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- All Subjects: Biomedical Engineering
- Creators: Stabenfeldt, Sarah
Description
Specificity and affinity towards a given ligand/epitope limit target-specific delivery. Companies can spend between $500 million to $2 billion attempting to discover a new drug or therapy; a significant portion of this expense funds high-throughput screening to find the most successful target-specific compound available. A more recent addition to discovering highly specific targets is the application of phage display utilizing single chain variable fragment antibodies (scFv). The aim of this research was to employ phage display to identify pathologies related to traumatic brain injury (TBI), particularly astrogliosis. A unique biopanning method against viable astrocyte cultures activated with TGF-β achieved this aim. Four scFv clones of interest showed varying relative affinities toward astrocytes. One of those four showed the ability to identify reactive astroctyes over basal astrocytes through max signal readings, while another showed a statistical significance in max signal reading toward basal astrocytes. Future studies will include further affinity characterization assays. This work contributes to the development of targeting therapeutics and diagnostics for TBI.
ContributorsMarsh, William (Author) / Stabenfeldt, Sarah (Thesis advisor) / Caplan, Michael (Committee member) / Sierks, Michael (Committee member) / Arizona State University (Publisher)
Created2013
Description
The objective of this small animal pre-clinical research project was to study quantitatively the long-term micro- and macro- structural brain changes employing multiparametric MRI (Magnetic Resonance Imaging) techniques. Two separate projects make up the basis of this thesis. The first part focuses on obtaining prognostic information at early stages in the case of Traumatic Brain Injury (TBI) in rat animal model using imaging data acquired at 24-hours and 7-days post injury. The obtained parametric T2 and diffusion values from DTI (Diffusion Tensor Imaging) showed significant deviations in the signal intensities from the control and were potentially useful as an early indicator of the severity of post-traumatic injury damage. DTI was especially critical in distinguishing between the cytotoxic and vasogenic edema and in identification of injury regions resolving to normal control values by day-7. These results indicate the potential of quantitative MRI as a clinical marker in predicting prognosis following TBI. The second part of this thesis focuses on studying the effect of novel therapeutic strategies employing dendritic cell (DC) based vaccinations in mice glioma model. The treatment cohorts included comparing a single dose of Azacytidine drug vs. mice getting three doses of drug per week. Another cohort was used as an untreated control group. The MRI results did not show any significant changes in between the two treated cohorts with no reduction in tumor volumes compared to the control group. The future studies would be focused on issues regarding the optimal dose for the application of DC vaccine. Together, the quantitative MRI plays an important role in the prognosis and diagnosis of the above mentioned pathologies, providing essential information about the anatomical location, micro-structural tissue environment, lesion volume and treatment response.
ContributorsAnnaldas, Bharat (Author) / Kodibagkar, Vikram (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Bhardwaj, Ratan (Committee member) / Arizona State University (Publisher)
Created2014
Description
Modern medical conditions, including cancer, traumatic brain injury, and cardiovascular disease, have elicited the need for cell therapies. The ability to non-invasively track cells in vivo in order to evaluate these therapies and explore cell dynamics is necessary. Magnetic Resonance Imaging provides a platform to track cells as a non-invasive modality with superior resolution and soft tissue contrast. A new methodology for cellular labeling and imaging uses Nile Red doped hexamethyldisiloxane (HMDSO) nanoemulsions as dual modality (Magnetic Resonance Imaging/Fluorescence), dual-functional (oximetry/ detection) nanoprobes. While Gadolinium chelates and super paramagnetic iron oxide-based particles have historically provided contrast enhancement in MRI, newer agents offer additional advantages. A technique using 1H MRI in conjunction with an oxygen reporter molecule is one tool capable of providing these benefits, and can be used in neural progenitor cell and cancer cell studies. Proton Imaging of Siloxanes to Map Tissue Oxygenation Levels (PISTOL) provides the ability to track the polydimethylsiloxane (PDMS) labeled cells utilizing the duality of the nanoemulsions. 1H MRI based labeling of neural stem cells and cancer cells was successfully demonstrated. Additionally, fluorescence labeling of the nanoprobes provided validation of the MRI data and could prove useful for quick in vivo verification and ex vivo validation for future studies.
ContributorsCusick, Alex (Author) / Kodibagkar, Vikram D. (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Kleim, Jeff (Committee member) / Arizona State University (Publisher)
Created2014
Description
Magnetic Resonance Imaging (MRI) is an efficient non-invasive imaging tool widely used in medical field to produce high quality images. The MRI signal is detected with specifically developed radio frequency (RF) systems or "coils". There are several key parameters to evaluate the performance of RF coils: signal-to-noise ratio (SNR), homogeneity, quality factor (Q factor), sensitivity, etc. The choice of coil size and configuration depends on the object to be imaged. While surface coils have better sensitivity, volume coils are often employed to image a larger region of interest (ROI) as they display better spatial homogeneity. For the cell labeling and imaging studies using the newly developed siloxane based nanoemulsions as 1H MR reporter probes, the first step is to determine the sensitivity of signal detection under controlled conditions in vitro. In this thesis, a novel designed 7 Tesla RF volume coil was designed and tested for detection of small quantities of siloxane probe as well as for imaging of labeled tumor spheroid. The procedure contains PCB circuit design, RF probe design, test and subsequent modification. In this report, both theory and design methodology will be discussed.
ContributorsWang, Haiqing (Author) / Kodibagkar, Vikram (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Sadleir, Rosalind (Committee member) / Arizona State University (Publisher)
Created2014
Description
This thesis presents research on innovative AC transmission design concepts and focused mathematics for electric power transmission design. The focus relates to compact designs, high temperature low sag conductors, and high phase order design. The motivation of the research is to increase transmission capacity with limited right of way.
Regarding compact phase spacing, insight into the possibility of increasing the security rating of transmission lines is the primary focus through increased mutual coupling and decreased positive sequence reactance. Compact design can reduce the required corridor width to as little as 31% of traditional designs, especially with the use of inter-phase spacers. Typically transmission lines are built with conservative clearances, with difficulty obtaining right of way, more compact phase spacing may be needed. With design consideration significant compaction can produce an increase by 5-25% in the transmission line security (steady state stability) rating. In addition, other advantages and disadvantages of compact phase design are analyzed. Also, the next two topics: high temperature low sag conductors and high phase order designs include the use of compact designs.
High temperature low sag (HTLS) conductors are used to increase the thermal capacity of a transmission line up to two times the capacity compared to traditional conductors. HTLS conductors can operate continuously at 150-210oC and in emergency at 180-250oC (depending on the HTLS conductor). ACSR conductors operate continuously at 50-110oC and in emergency conditions at 110-150oC depending on the utility, line, and location. HTLS conductors have decreased sag characteristics of up to 33% compared to traditional ACSR conductors at 100oC and up to 22% at 180oC. In addition to what HTLS has to offer in terms of the thermal rating improvement, the possibility of using HTLS conductors to indirectly reduce tower height and compact the phases to increase the security limit is investigated. In addition, utilizing HTLS conductors to increase span length and decrease the number of transmission towers is investigated. The phase compaction or increased span length is accomplished by utilization of the improved physical sag characteristics of HTLS conductors.
High phase order (HPO) focuses on the ability to increase the power capacity for a given right of way. For example, a six phase line would have a thermal rating of approximately 173%, a security rating of approximately 289%, and the SIL would be approximately 300% of a double circuit three phase line with equal right of way and equal voltage line to line. In addition, this research focuses on algorithm and model development of HPO systems. A study of the impedance of HPO lines is presented. The line impedance matrices for some high phase order configurations are circulant Toeplitz matrices. Properties of circulant matrices are developed for the generalized sequence impedances of HPO lines. A method to calculate the sequence impedances utilizing unique distance parameter algorithms is presented. A novel method to design the sequence impedances to specifications is presented. Utilizing impedance matrices in circulant form, a generalized form of the sequence components transformation matrix is presented. A generalized voltage unbalance factor in discussed for HPO transmission lines. Algorithms to calculate the number of fault types and number of significant fault types for an n-phase system are presented. A discussion is presented on transposition of HPO transmission lines and a generalized fault analysis of a high phase order circuit is presented along with an HPO analysis program.
The work presented has the objective of increasing the use of rights of way for bulk power transmission through the use of innovative transmission technologies. The purpose of this dissertation is to lay down some of the building blocks and to help make the three technologies discussed practical applications in the future.
Regarding compact phase spacing, insight into the possibility of increasing the security rating of transmission lines is the primary focus through increased mutual coupling and decreased positive sequence reactance. Compact design can reduce the required corridor width to as little as 31% of traditional designs, especially with the use of inter-phase spacers. Typically transmission lines are built with conservative clearances, with difficulty obtaining right of way, more compact phase spacing may be needed. With design consideration significant compaction can produce an increase by 5-25% in the transmission line security (steady state stability) rating. In addition, other advantages and disadvantages of compact phase design are analyzed. Also, the next two topics: high temperature low sag conductors and high phase order designs include the use of compact designs.
High temperature low sag (HTLS) conductors are used to increase the thermal capacity of a transmission line up to two times the capacity compared to traditional conductors. HTLS conductors can operate continuously at 150-210oC and in emergency at 180-250oC (depending on the HTLS conductor). ACSR conductors operate continuously at 50-110oC and in emergency conditions at 110-150oC depending on the utility, line, and location. HTLS conductors have decreased sag characteristics of up to 33% compared to traditional ACSR conductors at 100oC and up to 22% at 180oC. In addition to what HTLS has to offer in terms of the thermal rating improvement, the possibility of using HTLS conductors to indirectly reduce tower height and compact the phases to increase the security limit is investigated. In addition, utilizing HTLS conductors to increase span length and decrease the number of transmission towers is investigated. The phase compaction or increased span length is accomplished by utilization of the improved physical sag characteristics of HTLS conductors.
High phase order (HPO) focuses on the ability to increase the power capacity for a given right of way. For example, a six phase line would have a thermal rating of approximately 173%, a security rating of approximately 289%, and the SIL would be approximately 300% of a double circuit three phase line with equal right of way and equal voltage line to line. In addition, this research focuses on algorithm and model development of HPO systems. A study of the impedance of HPO lines is presented. The line impedance matrices for some high phase order configurations are circulant Toeplitz matrices. Properties of circulant matrices are developed for the generalized sequence impedances of HPO lines. A method to calculate the sequence impedances utilizing unique distance parameter algorithms is presented. A novel method to design the sequence impedances to specifications is presented. Utilizing impedance matrices in circulant form, a generalized form of the sequence components transformation matrix is presented. A generalized voltage unbalance factor in discussed for HPO transmission lines. Algorithms to calculate the number of fault types and number of significant fault types for an n-phase system are presented. A discussion is presented on transposition of HPO transmission lines and a generalized fault analysis of a high phase order circuit is presented along with an HPO analysis program.
The work presented has the objective of increasing the use of rights of way for bulk power transmission through the use of innovative transmission technologies. The purpose of this dissertation is to lay down some of the building blocks and to help make the three technologies discussed practical applications in the future.
ContributorsPierre, Brian J (Author) / Heydt, Gerald (Thesis advisor) / Karady, George G. (Committee member) / Shunk, Dan (Committee member) / Vittal, Vijay (Committee member) / Arizona State University (Publisher)
Created2015
Description
Alzheimer's disease (AD) is the most common form of dementia leading to cognitive dysfunction and memory loss as well as emotional and behavioral disorders. It is the 6th leading cause of death in United States, and the only one among top 10 death causes that cannot be prevented, cured or slowed. An estimated 5.4 million Americans live with AD, and this number is expected to triple by year 2050 as the baby boomers age. The cost of care for AD in the US is about $200 billion each year. Unfortunately, in addition to the lack of an effective treatment or AD, there is also a lack of an effective diagnosis, particularly an early diagnosis which would enable treatment to begin before significant neuronal damage has occurred.
Increasing evidence implicates soluble oligomeric forms of beta-amyloid and tau in the onset and progression of AD. While many studies have focused on beta-amyloid, soluble oligomeric tau species may also play an important role in AD pathogenesis. Antibodies that selectively identify and target specific oligomeric tau variants would be valuable tools for both diagnostic and therapeutic applications and also to study the etiology of AD and other neurodegenerative diseases.
Recombinant human tau (rhTau) in monomeric, dimeric, trimeric and fibrillar forms were synthesized and purified to perform LDH assay on human neuroblastoma cells, so that trimeric but not monomeric or dimeric rhTau was identified as extracellularly neurotoxic to neuronal cells. A novel biopanning protocol was designed based on phage display technique and atomic force microscopy (AFM), and used to isolate single chain antibody variable domain fragments (scFvs) that selectively recognize the toxic tau oligomers. These scFvs selectively bind tau variants in brain tissue of human AD patients and AD-related tau transgenic rodent models and have potential value as early diagnostic biomarkers for AD and as potential therapeutics to selectively target toxic tau aggregates.
Increasing evidence implicates soluble oligomeric forms of beta-amyloid and tau in the onset and progression of AD. While many studies have focused on beta-amyloid, soluble oligomeric tau species may also play an important role in AD pathogenesis. Antibodies that selectively identify and target specific oligomeric tau variants would be valuable tools for both diagnostic and therapeutic applications and also to study the etiology of AD and other neurodegenerative diseases.
Recombinant human tau (rhTau) in monomeric, dimeric, trimeric and fibrillar forms were synthesized and purified to perform LDH assay on human neuroblastoma cells, so that trimeric but not monomeric or dimeric rhTau was identified as extracellularly neurotoxic to neuronal cells. A novel biopanning protocol was designed based on phage display technique and atomic force microscopy (AFM), and used to isolate single chain antibody variable domain fragments (scFvs) that selectively recognize the toxic tau oligomers. These scFvs selectively bind tau variants in brain tissue of human AD patients and AD-related tau transgenic rodent models and have potential value as early diagnostic biomarkers for AD and as potential therapeutics to selectively target toxic tau aggregates.
ContributorsTian, Huilai (Author) / Sierks, Michael R (Thesis advisor) / Dai, Lenore (Committee member) / Tillery, Stephen H (Committee member) / Nielsen, David R (Committee member) / Stabenfeldt, Sarah (Committee member) / Arizona State University (Publisher)
Created2014
Description
For more than twenty years, clinical researchers have been publishing data regarding incidence and risk of adverse events (AEs) incurred during hospitalizations. Hospitals have standard operating policies and procedures (SOPP) to protect patients from AE. The AE specifics (rates, SOPP failures, timing and risk factors) during heart failure (HF) hospitalizations are unknown. There were 1,722 patients discharged with a primary diagnosis of HF from an academic hospital between January 2005 and December 2007. Three hundred eighty-one patients experienced 566 AEs, classified into four categories: medication (43.9%), infection (18.9%), patient care (26.3%), or procedural (10.9%). Three distinct analyses were performed: 1) patient's perspective of SOPP reliability including cumulative distribution and hazard functions of time to AEs; 2) Cox proportional hazards model to determine independent patient-specific risk factors for AEs; and 3) hospital administration's perspective of SOPP reliability through three years of the study including cumulative distribution and hazard functions of time between AEs and moving range statistical process control (SPC) charts for days between failures of each type. This is the first study, to our knowledge, to consider reliability of SOPP from both the patient's and hospital administration's perspective. AE rates in hospitalized patients are similar to other recently published reports and did not improve during the study period. Operations research methodologies will be necessary to improve reliability of care delivered to hospitalized patients.
ContributorsHuddleston, Jeanne (Author) / Fowler, John (Thesis advisor) / Montgomery, Douglas C. (Thesis advisor) / Gel, Esma (Committee member) / Shunk, Dan (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
The research question explored in this thesis is how CRISPR mediated editing is influenced by artificially opened chromatin in cells. Closed chromatin poses a barrier to Cas9 binding and editing at target genes. Synthetic pioneer factors (PFs) are a promising new approach to artificially open condensed heterochromatin allowing greater access of target DNA to Cas9. The Haynes lab has constructed fusions of enzymatic chromatin-modifying domains designed to remodel chromatin and increase Cas9 editing efficiency. With a library of PFs available, this research focuses on analyzing the behavior of Cas9 in chromatin that has been artificially opened by PFs. The types and frequency of INDELs (insertions & deletions) were determined after non-homologous end joining (NHEJ) in PF and Cas9-treated cells using quantitative Sanger sequencing and Synthego’s ICE software. Furthermore, NOME-seq analysis was carried out to map nucleosome position in PF and Cas9 treated cells. Although this experiment was unsuccessful, the heat map generated with data obtained from Synthego ICE predicts a possible presence of nucleosome in the vicinity suggesting that perhaps a fully open chromatin state was not achieved. Linear Regression analysis with certain assumptions confirms that with the increase in distance downstream of cut-site, the editing frequency decreases exponentially. Nevertheless, further experimental work should be carried out to investigate this hypothesis.
ContributorsHamna, Syeda Fatima (Author) / Haynes, Karmella A (Thesis advisor) / Stabenfeldt, Sarah (Thesis advisor) / Tian, Xiaojun (Committee member) / Arizona State University (Publisher)
Created2019
Description
Myocardial infarction (MI) remains the leading cause of mortality and morbidity in the U.S., accounting for nearly 140,000 deaths per year. Heart transplantation and implantation of mechanical assist devices are the options of last resort for intractable heart failure, but these are limited by lack of organ donors and potential surgical complications. In this regard, there is an urgent need for developing new effective therapeutic strategies to induce regeneration and restore the loss contractility of infarcted myocardium. Over the past decades, regenerative medicine has emerged as a promising strategy to develop scaffold-free cell therapies and scaffold-based cardiac patches as potential approaches for MI treatment. Despite the progress, there are still critical shortcomings associated with these approaches regarding low cell retention, lack of global cardiomyocytes (CMs) synchronicity, as well as poor maturation and engraftment of the transplanted cells within the native myocardium. The overarching objective of this dissertation was to develop two classes of nanoengineered cardiac patches and scaffold-free microtissues with superior electrical, structural, and biological characteristics to address the limitations of previously developed tissue models. An integrated strategy, based on micro- and nanoscale technologies, was utilized to fabricate the proposed tissue models using functionalized gold nanomaterials (GNMs). Furthermore, comprehensive mechanistic studies were carried out to assess the influence of conductive GNMs on the electrophysiology and maturity of the engineered cardiac tissues. Specifically, the role of mechanical stiffness and nano-scale topographies of the scaffold, due to the incorporation of GNMs, on cardiac cells phenotype, contractility, and excitability were dissected from the scaffold’s electrical conductivity. In addition, the influence of GNMs on conduction velocity of CMs was investigated in both coupled and uncoupled gap junctions using microelectrode array technology. Overall, the key contributions of this work were to generate new classes of electrically conductive cardiac patches and scaffold-free microtissues and to mechanistically investigate the influence of conductive GNMs on maturation and electrophysiology of the engineered tissues.
ContributorsNavaei, Ali (Author) / Nikkhah, Mehdi (Thesis advisor) / Brafman, David (Committee member) / Migrino, Raymond Q. (Committee member) / Stabenfeldt, Sarah (Committee member) / Vernon, Brent (Committee member) / Arizona State University (Publisher)
Created2018