Matching Items (5)
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- All Subjects: Traumatic Brain Injury
- Creators: LaBelle, Jeffrey
- Creators: Kleim, Jeffrey
Description
Traumatic brain injury (TBI) is a leading cause of disability worldwide with 1.7 million TBIs reported annually in the United States. Broadly, TBI can be classified into focal injury, associated with cerebral contusion, and diffuse injury, a widespread injury pathology. TBI results in a host of pathological alterations and may lead to a transient blood-brain-barrier (BBB) breakdown. Although the BBB dysfunction after TBI may provide a window for therapeutic delivery, the current drug delivery approaches remains largely inefficient due to rapid clearance, inactivation and degradation. One potential strategy to address the current therapeutic limitations is to employ nanoparticle (NP)-based technology to archive greater efficacy and reduced clearance compared to standard drug administration. However, NP application for TBI is challenging not only due to the transient temporal resolution of the BBB breakdown, but also due to the heterogeneous (focal/diffuse) aspect of the disease itself. Furthermore, recent literature suggests sex of the animal influences neuroinflammation/outcome after TBI; yet, the influence of sex on BBB integrity following TBI and subsequent NP delivery has not been previously investigated. The overarching hypothesis for this thesis is that TBI-induced compromised BBB and leaky vasculature will enable delivery of systemically injected NPs to the injury penumbra. This study specifically explored the feasibility and the temporal accumulation of NPs in preclinical mouse models of focal and diffuse TBI. Key findings from these studies include the following. (1) After focal TBI, NPs ranging from 20-500nm exhibited peak accumulation within the injury penumbra acutely (1h) post-injury. (2) A smaller delayed peak of NP accumulation (40nm) was observed sub-acutely (3d) after focal brain injury. (3) Mild diffuse TBI simulated with a mild closed head injury model did not display any measurable NP accumulation after 1h post-injury. (4) In contrast, a moderate diffuse model (fluid percussion injury) demonstrated peak accumulation at 3h post-injury with up to 500 nm size NPs accumulating in cortical tissue. (5) Robust NP accumulation (40nm) was found in female mice compared to the males at 24h and 3d following focal brain injury. Taken together, these results demonstrate the potential for NP delivery at acute and sub-acute time points after TBI by exploiting the compromised BBB. Results also reveal a potential sex dependent component of BBB disruption leading to altered NP accumulation. The applications of this research are far-reaching ranging from theranostic delivery to personalized NP delivery for effective therapeutic outcome.
ContributorsBharadwaj, Vimala Nagabhushana (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Kodibagkar, Vikram D (Thesis advisor) / Kleim, Jeffrey (Committee member) / Tian, Yanqing (Committee member) / Lifshitz, Jonathan (Committee member) / Anderson, Trent R (Committee member) / Arizona State University (Publisher)
Created2018
DescriptionMy main goal for my thesis is in conjunction with the research I started in the summer of 2010 regarding the creation of a TBI continuous-time sensor. Such goals include: characterizing the proteins in sensing targets while immobilized, while free in solution, and while in free solution in the blood.
ContributorsHaselwood, Brittney (Author) / LaBelle, Jeffrey (Thesis director) / Pizziconi, Vincent (Committee member) / Cook, Curtiss (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2011-12
Description
Concussions and traumatic brain injuries are mechanical events which can derive from no specific activity or event. However, these injuries occur often during athletic and sporting events but many athletes experiencing these symptoms go undiagnosed and continue playing without proper medical attention. The current gold standard for diagnosing athletes with concussions is to have medical professionals on the sidelines of events to perform qualitative standardized assessments which may not be performed frequently enough and are not specialized for each athlete. The purpose of this report is to discuss a study sanctioned by Arizona State University's Project HoneyBee and additional affiliations to validate a third-party mouth guard device product to recognize and detect force impacts blown to an athlete's head during athletic activity. Current technology in health monitoring medical devices can allow users to apply this device as an additional safety mechanism for early concussion awareness and diagnosis. This report includes the materials and methods used for experimentation, the discussion of its results, and the complications which occurred and areas for improvement during the preliminary efforts of this project. Participants in the study were five non-varsity ASU Wrestling athletes who volunteered to wear a third-party mouth guard device during sparring contact at practice. Following a needed calibration period for the devices, results were recorded both through visual observation and with the mouth guard devices using an accelerometer and gyroscope. This study provided a sound understanding for the operation and functionality of the mouth guard devices. The mouth guard devices have the capability to provide fundamental avenues of research for future investigations.
ContributorsTielke, Austin Wyatt (Author) / Ross, Heather (Thesis director) / LaBelle, Jeffrey (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
The purpose of this research was to determine and evaluate glutamate oxidase's ability to detect levels of glutamate as part of a working sensor capable of quantifying and detecting stress within the body in the case of adverse neurological events such as traumatic brain injury. Using electrochemical impedance spectroscopy (EIS), a linear dynamic range of glutamate was detected with a slope of 36.604 z/ohm/[pg/mL], a lower detection limit at 12.417 pg/mL, correlation of 0.97, and an optimal binding frequency of 117.20 Hz. After running through a frequency sweep the binding frequency was determined based on the highest consistent reproducibility and slope. The sensor was found to be specific against literature researched non-targets glucose, albumin, and epinephrine and working in dilutions of whole blood up to a concentration of 25%. With the implementation of Nafion, the sensor had a 250% improvement in signal and 155% improvement in correlation in 90% whole blood, illustrating the promise of a working blood sensor. Future work includes longitudinal studies and utilizing mesoporous carbon as the immobilization platform and incorporating this as part of a continuous, multiplexed blood sensor with glucose oxidase.
ContributorsLam, Alexandria Nicole (Author) / LaBelle, Jeffrey (Thesis director) / Ankeny, Casey (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
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