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- All Subjects: Biomedical Engineering
- Genre: Academic theses
- Creators: Wang, Xiao
- Creators: Goryll, Michael
Description
Continuous monitoring in the adequate temporal and spatial scale is necessary for a better understanding of environmental variations. But field deployments of molecular biological analysis platforms in that scale are currently hindered because of issues with power, throughput and automation. Currently, such analysis is performed by the collection of large sample volumes from over a wide area and transporting them to laboratory testing facilities, which fail to provide any real-time information. This dissertation evaluates the systems currently utilized for in-situ field analyses and the issues hampering the successful deployment of such bioanalytial instruments for environmental applications. The design and development of high throughput, low power, and autonomous Polymerase Chain Reaction (PCR) instruments, amenable for portable field operations capable of providing quantitative results is presented here as part of this dissertation. A number of novel innovations have been reported here as part of this work in microfluidic design, PCR thermocycler design, optical design and systems integration. Emulsion microfluidics in conjunction with fluorinated oils and Teflon tubing have been used for the fluidic module that reduces cross-contamination eliminating the need for disposable components or constant cleaning. A cylindrical heater has been designed with the tubing wrapped around fixed temperature zones enabling continuous operation. Fluorescence excitation and detection have been achieved by using a light emitting diode (LED) as the excitation source and a photomultiplier tube (PMT) as the detector. Real-time quantitative PCR results were obtained by using multi-channel fluorescence excitation and detection using LED, optical fibers and a 64-channel multi-anode PMT for measuring continuous real-time fluorescence. The instrument was evaluated by comparing the results obtained with those obtained from a commercial instrument and found to be comparable. To further improve the design and enhance its field portability, this dissertation also presents a framework for the instrumentation necessary for a portable digital PCR platform to achieve higher throughputs with lower power. Both systems were designed such that it can easily couple with any upstream platform capable of providing nucleic acid for analysis using standard fluidic connections. Consequently, these instruments can be used not only in environmental applications, but portable diagnostics applications as well.
ContributorsRay, Tathagata (Author) / Youngbull, Cody (Thesis advisor) / Goryll, Michael (Thesis advisor) / Blain Christen, Jennifer (Committee member) / Yu, Hongyu (Committee member) / Arizona State University (Publisher)
Created2013
Description
The object of this study is to charac terize the effect of focused ultrasound stimulation (FUS) on the rat ce rvix which has been observed to speed its ripening during pregnancy. Ce rvical ripening is required for successful fetal delivery. Timed-pregnant Sprague-Dawley rats (n=36) were used. On day 14 of gestation, the FUS system was placed on the body surface of the rat over the cervix and ultrasound energy was applied to cervix for variable times up to 1 hour in the control group, the FUS system was placed on rats but no energy was applied. Daily measurement of cervix light-induced florescence (LIF, photon counts of collagen x-bridge fluorescence) were made on days 16 of gestation and daily until spont-aneous delivery (day22) to estimate changes in cervical ripening. We found that pulses of 680 KHz ultrasound at 25 Hertz, 1 millisecond pulse duration at 1W/cm^2 applied for as little as 30 minutes would immediately afterwards show the cervix to hav e ripened to the degree seen just before delivery on day 22. Delivery times, fetal weights and viability were unaffected in the FUS-treated animals.
ContributorsLuo, Daishen (Author) / Towe, Bruce C (Thesis advisor) / Wang, Xiao (Committee member) / Caplan, Michael (Committee member) / Arizona State University (Publisher)
Created2012
Description
Sensitivity is a fundamental challenge for in vivo molecular magnetic resonance imaging (MRI). Here, I improve the sensitivity of metal nanoparticle contrast agents by strategically incorporating pure and doped metal oxides in the nanoparticle core, forming a soluble, monodisperse, contrast agent with adjustable T2 or T1 relaxivity (r2 or r1). I first developed a simplified technique to incorporate iron oxides in apoferritin to form "magnetoferritin" for nM-level detection with T2- and T2* weighting. I then explored whether the crystal could be chemically modified to form a particle with high r1. I first adsorbed Mn2+ ions to metal binding sites in the apoferritin pores. The strategic placement of metal ions near sites of water exchange and within the crystal oxide enhance r1, suggesting a mechanism for increasing relaxivity in porous nanoparticle agents. However, the Mn2+ addition was only possible when the particle was simultaneously filled with an iron oxide, resulting in a particle with a high r1 but also a high r2 and making them undetectable with conventional T1-weighting techniques. To solve this problem and decrease the particle r2 for more sensitive detection, I chemically doped the nanoparticles with tungsten to form a disordered W-Fe oxide composite in the apoferritin core. This configuration formed a particle with a r1 of 4,870mM-1s-1 and r2 of 9,076mM-1s-1. These relaxivities allowed the detection of concentrations ranging from 20nM - 400nM in vivo, both passively injected and targeted to the kidney glomerulus. I further developed an MRI acquisition technique to distinguish particles based on r2/r1, and show that three nanoparticles of similar size can be distinguished in vitro and in vivo with MRI. This work forms the basis for a new, highly flexible inorganic approach to design nanoparticle contrast agents for molecular MRI.
ContributorsClavijo Jordan, Maria Veronica (Author) / Bennett, Kevin M (Thesis advisor) / Kodibagkar, Vikram (Committee member) / Sherry, A Dean (Committee member) / Wang, Xiao (Committee member) / Yarger, Jeffery (Committee member) / Arizona State University (Publisher)
Created2012
Description
Flow measurement has always been one of the most critical processes in many industrial and clinical applications. The dynamic behavior of flow helps to define the state of a process. An industrial example would be that in an aircraft, where the rate of airflow passing the aircraft is used to determine the speed of the plane. A clinical example would be that the flow of a patient's breath which could help determine the state of the patient's lungs. This project is focused on the flow-meter that are used for airflow measurement in human lungs. In order to do these measurements, resistive-type flow-meters are commonly used in respiratory measurement systems. This method consists of passing the respiratory flow through a fluid resistive component, while measuring the resulting pressure drop, which is linearly related to volumetric flow rate. These types of flow-meters typically have a low frequency response but are adequate for most applications, including spirometry and respiration monitoring. In the case of lung parameter estimation methods, such as the Quick Obstruction Method, it becomes important to have a higher frequency response in the flow-meter so that the high frequency components in the flow are measurable. The following three types of flow-meters were: a. Capillary type b. Screen Pneumotach type c. Square Edge orifice type To measure the frequency response, a sinusoidal flow is generated with a small speaker and passed through the flow-meter that is connected to a large, rigid container. True flow is proportional to the derivative of the pressure inside the container. True flow is then compared with the measured flow, which is proportional to the pressure drop across the flow-meter. In order to do the characterization, two LabVIEW data acquisition programs have been developed, one for transducer calibration, and another one that records flow and pressure data for frequency response testing of the flow-meter. In addition, a model that explains the behavior exhibited by the flow-meter has been proposed and simulated. This model contains a fluid resistor and inductor in series. The final step in this project was to approximate the frequency response data to the developed model expressed as a transfer function.
ContributorsHu, Jianchen (Author) / Macia, Narciso (Thesis advisor) / Pollat, Scott (Committee member) / Rogers, Bradley (Committee member) / Arizona State University (Publisher)
Created2013
Description
This work explores how flexible electronics and display technology can be applied to develop new biomedical devices for medical, biological, and life science applications. It demonstrates how new biomedical devices can be manufactured by only modifying or personalizing the upper layers of a conventional thin film transistor (TFT) display process. This personalization was applied first to develop and demonstrate the world's largest flexible digital x-ray detector for medical and industrial imaging, and the world's first flexible ISFET pH biosensor using TFT technology. These new, flexible, digital x-ray detectors are more durable than conventional glass substrate x-ray detectors, and also can conform to the surface of the object being imaged. The new flexible ISFET pH biosensors are >10X less expensive to manufacture than comparable CMOS-based ISFETs and provide a sensing area that is orders of magnitude larger than CMOS-based ISFETs. This allows for easier integration with area intensive chemical and biological recognition material as well as allow for a larger number of unique recognition sites for low cost multiple disease and pathogen detection.
The flexible x-ray detector technology was then extended to demonstrate the viability of a new technique to seamlessly combine multiple smaller flexible x-ray detectors into a single very large, ultimately human sized, composite x-ray detector for new medical imaging applications such as single-exposure, low-dose, full-body digital radiography. Also explored, is a new approach to increase the sensitivity of digital x-ray detectors by selectively disabling rows in the active matrix array that are not part of the imaged region. It was then shown how high-resolution, flexible, organic light-emitting diode display (OLED) technology can be used to selectively stimulate and/or silence small groups of neurons on the cortical surface or within the deep brain as a potential new tool to diagnose and treat, as well as understand, neurological diseases and conditions. This work also explored the viability of a new miniaturized high sensitivity fluorescence measurement-based lab-on-a-chip optical biosensor using OLED display and a-Si:H PiN photodiode active matrix array technology for point-of-care diagnosis of multiple disease or pathogen biomarkers in a low cost disposable configuration.
The flexible x-ray detector technology was then extended to demonstrate the viability of a new technique to seamlessly combine multiple smaller flexible x-ray detectors into a single very large, ultimately human sized, composite x-ray detector for new medical imaging applications such as single-exposure, low-dose, full-body digital radiography. Also explored, is a new approach to increase the sensitivity of digital x-ray detectors by selectively disabling rows in the active matrix array that are not part of the imaged region. It was then shown how high-resolution, flexible, organic light-emitting diode display (OLED) technology can be used to selectively stimulate and/or silence small groups of neurons on the cortical surface or within the deep brain as a potential new tool to diagnose and treat, as well as understand, neurological diseases and conditions. This work also explored the viability of a new miniaturized high sensitivity fluorescence measurement-based lab-on-a-chip optical biosensor using OLED display and a-Si:H PiN photodiode active matrix array technology for point-of-care diagnosis of multiple disease or pathogen biomarkers in a low cost disposable configuration.
ContributorsSmith, Joseph T. (Author) / Allee, David (Thesis advisor) / Goryll, Michael (Committee member) / Kozicki, Michael (Committee member) / Blain Christen, Jennifer (Committee member) / Couture, Aaron (Committee member) / Arizona State University (Publisher)
Created2014
Description
Biogenic silica nanostructures, derived from diatoms, possess highly ordered porous hierarchical nanostructures and afford flexibility in design in large part due to the availability of a great variety of shapes, sizes, and symmetries. These advantages have been exploited for study of transport phenomena of ions and molecules towards the goal of developing ultrasensitive and selective filters and biosensors. Diatom frustules give researchers many inspiration and ideas for the design and production of novel nanostructured materials. In this doctoral research will focus on the following three aspects of biogenic silica: 1) Using diatom frustule as protein sensor. 2) Using diatom nanostructures as template to fabricate nano metal materials. 3) Using diatom nanostructures to fabricate hybrid platform.
Nanoscale confinement biogenetic silica template-based electrical biosensor assay offers the user the ability to detect and quantify the biomolecules. Diatoms have been demonstrated as part of a sensor. The sensor works on the principle of electrochemical impedance spectroscopy. When specific protein biomarkers from a test sample bind to corresponding antibodies conjugated to the surface of the gold surface at the base of each nanowell, a perturbation of electrical double layer occurs resulting in a change in the impedance.
Diatoms are also a new source of inspiration for the design and fabrication of nanostructured materials. Template-directed deposition within cylindrical nanopores of a porous membrane represents an attractive and reproducible approach for preparing metal nanopatterns or nanorods of a variety of aspect ratios. The nanopatterns fabricated from diatom have the potential of the metal-enhanced fluorescence to detect dye-conjugated molecules.
Another approach presents a platform integrating biogenic silica nanostructures with micromachined silicon substrates in a micro
ano hybrid device. In this study, one can take advantages of the unique properties of a marine diatom that exhibits nanopores on the order of 40 nm in diameter and a hierarchical structure. This device can be used to several applications, such as nano particles separation and detection. This platform is also a good substrate to study cell growth that one can observe the reaction of cell growing on the nanostructure of frustule.
Nanoscale confinement biogenetic silica template-based electrical biosensor assay offers the user the ability to detect and quantify the biomolecules. Diatoms have been demonstrated as part of a sensor. The sensor works on the principle of electrochemical impedance spectroscopy. When specific protein biomarkers from a test sample bind to corresponding antibodies conjugated to the surface of the gold surface at the base of each nanowell, a perturbation of electrical double layer occurs resulting in a change in the impedance.
Diatoms are also a new source of inspiration for the design and fabrication of nanostructured materials. Template-directed deposition within cylindrical nanopores of a porous membrane represents an attractive and reproducible approach for preparing metal nanopatterns or nanorods of a variety of aspect ratios. The nanopatterns fabricated from diatom have the potential of the metal-enhanced fluorescence to detect dye-conjugated molecules.
Another approach presents a platform integrating biogenic silica nanostructures with micromachined silicon substrates in a micro
ano hybrid device. In this study, one can take advantages of the unique properties of a marine diatom that exhibits nanopores on the order of 40 nm in diameter and a hierarchical structure. This device can be used to several applications, such as nano particles separation and detection. This platform is also a good substrate to study cell growth that one can observe the reaction of cell growing on the nanostructure of frustule.
ContributorsLin, Kai-Chun (Author) / Ramakrishna, B.L. (Thesis advisor) / Goryll, Michael (Thesis advisor) / Dey, Sandwip (Committee member) / Prasad, Shalini (Committee member) / Arizona State University (Publisher)
Created2014
Description
Single cell phenotypic heterogeneity studies reveal more information about the pathogenesis process than conventional bulk methods. Furthermore, investigation of the individual cellular response mechanism during rapid environmental changes can only be achieved at single cell level. By enabling the study of cellular morphology, a single cell three-dimensional (3D) imaging system can be used to diagnose fatal diseases, such as cancer, at an early stage. One proven method, CellCT, accomplishes 3D imaging by rotating a single cell around a fixed axis. However, some existing cell rotating mechanisms require either intricate microfabrication, and some fail to provide a suitable environment for living cells. This thesis develops a microvorterx chamber that allows living cells to be rotated by hydrodynamic alone while facilitating imaging access. In this thesis work, 1) the new chamber design was developed through numerical simulation. Simulations revealed that in order to form a microvortex in the side chamber, the ratio of the chamber opening to the channel width must be smaller than one. After comparing different chamber designs, the trapezoidal side chamber was selected because it demonstrated controllable circulation and met the imaging requirements. Microvortex properties were not sensitive to the chambers with interface angles ranging from 0.32 to 0.64. A similar trend was observed when chamber heights were larger than chamber opening. 2) Micro-particle image velocimetry was used to characterize microvortices and validate simulation results. Agreement between experimentation and simulation confirmed that numerical simulation was an effective method for chamber design. 3) Finally, cell rotation experiments were performed in the trapezoidal side chamber. The experimental results demonstrated cell rotational rates ranging from 12 to 29 rpm for regular cells. With a volumetric flow rate of 0.5 µL/s, an irregular cell rotated at a mean rate of 97 ± 3 rpm. Rotational rates can be changed by altering inlet flow rates.
ContributorsZhang, Wenjie (Author) / Frakes, David (Thesis advisor) / Meldrum, Deirdre (Thesis advisor) / Chao, Shih-hui (Committee member) / Wang, Xiao (Committee member) / Arizona State University (Publisher)
Created2011
Description
This research investigated using impedance as a minimally invasive oral cancer-screening tool by modeling healthy and diseased tissue. This research developed an ultra-structurally based tissue model for oral mucosa that is versatile enough to be easily modified to mimic the passive electrical impedance responses of multiple benign and cancerous tissue types. This new model provides answers to biologically meaningful questions related to the impedance response of healthy and diseased tissues. This model breaks away from the old empirical top down "black box" Thèvinin equivalent model. The new tissue model developed here was created from a bottom up perspective resulting in a model that is analogous to having a "Transparent Box" where each network element relating to a specific structural component is known. This new model was developed starting with sub cellular ultra-structural components such as membranes, proteins and electrolytes. These components formed the basic network elements and topology of the organelles. The organelle networks combine to form the cell networks. The cell networks combine to make networks of cell layers and the cell layers were combined into tissue networks. This produced the complete "Transparent Box" model for normal tissue. This normal tissue model was modified for disease based on the ultra-structural pathology of each disease. The diseased tissues evaluated include cancers type one through type three; necrotic-inflammation, hyperkeratosis and the compound condition of hyperkeratosis over cancer type two. The impedance responses for each of the disease were compared side by side with the response of normal healthy tissue. Comparative evidence from the models showed the structural changes in cancer produce a unique identifiable impedance "finger print." The evaluation of the "Transparent Box" model for normal tissues and diseased tissues show clear support for using comparative impedance measurements as a clinical tool for oral cancer screening.
ContributorsPelletier, Peter Robert (Author) / Kozicki, Michael (Thesis advisor) / Towe, Bruce (Committee member) / Saraniti, Marco (Committee member) / Goryll, Michael (Committee member) / Arizona State University (Publisher)
Created2012
Description
The past two decades have been monumental in the advancement of microchips designed for a diverse range of medical applications and bio-analysis. Owing to the remarkable progress in micro-fabrication technology, complex chemical and electro-mechanical features can now be integrated into chip-scale devices for use in biosensing and physiological measurements. Some of these devices have made enormous contributions in the study of complex biochemical processes occurring at the molecular and cellular levels while others overcame the challenges of replicating various functions of human organs as implant systems. This thesis presents test data and analysis of two such systems. First, an ISFET based pH sensor is characterized for its performance in a continuous pH monitoring application. Many of the basic properties of ISFETs including I-V characteristics, pH sensitivity and more importantly, its long term drift behavior have been investigated. A new theory based on frequent switching of electric field across the gate oxide to decrease the rate of current drift has been successfully implemented with the help of an automated data acquisition and switching system. The system was further tested for a range of duty cycles in order to accurately determine the minimum length of time required to fully reset the drift. Second, a microfluidic based vestibular implant system was tested for its underlying characteristics as a light sensor. A computer controlled tilt platform was then implemented to further test its sensitivity to inclinations and thus it‟s more important role as a tilt sensor. The sensor operates through means of optoelectronics and relies on the signals generated from photodiode arrays as a result of light being incident on them. ISFET results show a significant drop in the overall drift and good linear characteristics. The drift was seen to reset at less than an hour. The photodiodes show ideal I-V comparison between photoconductive and photovoltaic modes of operation with maximum responsivity at 400nm and a shunt resistance of 394 MΩ. Additionally, post-processing of the tilt sensor to incorporate the sensing fluids is outlined. Based on several test and fabrication results, a possible method of sealing the open cavity of the chip using a UV curable epoxy has been discussed.
ContributorsMamun, Samiha (Author) / Christen, Jennifer Blain (Thesis advisor) / Goryll, Michael (Committee member) / Yu, Hongyu (Committee member) / Arizona State University (Publisher)
Created2011
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