganic conducting films. PDM films exhibited an asymmetric impedance response to positive and negative dc biases with minimum interfacial impedance at 0.2V (vs Ag/AgCl). An explanation for the observed bias-dependent electrochemical behavior is presented.

Elastic ribbon-like piezoelectric energy harvester for wearable devices with stretchable surfaces.

This paper presents an elastic ribbon-like piezoelectric energy harvester which is targeted for skin-wearable devices by harnessing the movements of stretchable surfaces. The device aims to power up smart thin stick-on devices for healthcare monitoring. By embedding a ribbon-like PVDF film in a flexible elastomer, Ecoflex, the device is potentially able to stretch 34%, while maintaining internal strain of the film below its plastic deformation limit. Alternate electrode layout and bimorph configuration help to reduce charge cancellation, while increasing overall effectiveness. The harvester prototype with 225 mm3 active volume is able to output 15.6 V at open-circuit upon stretching 26% and is capable of generating at least 121 nJ per cycle.

A silicon neural probe fabricated using DRIE on bonded thin silicon.

A silicon neural probe fabricated using a deep reactive ion etching based process on 250 µm thin silicon wafers was developed. The fabricated probes replicate the design of soft parylene-C based probes embedded in dissolvable needles and can therefore also be used to test the encapsulation properties of parylene-C in-vivo without introducing additional effects introduced by the dissolvable gel. The process also demonstrates the possibility of performing conventional photolithography on substrates bonded to a handle wafer using a backgrinding liquid wax (BGL7080) as an adhesive. This technique would allow integration of Si wafer thinning into the fabrication of neural probes, potentially allowing a range of neural probes of different thicknesses to be fabricated. Fabricated probes were characterized using electrochemical impedance spectroscopy (EIS) yielding a measured impedance value of ~80 kΩ at 1 kHz for 15 µm by 115 µm platinum electrodes, indicating that extracellular neural recordings are possible. The neural probes were inserted into the substantia nigra of a mouse that showed successful recording of neural activity. Probes fabricated using this technique can thus be potentially used in the study of Parkinson's disease.

Chronic tissue response to carboxymethyl cellulose based dissolvable insertion needle for ultra-small neural probes.

Implantable neural electrodes must drastically improve chronic recording stability before they can be translated into long-term human clinical prosthetics. Previous studies suggest that sub-cellular sized and mechanically compliant probes may result in improved tissue integration and recording longevity. However, currently these design features are restricted by the opposing mechanical requirements needed for minimally damaging insertions. We designed a non-cytotoxic, carboxymethylcellulose (CMC) based dissolvable delivery vehicle (shuttle) to provide the mechanical support for insertion of ultra-small, ultra-compliant microfabricated neural probes. Stiff CMC-based shuttles rapidly soften immediately after being placed ∼1 mm above an open craniotomy as they absorb vapors from the brain. To address this, we developed a sophisticated targeting, high speed insertion (∼80 mm/s), and release system to implant these shuttles. After implantation, the goal is for the shuttle to dissolve away leaving only the electrodes behind. Here we show the histology of chronically implanted shuttles of large (300 µm × 125 µm) and small (100 µm × 125 µm) size at discrete time points over 12 weeks. Early time points show the CMC shuttle expanded after insertion as it absorbed moisture from the brain and slowly dissolved. At later time points neuronal cell bodies populate regions within the original shuttle tract. The large CMC shuttles show that the CMC expansion can cause extended secondary damage. On the other hand, the smaller CMC shuttles show limited secondary damage, wound closure by 4 weeks, absence of activated microglia at 12 weeks, as well as evidence suggesting neural regeneration at the implant site. This shuttle, therefore, shows great promise facilitating the implantation of nontraditional ultra-small, and ultra-compliant probes.

Ultra-compliant neural probes are subject to fluid forces during dissolution of polymer delivery vehicles.

Ultra-compliant neural probes implanted into tissue using a molded, biodissolvable sodium carboxymethyl cellulose (Na-CMC)-saccharide composite needle delivery vehicle are subjected to fluid-structure interactions that can displace the recording site of the probe with respect to its designed implant location. We applied particle velocimetry to analyze the behavior of ultra-compliant structures under different implantation conditions for a range of CMC-based materials and identified a fluid management protocol that resulted in the successful targeted depth placement of the recording sites.

Robust gold nanoparticles stabilized by trithiol for application in chemiresistive sensors.

The use of gold nanoparticles coated with an organic monolayer of thiol for application in chemiresistive sensors was initiated in the late 1990s; since then, such types of sensors have been widely pursued due to their high sensitivities and reversible responses to volatile organic compounds (VOCs). However, a major issue for chemical sensors based on thiol-capped gold nanoparticles is their poor long-term stability as a result of slow degradation of the monothiol-to-gold bonds. We have devised a strategy to overcome this limitation by synthesizing a more robust system using Au nanoparticles capped by trithiol ligands. Compared to its monothiol counterpart, the new system is significantly more stable and also shows improved sensitivity towards different types of polar or non-polar VOCs. Thus, the trithiol-Au nanosensor shows great promise for use in real world applications.

Picogram material dosing of microstructures.

A solution delivery platform comprised of a suspended microcapillary connected to a microwell enables picogram solute deposition on suspended structures. Precision material placement in the capillary from a 100 pl drop inkjetted into the well is achieved without the destruction of the microstructure and adjacent submicron electrostatic gaps. This method scales to smaller structures without the need for drop miniaturization. The theory behind the solute transfer in the system is developed. Three regions in the drying process are observed and match with the model. The "accumulation" region builds solute concentration in the capillary. The "solidification" region initiates the solidification of solute starting at the free end of the capillary. The "termination" region is characterized by a rapid increase in the solidification due to an increase in the well concentration near the end of the drop lifetime. The accumulation time and solidification rate dependence on concentration compare well with the model.

Volatile organic compound detection using nanostructured copolymers.

Regioregular polythiophene-based conductive copolymers with highly crystalline nanostructures are shown to hold considerable promise as the active layer in volatile organic compound (VOC) chemresistor sensors. While the regioregular polythiophene polymer chain provides a charge conduction path, its chemical sensing selectivity and sensitivity can be altered either by incorporating a second polymer to form a block copolymer or by making a random copolymer of polythiophene with different alkyl side chains. The copolymers were exposed to a variety of VOC vapors, and the electrical conductivity of these copolymers increased or decreased depending upon the polymer composition and the specific analytes. Measurements were made at room temperature, and the responses were found to be fast and appeared to be completely reversible. Using various copolymers of polythiophene in a sensor array can provide much better discrimination to various analytes than existing solid state sensors. Our data strongly indicate that several sensing mechanisms are at play simultaneously, and we briefly discuss some of them.

Endoscopic optical coherence tomography with a modified microelectromechanical systems mirror for detection of bladder cancers.

Experimental results of a modified micromachined microelectromechanical systems (MEMS) mirror for substantial enhancement of the transverse laser scanning performance of endoscopic optical coherence tomography (EOCT) are presented. Image distortion due to buckling of MEMS mirror in our previous designs was analyzed and found to be attributed to excessive internal stress of the transverse bimorph meshes. The modified MEMS mirror completely eliminates bimorph stress and the resultant buckling effect, which increases the wobbling-free angular optical actuation to greater than 37 degrees, exceeding the transverse laser scanning requirements for EOCT and confocal endoscopy. The new optical coherence tomography (OCT) endoscope allows for two-dimensional cross-sectional imaging that covers an area of 4.2 mm x 2.8 mm (limited by scope size) and at roughly 5 frames/s instead of the previous area size of 2.9 mm x 2.8 mm and is highly suitable for noninvasive and high-resolution imaging diagnosis of epithelial lesions in vivo. EOCT images of normal rat bladders and rat bladder cancers are compared with the same cross sections acquired with conventional bench-top OCT. The results clearly demonstrate the potential of EOCT for in vivo imaging diagnosis and precise guidance for excisional biopsy of early bladder cancers.