UC San Diego

There has been a growing body of evidence that impaired microvascular perfusion is an indicator for mortality in critical patients. However, there are limited clinical microvascular therapeutics targets. The objective of this thesis is to investigate and intervene upon microvascular disease found in hemorrhagic shock, neoplasia, and inflammation concurrent with acute respiratory distress (ARDS). Chapter one of this thesis focuses on engineering an intervention to improve microvascular perfusion by leveraging the Starling forces in capillaries. Specifically, we designed and implemented a device for the application of negative pressure to reduce tissue interstitial pressure, which transiently increased functional capillary density after hemorrhagic shock, a known metric for microvascular perfusion, without the need for volume resuscitation. Chapter two aims on engineering red blood cells to target the tumor microcirculation and microenvironment. Specifically, we studied red blood cells as a delivery vehicle for RRx-001, an anti-cancer agent, and altered their biomechanics, by selectively inducing tumor adhesion in the tumor microenvironment. This increase in adhesion had an anti-neoplastic effect, with our study showing a 40% decrease in tumor size. In chapter three, we engineered a new intervention for altering microvascular inflammation as seen in the acute respiratory distress syndrome (ARDS). Specifically, we aerosolized Nitric Oxide releasing nanoparticles (NO-nps) to mice suffering of ARDS and found a reduction in peripheral neutrophils, indicative of reduced inflammation. As demonstrated, engineering interventions to improve microvascular perfusion shows great potential as a therapeutic target for a broad range of pathophysiologies, including hemorrhagic shock, cancer, and ARDS.