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- All Subjects: Biomedical Engineering
- Genre: Academic theses
- Creators: Abbas, James
Description
Non-invasive visualization of the trigeminal nerve through advanced MR sequences and methods like tractography is important for studying anatomical and microstructural changes due to pathology like trigeminal neuralgia (TN), facial dystonia, multiple sclerosis, and for surgical pre-planning. The use of specific anatomical markers from CT, MPRAGE and cranial nerve imaging (CRANI) sequences, enabled successful tractography of patient-specific trajectory of the frontal, nasociliary, infraorbital, and mandibular nerve branches extending beyond the cisternal brain stem region and leading to the face. Performance of MPRAGE sequence together with the advanced T2-weighted CRANI sequence with and without a gadolinium contrast agent, was studied to characterize identification efficiency in smaller nerve structures in the extremities. A large FOV nerve visualization exam inclusive of the anatomy of all trigeminal nerve distal branches can be obtained within an acquisition time of 20 minutes using pre-contrast CRANI and MPRAGE. Post-processing with MPR and MIP images improved nerve visualization.Transcranial electrical stimulation techniques (TES) have been used for the treatment of multiple neurodegenerative diseases. These techniques involve placing electrodes on the scalp with multiple peripheral branches of the trigeminal nerve crossing directly under that may be stimulated. This was studied through hybrid computational realistic axon models. These models also facilitated studying the effects of electrode drift during experiments on the recruitment of peripheral nerves. An optimal point of lowest threshold was found while displacing the nerve horizontally i.e., the activation thresholds of both myelinated and unmyelinated axons increased when the electrodes were displaced medially and decreased to a certain extend when the electrodes were displaced laterally, after which further lateral displacement led to increase of thresholds. Inclusion of unmyelinated axons in the modeling provided the capability of finding maximum stimulation amplitude below which side effects like pain sensation may be avoided. In the case of F3 – F4 electrode montage the maximum amplitude was 2.39 mA and in case of RS – LS montage the maximum amplitude was 2.44 mA. Such modeling studies may be useful for personalization of TES devices for finding optimal positioning of electrodes with respect to target and stimulation amplitude range that minimizes side effects.
ContributorsSahu, Sulagna (Author) / Sadleir, Rosalind (Thesis advisor) / Tillery, Stephen H (Committee member) / Crook, Sharon (Committee member) / Beeman, Scott (Committee member) / Abbas, James (Committee member) / Arizona State University (Publisher)
Created2023
Description
Safety and efficacy of neuromodulation are influenced by abiotic factors like failure of implants, biotic factors like tissue damage, and molecular and cellular mechanisms of neuromodulation. Accelerated lifetime test (ALT) predict lifetime of implants by accelerating failure modes in controlled bench-top conditions. Current ALT models do not capture failure modes involving biological mechanisms. First part of this dissertation is focused on developing ALTs for predicting failure of chronically implanted tungsten stimulation electrodes. Three factors used in ALT are temperature, H2O2 concentration, and amount of charge delivered through electrode to develop a predictive model of lifetime for stimulation electrodes. Second part of this dissertation is focused on developing a novel method for evaluating tissue response to implants and electrical stimulation. Current methods to evaluate tissue damage in the brain require invasive and terminal procedures that have poor clinical translation. I report a novel non-invasive method that sampled peripheral blood monocytes (PBMCs) and used enzyme-linked immunoassay (ELISA) to assess level of glial fibrillary acidic protein (GFAP) expression and fluorescence-activated cell sorting (FACS) to quantify number of GFAP expressing PBMCs. Using this method, I was able to detect and quantify GFAP expression in PBMCs. However, there was no statistically significant difference in GFAP expression between stimulatory and non-stimulatory implants. Final part of this dissertation assessed molecular and cellular mechanisms of non-invasive ultrasound neuromodulation approach. Unlike electrical stimulation, cellular mechanisms of ultrasound-based neuromodulation are not fully known. Final part of this dissertation assessed role of mechanosensitive ion channels and neuronal nitric oxide production in cell cultures under ultrasound excitation. I used fluorescent imaging to quantify expression of nitric oxide in neuronal cell cultures in response to ultrasound stimulation. Results from these experiments indicate that neuronal nitric oxide production increased in response to ultrasound stimulation compared to control and decreased when mechanosensitive ion channels were suppressed. Two novel methods developed in this dissertation enable assessment of lifetime and safety of neuromodulation techniques that use electrical stimulation through implants. The final part of this dissertation concludes that non-invasive ultrasound neuromodulation may be mediated through neuronal nitric oxide even in absence of activation of mechanosensitive ion channels.
ContributorsVoziyanov, Vladislav (Author) / Muthuswamy, Jitendran (Thesis advisor) / Smith, Barbara (Committee member) / Greger, Bradley (Committee member) / Abbas, James (Committee member) / Okandan, Murat (Committee member) / Arizona State University (Publisher)
Created2022
Description
Annually, approximately 1.7 million people suffer a traumatic brain injury (TBI) in the United States. After initial insult, a TBI persists as a series of molecular and cellular events that lead to cognitive and motor deficits which have no treatment. In addition, the injured brain activates the regenerative niches of the adult brain presumably to reduce damage. The subventricular zone (SVZ) niche contains neural progenitor cells (NPCs) that generate astrocytes, oligodendrocyte, and neuroblasts. Following TBI, the injury microenvironment secretes signaling molecules like stromal cell derived factor-1a (SDF-1a). SDF-1a gradients from the injury contribute to the redirection of neuroblasts from the SVZ towards the lesion which may differentiate into neurons and integrate into existing circuitry. This repair mechanism is transient and does not lead to complete recovery of damaged tissue. Further, the mechanism by which SDF-1a gradients reach SVZ cells is not fully understood. To prolong NPC recruitment to the injured brain, exogenous SDF-1a delivery strategies have been employed. Increases in cell recruitment following stroke, spinal cord injury, and TBI have been demonstrated following SDF-1a delivery. Exogenous delivery of SDF-1a is limited by its 28-minute half-life and clearance from the injury microenvironment. Biomaterials-based delivery improves stability of molecules like SDF-1a and offer control of its release.
This dissertation investigates SDF-1a delivery strategies for neural regeneration in three ways: 1) elucidating the mechanisms of spatiotemporal SDF-1a signaling across the brain, 2) developing a tunable biomaterials system for SDF-1a delivery to the brain, 3) investigating SDF-1a delivery on SVZ-derived cell migration following TBI. Using in vitro, in vivo, and in silico analyses, autocrine/paracrine signaling was necessary to produce SDF-1a gradients in the brain. Native cell types engaged in autocrine/paracrine signaling. A microfluidics device generated injectable hyaluronic-based microgels that released SDF-1a peptide via enzymatic cleavage. Microgels (±SDF-1a peptide) were injected 7 days post-TBI in a mouse model and evaluated for NPC migration 7 days later using immunohistochemistry. Initial staining suggested complex presence of astrocytes, NPCs, and neuroblasts throughout the frontoparietal cortex.
Advancement of chemokine delivery was demonstrated by uncovering endogenous chemokine propagation in the brain, generating new approaches to maximize chemokine-based neural regeneration.
ContributorsHickey, Kassondra (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Holloway, Julianne (Committee member) / Caplan, Michael (Committee member) / Brafman, David (Committee member) / Newbern, Jason (Committee member) / Arizona State University (Publisher)
Created2021
Description
This work focuses on qualifying the performance of an optoelectrical measurement system designed to analyze ribonucleic acid (RNA) within a micro sample. The system is capable of measuring light intensity converted to voltage versus time and is a fast, inexpensive, and portable method for rapid detection of biologics such as SARS-CoV-2 virus, or Covid-19 disease. The measurement system consists of a microfluidic chip and a point of care fluorescent reader.The intent of this research is to measure consistency and robustness of the fluorescent reader combined with the microfluidic chip. The consistency and the robustness of the fluorescent reader within the duty cycle of the system power and the measurement system were analyzed with Six Sigma methods. Control charts, analysis of variance (ANOVAs), and variance components calculations were implemented to characterize the reader system. Through the process of this analysis, baseline characteristics were measured and documented providing valuable data for the improved instrument design.
The existing microfluidic chip is a prototype that works in combination with the reader based on fluorescent detection. Baseline studies were required to define any issues related to microfluidic autofluorescence. Multiple designs were tested to measure reduction in autofluorescence in the microfluidics. It was found that certain designs performed better than others. One approach for improvement in the microfluidic chip may be achieved by characterizing and source controlling materials, optimizing layers, mask apertures, and mask orientations to determine reliability in the measurable output through the fluorescent reader. Since the reader and the microfluidic are designed to work together, any future studies should explore testing where the two components are considered a coupled system.
ContributorsShabtai, Bat-El (Author) / Blain Christen, Jennifer (Thesis advisor) / Abbas, James (Thesis advisor) / Maass, Eric (Committee member) / Beeman, Scott (Committee member) / Arizona State University (Publisher)
Created2021
Description
Finite element models (FEMs) of spine segments validated in their intact states are often used to make predictions following structural modifications simulating surgical procedures, including posterior fusion with pedicle screws and rods (PSR) and laminectomy (removal of posterior column bone to decompress the spinal cord). The gold standard for spine FEM validation compares predicted vs. experimental intervertebral ranges of motion (ROM). Given that muscle co-contraction compresses the spine, validation that considers compression may produce a more robust FEM. One research goal was to evaluate an experimental method of compressing a lumbar spine segment through its sagittal plane balance (pivot) point (BP) using a 6DOF robotic test system. Experimental data supported the hypothesis that structural modifications, such as PSR and laminectomy alter the segment’s BP location and its compressive stiffness. However, evaluation showed that the experimental BP method is sensitive to specimen posture in the robotic test frame; slight flexion or extension produced shear loads during compression that affect BP location and should be included in specimen-specific FEMs to ensure similar load conditions. Another goal was to develop a uniquely calibrated specimen-specific FEM of an intact L4-5 motion segment using the experimental BP data. A specimen-specific FEM was created and calibrated using experimental BP compressive stiffness data, however matching experimental BP location data was unsuccessful. The BP-compression calibrated FEM was evaluated by comparing predicted responses to loads following simulated PSR and laminectomy to specimen-specific experimental data. Predictions using the BP-calibrated and ROM-calibrated FEMs were compared. The BP-calibration process helped identify an unrealistic FEM disc geometry (nucleus pulposus size and location). Both BP-compression and ROM-calibrated FEMs predicted effects of PSR on stiffness (compressive and flexural) that were greater than experimental, which helped identify a problem with simplified representations of bone in the posterior column and at the anterior column interface. The BP-compression calibrated FEMs predicted relative shifts in BP locations and bone surface strains during compression that were closer to experimental data than similarly modified ROM-calibrated FEMs. Collectively, these results support the use of BP measures in experimental and model-based investigations of surgical modifications of the spine.
ContributorsSawa, Anna Genowefa Ulrika (Author) / Abbas, James (Thesis advisor) / Crawford, Neil R (Thesis advisor) / Kelly, Brian P (Committee member) / Helms-Tillery, Stephen (Committee member) / Sadleir, Rosalind (Committee member) / Arizona State University (Publisher)
Created2023
Description
Achieving effective drug concentrations within the central nervous system (CNS) remains one of the greatest challenges for the treatment of brain tumors. The presence of the blood-brain barrier and blood-spinal cord barrier severely restricts the blood-to-CNS entry of nearly all systemically administered therapeutics, often leading to the development of peripheral toxicities before a treatment benefit is observed. To circumvent systemic barriers, intrathecal (IT) injection of therapeutics directly into the cerebrospinal fluid (CSF) surrounding the brain and spinal cord has been used as an alternative administration route; however, its widespread translation to the clinic has been hindered by poor drug pharmacokinetics (PK), including rapid clearance, inadequate distribution, as well as toxicity. One strategy to overcome the limitations of free drug PK and improve drug efficacy is to encapsulate drug within nanoparticles (NP), which solubilize hydrophobic molecules for sustained release in physiological environments. In this thesis, we will develop NP delivery strategies for brain tumor therapy in two model systems: glioblastoma (GBM), the most common and deadly malignant primary brain tumor, and medulloblastoma, the most common pediatric brain tumor. In the first research chapter, we developed 120 nm poly(lactic acid-co-glycolic acid) NPs encapsulating the chemotherapy, camptothecin, for intravenous delivery to GBM. NP encapsulation of camptothecin was shown to reduce the drug’s toxicity and enable effective delivery to orthotopic GBM. To build off the success of intravenous NP, the second research chapter explored the utility of 100 nm PEGylated NPs for use with IT administration. Using in vivo imaging and ex vivo tissue slices, we found the NPs were rapidly transported by the convective forces of the CSF along the entire neuraxis and were retained for over 3 weeks. Based on their wide spread delivery and prolonged circulation, we examine the ability of the NPs to localize with tumor lesions in a leptomeningeal metastasis (LM) model of medulloblastoma. NPs administered to LM bearing mice were shown to penetrate into LM mets seeded within the meninges around the brain. These data show the potential to translate our success with intravenous NPs for GBM to improve IT chemotherapy delivery to LM.
ContributorsHouseholder, Kyle Thomas (Author) / Sirianni, Rachael W. (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Vernon, Brent (Committee member) / Caplan, Michael (Committee member) / Wechsler-Reya, Robert (Committee member) / Arizona State University (Publisher)
Created2018
Description
Injuries and death associated with fall incidences pose a significant burden to society, both in terms of human suffering and economic losses. The main aim of this dissertation is to study approaches that can reduce the risk of falls. One major subset of falls is falls due to neurodegenerative disorders such as Parkinson’s disease (PD). Freezing of gait (FOG) is a major cause of falls in this population. Therefore, a new FOG detection method using wavelet transform technique employing optimal sampling window size, update time, and sensor placements for identification of FOG events is created and validated in this dissertation. Another approach to reduce the risk of falls in PD patients is to correctly diagnose PD motor subtypes. PD can be further divided into two subtypes based on clinical features: tremor dominant (TD), and postural instability and gait difficulty (PIGD). PIGD subtype can place PD patients at a higher risk for falls compared to TD patients and, they have worse postural control in comparison to TD patients. Accordingly, correctly diagnosing subtypes can help caregivers to initiate early amenable interventions to reduce the risk of falls in PIGD patients. As such, a method using the standing center-of-pressure time series data has been developed to identify PD motor subtypes in this dissertation. Finally, an intervention method to improve dynamic stability was tested and validated. Unexpected perturbation-based training (PBT) is an intervention method which has shown promising results in regard to improving balance and reducing falls. Although PBT has shown promising results, the efficacy of such interventions is not well understood and evaluated. In other words, there is paucity of data revealing the effects of PBT on improving dynamic stability of walking and flexible gait adaptability. Therefore, the effects
of three types of perturbation methods on improving dynamics stability was assessed. Treadmill delivered translational perturbations training improved dynamic stability, and adaptability of locomotor system in resisting perturbations while walking.
of three types of perturbation methods on improving dynamics stability was assessed. Treadmill delivered translational perturbations training improved dynamic stability, and adaptability of locomotor system in resisting perturbations while walking.
ContributorsRezvanian, Saba (Author) / Lockhart, Thurmon (Thesis advisor) / Buneo, Christopher (Committee member) / Lieberman, Abraham (Committee member) / Abbas, James (Committee member) / Deep, Aman (Committee member) / Arizona State University (Publisher)
Created2019
Description
Long-term monitoring of deep brain structures using microelectrode implants is critical for the success of emerging clinical applications including cortical neural prostheses, deep brain stimulation and other neurobiology studies such as progression of disease states, learning and memory, brain mapping etc. However, current microelectrode technologies are not capable enough of reaching those clinical milestones given their inconsistency in performance and reliability in long-term studies. In all the aforementioned applications, it is important to understand the limitations & demands posed by technology as well as biological processes. Recent advances in implantable Micro Electro Mechanical Systems (MEMS) technology have tremendous potential and opens a plethora of opportunities for long term studies which were not possible before. The overall goal of the project is to develop large scale autonomous, movable, micro-scale interfaces which can seek and monitor/stimulate large ensembles of precisely targeted neurons and neuronal networks that can be applied for brain mapping in behaving animals. However, there are serious technical (fabrication) challenges related to packaging and interconnects, examples of which include: lack of current industry standards in chip-scale packaging techniques for silicon chips with movable microstructures, incompatible micro-bonding techniques to elongate current micro-electrode length to reach deep brain structures, inability to achieve hermetic isolation of implantable devices from biological tissue and fluids (i.e. cerebrospinal fluid (CSF), blood, etc.). The specific aims are to: 1) optimize & automate chip scale packaging of MEMS devices with unique requirements not amenable to conventional industry standards with respect to bonding, process temperature and pressure in order to achieve scalability 2) develop a novel micro-bonding technique to extend the length of current polysilicon micro-electrodes to reach and monitor deep brain structures 3) design & develop high throughput packaging mechanism for constructing a dense array of movable microelectrodes. Using a combination of unique micro-bonding technique which involves conductive thermosetting epoxy’s with hermetically sealed support structures and a highly optimized, semi-automated, 90-minute flip-chip packaging process, I have now extended the repertoire of previously reported movable microelectrode arrays to bond conventional stainless steel and Pt/Ir microelectrode arrays of desired lengths to steerable polysilicon shafts. I tested scalable prototypes in rigorous bench top tests including Impedance measurements, accelerated aging and non-destructive testing to assess electrical and mechanical stability of micro-bonds under long-term implantation. I propose a 3D printed packaging method allows a wide variety of electrode configurations to be realized such as a rectangular or circular array configuration or other arbitrary geometries optimal for specific regions of the brain with inter-electrode distance as low as 25 um with an unprecedented capability of seeking and recording/stimulating targeted single neurons in deep brain structures up to 10 mm deep (with 6 μm displacement resolution). The advantage of this computer controlled moveable deep brain electrodes facilitates potential capabilities of moving past glial sheath surrounding microelectrodes to restore neural connection, counter the variabilities in signal amplitudes, and enable simultaneous recording/stimulation at precisely targeted layers of brain.
ContributorsPalaniswamy, Sivakumar (Author) / Muthuswamy, Jitendran (Thesis advisor) / Buneo, Christopher (Committee member) / Abbas, James (Committee member) / Arizona State University (Publisher)
Created2016
Description
Aortic pathologies such as coarctation, dissection, and aneurysm represent a
particularly emergent class of cardiovascular diseases and account for significant cardiovascular morbidity and mortality worldwide. Computational simulations of aortic flows are growing increasingly important as tools for gaining understanding of these pathologies and for planning their surgical repair. In vitro experiments are required to validate these simulations against real world data, and a pulsatile flow pump system can provide physiologic flow conditions characteristic of the aorta.
This dissertation presents improved experimental techniques for in vitro aortic blood flow and the increasingly larger parts of the human cardiovascular system. Specifically, this work develops new flow management and measurement techniques for cardiovascular flow experiments with the aim to improve clinical evaluation and treatment planning of aortic diseases.
The hypothesis of this research is that transient flow driven by a step change in volume flux in a piston-based pulsatile flow pump system behaves differently from transient flow driven by a step change in pressure gradient, the development time being substantially reduced in the former. Due to this difference in behavior, the response to a piston-driven pump can be predicted in order to establish inlet velocity and flow waveforms at a downstream phantom model.
The main objectives of this dissertation were: 1) to design, construct, and validate a piston-based flow pump system for aortic flow experiments, 2) to characterize temporal and spatial development of start-up flows driven by a piston pump that produces a step change from zero flow to a constant volume flux in realistic (finite) tube geometries for physiologic Reynolds numbers, and 3) to develop a method to predict downstream velocity and flow waveforms at the inlet of an aortic phantom model and determine the input waveform needed to achieve the intended waveform at the test section. Application of these newly improved flow management tools and measurement techniques were then demonstrated through in vitro experiments in patient-specific coarctation of aorta flow phantom models manufactured in-house and compared to computational simulations to inform and execute future experiments and simulations.
particularly emergent class of cardiovascular diseases and account for significant cardiovascular morbidity and mortality worldwide. Computational simulations of aortic flows are growing increasingly important as tools for gaining understanding of these pathologies and for planning their surgical repair. In vitro experiments are required to validate these simulations against real world data, and a pulsatile flow pump system can provide physiologic flow conditions characteristic of the aorta.
This dissertation presents improved experimental techniques for in vitro aortic blood flow and the increasingly larger parts of the human cardiovascular system. Specifically, this work develops new flow management and measurement techniques for cardiovascular flow experiments with the aim to improve clinical evaluation and treatment planning of aortic diseases.
The hypothesis of this research is that transient flow driven by a step change in volume flux in a piston-based pulsatile flow pump system behaves differently from transient flow driven by a step change in pressure gradient, the development time being substantially reduced in the former. Due to this difference in behavior, the response to a piston-driven pump can be predicted in order to establish inlet velocity and flow waveforms at a downstream phantom model.
The main objectives of this dissertation were: 1) to design, construct, and validate a piston-based flow pump system for aortic flow experiments, 2) to characterize temporal and spatial development of start-up flows driven by a piston pump that produces a step change from zero flow to a constant volume flux in realistic (finite) tube geometries for physiologic Reynolds numbers, and 3) to develop a method to predict downstream velocity and flow waveforms at the inlet of an aortic phantom model and determine the input waveform needed to achieve the intended waveform at the test section. Application of these newly improved flow management tools and measurement techniques were then demonstrated through in vitro experiments in patient-specific coarctation of aorta flow phantom models manufactured in-house and compared to computational simulations to inform and execute future experiments and simulations.
ContributorsChaudhury, Rafeed Ahmed (Author) / Frakes, David (Thesis advisor) / Adrian, Ronald J (Thesis advisor) / Vernon, Brent (Committee member) / Pizziconi, Vincent (Committee member) / Caplan, Michael (Committee member) / Arizona State University (Publisher)
Created2015
Description
Olecranon fractures account for approximately 10% of upper extremity fractures and 95% of them require surgical fixation. Most of the clinical, retrospective and biomechanical studies have supported plate fixation over other surgical fixation techniques since plates have demonstrated low incidence of reoperation, high fixation stability and resumption of activities of daily living (ADL) earlier. Thus far, biomechanical studies have been helpful in evaluating and comparing different plate fixation constructs based on fracture stability. However, they have not provided information that can be used to design rehabilitation protocols such as information that relates load at the hand with tendon tension or load at the interface between the plate and the bone. The set-ups used in biomechanical studies have included simple mechanical testing machines that either measured construct stiffness by cyclic loading the specimens or construct strength by performing ramp load until failure. Some biomechanical studies attempted to simulate tendon tension but the in-vivo tension applied to the tendon remains unknown. In this study, a novel procedure to test the olecranon fracture fixation using modern olecranon plates was developed to improve the biomechanical understanding of failures and to help determine the weights that can be safely lifted and the range of motion (ROM) that should be performed during rehabilitation procedures.
Design objectives were defined based on surgeon's feedback and analysis of unmet needs in the area of biomechanical testing. Four pilot cadaveric specimens were prepared to run on an upper extremity feedback controller and the set-up was validated based on the design objectives. Cadaveric specimen preparation included a series of steps such as dissection, suturing and potting that were standardized and improved iteratively after pilot testing. Additionally, a fracture and plating protocol was developed and fixture lengths were standardized based on anthropometric data. Results from the early pilot studies indicated shortcomings in the design, which was then iteratively refined for the subsequent studies. The final pilot study demonstrated that all of the design objectives were met. This system is planned for use in future studies that will assess olecranon fracture fixation and that will investigate the safety of rehabilitation protocols.
Design objectives were defined based on surgeon's feedback and analysis of unmet needs in the area of biomechanical testing. Four pilot cadaveric specimens were prepared to run on an upper extremity feedback controller and the set-up was validated based on the design objectives. Cadaveric specimen preparation included a series of steps such as dissection, suturing and potting that were standardized and improved iteratively after pilot testing. Additionally, a fracture and plating protocol was developed and fixture lengths were standardized based on anthropometric data. Results from the early pilot studies indicated shortcomings in the design, which was then iteratively refined for the subsequent studies. The final pilot study demonstrated that all of the design objectives were met. This system is planned for use in future studies that will assess olecranon fracture fixation and that will investigate the safety of rehabilitation protocols.
ContributorsJain, Saaransh (Author) / Abbas, James (Thesis advisor) / LaBelle, Jeffrey (Thesis advisor) / Jacofsky, Marc (Committee member) / Arizona State University (Publisher)
Created2015