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In the past decade, research on the motor control side of neuroprosthetics has steadily gained momentum. However, modern research in prosthetic development supplements a focus on motor control with a concentration on sensory feedback. Simulating sensation is a central issue because without sensory capabilities, the sophistication of the most advanced motor control system fails to reach its full potential. This research is an effort toward the development of sensory feedback specifically for neuroprosthetic hands. The present aim of this work is to understand the processing and representation of cutaneous sensation by evaluating performance and neural activity in somatosensory cortex (SI) during a grasp task. A non-human primate (Macaca mulatta) was trained to reach out and grasp textured instrumented objects with a precision grip. Two different textures for the objects were used, 100% cotton cloth and 60-grade sandpaper, and the target object was presented at two different orientations. Of the 167 cells that were isolated for this experiment, only 42 were recorded while the subject executed a few blocks of successful trials for both textures. These latter cells were used in this study's statistical analysis. Of these, 37 units (88%) exhibited statistically significant task related activity. Twenty-two units (52%) exhibited statistically significant tuning to texture, and 16 units (38%) exhibited statistically significant tuning to posture. Ten of the cells (24%) exhibited statistically significant tuning to both texture and posture. These data suggest that single units in somatosensory cortex can encode multiple phenomena such as texture and posture. However, if this information is to be used to provide sensory feedback for a prosthesis, scientists must learn to further parse cortical activity to discover how to induce specific modalities of sensation. Future experiments should therefore be developed that probe more variables and that more systematically and comprehensively scan somatosensory cortex. This will allow researchers to seek out the existence or non-existence of cortical pockets reserved for certain modalities of sensation, which will be valuable in learning how to later provide appropriate sensory feedback for a prosthesis through cortical stimulation.
Anticipatory planning of digit positions and forces is critical for successful dexterous object manipulation. Anticipatory (feedforward) planning bypasses the inherent delays in reflex responses and sensorimotor integration associated with reactive (feedback) control. It has been suggested that feedforward and feedback strategies can be distinguished based on the profile of grip and load force rates during the period between initial contact with the object and object lift. However, this has not been validated in tasks that do not constrain digit placement. The purposes of this thesis were (1) to validate the hypothesis that force rate profiles are indicative of the control strategy used for object manipulation and (2) to test this hypothesis by comparing manipulation tasks performed with and without digit placement constraints. The first objective comprised two studies. In the first study an additional light or heavy mass was added to the base of the object. In the second study a mass was added, altering the object's center of mass (CM) location. In each experiment digit force rates were calculated between the times of initial digit contact and object lift. Digit force rates were fit to a Gaussian bell curve and the goodness of fit was compared across predictable and unpredictable mass and CM conditions. For both experiments, a predictable object mass and CM elicited bell shaped force rate profiles, indicative of feedforward control. For the second objective, a comparison of performance between subjects who performed the grasp task with either constrained or unconstrained digit contact locations was conducted. When digit location was unconstrained and CM was predictable, force rates were well fit to a bell shaped curve. However, the goodness of fit of the force rate profiles to the bell shaped curve was weaker for the constrained than the unconstrained digit placement condition. These findings seem to indicate that brain can generate an appropriate feedforward control strategy even when digit placement is unconstrained and an infinite combination of digit placement and force solutions exists to lift the object successfully. Future work is needed that investigates the role digit positioning and tactile feedback has on anticipatory control of object manipulation.
Current treatment methods for cerebral aneurysms are providing life-saving measures for patients suffering from these blood vessel wall protrusions; however, the drawbacks present unfortunate circumstances in the invasive procedure or with efficient occlusion of the aneurysms. With the advancement of medical devices, liquid-to-solid gelling materials that could be delivered endovascularly have gained interest. The development of these systems stems from the need to circumvent surgical methods and the requirement for improved occlusion of aneurysms to prevent recanalization and potential complications. The work presented herein reports on a liquid-to-solid gelling material, which undergoes gelation via dual mechanisms. Using a temperature-responsive polymer, poly(N-isopropylacrylamide) (poly(NIPAAm), the gelling system can transition from a solution at low temperatures to a gel at body temperature (physical gelation). Additionally, by conjugating reactive functional groups onto the polymers, covalent cross-links can be formed via chemical reaction between the two moieties (chemical gelation). The advantage of this gelling system comprises of its water-based properties as well as the ability of the physical and chemical gelation to occur within physiological conditions. By developing the polymer gelling system in a ground-up approach via synthesis, its added benefit is the capability of modifying the properties of the system as needed for particular applications, in this case for embolization of cerebral aneurysms. The studies provided in this doctoral work highlight the synthesis, characterization and testing of these polymer gelling systems for occlusion of aneurysms. Conducted experiments include thermal, mechanical, structural and chemical characterization, as well as analysis of swelling, degradation, kinetics, cytotoxicity, in vitro glass models and in vivo swine study. Data on thermoresponsive poly(NIPAAm) indicated that the phase transition it undertakes comes as a result of the polymer chains associating as temperature is increased. Poly(NIPAAm) was functionalized with thiols and vinyls to provide for added chemical cross-linking. By combining both modes of gelation, physical and chemical, a gel with reduced creep flow and increased strength was developed. Being waterborne, the gels demonstrated excellent biocompatibility and were easily delivered via catheters and injected within aneurysms, without undergoing degradation. The dual gelling polymer systems demonstrated potential in use as embolic agents for cerebral aneurysm embolization.
The effects of specific histone deacetylase inhibitors (HDACi) on transgene expression in combination with a novel polymer as a delivery vehicle are investigated in this research. Polymer vectors, although safer than viruses, are notorious for low levels of gene expression. In this investigation, the use of an emerging chemotherapeutic anti-cancer drug molecule, HDACi, was used to enhance the polymer-mediated gene expression. HDACi are capable of inhibiting deacetylation activities of histones and other non-histone proteins in the cytoplasm and nucleus, as well as increase transcriptional activities necessary for gene expression. In a prior study, a parallel synthesis and screening of polymers yielded a lead cationic polymer with high DNA-binding properties, and even more attractive, high transgene expressions. Previous studies showed the use of this polymer in conjunction with cytoplasmic HDACi significantly enhanced gene expression in PC3-PSMA prostate cancer cells. This led to the basis for the investigation presented in this thesis, but to use nuclear HDACi to potentially achieve similar results. The HDACi, HDACi_A, was a previously discovered lead drug that had potential to significantly enhance luciferase expression in PC3-PSMA cells. The results of this study found that the 20:1 polymer:plasmid DNA weight ratio was effective with 1 uM and 2 uM HDACI_A concentrations, showing up to a 9-fold enhancement. This enhancement suggested that HDACi_A was effectively aiding transfection. While not an astounding enhancement, it is still interesting enough to investigate further. Cell viabilities need to be determined to supplement the results.
Human operators have difficulty driving cranes quickly, accurately, and safely because of the slow response of heavy crane structures, non-intuitive control interfaces, and payload oscillations. Recently, a novel hand-motion crane control system has been proposed to improve performance by coupling an intuitive control interface with an element that reduces the complex oscillatory behavior of the payload. Hand-motion control allows operators to drive a crane by simply moving a hand-held radio-frequency tag through the desired path. Real-time location sensors are used to track the movements of the tag and the tag position is used in a feedback control loop to drive the crane. An input shaper is added to eliminate dangerous payload oscillations. However, tag position measurements are corrupted by noise. It is important to understand the noise properties so that appropriate filters can be designed to mitigate the effects of noise and improve tracking accuracy. This work discusses implementing filtering techniques to address the issue of noise in the operating environment. Five different filters are used on experimentally-acquired tag trajectories to reduce noise. The filtered trajectories are then used to drive crane simulations. Filter performance is evaluated with respect to the energy usage of the crane trolley, the settling time of the crane payload oscillations, and the safety corridor of the crane trajectory. The effects of filter window lengths on these parameters are also investigated. An adaptive filtering technique, namely the Kalman filter, adapts to the noise characteristics of the workspace to minimize the tag tracking error and performs better than the other filtering techniques examined.
Approximately 1% of the world population suffers from epilepsy. Continuous long-term electroencephalographic (EEG) monitoring is the gold-standard for recording epileptic seizures and assisting in the diagnosis and treatment of patients with epilepsy. However, this process still requires that seizures are visually detected and marked by experienced and trained electroencephalographers. The motivation for the development of an automated seizure detection algorithm in this research was to assist physicians in such a laborious, time consuming and expensive task. Seizures in the EEG vary in duration (seconds to minutes), morphology and severity (clinical to subclinical, occurrence rate) within the same patient and across patients. The task of seizure detection is also made difficult due to the presence of movement and other recording artifacts. An early approach towards the development of automated seizure detection algorithms utilizing both EEG changes and clinical manifestations resulted to a sensitivity of 70-80% and 1 false detection per hour. Approaches based on artificial neural networks have improved the detection performance at the cost of algorithm's training. Measures of nonlinear dynamics, such as Lyapunov exponents, have been applied successfully to seizure prediction. Within the framework of this MS research, a seizure detection algorithm based on measures of linear and nonlinear dynamics, i.e., the adaptive short-term maximum Lyapunov exponent (ASTLmax) and the adaptive Teager energy (ATE) was developed and tested. The algorithm was tested on long-term (0.5-11.7 days) continuous EEG recordings from five patients (3 with intracranial and 2 with scalp EEG) and a total of 56 seizures, producing a mean sensitivity of 93% and mean specificity of 0.048 false positives per hour. The developed seizure detection algorithm is data-adaptive, training-free and patient-independent. It is expected that this algorithm will assist physicians in reducing the time spent on detecting seizures, lead to faster and more accurate diagnosis, better evaluation of treatment, and possibly to better treatments if it is incorporated on-line and real-time with advanced neuromodulation therapies for epilepsy.
Due to heterogeneity at the cellular level, single cell analysis (SCA) has become a necessity to study cellomics for the early detection of diseases like cancer. Development of single cell manipulation systems is very critical for performing SCA. In this thesis, electrorotation (ROT) chips to trap and rotate single cells using electrokinetic forces have been developed. The ROT chip mainly consists of a set of closely spaced metal electrodes (60µm interspacing between opposite electrodes) that forms a closed electric field cage (electrocage) when driven with high frequency AC voltages. Cells were flowed through a microchannel to the electrocage where they could be precisely trapped, levitated and rotated in 3-D along the axis of interest. The dielectrophoresis based ROT chip design and relevant electrokinetic effects have been simulated using COMSOL 3.4 to optimize the design parameters. Also, various semiconductor technology fabrication process steps have been developed and optimized for better yield and repeatability in the manufacture of the ROT chip. The ROT chip thus fabricated was used to characterize rotation of single cells with respect to the control parameters namely excitation voltage, frequency and cell line. The longevity of cell rotation under electric fields has been probed. Also, the Joule heating inside the ROT chip due to applied voltage has been characterized to know the thermal stress on the cells. The major advantages of the ROT chip developed are precise electrorotation of cells, simple design and straight forward fabrication process.
Development of post-traumatic epilepsy (PTE) after traumatic brain injury (TBI) is a major health concern (5% - 50% of TBI cases). A significant problem in TBI management is the inability to predict which patients will develop PTE. Such prediction, followed by timely treatment, could be highly beneficial to TBI patients. Six male Sprague-Dawley rats were subjected to a controlled cortical impact (CCI). A 6mm piston was pneumatically driven 3mm into the right parietal cortex with velocity of 5.5m/s. The rats were subsequently implanted with 6 intracranial electroencephalographic (EEG) electrodes. Long-term (14-week) continuous EEG recordings were conducted. Using linear (coherence) and non-linear (Lyapunov exponents) measures of EEG dynamics in conjunction with measures of network connectivity, we studied the evolution over time of the functional connectivity between brain sites in order to identify early precursors of development of epilepsy. Four of the six TBI rats developed PTE 6 to 10 weeks after the initial insult to the brain. Analysis of the continuous EEG from these rats showed a gradual increase of the connectivity between critical brain sites in terms of their EEG dynamics, starting at least 2 weeks prior to their first spontaneous seizure. In contrast, for the rats that did not develop epilepsy, connectivity levels did not change, or decreased during the whole course of the experiment across pairs of brain sites. Consistent behavior of functional connectivity changes between brain sites and the "focus" (site of impact) over time was demonstrated for coherence in three out of the four epileptic and in both non-epileptic rats, while for STLmax in all four epileptic and in both non-epileptic rats. This study provided us with the opportunity to quantitatively investigate several aspects of epileptogenesis following traumatic brain injury. Our results strongly support a network pathology that worsens with time. It is conceivable that the observed changes in spatiotemporal dynamics after an initial brain insult, and long before the development of epilepsy, could constitute a basis for predictors of epileptogenesis in TBI patients.
Aqueous solutions of temperature-responsive copolymers based on N-isopropylacrylamide (NIPAAm) hold promise for medical applications because they can be delivered as liquids and quickly form gels in the body without organic solvents or chemical reaction. However, their gelation is often followed by phase-separation and shrinking. Gel shrinking and water loss is a major limitation to using NIPAAm-based gels for nearly any biomedical application. In this work, a graft copolymer design was used to synthesize polymers which combine the convenient injectability of poly(NIPAAm) with gel water content controlled by hydrophilic side-chain grafts based on Jeffamine® M-1000 acrylamide (JAAm). The first segment of this work describes the synthesis and characterization of poly(NIPAAm-co-JAAm) copolymers which demonstrates controlled swelling that is nearly independent of LCST. The graft copolymer design was then used to produce a degradable antimicrobial-eluting gel for prevention of prosthetic joint infection. The resorbable graft copolymer gels were shown to have three unique characteristics which demonstrate their suitability for this application. First, antimicrobial release is sustained and complete within 1 week. Second, the gels behave like viscoelastic fluids, enabling complete surface coverage of an implant without disrupting fixation or movement. Finally, the gels degrade rapidly within 1-6 weeks, which may enable their use in interfaces where bone healing takes place. Graft copolymer hydrogels were also developed which undergo Michael addition in situ with poly(ethylene glycol) diacrylate to form elastic gels for endovascular embolization of saccular aneurysms. Inclusion of JAAm grafts led to weaker physical crosslinking and faster, more complete chemical crosslinking. JAAm grafts prolonged the delivery window of the system from 30 seconds to 220 seconds, provided improved gel swelling, and resulted in stronger, more elastic gels within 30 minutes after delivery.
Approximately 1.7 million people in the United States are living with limb loss and are in need of more sophisticated devices that better mimic human function. In the Human Machine Integration Laboratory, a powered, transtibial prosthetic ankle was designed and build that allows a person to regain ankle function with improved ankle kinematics and kinetics. The ankle allows a person to walk normally and up and down stairs, but volitional control is still an issue. This research tackled the problem of giving the user more control over the prosthetic ankle using a force/torque circuit. When the user presses against a force/torque sensor located inside the socket the prosthetic foot plantar flexes or moves downward. This will help the user add additional push-off force when walking up slopes or stairs. It also gives the user a sense of control over the device.