Polyurethane resin injection is a treatment being considered as a replacement for traditional methods of ground improvement. It has been used to re-level foundations and concrete slabs that have settled over time. Additional claimed benefits of the treatment have been noted recently, including improved factors of safety against soil liquefaction and reduced earthquake-induced settlements. To investigate the capability of the polyurethane resin injection treatment to mitigate liquefaction, two full-scale blast liquefaction tests were performed; one test was conducted in an improved panel (IP), an 8 m circular area treated with the polyurethane resin in a 1.2 m triangular grid from a depth of 1 to 6 m, and another test in an untreated 8 m circular area, the natural panel (NP). Each blast test was severe enough to produce liquefaction (ru ≈1.0) in the respective panel, with blast-induced settlements in the range of 70 to 80 mm. Despite similar levels of ground-surface settlement in the IP and NP, settlement within the top 6 m of the IP was about half that of the NP. A CPT-based predicted settlement for each panel was employed using the Zhang et al. (2002) methodology. Good correlation was found between the observed settlements and predicted settlements in both panels. Differential settlements across the panels were calculated based on ground-based lidar surveys, with a reduction of 42 to 49% between the IP and NP. The measured total and differential settlements following resin injection were at the bottom of the range observed in blast tests on a variety of shallow ground improvement methods conducted by the New Zealand Earthquake Commission in 2013. The persistence of the polyurethane resin injection ground improvement three years following its installation was indicated by the lasting increase of fundamental in situ test parameters. The results of the study indicate that resin injection is a viable method of ground improvement to reduce liquefaction-induced settlements by creating a stiffer surficial crust.

Blast-induced neurotrauma (BINT) is a prevalent brain injury within both military and civilian populations due to current engagement in overseas conflict and ongoing terrorist events worldwide. In the early 2000s, 78% of injuries were attributable to an explosive mechanism during overseas conflicts, which has led to increased incidences of BINT [1a]. Clinical manifestations of BINT include long-term psychological impairments, which are driven by the underlying cellular and molecular sequelae of the injury. Development of effective treatment strategies is limited by the lack of understanding on the cellular and molecular level [2a]. The overall hypothesis of this work is that epigenetic regulatory mechanisms contribute to the progression of the BINT pathology and neurological impairments. Epigenetic mechanisms, including DNA methylation and histone acetylation, are important processes by which cells coordinate neurological and cellular response to environmental stimuli. To date, the role of epigenetics in BINT remains largely unknown. To test this hypothesis, an established rodent model of BINT was employed [3a]. Analysis of DNA methylation, which is involved in memory processes, showed decreased levels one week following injury, which was accompanied by decreased expression of the enzyme responsible for facilitating the addition of methyl groups to DNA. The one week time point also showed dramatic decreases in histone acetylation which correlated to decline in memory. This change was observed in astrocytes and may provide a mechanistic understanding for a hallmark characteristic of the injury. Treatment with a specific enzyme inhibitor was able to mitigate some of the histone acetylation changes. This corresponded with reduced astrocyte activation and an altered behavioral phenotype, which was characterized by high response to novelty. The diagnostic efficacy of epigenetic changes following blast was elucidated by the accumulation of cell-free nucleic acids in cerebrospinal fluid one month after injury. Concentrations of these molecules shows promise in discriminating between injured and non-injured individuals. To date, the diagnostic and therapeutic efforts of BINT have been limited by the lack of a mechanistic understanding of the injury. This work provides novel diagnostic and therapeutic targets. The clinical potential impact on diagnosis and therapeutic intervention has been demonstrated. / Ph. D.

To investigate the liquefaction mitigation capability of Rammed Aggregate Piers® (RAP) in silty sand, blast liquefaction testing was performed at a soil profile treated with a full-scale RAP group relative to an untreated soil profile. The RAP group consisted of 16 piers in a 4x4 arrangement at 2 m center-to-center spacing extending to a depth of 9.5 m. Blasting around the untreated area induced liquefaction (ru ≈1.0) from 3 m to 11 m depth, producing several large sand boils, and causing settlement of 10 cm. In contrast, installation of the RAP group reduced excess pore water pressure (ru ≈0.75), eliminated sand ejecta, and reduced average settlement to between 2 to 5 cm when subjected to the same blast charges. Although the liquefaction-induced settlement in the untreated area could be accurately estimated using the CPT-based settlement approach proposed by Zhang et al. (2002), settlement in the RAP treated area was significantly overestimated with the same approach even after considering RAP treatment-induced densification. Analyses indicate that settlement after RAP treatment could be successfully estimated from elastic compression of the sand and RAP acting as a composite material. The composite reinforced soil mass, surrounded by liquefied soil, transferred load to the base of the RAP group inducing settlement in the non-liquefied sand below the group. This test program identifies a mechanism that explains how settlement was reduced for the RAP group despite the elevated ru values in the silty sands that are often difficult to improve with vibratory methods.

Indiana University-Purdue University Indianapolis (IUPUI) / Social support is a powerful therapeutic against fear and anxiety and is utilized in many psychotherapies. The concept that a familiar or friendly presence helps a person learn to overcome anxiety has been well-known for decades, yet, the basic neural mechanisms that regulate this psychosocial learning remain unknown. A first step towards elucidating these basic mechanisms is the development of a valid preclinical animal model. However, preclinical behavioral models exploring the use of a social presence in reducing anxiety have not been fully characterized. Therefore, it was our goal to identify a useful way in which to study the mechanisms of how a social presence can induce anxiolysis (the reduction of anxiety). We accomplished this goal by characterizing and validating a preclinical model, as well as demonstrating that the model was capable of measuring deficits in rats given a mild traumatic brain injury. To this end, we identified an existing, but uncharacterized model, the social interaction-habituation model, as an effective model of social familiarity-induced anxiolysis (SoFiA), which demonstrates socially enhanced safety learning, or psychosocial learning. We find that as social familiarity develops across time, anxiolysis develops. We identified that the use of a Bright Light Challenge is a useful anxiogenic stimulus to use during SI-habituation training. The anxiolysis acquired following SI-habituation testing is partner specific, and can be blocked by an inhibition of the medical prefrontal cortex, while it can be enhanced by D-cycloserine. We found that this model identified deficits in SoFiA acquisition in rodents exposed to a mild traumatic brain injury, which, in humans, has been linked to psychosocial deficits. This work is a step in creating ways in which we can study and better understand the regulatory processes of emotions mediated by social behavior.

Mild blast-induced traumatic brain injury (bTBI) is a modality of injury that has been of major concern considering a large number of military personnel exposed to the blast wave from explosives. bTBI results from the propagation of high-pressure static blast forces and their subsequent energy transmission within brain tissue. Current literature presents a neuro-centric approach to the role of mitochondria dynamics dysfunction in bTBI; however, changes in astrocyte-specific mitochondrial dynamics have not been characterized. As a result of fission and fusion, the mitochondrial structure is constantly altering shape to respond to physiological stimuli or stress insults by adapting structure and function, which are intimately connected. Dysregulation of the protein regulator of mitochondrial fission, DRP1, and upregulation in the phosphorylation of DRP1 at the serine 616 site is reported to play a crucial role in astrocytic mitochondrial dysfunction, favoring fission over fusion post-TBI. Astrocytic mitochondria are starting to be recognized to play an essential role in overall brain metabolism, synaptic transmission, and neuron protection. Mitochondria are vulnerable to injury insults leading to the worsening of mitochondrial fission and increased mitochondrial fragmentation. In this study, a combination of in vitro and in vivo bTBI models were used to examine the effect of blast on astrocytic mitochondrial dynamics. Acute differential remodeling of the astrocytic mitochondrial network was observed, accompanied by an acute (4hr) and sub-acute (7 days) activation of the GTP-protein DRP1. Further, results showed a time-dependent reactive astrocyte phenotype transition in the rat hippocampus. This discovery can lead to innovative therapeutics targets to help prevent secondary injury cascades that involve mitochondria dysfunction. / Doctor of Philosophy / Blast-induced traumatic brain injury (bTBI) is a modality of injury that has become prominent considering a large number of military personnel exposed to a blast wave caused by explosives. Blast injury results from the energy transmission of the blast wave to the brain. Within the brain, there are specialized cells, called astrocytes, that help maintain a healthy environment. This work investigates the role that astrocytes play during the injury recovery process. Within the astrocytes, there are organelles called mitochondria, that help maintain the energy for the cell. The number and function of mitochondria can change in response to the brain injury. They can increase in number by a process called fission and they can decrease in number by a process called fusion. These events effect the function of the mitochondria. Researchers have methods that can identify changes in the number and function of the mitochondria. In this work, astrocyte mitochondrial dynamics were examined and compared using models of bTBI. We found significant changes in the mitochondria of astrocytes, which could lead to an unhealthy environment in the brain. This discovery can lead to new treatments for patients that may improve their quality of life following bTBI.

Blast-induced traumatic brain injury (bTBI) remains a significant problem among military populations. When an explosion occurs, a high magnitude positive pressure rapidly propagates away from the detonation source. Upon contact, biological tissues throughout the body undergo deformation at high strain rates and then return to equilibrium following a brief negative pressure phase. This mechanical disruption of the tissue is known to cause oxidative stress and neuroinflammation in the brain, which can lead to neurodegeneration and consequently poor cognitive and behavioral outcomes. Further, these clinical outcomes, which can include chronic headaches, problems with balance, light and noise sensitivity, anxiety, and depression, may be sustained years following blast exposure and there are currently no effective treatments. Thus, there is a need to investigate the acute molecular responses following bTBI in order to motivate the development of effective therapeutic strategies and ultimately improve or prevent long-term patient outcomes. It is important to not only understand the acute molecular response, but how the brain tissue mechanics drive these metabolic changes. The objective of this work was to identify the interplay between the tissue-level biomechanics and the acute bTBI pathophysiology. In a rodent bTBI model, using adult rats, intracranial pressure was mapped throughout the brain during blast exposure where frequency contributions from skull flexure and wave dynamics were significantly altered between brain regions and were largely dependent on blast magnitude. These findings informed the subsequent spatial and temporal changes in neurometabolism. Amino acid molecular precursor concentrations decreased at four hours post-blast in the cortex and hippocampus regions. This motivates further investigation of amino acids as therapeutic targets aimed to reduce oxidative stress and prevent prolonged injury cascades. However, neurochemical changes were not consistent across blast magnitudes, which may be explained by the disparities in biomechanics at lower blast pressures. Lastly, we investigated the acute changes in metabolic regulators influencing excitotoxicity where it was found that astrocytes maintained normal clearance of excitatory and inhibitory neurotransmitters prior to astrocyte reactivity. Outcomes of this work provide improved understanding of blast mechanics and associated acute pathophysiology and inform future therapeutic and diagnostic approaches following bTBI. / Doctor of Philosophy / Blast-induced traumatic brain injury (bTBI) remains a significant problem among military populations. When an explosion occurs, a high magnitude positive pressure wave rapidly propagates away from the detonation source. Upon contact, biological tissues throughout the body undergo deformation that can cause injury. This mechanical disruption of the tissue is known to trigger negative biological processes that lead to persistent cognitive and behavioral deficits. Further, these clinical outcomes, which can include chronic headaches, problems with balance, light and noise sensitivity, anxiety, and depression, may be sustained years following blast exposure. There are currently no effective treatments that can help those afflicted, and biomarkers for injury diagnostics are limited. Thus, there is a great need to investigate the early biological responses following bTBI in order to motivate the development of effective therapeutic strategies and ultimately improve or prevent long-term patient outcomes. It is important to not only understand the immediate responses, but also how the brain tissue mechanics drive these metabolic changes. The objective of this work was to identify the interplay between the brain biomechanics and the acute bTBI pathophysiology. Using a translational animal model, pressure inside the brain was measured with pressure sensors during blast exposure. Subsequent spatial and temporal changes in neurochemical concentrations were quantified. The results showed (1) significant disparities in the pressure dynamics inside the brain and it varied across brain regions, (2) neurochemical precursors may have therapeutic potential post-injury, and (3) biomechanical and neurochemical responses were dependent on blast severity. Outcomes of this work provide improved understanding of blast mechanics and associated pathophysiology and inform future therapeutic and diagnostic approaches to prevent prolonged injury cascades.

A method to estimate blast-induced damage in rock considering both stress waves and gas expansion phases is presented. The method was developed by assuming a strong correlation between blast-induced damage and stress wave amplitudes, and also by adapting a 2D numerical method to estimate damage in a 3D real case. The numerical method is used to determine stress wave damage and provides an indication of zones prone to suffer greater damage by gas expansion. The specific steps carried out in this study are: i) extensive blast monitoring in hard rock at surface and underground test sites; ii) analysis of seismic waveforms in terms of amplitude and frequency and their azimuthal distribution with respect to borehole axis, iii) measurement of blast-induced damage from single-hole blasts; iv) assessment and implementation of method to utilize 2D numerical model to predict blast damage in 3D situation; v) use of experimental and numerical results to estimate relative contribution of stress waves and gas penetration to damage, and vi) monitoring and modeling of full-scale production blasts to apply developed method to estimate blast-induced damage from stress waves. The main findings in this study are: i) both P and S-waves are generated and show comparable amplitudes by blasting in boreholes; ii) amplitude and frequency of seismic waves are strongly dependent on initiation mode and direction of propagation of explosive reaction in borehole; iii) in-situ measurements indicate strongly non-symmetrical damage dependent on confinement conditions and initiation mode, and existing rock structure, and iv) gas penetration seems to be mainly responsible for damage (significant damage extension 2-4 borehole diameters from stress waves; > 22 from gas expansion). The method has the potential for application in regular production blasts for control of over-breaks and dilution in operating mines. The main areas proposed for future work are: i) verification of seismic velocity changes in rock by blast-induced damage from controlled experiments; ii) incorporation of gas expansion phase into numerical models; iii) use of 3D numerical model and verification of crack distribution prediction; iv) further studies on strain rate dependency of material strength parameters, and v) accurate measurements of in-hole pressure function considering various confinement conditions.

A method to estimate blast-induced damage in rock considering both stress waves and gas expansion phases is presented. The method was developed by assuming a strong correlation between blast-induced damage and stress wave amplitudes, and also by adapting a 2D numerical method to estimate damage in a 3D real case. The numerical method is used to determine stress wave damage and provides an indication of zones prone to suffer greater damage by gas expansion. The specific steps carried out in this study are: i) extensive blast monitoring in hard rock at surface and underground test sites; ii) analysis of seismic waveforms in terms of amplitude and frequency and their azimuthal distribution with respect to borehole axis, iii) measurement of blast-induced damage from single-hole blasts; iv) assessment and implementation of method to utilize 2D numerical model to predict blast damage in 3D situation; v) use of experimental and numerical results to estimate relative contribution of stress waves and gas penetration to damage, and vi) monitoring and modeling of full-scale production blasts to apply developed method to estimate blast-induced damage from stress waves. The main findings in this study are: i) both P and S-waves are generated and show comparable amplitudes by blasting in boreholes; ii) amplitude and frequency of seismic waves are strongly dependent on initiation mode and direction of propagation of explosive reaction in borehole; iii) in-situ measurements indicate strongly non-symmetrical damage dependent on confinement conditions and initiation mode, and existing rock structure, and iv) gas penetration seems to be mainly responsible for damage (significant damage extension 2-4 borehole diameters from stress waves; > 22 from gas expansion). The method has the potential for application in regular production blasts for control of over-breaks and dilution in operating mines. The main areas proposed for future work are: i) verification of seismic velocity changes in rock by blast-induced damage from controlled experiments; ii) incorporation of gas expansion phase into numerical models; iii) use of 3D numerical model and verification of crack distribution prediction; iv) further studies on strain rate dependency of material strength parameters, and v) accurate measurements of in-hole pressure function considering various confinement conditions.

A combination of theoretical, numerical, and experimental methods were utilized to determine that shock waves can form in brain tissue from smooth boundary conditions. The conditions that lead to the formation of shock waves were determined. The implication of this finding was that the high gradients of stress and strain that could occur at the shock wave front could contribute to mechanism of brain injury in blast loading conditions. The approach consisted of three major steps. In the first step, a viscoelastic constitutive model of bovine brain tissue under finite step-and-hold uniaxial compression with 10 1/s ramp rate and 20 s hold time has been developed. The assumption of quasi-linear viscoelasticity (QLV) was validated for strain levels of up to 35%. A generalized Rivlin model was used for the isochoric part of the deformation and it was shown that at least three terms (C_10, C_01 and C_11) are needed to accurately capture the material behavior. Furthermore, for the volumetric deformation, a linear bulk modulus model was used and the extent of material incompressibility was studied. The hyperelastic material parameters were determined through extracting and fitting to two isochronous curves (0.06 s and 14 s) approximating the instantaneous and steady-state elastic responses. Viscoelastic relaxation was characterized at five decay rates (100, 10, 1, 0.1, 0 1/s) and the results in compression and their extrapolation to tension were compared against previous models. In the next step, a framework for understanding the propagation of stress waves in brain tissue under blast loading was developed. It was shown that tissue nonlinearity and rate dependence are key parameters in predicting the mechanical behavior under such loadings, as they determine whether traveling waves could become steeper and eventually evolve into shock discontinuities. To investigate this phenomenon, the QLV material model developed based on finite compression results mentioned above was extended to blast loading rates, by utilizing the stress data published on finite torsion of brain tissue at high rates (up to 700 1/s). It was shown that development of shock waves is possible inside the head in response to compressive pressure waves from blast explosions. Furthermore, it was argued that injury to the nervous tissue at the microstructural level could be attributed to the high stress and strain gradients with high temporal rates generated at the shock front and this was proposed as a mechanism of injury in brain tissue. In the final step, the phenomenon of shock wave formation and propagation in brain tissue was further studied by developing a one-dimensional model of brain tissue using the Discontinuous Galerkin finite element method. This model is capable of capturing high-gradient waves with higher accuracy than commercial finite element software. The deformation of brain tissue was investigated under displacement input and pressure input boundary conditions relevant to blast over-pressure reported in the literature. It was shown that a continuous wave can become a shock wave as it propagates in the tissue when the initial changes in acceleration are beyond a certain limit. The high spatial gradients of stress and strain at the shock front cause large relative motions at the cellular scale at high temporal rates even when the maximum strains and stresses are relatively low. This gradient-induced local deformation occurs away from the boundary and can therefore contribute to the diffuse nature of blast-induced injuries.   / Mechanical Engineering

The pro-oxidative and pro-inflammatory mechanisms have been implicated in various human diseases including neurological and psychiatric disorders. However, there is only limited information available on the etiology in the progression of neurological damage to brain. The emergence of tissue engineering with the growing interest in mechanistic studies of brain injury now raises great opportunities to study complex physiological and pathophysiological process in vitro. Therefore, the prime goals of this study include: (1) Determination of the molecular and cellular mechanisms responsible for blast- and radiation-induced brain injuries and (2) Development of a three-dimensional (3D) model system in order to mimic in vivo-like microenvironments to further broaden our knowledge in pro-oxidative and pro-inflammatory mechanisms and their cellular responses within 3D constructs. In the first study, we demonstrated that blast exposure induced specific molecular and cellular alterations in pro-oxidative and pro-inflammatory environments in the brain and neuronal loss with adverse behavioral outcome. The results provide evidence that pro-oxidative and pro-inflammatory environments in the brain could play a potential role in blast-induced neuronal loss and behavioral deficits. In the second study, we investigated that fractionated whole-brain irradiation induced specific molecular and cellular alterations in pro-oxidative and pro-inflammatory environments in the brain along with elevation of reactive oxygen species (ROS)-generating protein (NOX-2) and microglial activation. Additionally, the contribution of NOX-2 in fractionated whole-brain radiation-induced oxidative stress was observed by dramatic amelioration of ROS generation after pharmacological inhibition of NOX-2. These results support that NOX-2 may play a pivotal role in fractionated whole-brain radiation-induced pro-oxidative and pro-inflammatory pathways in mouse brain. In the third study, we developed an in vitro 3D experimental model of brain inflammation by encapsulating microglia in collagen hydrogel with computational analysis of 3D constructs. The results indicated that our newly developed in vitro 3D model system provides a more physiologically relevant environment to mimic in vivo responses. In conclusion, these data may be beneficial in defining a cellular and molecular basis of pathophysiological mechanisms of brain injuries. Furthermore, it may provide new opportunities for preventive and therapeutic interventions for patients with brain injuries and associated neurological disorders. / Ph. D.