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- All Subjects: Biomedical Engineering
- Genre: Doctoral Dissertation
- Creators: Arizona State University
Description
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.
ContributorsOverstreet, Derek (Author) / Caplan, Michael (Thesis advisor) / Massia, Stephen (Committee member) / Mclaren, Alexander (Committee member) / Vernon, Brent (Committee member) / McLemore, Ryan (Committee member) / Arizona State University (Publisher)
Created2012
Description
Gold nanoparticles as potential diagnostic, therapeutic and sensing systems have a long history of use in medicine, and have expanded to a variety of applications. Gold nanoparticles are attractive in biological applications due to their unique optical, chemical and biological properties. Particularly, gold nanorods (GNRs) are increasingly used due to superior optical property in the near infrared (NIR) window. Light absorbed by the nanorod can be dissipated as heat efficiently or re-emitted by the particle. However, the limitations for clinical translation of gold nanorods include low yields, poor stability, depth-restricted imaging, and resistance of cancer cells to hyperthermia, are severe. A novel high-throughput synthesis method was employed to significantly increase in yields of solid and porous gold nanorods/wires. Stable functional nanoassemblies and nanomaterials were generated by interfacing gold nanorods with a variety of polymeric and polypeptide-based coatings, resulting in unique properties of polymer-gold nanorod assemblies and composites. Here the use of these modified gold nanorods in a variety of applications including optical sensors, cancer therapeutics, and nanobiomaterials were described.
ContributorsHuang, Huang-Chiao (Author) / Rege, Kaushal (Thesis advisor) / Sierks, Michael (Committee member) / Dai, Lenore (Committee member) / Ramakrishna, B (Committee member) / Vogt, Bryan (Committee member) / Arizona State University (Publisher)
Created2012
Description
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.
ContributorsBearat, Hanin H (Author) / Vernon, Brent L (Thesis advisor) / Frakes, David (Committee member) / Massia, Stephen (Committee member) / Pauken, Christine (Committee member) / Preul, Mark (Committee member) / Solis, Francisco (Committee member) / Arizona State University (Publisher)
Created2012
Description
Biosensors offer excellent diagnostic methods through precise quantification of bodily fluid biomarkers and could fill an important niche in diagnostic screening. The long term goal of this research is the development of an impedance immunosensor for easy-to-use, rapid, sensitive and selective simultaneously multiplexed quantification of bodily fluid disease biomarkers. To test the hypothesis that various cytokines induce empirically determinable response frequencies when captured by printed circuit board (PCB) impedance immunosensor surface, cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) methods were used to test PCB biosensors versus multiple cytokine biomarkers to determine limits of detection, background interaction and response at all sweep frequencies. Results indicated that sensors for cytokine Interleukin-12 (IL-12) detected their target over three decades of concentration and were tolerant to high levels of background protein. Further, the hypothesis that cytokine analytes may be rapidly detected via constant frequency impedance immunosensing without sacrificing undue sensitivity, CV, EIS, impedance-time (Zt) methods and modeling were used to test CHITM gold electrodes versus IL-12 over different lengths of time to determine limits of detection, detection time, frequency of response and consistent cross-platform sensor performance. Modeling and Zt studies indicate interrogation of the electrode with optimum frequency could be used for detection of different target concentrations within 90 seconds of sensor exposure and that interrogating the immunosensor with fixed, optimum frequency could be used for sensing target antigen. This informs usability of fixed-frequency impedance methods for biosensor research and particularly for clinical biosensor use. Finally, a multiplexing impedance immunosensor prototype for quantification of biomarkers in various body fluids was designed for increased automation of sample handling and testing. This enables variability due to exogenous factors and increased rapidity of assay with eased sensor fabrication. Methods were provided for simultaneous multiplexing through multisine perturbation of a sensor, and subsequent data processing. This demonstrated ways to observe multiple types of antibody-antigen affinity binding events in real time, reducing the number of sensors and target sample used in the detection and quantification of multiple biomarkers. These features would also improve the suitability of the sensor for clinical multiplex detection of disease biomarkers.
ContributorsFairchild, Aaron (Author) / La Belle, Jeffrey T (Thesis advisor) / Muthuswamy, Jitendran (Committee member) / Nagaraj, Vinay (Committee member) / Pizziconi, Vince (Committee member) / Vernon, Brent (Committee member) / Arizona State University (Publisher)
Created2012
Description
This dissertation presents methods for the evaluation of ocular surface protection during natural blink function. The evaluation of ocular surface protection is especially important in the diagnosis of dry eye and the evaluation of dry eye severity in clinical trials. Dry eye is a highly prevalent disease affecting vast numbers (between 11% and 22%) of an aging population. There is only one approved therapy with limited efficacy, which results in a huge unmet need. The reason so few drugs have reached approval is a lack of a recognized therapeutic pathway with reproducible endpoints. While the interplay between blink function and ocular surface protection has long been recognized, all currently used evaluation techniques have addressed blink function in isolation from tear film stability, the gold standard of which is Tear Film Break-Up Time (TFBUT). In the first part of this research a manual technique of calculating ocular surface protection during natural blink function through the use of video analysis is developed and evaluated for it's ability to differentiate between dry eye and normal subjects, the results are compared with that of TFBUT. In the second part of this research the technique is improved in precision and automated through the use of video analysis algorithms. This software, called the OPI 2.0 System, is evaluated for accuracy and precision, and comparisons are made between the OPI 2.0 System and other currently recognized dry eye diagnostic techniques (e.g. TFBUT). In the third part of this research the OPI 2.0 System is deployed for use in the evaluation of subjects before, immediately after and 30 minutes after exposure to a controlled adverse environment (CAE), once again the results are compared and contrasted against commonly used dry eye endpoints. The results demonstrate that the evaluation of ocular surface protection using the OPI 2.0 System offers superior accuracy to the current standard, TFBUT.
ContributorsAbelson, Richard (Author) / Montgomery, Douglas C. (Thesis advisor) / Borror, Connie (Committee member) / Shunk, Dan (Committee member) / Pan, Rong (Committee member) / Arizona State University (Publisher)
Created2012
Description
This dissertation provides a fundamental understanding of the properties of mesoporous carbon based materials and the utilization of those properties into different applications such as electrodes materials for super capacitors, adsorbents for water treatments and biosensors. The thickness of mesoporous carbon films on Si substrates are measured by Ellipsometry method and pore size distribution has been calculated by Kelvin equation based on toluene adsorption and desorption isotherms monitored by Ellipsometer. The addition of organometallics cobalt and vanalyl acetylacetonate in the synthesis precursor leads to the metal oxides in the carbon framework, which largely decreased the shrink of the framework during carbonization, resulting in an increase in the average pore size. In addition to the structural changes, the introduction of metal oxides into mesoporous carbon framework greatly enhances the electrochemical performance as a result of their pseudocapacitance. Also, after the addition of Co into the framework, the contraction of mesoporous powders decreased significantly and the capacitance increased prominently because of the solidification function of CoO nanoparticles. When carbon-cobalt composites are used as adsorbent, the adsorption capacity of dye pollutant in water is remarkably higher (90 mg/g) after adding Co than the mesoporous carbon powder (2 mg/g). Furthermore, the surface area and pore size of mesoporous composites can be greatly increased by addition of tetraethyl orthosilicate into the precursor with subsequent etching, which leads to a dramatic increase in the adsorption capacity from 90 mg/g up to 1151 mg/g. When used as electrode materials for amperometric biosensors, mesoporous carbons showed good sensitivity, selectivity and stability. And fluorine-free and low-cost poly (methacrylate)s have been developed as binders for screen printed biosensors. With using only 5wt% of poly (hydroxybutyl methacrylate), the glucose sensor maintained mechanical integrity and exhibited excellent sensitivity on detecting glucose level in whole rabbit blood. Furthermore, extremely high surface area mesoporous carbons have been synthesized by introducing inorganic Si precursor during self-assembly, which effectively determined norepinephrine at very low concentrations.
ContributorsDai, Mingzhi (Author) / Vogt, Bryan D (Thesis advisor) / La Belle, Jeffrey T (Committee member) / Dai, Lenore (Committee member) / Nielsen, David R (Committee member) / Torres, César I (Committee member) / Arizona State University (Publisher)
Created2012
Description
The goal of the works presented in this volume is to develop a magnetic resonance imaging (MRI) probe for non-invasive detection of extracellular matrix (ECM) underlying fenestrated endothelia. The ECM is the scaffold that supports tissue structure in all organs. In fenestrated structures the such as the kidney glomerulus and the hepatic sinusoid the ECM serves a unique role in blood filtration and is directly exposed to blood plasma. An assessment of the ECM in fenestrated organs such as the kidney and liver reports on the organ's ability to filter blood - a process critical to maintaining homeostasis. Unfortunately, clinical assessment of the ECM in most organs requires biopsy, which is focal and invasive. This work will focus on visualizing the ECM underlying fenestrated endothelia with natural nanoparticles and MRI. The superparamagnetic ferritin protein has been proposed as a useful naturally-derived, MRI-detectable nanoparticle due to its biocompatibility, ease of functionalization, and modifiable metallic core. We will show that cationized ferritin (CF) specifically binds to the anionic proteoglycans of the ECM underlying fenestrated endothelia and that its accumulation is MRI-detectable. We will then demonstrate the use of CF and MRI in identifying and measuring all glomeruli in the kidney. We will also explore the toxicity of intravenously injected CF and consider other avenues for its application, including detection of microstructural changes in the liver due to chronic liver disease. This work will show that CF is useful in detected fenestrated microstructures in small animals and humans alike, indicating that CF may find broad application in detecting and monitoring disease in both preclinical and clinical settings.
ContributorsBeeman, Scott (Author) / Bennett, Kevin M (Thesis advisor) / Kodibagkar, Vikram D (Committee member) / Fayad, Zahi A (Committee member) / Pizziconi, Vincent B (Committee member) / Pipe, James G (Committee member) / Arizona State University (Publisher)
Created2012
Description
Noninvasive neuromodulation could help treat many neurological disorders, but existing techniques have low resolution and weak penetration. Ultrasound (US) shows promise for stimulation of smaller areas and subcortical structures. However, the mechanism and parameter design are not understood. US can stimulate tail and hindlimb movements in rats, but not forelimb, for unknown reasons. Potentially, US could also stimulate peripheral or enteric neurons for control of blood glucose.
To better understand the inconsistent effects across rat motor cortex, US modulation of electrically-evoked movements was tested. A stimulation array was implanted on the cortical surface and US (200 kHz, 30-60 W/cm2 peak) was applied while measuring changes in the evoked forelimb and hindlimb movements. Direct US stimulation of the hindlimb was also studied. To test peripheral effects, rat blood glucose levels were measured while applying US near the liver.
No short-term motor modulation was visible (95% confidence interval: -3.5% to +5.1% forelimb, -3.8% to +5.5% hindlimb). There was significant long-term (minutes-order) suppression (95% confidence interval: -3.7% to -10.8% forelimb, -3.8% to -11.9% hindlimb). This suppression may be due to the considerable heating (+1.8°C between US
on-US conditions); effects of heat and US were not separable in this experiment. US directly evoked hindlimb and scrotum movements in some sessions. This required a long interval, at least 3 seconds between US bursts. Movement could be evoked with much shorter pulses than used in literature (3 ms). The EMG latency (10 ms) was compatible with activation of corticospinal neurons. The glucose modulation test showed a strong increase in a few trials, but across all trials found no significant effect.
The single motor response and the long refractory period together suggest that only the beginning of the US burst had a stimulatory effect. This would explain the lack of short-term modulation, and suggests future work with shorter pulses could better explore the missing forelimb response. During the refractory period there was no change in the electrically-evoked response, which suggests the US stimulation mechanism is independent of normal brain activity. These results challenge the literature-standard protocols and provide new insights on the unknown mechanism.
To better understand the inconsistent effects across rat motor cortex, US modulation of electrically-evoked movements was tested. A stimulation array was implanted on the cortical surface and US (200 kHz, 30-60 W/cm2 peak) was applied while measuring changes in the evoked forelimb and hindlimb movements. Direct US stimulation of the hindlimb was also studied. To test peripheral effects, rat blood glucose levels were measured while applying US near the liver.
No short-term motor modulation was visible (95% confidence interval: -3.5% to +5.1% forelimb, -3.8% to +5.5% hindlimb). There was significant long-term (minutes-order) suppression (95% confidence interval: -3.7% to -10.8% forelimb, -3.8% to -11.9% hindlimb). This suppression may be due to the considerable heating (+1.8°C between US
on-US conditions); effects of heat and US were not separable in this experiment. US directly evoked hindlimb and scrotum movements in some sessions. This required a long interval, at least 3 seconds between US bursts. Movement could be evoked with much shorter pulses than used in literature (3 ms). The EMG latency (10 ms) was compatible with activation of corticospinal neurons. The glucose modulation test showed a strong increase in a few trials, but across all trials found no significant effect.
The single motor response and the long refractory period together suggest that only the beginning of the US burst had a stimulatory effect. This would explain the lack of short-term modulation, and suggests future work with shorter pulses could better explore the missing forelimb response. During the refractory period there was no change in the electrically-evoked response, which suggests the US stimulation mechanism is independent of normal brain activity. These results challenge the literature-standard protocols and provide new insights on the unknown mechanism.
ContributorsGulick, Daniel Withers (Author) / Kleim, Jeffrey (Thesis advisor) / Towe, Bruce (Thesis advisor) / Muthuswamy, Jitendran (Committee member) / Herman, Richard (Committee member) / Helms Tillery, Steven (Committee member) / Arizona State University (Publisher)
Created2015
Description
Detection of molecular interactions is critical for understanding many biological processes, for detecting disease biomarkers, and for screening drug candidates. Fluorescence-based approach can be problematic, especially when applied to the detection of small molecules. Various label-free techniques, such as surface plasmon resonance technique are sensitive to mass, making it extremely challenging to detect small molecules. In this thesis, novel detection methods for molecular interactions are described.
First, a simple detection paradigm based on reflectance interferometry is developed. This method is simple, low cost and can be easily applied for protein array detection.
Second, a label-free charge sensitive optical detection (CSOD) technique is developed for detecting of both large and small molecules. The technique is based on that most molecules relevant to biomedical research and applications are charged or partially charged. An optical fiber is dipped into the well of a microplate. It detects the surface charge of the fiber, which does not decrease with the size (mass) of the molecule, making it particularly attractive for studying small molecules.
Third, a method for mechanically amplification detection of molecular interactions (MADMI) is developed. It provides quantitative analysis of small molecules interaction with membrane proteins in intact cells. The interactions are monitored by detecting a mechanical deformation in the membrane induced by the molecular interactions. With this novel method small molecules and membrane proteins interaction in the intact cells can be detected. This new paradigm provides mechanical amplification of small interaction signals, allowing us to measure the binding kinetics of both large and small molecules with membrane proteins, and to analyze heterogeneous nature of the binding kinetics between different cells, and different regions of a single cell.
Last, by tracking the cell membrane edge deformation, binding caused downstream event – granule secretory has been measured. This method focuses on the plasma membrane change when granules fuse with the cell. The fusion of granules increases the plasma membrane area and thus the cell edge expands. The expansion is localized at the vesicle release location. Granule size was calculated based on measured edge expansion. The membrane deformation due to the granule release is real-time monitored by this method.
First, a simple detection paradigm based on reflectance interferometry is developed. This method is simple, low cost and can be easily applied for protein array detection.
Second, a label-free charge sensitive optical detection (CSOD) technique is developed for detecting of both large and small molecules. The technique is based on that most molecules relevant to biomedical research and applications are charged or partially charged. An optical fiber is dipped into the well of a microplate. It detects the surface charge of the fiber, which does not decrease with the size (mass) of the molecule, making it particularly attractive for studying small molecules.
Third, a method for mechanically amplification detection of molecular interactions (MADMI) is developed. It provides quantitative analysis of small molecules interaction with membrane proteins in intact cells. The interactions are monitored by detecting a mechanical deformation in the membrane induced by the molecular interactions. With this novel method small molecules and membrane proteins interaction in the intact cells can be detected. This new paradigm provides mechanical amplification of small interaction signals, allowing us to measure the binding kinetics of both large and small molecules with membrane proteins, and to analyze heterogeneous nature of the binding kinetics between different cells, and different regions of a single cell.
Last, by tracking the cell membrane edge deformation, binding caused downstream event – granule secretory has been measured. This method focuses on the plasma membrane change when granules fuse with the cell. The fusion of granules increases the plasma membrane area and thus the cell edge expands. The expansion is localized at the vesicle release location. Granule size was calculated based on measured edge expansion. The membrane deformation due to the granule release is real-time monitored by this method.
ContributorsGuan, Yan (Author) / Tao, Nongjian (Thesis advisor) / LaBaer, Joshua (Committee member) / Goryll, Michael (Committee member) / Wang, Shaopeng (Committee member) / Arizona State University (Publisher)
Created2015
Description
Epilepsy is a group of disorders that cause seizures in approximately 2.2 million people in the United States. Over 30% of these patients have epilepsies that do not respond to treatment with anti-epileptic drugs. For this population, focal resection surgery could offer long-term seizure freedom. Surgery candidates undergo a myriad of tests and monitoring to determine where and when seizures occur. The “gold standard” method for focus identification involves the placement of electrocorticography (ECoG) grids in the sub-dural space, followed by continual monitoring and visual inspection of the patient’s cortical activity. This process, however, is highly subjective and uses dated technology. Multiple studies were performed to investigate how the evaluation process could benefit from an algorithmic adjust using current ECoG technology, and how the use of new microECoG technology could further improve the process.
Computational algorithms can quickly and objectively find signal characteristics that may not be detectable with visual inspection, but many assume the data are stationary and/or linear, which biological data are not. An empirical mode decomposition (EMD) based algorithm was developed to detect potential seizures and tested on data collected from eight patients undergoing monitoring for focal resection surgery. EMD does not require linearity or stationarity and is data driven. The results suggest that a biological data driven algorithm could serve as a useful tool to objectively identify changes in cortical activity associated with seizures.
Next, the use of microECoG technology was investigated. Though both ECoG and microECoG grids are composed of electrodes resting on the surface of the cortex, changing the diameter of the electrodes creates non-trivial changes in the physics of the electrode-tissue interface that need to be accounted for. Experimenting with different recording configurations showed that proper grounding, referencing, and amplification are critical to obtain high quality neural signals from microECoG grids.
Finally, the relationship between data collected from the cortical surface with micro and macro electrodes was studied. Simultaneous recordings of the two electrode types showed differences in power spectra that suggest the inclusion of activity, possibly from deep structures, by macroelectrodes that is not accessible by microelectrodes.
Computational algorithms can quickly and objectively find signal characteristics that may not be detectable with visual inspection, but many assume the data are stationary and/or linear, which biological data are not. An empirical mode decomposition (EMD) based algorithm was developed to detect potential seizures and tested on data collected from eight patients undergoing monitoring for focal resection surgery. EMD does not require linearity or stationarity and is data driven. The results suggest that a biological data driven algorithm could serve as a useful tool to objectively identify changes in cortical activity associated with seizures.
Next, the use of microECoG technology was investigated. Though both ECoG and microECoG grids are composed of electrodes resting on the surface of the cortex, changing the diameter of the electrodes creates non-trivial changes in the physics of the electrode-tissue interface that need to be accounted for. Experimenting with different recording configurations showed that proper grounding, referencing, and amplification are critical to obtain high quality neural signals from microECoG grids.
Finally, the relationship between data collected from the cortical surface with micro and macro electrodes was studied. Simultaneous recordings of the two electrode types showed differences in power spectra that suggest the inclusion of activity, possibly from deep structures, by macroelectrodes that is not accessible by microelectrodes.
ContributorsAshmont, Kari Rich (Author) / Greger, Bradley (Thesis advisor) / Helms Tillery, Stephen (Committee member) / Buneo, Christopher (Committee member) / Adelson, P David (Committee member) / Dudek, F Edward (Committee member) / Arizona State University (Publisher)
Created2015