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A premixed gaseous rocket injector was designed and successfully operated over a limited range of fuel-rich operating conditions for the purpose of soot modeling for ethylene and oxygen mixtures. The injector had the advantage of delivering a homogenous mixture to the combustion chamber, lower soot production, and higher performance potential by removing the fuel atomization process which affects the combustion process and is inherent for non-premixed injectors. The premixed injector was operated at oxygen-fuel ratios from 1.0 to 1.8 with a mass flow of 0.024 kg/sec achieving a chamber pressure of 76 psi without propensity of flashback for 0.032[gamma] injector orifices. Increased mass flow rates of 0.027 kg/sec were achieved by increasing the injector orifice diameters to 0.0625[gamma] which produced a chamber pressure of 127 psi and a characteristic exhaust velocity efficiency of 90.1 %. Flashback was eventually observed at an oxygen-to-fuel ratio of 1.2 where the pressure drop was across the injector was less than 388.6 kPa and the bulk mixture velocity through the injector orifices was approximately 90 m/s. Maintaining bulk velocity sufficiently above this value should prevent flashback from occurring, but will likely need to be characterized for additional orifice diameters and pressure differentials. / Funded by: SEinc307.

PURPOSE: This study examined the effects of normobaric oxygen in patients diagnosed with either a Central Retinal Vein Occlusion (CRVO) or Branched Retinal Vein Occlusion (BRVO) who had previously undergone treatment via Anti-VEGF or PRP treatment. The investigation looked into the changes in Macular Thickness (MT) and Visual Acuity (VA). METHODS: This pilot study analyzed patient data from Beth Israel Deaconess Medical Center (Boston, MA) that had been diagnosed with Retinal Vein Occlusions. The patients were brought in and given 3 hours of normobaric oxygen via an oxygen concentrator with imaging and vision checked both before and after the therapy. RESULTS: Eighty-eight percent of our patients in this pilot study saw a decrease in macular thickness after 3-hour oxygen therapy. The mean change in Maximal Macular Thickness was a decrease of 7.1% which was statistically significant when compared to healthy eyes (p<0.001). Additionally, 44% of patients saw an increase in visual acuity, the primary measure of vision. Visual acuity showed a statistically significant change when compared to changes in healthy eyes (p=0.015). No statistical significance was found in the testing of contrast sensitivity nor intraocular pressure. CONCLUSION: Our study showed improvement in central macular thickness and quality of life for individuals using noninvasive normobaric hyperoxia as a treatment for retinal vein occlusions. However, further research is needed to improve the impact of the study and a full randomized control trial should be implemented to further understand the potential impacts of a noninvasive normobaric hyperoxia treatment as a means to alleviate symptoms in retinal vein occlusions. In addition, in the future oxygen supplementation in conjunction with periodic injections of Anti- VEGF could be investigated as a treatment regimen with potential benefits beyond individual therapy. / 2020-06-17T00:00:00Z

PURPOSE: To investigate the plausibility of clinically significant oxygen toxicity in patients with retinal disorders being treated with hyperoxia therapy. Supplemental oxygen therapy is a promising form of treatment that may help reduce ischemia and the subsequent symptoms in patients suffering from diabetic retinopathy (DR), retinal vein occlusions (RVOs), and age-related macular degeneration (AMD). Currently, few studies perform ongoing assessments of current hyperoxia trials in patient populations. By investigating a current cohort of patients using supplemental oxygen to mitigate symptoms in their ocular conditions, we hope to demonstrate the extremely low likelihood of oxygen toxicity in patients utilizing hyperoxia therapy. Through these results, we hope to demonstrate that supplemental oxygen therapy is a viable, safe method of treatment for patients with ocular disorders. METHODS: A cohort of 16 patients was analyzed for changes in their C Reactive Protein (CRP), white blood cell count (WBC), hematocrit (Hct), and hemoglobin (Hb) levels after continuous use of hyperoxia therapy as part of treatment for varying retinal disorders. All study patients were diagnosed and under treatment at Beth Israel Deaconess Medical Center in Boston, MA. Patients diagnosed with diabetic retinopathy, retinal vein occlusions, or age-related macular degeneration were included in the study. Each of these patients must have also been prescribed 5 L/min of nocturnal hyperoxia therapy. Patients with insufficient data either before or after beginning the hyperoxia therapy were excluded. Primary outcome variables were arranged as pre- and post- hyperoxia therapy data points for CRP, WBC, Hb, and Hct. P-values below 0.05 would indicate statistically significant risk of oxygen toxicity in these variables under the current hyperoxia treatment. RESULTS: The mean age of the sample population was 64, with 6 of the 16 patients diagnosed with diabetes (37.5%). Patient groups were divided into diabetic vs. non-diabetic to assess whether or not one group was affected differently by the hyperoxia therapy. Results showed p-values well over 0.05 for both groups, indicating that oxygen toxicity is not a major risk factor when using supplemental oxygen under the study’s conditions. CONCLUSION: A large number of patients with diabetes suffer from retinal problems, especially with the onset of old age. These problems eventually require treatment via eye injections, laser, and even surgery in order to preserve vision and mitigate edema and ischemia. Given the high cost and invasive nature of these procedures, hyperoxia therapy provides a safe and potentially beneficial alternative to mitigate the symptoms of these disorders. This study hoped to demonstrate the plausibility of widespread clinical application for supplemental oxygen therapy in retina patients, while concluding that oxygen toxicity is not a significant risk factor in this type of treatment. The outcomes of this study support this hypothesis, and lay the groundwork for future studies that may assess the risks of oxygen toxicity on a larger scale. More research is required to gauge the true risks of oxygen toxicity in patients using supplemental oxygen. A case-controlled longitudinal study would also prove useful in providing data on changes in visual acuity and other experimental factors of interest, while accounting for several limitations present in this study. / 2021-06-17T00:00:00Z

Oxygen tension and biomechanical signals are factors that regulate inflammatory mechanisms in chondrocytes. We examined whether low oxygen tension influenced the cells response to TNFα and dynamic compression. Chondrocyte/agarose constructs were treated with varying concentrations of TNFα (0.1 to 100 ng/ml) and cultured at 5% and 21% oxygen tension for 48 hours. In separate experiments, constructs were subjected to dynamic compression (15%) and treated with TNFα (10 ng/ml) and/or L-NIO (1 mM) at 5% and 21% oxygen tension using an ex-vivo bioreactor for 48 hours. Markers for catabolic activity (NO, PGE2) and tissue remodelling (GAG, MMPs) were quantified by biochemical assay. ADAMTS-5 and MMP-13 expression were examined by real-time qPCR. 2-way ANOVA and a post hoc Bonferroni-corrected t-test were used to analyse data. TNFα dose-dependently increased NO, PGE2 and MMP activity (all p < 0.001) and induced MMP-13 (p < 0.05) and ADAMTS-5 gene expression (p < 0.01) with values greater at 5% oxygen tension than 21%. The induction of catabolic mediators by TNFα was reduced by dynamic compression and/or L-NIO (all p < 0.001), with a greater inhibition observed at 5% than 21%. The stimulation of GAG synthesis by dynamic compression was greater at 21% than 5% oxygen tension and this response was reduced with TNFα or reversed with L-NIO. The present findings revealed that TNFα has dose-dependent catabolic activities and increased production of inflammatory mediators at low oxygen tension. Dynamic compression or the NOS inhibitor downregulated the inflammatory effects induced by TNFα, linking both types of stimuli to reparative activities. Future therapeutics should develop oxygen-sensitive antagonists which are directed to interfering with the TNFα induced pathways.

Pre-eclampsia, fetal growth restriction and stillbirth are major pregnancy disorders throughout the world. The underlying pathogenesis of these diseases is defective placentation characterised by inadequate invasion of extravillous trophoblast (EVT) cells into the uterine decidua. This invasion is necessary to transform the uterine arteries, ensuring an adequate maternal blood supply into the intervillous space for normal fetal growth and development. The mechanisms that regulate trophoblast invasion remains poorly understood, but it is known to be influenced by a number of factors in the uterine environment. These include interactions with maternal immune cells as well as cytokines and the products from the uterine glands. In this thesis, physical factors, specifically, tissue stiffness and oxygen are studied as regulators of trophoblast invasion. The mechanical environment is known to regulate cell fate and the migratory behaviour of cells. Despite invasion of EVT cells through decidual tissue rich in extracellular matrix (ECM) proteins, there has been no study investigating how tissue stiffness might regulate EVT invasion. Oxygen has also long been investigated as a regulator for trophoblast invasion, but evidence is conflicting on whether low oxygen promotes or inhibits invasion. This is in part because of the wide variation in methods used and the over-reliance on trophoblast cell lines. To examine the effects of tissue stiffness and oxygen tension, a robust in vitro method to examine the motility and migration of primary EVT cells in three-dimensions (3D) was first established. This system offers significant benefits compared with two-dimensional (2D) systems used previously. Importantly, only cells expressing the HLAG antigen, a marker for the extravillous phenotype are analysed. The stiffness of decidual tissues at the maternal-fetal interface was determined using atomic force microscopy. In patient matched samples, a 3-4 fold increase in stiffness was found where the placenta implants into the decidua, compared to where there is no implantation. Migration of single EVT cells under different matrix stiffness and oxygen concentrations in 3D were investigated. To determine whether EVT migration is directed, a microfluidic system was established, which models the oxygen gradient at the maternal-fetal interface in the first trimester of pregnancy. This system is simple and economical to setup, and permits analysis of the migration dynamics of trophoblast cells in 3D and in real-time under different oxygen concentrations. In conclusion, the change in stiffness at the site of implantation, is further evidence of the dramatic change that occurs in the uterine wall during pregnancy. A microfluidic system to study whether primary EVT cell invasion is directed under oxygen gradients was developed.

Introduction – Severe pulmonary bacterial infections are frequently complicated by systemic hypoxaemia and, in the context of acute respiratory distress syndrome (ARDS), inappropriately prolonged neutrophilic inflammation. This combination of acute hypoxaemia and persistent inflammatory response carries significant morbidity and mortality. However, patients with chronic lung disease function in the community with chronic systemic hypoxaemia and bacterial colonisation with much lower acute mortality. The HIF/PHD pathway tightly regulates neutrophilic responses to hypoxia and bacteria. Here, using acute bacterial pneumonia models, I have dissected the differences in innate immune responses to infection in acute hypoxia and following exposure to hypoxia prior to infection (‘preconditioning’). Methods – C57BL/6 mice were housed in room air or ‘preconditioned’ by exposure to 10% ambient hypoxia for seven days. They were then instilled with intratracheal Streptococcus pneumoniae (1x104 or 1x107 cfu to assess macrophage and neutrophil function respectively) under recovery anaesthesia and housed in normoxia (21% O2) or hypoxia (10% O2). At pre-determined time-points, the animals were assessed clinically for sickness and rectal temperature. Blood, bronchoalveolar lavage and tissues were taken for analysis. Transcriptome analysis by RNA-sequencing and functional glycolysis by Seahorse was performed on blood leucocytes. Results – Concurrent exposure to hypoxia and infection resulted in neutrophil-mediated morbidity and mortality. Acute hypoxia caused rapid utilisation of glucose, glycogen and fat stores resulting in systemic hypoglycaemia and death. Preconditioning with exposure to hypoxia prior to infection completely protected the host against hypoxia-induced morbidity and mortality by suppressing leucocyte glycolysis, through suppression of HIF1α, and resultant rescue from the negative energy state and cardiovascular compromise. Conclusion – Hypoxia preconditions the innate immune response by suppression of HIF1α and glycolysis in leucocytes, thereby protecting against acute hypoxia-induced mortality outcomes in acute bacterial pulmonary infection.

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