Traumatic brain injury (TBI) affects millions of individuals annually resulting in damaged neuronal circuitry and persistent neurological deficits. Subsequent neuroinflammation that follows TBI can exacerbate tissue damage and induce neurodegeneration that is many times worse than the original injury. Neuroinflammation is largely driven by two cell types:​ resident microglia and infiltrating monocyte-derived macrophages. It has long been established that microglia contribute to TBI-induced neuroinflammation, however, little is known about acute microglial reactivity following diffuse TBI – the most common clinical presentation that includes all concussions. Additionally, recent evidence suggests that monocyte-derived macrophages, the primary peripheral innate immune cells, are essential for tissue regeneration outside the central nervous system. In contrast, monocytes home to the brain after TBI, attempt to clear cellular debris, but fail as a result of toxic environmental stimuli. These frustrated macrophages induce rapid and persistent inflammation that amplifies the neurotoxic environment.

Therefore, the purpose of this thesis is to (1) characterize the acute contributions of resident microglia to diffuse TBI and (2) develop a biomaterial strategy to reprogram infiltrating monocyte-derived macrophages to promote anti-inflammatory and tissue regenerative behaviors as a cell therapy for TBI. This research project was designed to develop a bioengineered drug delivery platform to address unsolved biological questions about the immune system’s role in TBI, macrophage-biomaterial interactions, and the microenvironment’s influence on macrophage behavior while simultaneously developing a translational treatment option.

Within this study, I characterized microglia interactions with mechanically-permeabilized neurons acutely after a closed-head model of rapid angular acceleration diffuse TBI. Thereafter, I fabricated anti-inflammatory microparticles that were rapidly phagocytosed by monocytes, stored intracellularly for up to one week, and promoted and maintained a desirable macrophage phenotype. This project represents a novel strategy for long-term maintenance of anti-inflammatory macrophage phenotype using a translational monocyte-based cell therapy strategy without the use of genetic modification. Because of the ubiquitous nature of monocyte-derived macrophage involvement in pathology and regeneration, this strategy holds potential as a treatment for a vast number of diseases and disorders.