Microfabrication of Biomimetic Structures for Neural Interfaces

Interfacing with the brain is a challenging problem. While many innovative methods for providing input and output to neural systems have been developed and demonstrated successfully in human patients, these invasive systems use less biologically compatible means than are realizable. Materials and mechanisms which are closer mimics to biological systems in their behaviors can lead to more stable and effective medical prosthetic and research devices. Retinal prosthetics, as well as Cochlear implants, are neural implants which provide stimulation via electrical impulses. Currents passing across neurons trigger neurons to begin firing or generating action potentials down their axons, stimulating neurons with dendrites connected to those axons terminals. This scheme transduces the desired simulation into neural firing spikes, but the majority of applied current is shunted around neurons rather than contributing to stimulation. Excess current contributes to the power and thermal budgets of neural simulation devices, which are implanted in tissue, limiting their functionality. Additionally, the electrical contacts which provide a source and return for the stimulation currents are subject to degradation over time, as currents are repeatedly applied during stimulation events. Stimulation of neurons via local delivery of potassium in excess of available intercellular potassium can be used in place of direct electrical stimulation and promises to be a more biologically compatible method.Several forms of neural recording devices have been developed and the widest know and highest density is the Utah Array, a 3D array of silicon spires, which can record from their tips when inserted into neural tissue. While this 3D array topology can access a field of neural activity, the stiffness of these silicon spires is very different than that of neural tissue, which can lead to an unwanted inflammatory response. Conductive polymer pillars made of softer materials that are a closer match to neural tissues, while mirroring the same density and insertion length as the Utah Array, may provide a better recording mechanism due to their improved mechanical compatibility with neural tissues. This thesis investigates microfabrication schemes to produce biomimetic structures that can enable neural simulation and recording devices which feature greater biological stability and improve utility

Silicon Neural Probes for Stimulation of Neurons and the Excitation and Detection of Proteins in the Brain

This thesis describes the development of a number of novel microfabricated neural probes for a variety of specific neuroscience applications. These devices rely on single mode waveguides and grating couplers constructed from silicon nitride thin films, which allows the use of planar lightwave circuits to create advanced device geometries and functions. These probes utilize array waveguide gratings to select an individual emitter from a large array of emitters using the wavelength of incoming light, allowing for spatial multiplexing of optical stimulation. These devices were tested in the laboratory and in living tissue to verify their efficacy. This technology was then modified to create steerable beam forming for stimulation of neurons using optical phase arrays. This technology was also tested for use in fluoresence lifetime imaging microscopy and the first application of pulsed light through the photonic circuits. Finally, this technology was again modified to create laminar illumination patterns for light sheet fluorescence microscopy applications. These devices were further improved by adding embedded microfluidics to the probes. The process of creating embedded microfluidic channels by the dig and seal method is described in detail, including modifications to the procedure that were added to address potential pitfalls in the fabrication process. Next, two projects which combine microfluidics with the optical devices described in the previous chapter are detailed. One project involves combining the use of optical emitters with microfluidic injections containing caged neurotransmitters to stimulate neurons is described. The other project involves microfluidic sampling of the extracellular space for neuropeptides which are detected using ring resonator biosensors. The sensitivity of these biosensors was analyzed in detail, determining both the physical limit of detection and the effect of biological noise due to non-specific binding on the sensors

Nano-Bio Hybrid Electronic Sensors for Chemical Detection and Disease Diagnostics

The need to detect low concentrations of chemical or biological targets is ubiquitous in environmental monitoring and biomedical applications. The goal of this work was to address challenges in this arena by combining nanomaterials grown via scalable techniques with chemical receptors optimized for the detection problem at hand. Advances were made in the CVD growth of graphene, carbon nanotubes and molybdenum disulfide. Field effect transistors using these materials as the channel were fabricated using methods designed to avoid contamination of the nanomaterial surfaces. These devices were used to read out electronic signatures of binding events of molecular targets in both vapor and solution phases. Single-stranded DNA functionalized graphene and carbon nanotubes were shown to be versatile receptors for a wide variety of volatile molecular targets, with characteristic responses that depended on the DNA sequence and the identity of the target molecule, observable down to part-per-billion concentrations. This technology was applied to increasingly difficult detection challenges, culminating in a study of blood plasma samples from patients with ovarian cancer. By working with large arrays of devices and studying the devices\u27 responses to pooled plasma samples and plasma samples from 24 individuals, sufficient data was collected to identify statistically robust patterns that allow samples to be classified as coming from individuals who are healthy or have either benign or malignant ovarian tumors. Solution-phase detection experiments focused on the design of surface linkers and specific receptors for medically relevant molecular targets. A non-covalent linker was used to attach a known glucose receptor to carbon nanotubes and the resulting hybrid was shown to be sensitive to glucose at the low concentrations found in saliva, opening up a potential pathway to glucose monitoring without the need for drawing blood. In separate experiments, molybdenum disulfide transistors were functionalized with a re-engineered variant of a μ-opiod receptor, a cell membrane protein that binds opiods and regulates pain and reward signaling in the body. The resulting devices were shown to bind opiods with affinities that agree with measurements in the native state. This result could enable not only an advanced opiod sensor but moreover could be generalized into a solid-state drug testing platform, allowing the interactions of novel pharmaceuticals and their target proteins to be read out electronically. Such a system could have high throughput due to the quick measurement, scalable device fabrication and high sensitivity of the molybdenum disulfide transistor

High density microelectrode arrays for in vitro retinal studies

Neurophysiologists traditionally studied the behaviour of individual neurons by measuring their extracellular signalling on a single electrode. This PhD has involved developing a technology to enable the behaviour of populations of neurons in the retina to be studied. By recording simultaneously from hundreds of neurons a much greater insight into retinal processing and encoding is achievable. To this end, a large area, high density, transparent microelectrode array, of unprecedented dimensions, was manufactured on a glass/indium tin oxide (ITO) substrate. This state-of-the-art device has 519 hexagonally close-packed, 5 mum diameter electrodes spaced by 30 mum. Al-1 channels are electrically well isolated with typical interchannel resistance and capacitance values of ~200 GO and 1 pF respectively. Electrodes are electroplated with platinum to form a low impedance (200 kO at 1 kHz) interface between the electrodes and electrolyte. Fabrication and modelling tests also proved the electrical and physical feasibility of future larger area and higher density arrays. Investigations were carried out to establish an electrode/electrolyte interface capable of delivering enough charge to directly stimulate neurons in the retina. Iridium oxide films formed by an electrochemical activation technique were found to create 5 mum diameter electrodes with 4 mC/cm2 charge capacity and 150 kO (at 1 kHz) impedance which are ideal characteristics for direct electrical stimulation of neurons. The state-of-the-art microelectrode array technology developed in this thesis has allowed amongst the most complete datasets from primate retina to be produced

Diamond at the brain-machine interface

Electrodes at the Brain Machine Interface (BMI) must fulfil tall specifications: They must have excellent electrical properties to transduce electrogenic activity, be highly biocompatible and not degrade in a saline environment over the lifetime of the patient. In this respect, diamond is an excellent BMI material. In this thesis, the application of diamond at the BMI is investigated. Results Chapter 5 discusses the use of nanodiamond (ND) monolayers to promote the formation of functional neuronal networks. Neurons cultured on ND-coated substrates perform remarkably well, and similar to those grown on standard protein-coated materials with respect to their initial cell attachment, outgrowth, neuronal excitability and functionality of the resulting networks. NDs bypass the necessity of protein coating and show great potential for chronic medical implants. Chapter 6 describes the fabrication of nanocrystalline diamond (NCD) Micro-Electrode Arrays (MEAs) for the recording of electrogenic cells. MEAs are fabricated with metallic boron-doped nanocrystalline diamond (BNCD) and passivated with NCD, SiO2/Si3N4/SiO2 stacks and SU-8 epoxy. The recording of electrogenic activity of HL-1 cardiac cells is demonstrated with high signal-to-noise ratios and low signal loss. Chapter 7 and Chapter 8 describe the development of boron-doped (111) diamond Solution Gate Field-Effect Transistors (SGFETs). In Chapter 7 an optimised Plasma Enhanced Chemical Vapour Deposition (PECVD)-doping recipe using the (111) diamond plane is presented. AC Hall characterisation yields desirable sheet carrier densities for FET application with enhanced carrier mobilities, and Impedance Spectroscopy (IS) measurements divulge metallic electrical properties with low activation energies, indicative of heavily doped diamond as confirmed by Secondary Ion Mass Spectroscopy (SIMS). Chapter 8 describes the fabrication of boron δ-doped (111) diamond SGFETs (δ-SGFETs). δ-SGFETs show improved I-V characteristics in comparison to previous similar devices, whereby the enhancement mode operation, channel pinch-off and current saturation are achieved within the electrochemical window of diamond. Considering the biocompatibility of diamond towards cells, δ-SGFETs are promising for recording electrogenic cells

The Journal of Microelectronic Research

https://scholarworks.rit.edu/meec_archive/1015/thumbnail.jp

Development of novel alternative chemistry processes for dielectric etch applications

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2000.Includes bibliographical references.The removal of dielectric films in semiconductor processing relies almost exclusively on the use of perfluorocompounds (PFCs), which are suspected global warming agents. The two applications in semiconductor manufacture that account for the largest use and emissions of PFCs are the patterning of dielectric films and the cleaning of dielectric film plasma enhanced chemical vapor deposition (PECVD) chambers. The work discussed in the author's Ph.D. thesis was conducted as part of a project whose goal is to identify and develop novel replacement etchants for these applications. The focus of the author's Ph.D. thesis is the patterning application. The research discussed in this document constitutes a follow up to the author's M.S. thesis, which discussed the initial stages of this project. These stages consisted primarily of preliminary screening tests involving a class of chemistries which was expected to be promising from a process standpoint at an early point in the project. The work carried out subsequently covered a far greater scope of activities and included additional preliminary screening tests with chemistries that were not covered by the author's M.S. thesis as well as extensive concept-and-feasibility tests and subsequent process development efforts using several of the more promising chemistries in a dielectric wafer patterning application. Much of this experimental work had been carried out in collaboration with industrial partners belonging to the semiconductor manufacturer, equipment supplier, and gas supplier communities. These tests were carried out on process tools housed both within MTL's Integrated Circuits Laboratory and at an industrial location, namely Motorola Inc.'s Advanced Products Research and Development Laboratory (APRDL). The project to identify and develop alternative chemistries for dielectric film removal applications is continuing after the completion of the author's thesis, with subsequent studies that will build on the results of the work done to date. The research presented in this document involved the evaluation of fluorinated compounds belonging to three principal families of modified fluorocarbon molecules: hydrofluorocarbons (HFCs), iodofluorocarbons (IFCs), and unsaturated fluorocarbons (UFCs). In addition, other chemistries, namely trifluoroacetic anhydride (TFAA), oxalyl fluoride, and octafluorotetrahydrofuran, were also examined. The focus of much of the work was on the etching of patterned silicon oxide films in back-end-of-the-line (BEOL) applications such as via etch. In its mature phases, the work conducted relied on a two pronged approach toward evaluating new etchants: characterization of their process performance and characterization of their process emissions prior to release into the atmosphere. Cross-sectional scanning electron microscopy (SEM) was the principal means of process performance characterization, whereas Fourier transform infrared (FTIR) spectroscopy was the principal technique employed for effluent characterization. At appropriate times, other diagnostic techniques, namely x-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry (TOF-SIMS), Auger electron spectroscopy (AES), and quadrupole mass spectrometry (QMS) were also used for film or effluent characterization. Within the HFC family, candidates were identified that exhibited generally good process results with emissions reductions ranging from -40% into the 70% range relative to a PFC based reference. More comprehensive tests with IFC compounds demonstrated that emissions reductions in the 80% range are attainable for working processes. Good performance was obtained with respect to some, but not all, key process metrics, demonstrating the potential utility of IFCs in certain dielectric etch applications, but also indicating that there were significant limitations to their use, stemming mostly from selectivity problems. In tests with UFC compounds, emissions reductions on the order of 85%, combined with good process performance, were obtained. This family of compounds showed the greatest promise from both an emissions standpoint and a process standpoint. In particular, compounds in this family showed very good mask layer and stop layer selectivity, in addition to good etch rates and good profile control. It is particularly encouraging that the use of some of these compounds, in addition to offering emissions reductions, may, in fact, offer a process advantage over conventional chemistries in applications requiring high selectivity. At the time of this writing, unsaturated fluorocarbons are viewed as a major avenue for further exploration within the ongoing PFC alternatives project.by Simon Martin Karecki.Ph.D