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Description
The ability to inhibit a planned but inappropriate response, and switch to executing a goal-relevant motor response, is critically important for the regulation of motor behaviors. Inhibition and switching could be mediated by various control mechanisms. Proactive control uses contextual information (cues) to plan the response for the target stimulus (probe) based on the expectation of a response inhibition or switching stimulus combination. Previous work has reported the involvement of several brain areas associated with proactive inhibition and switching, e.g., dorsolateral prefrontal cortex, anterior cingulate cortex, inferior frontal junction, and pre-supplementary motor area. However, how these areas interact and their functional role in different types of cognitive control is still debated. An AX-version of the continuous performance task (AX-CPT) was used to examine proactive inhibition and switching of motor actions. In a typical AX-CPT trial, a contextual cue stimulus is presented, followed by a probe stimulus after a specific inter-stimulus interval. As part of a trial sequence, if a target cue and target probe are presented, a target response is to be provided when the probe is observed. Otherwise, a non-target response is to be provided for all other stimuli. A behavioral switching AX-CPT experiment (48 subjects) was conducted to explore the parameters that induce a proactive shift in the motor response. Participants who performed the AX-CPT task with relatively shorter interstimulus interval predominantly and consistently exhibited proactive control behavior. A follow-up pilot study (3 subjects) of response inhibition versus response switching AX-CPT was performed using 256-channel high-density electroencephalography (HD-EEG). HD-EEG was used to identify the time course of cortical activation in brain areas associated with response inhibition. It was observed that one out of three participants used a proactive strategy for response switching based on probe response error and probe response reaction time. Instantaneous amplitude spatial maps obtained from HD-EEG revealed cortical activity corresponding to conflict between proactively-prepared incorrect responses and reactively-corrected goal-relevant responses after the probe was presented.
ContributorsMysore, Archana Shashidhar (Author) / Santello, Marco (Thesis advisor) / Blais, Christopher (Committee member) / Brewer, Gene (Committee member) / Tillery, Stephen Helms (Committee member) / Arizona State University (Publisher)
Created2020
Description
Extracellular vesicles (EVs) are membranous particles that are abundantly secreted in the circulation system by most cells and can be found in most biological fluids. Among different EV subtypes, exosomes are small particles (30 – 150 nm) that are generated through the double invagination of the lipid bilayer membrane of cell. Therefore, they mirror the cell membrane proteins and contain proteins, RNAs, and DNAs that can represent the phenotypic state of their cell of origin, hence considered promising biomarker candidates. Importantly, in most pathological conditions, such as cancer and infection, diseased cells secrete more EVs and the disease associated exosomes have shown great potential to serve as biomarkers for early diagnosis, disease staging, and treatment monitoring. However, using EVs as diagnostic or prognostic tools in the clinic is hindered by the lack of a rapid, sensitive, purification-free technique for their isolation and characterization. Developing standardized assays that can translate the emerging academic EV biomarker discoveries to clinically relevant procedures is a bottleneck that have slowed down advancements in medical research. Integrating widely known immunoassays with plasmonic sensors has shown the promise to detect minute amounts of antigen present in biological sample, based on changes of ambient optical refractive index, and achieve ultra-sensitivity. Plasmonic sensors take advantage of the enhanced interaction of electromagnetic radiations with electron clouds of plasmonic materials at the dielectric-metal interface in tunable wavelengths.
ContributorsAmrollahi, Pouy (Author) / Wang, Xiao (Thesis advisor) / Forzani, Erica (Committee member) / Hu, Tony Ye (Committee member) / Arizona State University (Publisher)
Created2020
Description
The recording of biosignals enables physicians to correctly diagnose diseases and prescribe treatment. Existing wireless systems failed to effectively replace the conventional wired methods due to their large sizes, high power consumption, and the need to replace batteries. This thesis aims to alleviate these issues by presenting a series of wireless fully-passive sensors for the acquisition of biosignals: including neuropotential, biopotential, intracranial pressure (ICP), in addition to a stimulator for the pacing of engineered cardiac cells. In contrast to existing wireless biosignal recording systems, the proposed wireless sensors do not contain batteries or high-power electronics such as amplifiers or digital circuitries. Instead, the RFID tag-like sensors utilize a unique radiofrequency (RF) backscattering mechanism to enable wireless and battery-free telemetry of biosignals with extremely low power consumption. This characteristic minimizes the risk of heat-induced tissue damage and avoids the need to use any transcranial/transcutaneous wires, and thus significantly enhances long-term safety and reliability. For neuropotential recording, a small (9mm x 8mm), biocompatible, and flexible wireless recorder is developed and verified by in vivo acquisition of two types of neural signals, the somatosensory evoked potential (SSEP) and interictal epileptic discharges (IEDs). For wireless multichannel neural recording, a novel time-multiplexed multichannel recording method based on an inductor-capacitor delay circuit is presented and tested, realizing simultaneous wireless recording from 11 channels in a completely passive manner. For biopotential recording, a wearable and flexible wireless sensor is developed, achieving real-time wireless acquisition of ECG, EMG, and EOG signals. For ICP monitoring, a very small (5mm x 4mm) wireless ICP sensor is designed and verified both in vitro through a benchtop setup and in vivo through real-time ICP recording in rats. Finally, for cardiac cell stimulation, a flexible wireless passive stimulator, capable of delivering stimulation current as high as 60 mA, is developed, demonstrating successful control over the contraction of engineered cardiac cells. The studies conducted in this thesis provide information and guidance for future translation of wireless fully-passive telemetry methods into actual clinical application, especially in the field of implantable and wearable electronics.
ContributorsLiu, Shiyi (Author) / Christen, Jennifer (Thesis advisor) / Nikkhah, Mehdi (Committee member) / Phillips, Stephen (Committee member) / Cao, Yu (Committee member) / Goryll, Michael (Committee member) / Arizona State University (Publisher)
Created2020
Description
Stroke is a debilitating disorder and 75% of individuals with stroke (iwS) have upper extremity deficits. IwS are prescribed therapies to enhance upper-extremity mobility, but current most effective therapies have minimum requirements that the individuals with severe impairment do not meet. Thus, there is a need to enhance the therapies. Recent studies have shown that StartReact -the involuntary release of a planned movement, triggered by a startling stimulus (e.g., loud sound)- elicits faster and larger muscle activation in iwS compared to voluntary-initiated movement. However, StartReact has been only cursorily studied to date and there are some gaps in the StartReact knowledge. Previous studies have only evaluated StartReact on single-jointed movements in iwS, ignoring more functional tasks. IwS usually have abnormal flexor activity during extension tasks and abnormal muscle synergy especially during multi-jointed tasks; therefore, it is unknown 1) if more complex multi-jointed reach movements are susceptible to StartReact, and 2) if StartReact multi-jointed movements will be enhanced in the same way as single-jointed movements in iwS. In addition, previous studies showed that individuals with severe stroke, especially those with higher spasticity, experienced higher abnormal flexor muscle activation during StartReact trials. However, there is no study evaluating the impact of this elevated abnormal flexor activity on movement, muscle activation and muscle synergy alterations during voluntary-initiated movements after exposure to StartReact.
This dissertation evaluates StartReact and the voluntary trials before and after exposure to StartReact during a point-to-point multi-jointed reach task to three different targets covering a large workspace. The results show that multi-jointed reach tasks are susceptible to StartReact in iwS and the distance, muscle and movement onset speed, and muscle activations percentages and amplitude increase during StartReact trials. In addition, the distance, accuracy, muscle and movement onsets speeds, and muscle synergy similarity indices to the norm synergies increase during the voluntary-initiated trials after exposure to StartReact. Overall, this dissertation shows that exposure to StartReact did not impair voluntary-initiated movement and muscle synergy, but even improved them. Therefore, this study suggests that StartReact is safe for more investigations in training studies and therapy.
This dissertation evaluates StartReact and the voluntary trials before and after exposure to StartReact during a point-to-point multi-jointed reach task to three different targets covering a large workspace. The results show that multi-jointed reach tasks are susceptible to StartReact in iwS and the distance, muscle and movement onset speed, and muscle activations percentages and amplitude increase during StartReact trials. In addition, the distance, accuracy, muscle and movement onsets speeds, and muscle synergy similarity indices to the norm synergies increase during the voluntary-initiated trials after exposure to StartReact. Overall, this dissertation shows that exposure to StartReact did not impair voluntary-initiated movement and muscle synergy, but even improved them. Therefore, this study suggests that StartReact is safe for more investigations in training studies and therapy.
ContributorsRahimiTouranposhti, Marziye (Author) / Honeycutt, Claire F. (Thesis advisor) / Roh, Jinsook (Committee member) / Berman, Spring (Committee member) / Lee, Hyunglae (Committee member) / Marvi, Hamid (Committee member) / Schaefer, Sydney (Committee member) / Arizona State University (Publisher)
Created2020
Description
Traditionally, wearable exoskeletons for gait assistance have addressed the issue of high power requirement of providing support during walking. However, exoskeletons often are bulky, and suffer from misalignment of joints between the robot and the user. Soft robots in recent work have shown the ability to provide a high degree of compliance with a light weight and lower cost. This work presents the design, control, and evaluation of a soft inflatable exosuit to assist knee extension. First, the design of novel soft inflatable actuators of I cross-section and their application in the soft inflatable exosuit is presented. The actuators are applied to a soft and lightweight garment interface to assist in knee extension during the swing phase demonstrating reduced muscle activity for the quadriceps. Second, the control of the soft exosuit is presented with the introduction of a knee angle measurement system and smart shoe insole sensors. A new control method using human joint stiffness models as well as actuator models is developed. The new control method is evaluated with three users and a reduction in the sEMG activity of the quadriceps is observed with an increase in the activity of the hamstrings. Third, an improved version of the exosuit and a controller to assist knee extension in swing phase and initial stance are presented. The exosuit is applied to seven healthy and three impaired participants. Kinematics, muscle activity and gait compensations are studied. Reduced muscle activity for the quadriceps is seen in healthy participants with reduced execution times for functional activities such as timed up-and-go as well as sit-to-stand transitions in impaired participants. Finally, an untethered version of the soft exosuit using inflatable actuator composites and a portable pneumatic source are presented. Finite element models for the composites and inflatable actuators are generated and the actuators are characterized for performance. The design of a portable source for the exosuit is also presented. The inflatable actuator composites and the portable source are implemented in a portable exosuit system which demonstrated a reduction in the Vastus Lateralis activity during incline walking for three participants. Overall, this work investigated the feasibility of several versions of the soft exosuit for gait assistance.
ContributorsSridar, Saivimal (Author) / Zhang, Wenlong (Thesis advisor) / Sugar, Thomas (Committee member) / Lockhart, Thurmon (Committee member) / Arizona State University (Publisher)
Created2020
Description
Traumatic brain injury (TBI) affects an estimated 1.7 million people in the United States each year and is a leading cause of death and disability for children and young adults in industrialized countries. Unfortunately, the molecular and cellular mechanisms of injury progression have yet to be fully elucidated. Consequently, this complexity impacts the development of accurate diagnosis and treatment options. Biomarkers, objective signatures of injury, can inform and facilitate development of sensitive and specific theranostic devices. Discovery techniques that take advantage of mining the temporal complexity of TBI are critical for the identification of high specificity biomarkers.
Domain antibody fragment (dAb) phage display, a powerful screening technique to uncover protein-protein interactions, has been applied to biomarker discovery in various cancers and more recently, neurological conditions such as Alzheimer’s Disease and stroke. The small size of dAbs (12-15 kDa) and ability to screen against brain vasculature make them ideal for interacting with the neural milieu in vivo. Despite these characteristics, implementation of dAb phage display to elucidate temporal mechanisms of TBI has yet to reach its full potential.
My dissertation employs a unique target identification pipeline that entails in vivo dAb phage display and next generation sequencing (NGS) analysis to screen for temporal biomarkers of TBI. Using a mouse model of controlled cortical impact (CCI) injury, targeting motifs were designed based on the heavy complementarity determining region (HCDR3) structure of dAbs with preferential binding to acute (1 day) and subacute (7 days) post-injury timepoints. Bioreactivity for these two constructs was validated via immunohistochemistry. Further, immunoprecipitation-mass spectrometry analysis identified temporally distinct candidate biological targets in brain tissue lysate.
The pipeline of phage display followed by NGS analysis demonstrated a unique approach to discover motifs that are sensitive to the heterogeneous and diverse pathology caused by neural injury. This strategy successfully achieves 1) target motif identification for TBI at distinct timepoints and 2) characterization of their spatiotemporal specificity.
Domain antibody fragment (dAb) phage display, a powerful screening technique to uncover protein-protein interactions, has been applied to biomarker discovery in various cancers and more recently, neurological conditions such as Alzheimer’s Disease and stroke. The small size of dAbs (12-15 kDa) and ability to screen against brain vasculature make them ideal for interacting with the neural milieu in vivo. Despite these characteristics, implementation of dAb phage display to elucidate temporal mechanisms of TBI has yet to reach its full potential.
My dissertation employs a unique target identification pipeline that entails in vivo dAb phage display and next generation sequencing (NGS) analysis to screen for temporal biomarkers of TBI. Using a mouse model of controlled cortical impact (CCI) injury, targeting motifs were designed based on the heavy complementarity determining region (HCDR3) structure of dAbs with preferential binding to acute (1 day) and subacute (7 days) post-injury timepoints. Bioreactivity for these two constructs was validated via immunohistochemistry. Further, immunoprecipitation-mass spectrometry analysis identified temporally distinct candidate biological targets in brain tissue lysate.
The pipeline of phage display followed by NGS analysis demonstrated a unique approach to discover motifs that are sensitive to the heterogeneous and diverse pathology caused by neural injury. This strategy successfully achieves 1) target motif identification for TBI at distinct timepoints and 2) characterization of their spatiotemporal specificity.
ContributorsMartinez, Briana Isabella (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Lifshitz, Jonathan (Committee member) / Sierks, Michael (Committee member) / Kleim, Jeffrey (Committee member) / Arizona State University (Publisher)
Created2020
Biomechanical Micromotion at the Neural Interface Modulates Intercellular Membrane Potential In-Vivo
Description
Brain micromotion is a phenomenon that arises from basic physiological functions such as respiration (breathing) and vascular pulsation (pumping blood or heart rate). These physiological processes cause small micro displacements of 2-4µm for vascular pulsation and 10-30µm for respiration, in rat models. One problem related to micromotion is the instability of the probe and its ability to acquire stable neural recordings in chronic studies. It has long been thought the membrane potential (MP) changes due to micromotion in the presence of brain implants were an artefact caused by the implant. Here is shown that intracellular membrane potential changes are a consequence of the activation of mechanosensitive ion channels at the neural interface. A combination of aplysia and rat animal models were used to show activation of mechanosensitive ion channels is occurring during a neural recording. During simulated micromotion of displacements of 50μm and 100μm at a frequency of 1 Hz, showed a change of 8 and 10mV respectively and that the addition of Ethylenediaminetetraacetic acid (EDTA) inhibited the membrane potential changes. The application of EDTA showed a 71% decrease in changes in membrane potential changes due to micromotion. Simulation of breathing using periodic motion of a probe in an Aplysia model showed that there were no membrane potential changes for <1.5kPa and action potentials were observed at >3.1kPa. Drug studies utilizing 5-HT showed an 80% reduction in membrane potentials. To validate the electrophysiological changes due to micromotion in a rat model, a double barrel pipette for simultaneous recording and drug delivery was designed, the drug delivery tip was recessed from the recording tip no greater than 50μm on average. The double barrel pipette using iontophoresis was used to deliver 30 μM of Gadolinium Chloride (Gd3+) into the microenvironment of the cell. Here is shown a significant reduction in membrane potential for n = 13 cells across 4 different rats tested using Gd3+. Membrane potential changes related to breathing and vascular pulsation were reduced between approximately 0.25-2.5 mV for both breathing and heart rate after the addition of Gd3+, a known mechanosensitive ion channel blocker.
ContributorsDuncan, Jonathan Leroy (Author) / Muthuswamy, Jitendran (Thesis advisor) / Greger, Bradley (Committee member) / Sridharan, Arati (Committee member) / Arizona State University (Publisher)
Created2020
Description
It has been repeatedly shown that females have lower stability and increased risk of ankle injury when compared to males participating in similar sports activities (e.g., basketball and soccer), yet sex differences in neuromuscular control of the ankle, including the modulation of ankle stiffness, and their contribution to stability remain unknown. To identify sex differences in human ankle stiffness, this study quantified 2- dimensional (2D) ankle stiffness in 20 young, healthy men and 20 young, healthy women during upright standing over a range of tasks, specifically, ankle muscle co-contraction tasks (4 levels up to 20% maximum voluntary co-contraction of ankle muscles), weight-bearing tasks (4 levels up to 90% of body weight), and ankle torque generation tasks accomplished by maintaining offset center-of-pressure (5 levels up to +6 cm to the center-of-pressure during quiet standing). A dual-axial robotic platform, capable of perturbing the ankle in both the sagittal and frontal planes and measuring the corresponding ankle torques, was used to reliably quantify the 2D ankle stiffness during upright standing. In all task conditions and in both planes of ankle motion, ankle stiffness in males was consistently greater than that in females. Among all 26 experimental conditions, all but 2 conditions in the frontal plane showed statistically significant sex differences. Further analysis on the normalized ankle stiffness scaled by weight times height suggests that while sex differences in ankle stiffness in the sagittal plane could be explained by sex differences in anthropometric factors as well as neuromuscular factors, the differences in the frontal plane could be mostly explained by anthropometric factors. This study also demonstrates that the sex differences in the sagittal plane were significantly higher as compared to those in the frontal plane. The results indicate that females have lower ankle stiffness during upright standing thereby providing the neuromuscular basis for further investigations on the correlation of ankle stiffness and the higher risk of ankle injury in females.
ContributorsAdjei, Ermyntrude (Author) / Lee, Hyunglae (Thesis advisor) / Santello, Marco (Committee member) / Lockhart, Thurmon E (Committee member) / Arizona State University (Publisher)
Created2020
Description
One of the single-most insightful, and visionary talks of the 20th century, “There’s plenty of room at the bottom,” by Dr. Richard Feynman, represented a first foray into the micro- and nano-worlds of biology and chemistry with the intention of direct manipulation of their individual components. Even so, for decades there has existed a gulf between the bottom-up molecular worlds of biology and chemistry, and the top-down world of nanofabrication. Creating single molecule nanoarrays at the limit of diffraction could incentivize a paradigm shift for experimental assays. However, such arrays have been nearly impossible to fabricate since current nanofabrication tools lack the resolution required for precise single-molecule spatial manipulation. What if there existed a molecule which could act as a bridge between these top-down and bottom-up worlds?
At ~100-nm, a DNA origami macromolecule represents one such bridge, acting as a breadboard for the decoration of single molecules with 3-5 nm resolution. It relies on the programmed self-assembly of a long, scaffold strand into arbitrary 2D or 3D structures guided via approximately two hundred, short, staple strands. Once synthesized, this nanostructure falls in the spatial manipulation regime of a nanofabrication tool such as electron-beam lithography (EBL), facilitating its high efficiency immobilization in predetermined binding sites on an experimentally relevant substrate. This placement technology, however, is expensive and requires specialized training, thereby limiting accessibility.
The work described here introduces a method for bench-top, cleanroom/lithography-free, DNA origami placement in meso-to-macro-scale grids using tunable colloidal nanosphere masks, and organosilane-based surface chemistry modification. Bench-top DNA origami placement is the first demonstration of its kind which facilitates precision placement of single molecules with high efficiency in diffraction-limited sites at a cost of $1/chip. The comprehensive characterization of this technique, and its application as a robust platform for high-throughput biophysics and digital counting of biomarkers through enzyme-free amplification are elucidated here. Furthermore, this technique can serve as a template for the bottom-up fabrication of invaluable biophysical tools such as zero mode waveguides, making them significantly cheaper and more accessible to the scientific community. This platform has the potential to democratize high-throughput single molecule experiments in laboratories worldwide.
At ~100-nm, a DNA origami macromolecule represents one such bridge, acting as a breadboard for the decoration of single molecules with 3-5 nm resolution. It relies on the programmed self-assembly of a long, scaffold strand into arbitrary 2D or 3D structures guided via approximately two hundred, short, staple strands. Once synthesized, this nanostructure falls in the spatial manipulation regime of a nanofabrication tool such as electron-beam lithography (EBL), facilitating its high efficiency immobilization in predetermined binding sites on an experimentally relevant substrate. This placement technology, however, is expensive and requires specialized training, thereby limiting accessibility.
The work described here introduces a method for bench-top, cleanroom/lithography-free, DNA origami placement in meso-to-macro-scale grids using tunable colloidal nanosphere masks, and organosilane-based surface chemistry modification. Bench-top DNA origami placement is the first demonstration of its kind which facilitates precision placement of single molecules with high efficiency in diffraction-limited sites at a cost of $1/chip. The comprehensive characterization of this technique, and its application as a robust platform for high-throughput biophysics and digital counting of biomarkers through enzyme-free amplification are elucidated here. Furthermore, this technique can serve as a template for the bottom-up fabrication of invaluable biophysical tools such as zero mode waveguides, making them significantly cheaper and more accessible to the scientific community. This platform has the potential to democratize high-throughput single molecule experiments in laboratories worldwide.
ContributorsShetty, Rishabh Manoj (Author) / Hariadi, Rizal F (Thesis advisor) / Gopinath, Ashwin (Committee member) / Varsani, Arvind (Committee member) / Nikkhah, Mehdi (Committee member) / Tillery, Stephen H (Committee member) / Hu, Ye (Committee member) / Arizona State University (Publisher)
Created2019
Description
Glioblastoma multiforme (GBM) is an aggressive brain cancer without effectivetreatment options, leaving patient survival rates extremely low.
HDAC1 knockdown was found to initiate an invasive phenotype in vivo,
particularly within the BT145 human glioma stem cell (hGSC) line. Analysis through RNA
sequencing (RNA-seq) gene expression and regulatory networks found both CEBPβ, a
known transcription factor (TF) involved in cellular invasion, and the STAT3 pathway, a
notorious genetic component of GBM, were differentially expressed in BT145 hGSCs
after HDAC1 knockdown. Furthermore, overlap of genes regulated by CEBPβ and
STAT3 indicate the CEBPβ/STAT3 pathway may be involved in the observed BT145-
specific invasive phenotype.
The SYstems Genetics Network AnaLysis (SYGNAL) pipeline was applied to
construct sex-specific gene regulatory networks from The Cancer Genome Atlas (TCGA)
GBM patient expression data. Unique bicluster eigengenes were discovered separately
for all, female, and male patients. Through the application of these bicluster eigengenes
to a GBM cohort with multiparametric magnetic resonance imaging (mpMRI) localized
biopsies, sex-specific associations between bicluster expression, mpMRI readout, and
hallmarks of cancer were determined. Distinctive cancer functions were revealed
transcriptionally through bicluster expression, and connected to a unique mpMRI feature.
Specifically, SPGRC mpMRI indicated a strong signal for both immune hallmarks
(evading immune detection and tumor-promoting inflammation). At the same time, MD
mpMRI displayed a tendency toward sustained angiogenesis, possibly signaling the
formation of new blood vessels. Uncovering each mpMRI feature’s underlying biological
processes enables improved GBM diagnosis and treatment utilizing an individualized,
non-invasive approach.
ContributorsLewis, Erika (Author) / Plaisier, Christopher L (Thesis advisor) / Nikkhah, Medhi (Committee member) / Hu, Leland (Committee member) / Arizona State University (Publisher)
Created2021