Injuries involving the nervous system are among the most devastating and life altering of all neurological disorders. The resulting loss of sensation and voluntary muscle control represent a drastic change in the individuals lifestyle and independence. Spinal cord injury affects over two hundred thousand people within the United States alone. While there have been many attempts to develop neural interfaces that can be used as part of a prosthetic device to improve the quality of life of such patients and contribute to the reduction of ongoing health care costs, the design of such a device has proved elusive. Direct access to the spinal cord requires potentially life threatening surgery during which the dura, the protective covering surrounding the cord, must be opened with a resulting high risk of infection. For this reason research has been focussed on the stimulation of and recording from the peripheral nerves in an attempt to restore the functionality that has been lost through spinal cord injury. This thesis is concerned with the current status and limitations of peripheral nerve interfaces that are designed for recording electrical signals directly from the nervous system using a technique called velocity selective recording. This technique exploits the relationship between axonal diameter, which is linked via anatomy to function, and the speed with which the axon conducts excitation. New techniques are developed that improve current methods for identifying and simulating neural signals and power efficient implementations of these methods are presented in modern microelectronic platforms. Results are presented from pioneering experiments in rat and pig that for the first time demonstrate the recording and analysis of the physiological electroneurogram using velocity based methods. New methods are developed that enable the extraction of neuronal firing rates and thus the extraction of the information encoded within the nervous system.

Creating effective cellular interfaces that can provide specific cellular signals is important for a number of fields ranging from tissue engineering to biosensors. Electroconducting polymers, especially polypyrrole (PPy), have attracted much attention for use in numerous biomedical applications since they provide a potential platform for local delivery of electrical stimuli to target tissues. To effectively modulate cellular functions at neural interfaces, it is essential to incorporate a range of extracellular cues into conducting polymers according to specific applications, such as nerve guidance conduits and implantable neural probes. For nerve regeneration scaffolds, three dimensional forms are desired for control of critical properties, such as porosity, mechanical strength, and topography. However, most researchers have worked on conventional two-dimensional PPy films, which cannot mimic a native three-dimensional architecture. Thus, a portion of my work has focused on introducing three-dimensional nanofibrous features into PPy. I have investigated various coating conditions to obtain uniform and conductive nanofibers. Effectiveness of electrical stimulation through the conducting nanofibers was confirmed by in vitro PC12 cell culture. The effects of different conducting nanofiber topographies (random and aligned) on cell adhesion and neurite outgrowth were examined in conjunction with electrical stimulation. The benefits of immobilized-NGF could be combined with electrical stimuli, which could be an ideal platform for neural tissue engineering scaffolds. Thus, I have modified conducting polymers to display neurotrophic activity. Nerve growth factor (NGF) was chemically immobilized on two dimensional and three dimensional PPy substrates. Specific chemical conjugation was achieved and characterized using diverse techniques. Immobilized NGF was as effective as exogenous NGF in medium in inducing neurite development and extension. NGF immobilized on functionalized PPy substrates was stable in a physiological solution and under electrical stimulation, indicating effective prolonged activity. I also investigated another important application of conducting polymer-based materials for neural interfacing - passivating electrodes with a biocompatible polysaccharide, hyaluronic acid (HA). I synthesized electrically polymerizable HA by chemically conjugating amine-functionalized pyrrole derivatives with HA. This coating was stable under physiological conditions for three months and resistant to enzymatic degradation. In vitro studies have shown the minimal adhesion and migration of astrocytes on the HA-coated electrodes. Implantation of HA-coated commercial probes into rat cortices for three weeks revealed attenuated reactive astrocyte responses from the coated wires, and the importance of glial interaction with non-conducting sites was demonstrated. / text

<p>Electrophysiological intracellular recordings from freely behaving animals can provide information and insights, which have been speculated or cannot be reached by traditional recordings from confined animals. Intracellular recordings can reveal a neuron's intrinsic properties and their communication with other neurons. Utilizing this technology in an awake and socially behaving brain can bring brain research one step further. </p><p>In this dissertation, a customized miniature electronics and microdrive assembly is introduced for intracellular recording from small behaving animals. This solution has realized in vivo intracellular recording from freely behaving zebra finches and mice. Also, a new carbon nanotube probe is presented as a surface scanning tip and a neural electrode. With the carbon nanotube probe, intracellular and extracellular neural signals were successfully recorded from mouse brains. Previously, carbon nanotubes have only been used as a coating material on a cell-culturing platform or on a metal based neural electrode. This probe is the first pure carbon nanotube neural electrode without an underlying platform or wire, and it is the first one that has achieved intracellular and extracellular recordings from vertebrate cortical neurons.</p> / Dissertation

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Biomedical devices play a crucial role in the healthcare system, enabling more effective treatments, less invasive procedures, and more precise diagnoses. Due to these compelling reasons, development of new biomedical devices and biomaterials have always been in high demand. Exploring and refining fabrication methods are essential to the development of new biomedical devices. Some of the common fabrication methods include microfabrication methods (photolithography and soft lithography), 3D printing (additive manufacturing), laser machining, thermal drawing, and electrospinning. The choice of fabrication methods heavily depends on the materials, geometry, and functionalities of biomedical devices. Currently, the thermal drawing process has proven to be an excellent scalable fabrication platform for neural interface, tissue engineering, tumor/cancer treatment, soft robotics, and smart textiles. This Ph.D. dissertation summarizes my research on the fabrication and validation of thermally drawn multifunctional polymer fiber probes for modern biomedical applications, primarily in the fields of neural interfaces and tumor treatments. Understanding the neural basis of behavior requires monitoring and manipulating combinations of physiological elements and their interactions in behaving animals. Utilizing the thermal drawing process, we developed T-DOpE (Tapered Drug delivery, Optical stimulation, and Electrophysiology) probes and Tetro-DOpE (Tetrode-like Drug delivery, Optical stimulation, and Electrophysiology) probes that can simultaneously record and manipulate neural activity in behaving rodents. Taking advantage of the triple-functionality, we monitored local field potential (LFP) while manipulating cannabinoid receptors (CB1R; microfluidic agonist delivery) and CA1 neuronal activity using optogenetics. Focal infusion of CB1R agonist downregulated theta and sharp wave-ripple oscillations (SPW-Rs). Furthermore, we found that CB1R activation reduces sharp wave-ripples by impairing the innate SPW-R-generating ability of the CA1 circuit. Microscale electroporation devices are mostly restricted to in vitro experiments (i.e., microchannel and microcapillary). We developed a flexible microscale electroporation fiber probe through a thermal drawing process and femtosecond laser micromachining techniques. The novel fiber microprobes enable microscale electroporation and arbitrarily select the cell groups of interest to electroporate. Successful reversible and irreversible microscale electroporation was observed in a 3D collagen scaffold (seeded with U251 human glioma cells) using fluorescent staining. Leveraging the scalable thermal drawing process, we envision a wide distribution of multifunctional polymer fiber probes in research facilities and hospitals. Along with the fiber probes presented in this dissertation, additional insight and future perspective on thermally drawn biomedical devices are discussed. / Doctor of Philosophy / The thermal drawing process is a versatile and scalable platform for fabricating functional fiber technology. The process was formerly adapted from fabrication method for silica optical fibers, widely used in telecommunication (e.g., telephone, internet, cable TV, etc.). To name some functionalities of these fibers, they can move, hear, sense touch, change colors, harvest and store energy, record and manipulate brain activity, and ablate tumors. As imagined, these functionalities are derived from the unique geometry and functional materials embedded along the fiber. Therefore, developing the fiber design tailored to a specific application is a critical step to making a successful fiber product. In this dissertation, I will present my work on biomedical devices fabricated with the thermal drawing process and their application in neuroscience and tumor/cancer treatment. Utilizing the thermal drawing process, we developed neural interfaces that can be implanted into the deep brain and record and simultaneously manipulate the neural activity. These neural interfaces (Chapter 2,3; T-DOpE and Tetro-DOpE probes, respectively) are able to record both local field potentials (LFP; activity of thousands or more neurons) and single action potentials (single on/off signal from individual neurons nearby). By manipulating the gene expression, we can control the activity of neurons with specific light (λ= 470nm; blue light) exposure. We implemented optical waveguide in our probes to guide light from a laser source to the tip of the probe and manipulate the neural activity. Furthermore, we fabricated micro-channels within the device to enable focal drug delivery at the tip of the device. Using the T-DOpE probe, we studied the effect of local synthetic cannabinoid injection in the hippocampus. We found that the local injection of the drug in hippocampus CA1 makes neurons incapable of generating sharp wave-ripples (a neural signal associated with memory). Electroporation is a biophysical phenomenon where short high electric field pulses introduce nanoscale defects in cell membrane. These defects can cause unstable cellular homeostasis and eventually leads to cell death. Due to reduced treatment time, no heat effect, and tissue selectivity, electroporation has been used in clinical trials for cancer treatments. Using the thermal drawing process and laser micromachining techniques, we developed a flexible microscale electroporation fiber probe capable of ablating tumor cells. Due to the low-cost and scalability of thermal drawing process, we envision the use of thermally drawn functional fiber technology in biomedical fields. In this dissertation, I also address some challenges and future directions of thermally drawn functional fibers in biomedical fields.

This work presents a high-voltage, high-precision bi-directional multi-channel system capable of stimulating neural activity through bi-phasic pulses of amplitude up to ∓50 V while recording very low-voltage responses as low as tens of microvolts. Most of the systems reported from the scientific community possess at least one of the following common limitations: low stimulation voltages, low gain capabilities, or insufficient bandwidth to acquire a wide range of different neural activities. While systems can be found that present remarkable capabilities in one or more specific areas, a versatile system that performs over all these aspects is missing. Moreover, as many novel materials, like silicon carbide, are emerging as biocompatible interfaces, and more specifically as neuronal interfaces, it becomes mandatory to have a system operating across a wide range of voltages and frequencies for both physiological and electrical compatibility testing. The system designed and proven during this doctoral research effort features a ∓50 V bi-phasic pulse generator, 62 to 100 dB of software selectable amplification, and a wide 18 Hz to 12 kHz bandwidth. In addition to design and realization we report about biological testing consisting in the acquisition of neural signals from tissue cultures using an MEA where faithful signal recording was achieved with superior fidelity to a commercial system used to sample signals from the same culture. The only system parameter that was less robust than the commercial system was the noise level, which due to our higher bandwidth was somewhat expected. More importantly our custom electronics outperformed in terms of lower delay and lower cost of realization. All of these results plus suggested future works are listed for the reader's convenience.

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<p>In this dissertation, we show three approaches towards selective vagus nerve stimulation (VNS). First, we investigated VNS using microelectrode with circle and Vicsek fractal shape. Our rat study shows that fractal microelectrode can activate C-fibers in cervical vagus nerve with higher energy efficiency compared to circle microelectrode. Secondly, we developed stretchable and adhesive cuff device for a compliant neural interface for a long-term stability. We designed Y-shaped kirigami thin-film device for stretchable neural interface and applied a tissue-adhesive hydrogel to enable tough adhesion of the cuff electrode, which can be potentially used to fix the position of microelectrode for a reliable selective stimulation with minimal mechanical mismatch. Lastly, we developed a microchannel electrode array device to potentially measure high-quality of single fiber action potential (SFAP) from the abdominal vagal trunk of rat to explore natural patterns selective organ activities which can be used for a fine-tuned selective VNS. Our results show the potential of measuring C-fiber activities evoked by cervical VNS.</p>

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