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- Genre: Doctoral Dissertation
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
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
The microelectronics technology has seen a tremendous growth over the past sixty years. The advancements in microelectronics, which shows the capability of yielding highly reliable and reproducible structures, have made the mass production of integrated electronic components feasible. Miniaturized, low-cost, and accurate sensors became available due to the rise of the microelectronics industry. A variety of sensors are being used extensively in many portable applications. These sensors are promising not only in research area but also in daily routine applications.
However, many sensing systems are relatively bulky, complicated, and expensive and main advantages of new sensors do not play an important role in practical applications. Many challenges arise due to intricacies for sensor packaging, especially operation in a solution environment. Additional problems emerge when interfacing sensors with external off-chip components. A large amount of research in the field of sensors has been focused on how to improve the system integration.
This work presents new methods for the design, fabrication, and integration of sensor systems. This thesis addresses these challenges, for example, interfacing microelectronic system to a liquid environment and developing a new technique for impedimetric measurement. This work also shows a new design for on-chip optical sensor without any other extra components or post-processing.
However, many sensing systems are relatively bulky, complicated, and expensive and main advantages of new sensors do not play an important role in practical applications. Many challenges arise due to intricacies for sensor packaging, especially operation in a solution environment. Additional problems emerge when interfacing sensors with external off-chip components. A large amount of research in the field of sensors has been focused on how to improve the system integration.
This work presents new methods for the design, fabrication, and integration of sensor systems. This thesis addresses these challenges, for example, interfacing microelectronic system to a liquid environment and developing a new technique for impedimetric measurement. This work also shows a new design for on-chip optical sensor without any other extra components or post-processing.
ContributorsLuo, Tao (Author) / Blain Christen, Jennifer (Thesis advisor) / Song, Hongjiang (Committee member) / Goryll, Michael (Committee member) / Yu, Hongbin (Committee member) / Arizona State University (Publisher)
Created2015
Description
Engineered nanoporous substrates made using materials such as silicon nitride or silica have been demonstrated to work as particle counters or as hosts for nano-lipid bilayer membrane formation. These mechanically fabricated porous structures have thicknesses of several hundred nanometers up to several micrometers to ensure mechanical stability of the membrane. However, it is desirable to have a three-dimensional structure to ensure increased mechanical stability. In this study, circular silica shells used from Coscinodiscus wailesii, a species of diatoms (unicellular marine algae) were immobilized on a silicon chip with a micrometer-sized aperture using a UV curable polyurethane adhesive. The current conducted by a single nanopore of 40 nm diameter and 50 nm length, during the translocation of a 27 nm polystyrene sphere was simulated using COMSOL multiphysics and tested experimentally. The current conducted by a single 40 nm diameter nanopore of the diatom shell during the translocation of a 27 nm polystyrene sphere was simulated using COMSOL Multiphysics (28.36 pA) and was compared to the experimental measurement (28.69 pA) and Coulter Counting theory (29.95 pA).In addition, a mobility of 1.11 x 10-8 m2s-1V-1 for the 27 nm polystyrene spheres was used to convert the simulated current from spatial dependence to time dependence.
To achieve a sensing diameter of 1-2 nanometers, the diatom shells were used as substrates to perform ion-channel reconstitution experiments. The immobilized diatom shell was functionalized using silane chemistry and lipid bilayer membranes were formed. Functionalization of the diatom shell surface improves bilayer formation probability from 1 out of 10 to 10 out of 10 as monitored by impedance spectroscopy. Self-insertion of outer membrane protein OmpF of E.Coli into the lipid membranes could be confirmed using single channel recordings, indicating that nano-BLMs had formed which allow for fully functional porin activity. The results indicate that biogenic silica nanoporous substrates can be simulated using a simplified two dimensional geometry to predict the current when a nanoparticle translocates through a single aperture. With their tiered three-dimensional structure, diatom shells can be used in to form nano-lipid bilayer membranes and can be used in ion-channel reconstitution experiments similar to synthetic nanoporous membranes.
To achieve a sensing diameter of 1-2 nanometers, the diatom shells were used as substrates to perform ion-channel reconstitution experiments. The immobilized diatom shell was functionalized using silane chemistry and lipid bilayer membranes were formed. Functionalization of the diatom shell surface improves bilayer formation probability from 1 out of 10 to 10 out of 10 as monitored by impedance spectroscopy. Self-insertion of outer membrane protein OmpF of E.Coli into the lipid membranes could be confirmed using single channel recordings, indicating that nano-BLMs had formed which allow for fully functional porin activity. The results indicate that biogenic silica nanoporous substrates can be simulated using a simplified two dimensional geometry to predict the current when a nanoparticle translocates through a single aperture. With their tiered three-dimensional structure, diatom shells can be used in to form nano-lipid bilayer membranes and can be used in ion-channel reconstitution experiments similar to synthetic nanoporous membranes.
ContributorsRamakrishnan, Shankar (Author) / Goryll, Michael (Thesis advisor) / Blain Christen, Jennifer (Committee member) / Dey, Sandwip (Committee member) / Thornton, Trevor (Committee member) / Arizona State University (Publisher)
Created2015
Description
Over the past fifty years, the development of sensors for biological applications has increased dramatically. This rapid growth can be attributed in part to the reduction in feature size, which the electronics industry has pioneered over the same period. The decrease in feature size has led to the production of microscale sensors that are used for sensing applications, ranging from whole-body monitoring down to molecular sensing. Unfortunately, sensors are often developed without regard to how they will be integrated into biological systems. The complexities of integration are underappreciated. Integration involves more than simply making electrical connections. Interfacing microscale sensors with biological environments requires numerous considerations with respect to the creation of compatible packaging, the management of biological reagents, and the act of combining technologies with different dimensions and material properties. Recent advances in microfluidics, especially the proliferation of soft lithography manufacturing methods, have established the groundwork for creating systems that may solve many of the problems inherent to sensor-fluidic interaction. The adaptation of microelectronics manufacturing methods, such as Complementary Metal-Oxide-Semiconductor (CMOS) and Microelectromechanical Systems (MEMS) processes, allows the creation of a complete biological sensing system with integrated sensors and readout circuits. Combining these technologies is an obstacle to forming complete sensor systems. This dissertation presents new approaches for the design, fabrication, and integration of microscale sensors and microelectronics with microfluidics. The work addresses specific challenges, such as combining commercial manufacturing processes into biological systems and developing microscale sensors in these processes. This work is exemplified through a feedback-controlled microfluidic pH system to demonstrate the integration capabilities of microscale sensors for autonomous microenvironment control.
ContributorsWelch, David (Author) / Blain Christen, Jennifer (Thesis advisor) / Muthuswamy, Jitendran (Committee member) / Frakes, David (Committee member) / LaBelle, Jeffrey (Committee member) / Goryll, Michael (Committee member) / Arizona State University (Publisher)
Created2012
Description
For two centuries, electrical stimulation has been the conventional method for interfacing with the nervous system. As interfaces with the peripheral nervous system become more refined and higher-resolution, several challenges appear, including immune responses to invasive electrode application, large-to-small axon recruitment order, and electrode size-dependent spatial selectivity. Optogenetics offers a solution that is less invasive, more tissue-selective, and has small-to-large axon recruitment order. By adding genes to express photosensitive proteins optogenetics provides neuroscientists the ability to genetically select cell populations to stimulate with simple illumination. However, optogenetic stimulation of peripheral nerves uses diffuse light to activate the photosensitive neural cell lines. To increase the specificity of stimulus response, research was conducted to test the hypothesis that multiple, focused light emissions placed around the circumference of optogenetic mouse sciatic nerve could be driven to produce differential responses in hindlimb motor movement depending on the pattern of light presented. A Monte Carlo computer simulation was created to model the number of emitters, the light emission size, and the focal power of accompanying micro-lenses to provide targeted stimulation to select regions within the sciatic nerve. The computer simulation results were used to parameterize the design of micro-lenses. By modeling multiple focused beams, only fascicles within a nerve diameter less than 1 mm are expected to be fully accessible to focused optical stimulation; a minimum of 4 light sources is required to generate a photon intensity at a point in a nerve over the initial contact along its surface. To elicit the same effect in larger nerves, focusing lenses would require a numerical aperture > 1. Microlenses which met the simulation requirements were fabricated and deployed on a flexible nerve cuff which was used to stimulate the sciatic nerve in optogenetic mice. Motor neuron responses from this stimulation were compared to global illumination; stimulation using the optical cuff resulted in fine motor movement of the extensor muscles of the digits in the hindlimb. Increasing optical power resulted in a shift to gross motor movement of hindlimb. Finally, varying illumination intensity across the cuff showed changes in the extension of individual digits.
ContributorsFritz, Nicholas (Author) / Blain Christen, Jennifer (Thesis advisor) / Abbas, James (Committee member) / Goryll, Michael (Committee member) / Sadleir, Rosalind (Committee member) / Helms-Tillery, Stephen (Committee member) / Arizona State University (Publisher)
Created2021
Description
Neurological disorders are the leading cause of physical and cognitive declineglobally and affect nearly 15% of the current worldwide population. These disorders
include, but are not limited to, epilepsy, Alzheimer’s disease, Parkinson’s disease,
and multiple sclerosis. With the aging population, an increase in the prevalence of
neurodegenerative disorders is expected. Electrophysiological monitoring of neural
signals has been the gold standard for clinicians in diagnosing and treating neurological
disorders. However, advances in detection and stimulation techniques have paved the
way for relevant information not seen by standard procedures to be captured and
used in patient treatment. Amongst these advances have been improved analysis of
higher frequency activity and the increased concentration of alternative biomarkers,
specifically pH change, during states of increased neural activity. The design and
fabrication of devices with the ability to reliably interface with the brain on multiple
scales and modalities has been a significant challenge.
This dissertation introduces a novel, concentric, multi-scale micro-ECoG array
for neural applications specifically designed for seizure detection in epileptic patients.
This work investigates simultaneous detection and recording of adjacent neural tissue
using electrodes of different sizes during neural events. Signal fidelity from electrodes
of different sizes during in vivo experimentation are explored and analyzed to highlight
the advantages and disadvantages of using varying electrode sizes. Furthermore, the
novel multi-scale array was modified to perform multi-analyte detection experiments
of pH change and electrophysiological activity on the cortical surface during epileptic
events. This device highlights the ability to accurately monitor relevant information
from multiple electrode sizes and concurrently monitor multiple biomarkers during
clinical periods in one procedure that typically requires multiple surgeries.
ContributorsAkamine, Ian (Author) / Blain Christen, Jennifer (Thesis advisor) / Abbas, Jimmy (Committee member) / Muthuswamy, Jitendran (Committee member) / Goryll, Michael (Committee member) / Helms Tillery, Stephen (Committee member) / Arizona State University (Publisher)
Created2024
Description
Wearable technology has brought in a rapid shift in the areas of healthcare and lifestyle management. The recent development and usage of wearable devices like smart watches has created significant impact in areas like fitness management, exercise tracking, sleep quality assessment and early diagnosis of diseases like asthma, sleep apnea etc. This thesis is dedicated to the development of wearable systems and algorithms to fulfill unmet needs in the area of cardiorespiratory monitoring.
First, a pneumotach based flow sensing technique has been developed and integrated into a face mask for respiratory profile tracking. Algorithms have been developed to convert the pressure profile into respiratory flow rate profile. Gyroscope-based correction is used to remove motion artifacts that arise from daily activities. By using Principal Component Analysis, the follow-up work established a unique respiratory signature for each subject based on the flow profile and lung parameters computed using the wearable mask system.
Next, wristwatch devices to track transcutaneous gases like oxygen (TcO2) and carbon dioxide (TcCO2), and oximetry (SpO2) have been developed. Two chemical sensing approaches have been explored. In the first approach, miniaturized low-cost commercial sensors have been integrated into the wristwatch for transcutaneous gas sensing. In the second approach, CMOS camera-based colorimetric sensors are integrated into the wristwatch, where a part of camera frame is used for photoplethysmography while the remaining part tracks the optical signal from colorimetric sensors.
Finally, the wireless connectivity using Bluetooth Low Energy (BLE) in wearable systems has been explored and a data transmission protocol between wearables and host for reliable transfer has been developed. To improve the transmission reliability, the host is designed to use queue-based re-request routine to notify the wearable device of the missing packets that should be re-transmitted. This approach avoids the issue of host dependent packet losses and ensures that all the necessary information is received.
The works in this thesis have provided technical solutions to address challenges in wearable technologies, ranging from chemical sensing, flow sensing, data analysis, to wireless data transmission. These works have demonstrated transformation of traditional bench-top medical equipment into non-invasive, unobtrusive, ergonomic & stand-alone healthcare devices.
First, a pneumotach based flow sensing technique has been developed and integrated into a face mask for respiratory profile tracking. Algorithms have been developed to convert the pressure profile into respiratory flow rate profile. Gyroscope-based correction is used to remove motion artifacts that arise from daily activities. By using Principal Component Analysis, the follow-up work established a unique respiratory signature for each subject based on the flow profile and lung parameters computed using the wearable mask system.
Next, wristwatch devices to track transcutaneous gases like oxygen (TcO2) and carbon dioxide (TcCO2), and oximetry (SpO2) have been developed. Two chemical sensing approaches have been explored. In the first approach, miniaturized low-cost commercial sensors have been integrated into the wristwatch for transcutaneous gas sensing. In the second approach, CMOS camera-based colorimetric sensors are integrated into the wristwatch, where a part of camera frame is used for photoplethysmography while the remaining part tracks the optical signal from colorimetric sensors.
Finally, the wireless connectivity using Bluetooth Low Energy (BLE) in wearable systems has been explored and a data transmission protocol between wearables and host for reliable transfer has been developed. To improve the transmission reliability, the host is designed to use queue-based re-request routine to notify the wearable device of the missing packets that should be re-transmitted. This approach avoids the issue of host dependent packet losses and ensures that all the necessary information is received.
The works in this thesis have provided technical solutions to address challenges in wearable technologies, ranging from chemical sensing, flow sensing, data analysis, to wireless data transmission. These works have demonstrated transformation of traditional bench-top medical equipment into non-invasive, unobtrusive, ergonomic & stand-alone healthcare devices.
ContributorsTipparaju, Vishal Varun (Author) / Xian, Xiaojun (Thesis advisor) / Forzani, Erica (Thesis advisor) / Blain Christen, Jennifer (Committee member) / Angadi, Siddhartha (Committee member) / Arizona State University (Publisher)
Created2020
Description
Quantifying molecular interactions is critical to the understanding of many biological processes and drug screening. To date, various detection techniques have been developed to determine the binding kinetics. However, because most of the mainstream detection technologies detect signals that scale with the mass of ligands bond to the sensor surface, it is still challenging to quantify the binding kinetics of small molecules. To address this problem, two different detection technologies, charge-sensitive optical detection (CSOD) and critical angle reflection (CAR), are developed for label-free detection of molecular interactions with the ability to detect a wide range of molecules including small molecules. In particular, CSOD technique detects the charge rather than the mass of a molecule with an optical fiber. However, the effective charge of a molecule decreases with the buffer ionic strength. For this reason, the previous CSOD works with diluted buffers, which could affect the measured molecular binding kinetics. Here a technique capable of detecting molecular binding kinetics in normal ionic strength buffers is presented. An H-shaped sample well was developed to overcome this problem. With this new design, the binding kinetics between G-protein-coupled receptors (GPCRs) and their small molecule ligands were measured in normal buffer. To further improve the signal-to-noise ratio of CSOD and move it toward high-throughput detection, CSOD was implemented with a quadrant-cell detector to achieve detection in higher frequency range and decrease low-frequency noise.This improved CSOD technique is capable for direct quantification of binding kinetics of phage-displayed peptides to their target protein using the whole phages. CAR imaging can be performed on surface plasmon resonance (SPR) imaging setups. It was shown that CAR is capable of measuring molecular interactions including proteins, nucleic acids and cell-based detections. In addition, it was shown that CAR can detect small molecule bindings and intracellular signals beyond SPR sensing limit. CAR exhibits several distinct characteristics over SPR, including tunable sensitivity and dynamic range, deeper vertical sensing range, and fluorescence compatibility. CAR is anticipated to have the ability to expand SPR capability in small molecule detection, whole cell-based detection, simultaneous fluorescence imaging, and broader conjugation chemistry.
ContributorsLiang, Runli (Author) / Wang, Shaopeng (Thesis advisor) / Blain Christen, Jennifer (Thesis advisor) / Jing, Tianwei (Committee member) / Wang, Chao (Committee member) / Arizona State University (Publisher)
Created2021