Browsing by Author "Lavik, Erin B."

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    Evaluating Microglia Dynamics in Blast and Impact-Induced Neurotrauma and Assessing the Role of Hemostatic Nanoparticles in Microglia Activation
    White, Michelle Renee (Virginia Tech, 2022-10-03)
    Traumatic brain injury (TBI) is a major medical concern that has demonstrated to be particularly challenging to treat because of the disparity amongst injury modes and severities. Increased use of explosive devices during combat has caused blast TBI (bTBI) to become a widespread consequence in military and Veteran populations, and impact-related trauma from contact-related sports or motor vehicle accidents has made mild impact-induced TBIs (concussion) a major health problem. There is a high risk for those who have sustained a TBI to develop behavioral and cognitive disorders following injury, and these symptoms can present as delayed onset, causing diagnosis to be a major feat when planning for treatment and long-term healthcare. Both preclinical and clinical studies report the neuropathological changes following TBI, yet investigating the distinct mechanistic changes in blast and impact trauma that contribute to pathological disparities has yet to be elucidated. Microglia dynamics play a key role in initiating the inflammatory response after injury, as microglia become activated by undergoing morphological changes that influence their function in the injured brain, and unique signaling pathways influence their functional inflammatory states. While previous literature report on the unique responses of microglia, their mediated-inflammatory responses are still not well defined. This work aimed to investigate the acute and subacute responses of microglia to injury through their diverse activation states following blast and impact trauma. The work herein employed rodent models to investigate these changes, finding that microglia activation was spatially and temporally heterogeneous within and across injury paradigms. Three days following bTBI, activated microglia in the cortex displayed morphologies similar to microglia that are known to increase their interactions with dysfunctional synapses, while dystrophic microglia were prevalent in the hippocampus seven days following injury. Moreover, transhemispheric changes in microglia activation were noted following impact TBI, with stressed/primed microglia responding to immune challenges of the cortex at three days, whereas a unique morphological state that was markedly different from those traditionally reported in CNS injury and disease was present within the hippocampus three- and seven-days following injury. State-of-the-art cell sorting techniques were used for in vivo analysis of microglia, which also exhibited that functional changes of microglia vary between injury paradigms, providing insight into how differences in primary insult may elicit distinct signaling pathways involved in microglia-mediated inflammatory responses. These in vivo studies were then crucial in understanding the malleable responses of microglia to complex injuries such as "blast plus impact" TBI, indicating that phenotypic changes in microglia following this injury are also unique and spatially heterogeneous. To date, therapeutic efforts for TBI are limited due to the lack of understanding the underlying mechanisms that influence TBI pathology. This work also investigated novel therapeutic targets, noting that administration of polyester nanoparticles restored microglia to baseline levels following impact. The fundamental research presented in this study is innovative and advantageous as it can provide essential data into targeted and personalized treatments that can improve long-term healthcare and ultimately, the quality of life for those suffering from a TBI.
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    Investigating Injury Pathology of Blast-induced Polytrauma and Assessing the Therapeutic Role of Hemostatic Nanoparticles after Blast Exposure
    Hubbard, W. Brad (Virginia Tech, 2016-09-26)
    Explosions cause the majority of injuries in the current conflicts, accounting for 79% of combat related injuries (Ramasamy et al. 2008). Blast overpressure from explosions can cause barotrauma to the lungs and the brain. Blast-induced mild traumatic brain injury has been labeled the "signature wound" of current military conflicts in Iraq and Afghanistan (Snell and Halter 2010). In addition to elevated number of blast-induced traumatic brain injuries due to increased military conflicts overseas and the usage of improvised explosive devices, the incidence of blast-induced polytrauma has risen due to the prevalence of terrorist events around the world (Arnold et al. 2004, Rodoplu et al. 2004). Blast-induced polytrauma is a major concern as lung injury can cause immediate mortality and brain injury causes long-lasting neurocognitive impairment. There is a critical lack of understanding the pathology of blast-induced polytrauma since the needs are multifaceted and therefore few options for treatment. Thus, the research presented in this dissertation required the development of a military-relevant blast polytrauma model to examine injury pathology and subsequently study the effects of hemostatic nanoparticle therapy after blast-induced polytrauma. The pre-clinical model was characterized and static overpressure thresholds were determined for lethality risk. It was confirmed to have many of the classic hallmarks of primary blast lung injury (PBLI), as well as blast-induced neurotrauma (BINT) (Clemedson 1950). Global hemorrhaging was found in the lungs and well as reduced oxygen saturation. Markers of astrogliosis and blood-brain barrier disruption were examined in the amygdala after blast. The novel nanoparticle configuration (hemostatic dexamethasone-loaded nanoparticles (hDNP) functionalized with a peptide that binds with activated platelets) was investigated and hypothesized to increase survival, reduce cellular injury and reduce anxiety-like disorders after blast polytrauma. After investigating hDNP, it was found that the hDNP treatment benefited survival percentage after injury as well as reduced percent hemorrhage in the lungs and improved physiology. Elevated anxiety parameters found in the controls were lower as compared to the hDNP group. Glial fibrillary acidic protein (GFAP) and cleaved caspase-3 were significantly elevated in the controls compared to the hDNP group in the amygdala. SMI-71 was also significantly elevated with the hDNP and hemostatic nanoparticle (hNP) treatments, similar to sham. In addition to the nanoparticles offering immediate life-saving qualities, administration of hemostatic nanoparticles improved amygdala pathology attributed to secondary mechanisms of blast injury, including blood-brain barrier disruption. This model of polytrauma can serve as a foundation for detailed pathological studies as well as testing therapeutics for injury modalities. References (Abstract) Arnold, J. L., P. Halpern, M. C. Tsai and H. Smithline (2004). "Mass casualty terrorist bombings: a comparison of outcomes by bombing type." Ann Emerg Med 43(2): 263-273. Clemedson, C. J., Granstom, S.A. (1950). "Studies on the genesis of "rib markings" in lung blast injury." Acta Physiol Scand. 21: 131-144. Ramasamy, A., S. E. Harrisson, J. C. Clasper and M. P. Stewart (2008). "Injuries from roadside improvised explosive devices." J Trauma 65(4): 910-914. Rodoplu, U., Arnold, J. L., Tokyay, R., Ersoy, G., Cetiner, S., Yucel, T. (2004) "Mass-casualty terrorist bombings in Istanbul, Turkey, November 2003: reports of the events and the prehospital emergency response." Prehosp Disaster Med 19(2):133-145. Snell, F. I. and M. J. Halter (2010). "A signature wound of war: mild traumatic brain injury." J Psychosoc Nurs Ment Health Serv 48(2): 22-28.