DescriptionTraumatic brain injury (TBI) is a leading cause of death and disability worldwide and is often divided into two stages, primary and secondary injury. Primary injury is the immediate result of blunt force trauma, and it cannot be treated. Secondary injury is a degenerative cascade of events that varies in severity and can last anywhere from a few days to months. Tissue and cellular degeneration induced by secondary injury is caused by a combination of free radical formation, excitotoxicity, ischemia, hypoxia, and neuroinflammation. Treatment of TBI includes stabilizing the patient and easing the associated symptoms, with a focus on mitigating the neuroinflammatory response. There are a wide range of treatments available which can address the inflammatory response, such as dexamethasone (dex), a corticosteroid. However, while the symptoms of TBI can be managed, the damage induced by secondary injury can cause life-long complications. Unfortunately, there are no commercially available therapeutics which can promote neuroprotection and enable complete functional restoration, especially in severe cases. A promising method for addressing TBI induced neurodegeneration is brain-derived neurotrophic factor (BDNF), which is critical for neuronal maturation and function. It has been used in clinical trials for the treatment of amyotrophic lateral sclerosis (ALS), however, it ultimately failed due to its instability. We address this limitation in this dissertation by developing a novel BDNF delivery formulation comprised of alginate encapsulation of BDNF loaded PLGA NPs. This formulation will allow for the protection and controlled release of BDNF as well as enable for localization to a region of treatment. Our formulation can deliver BDNF for at least 28 days and was shown to be bioactive in an in vitro neuronal injury model.
In addition, we also investigated a novel in vitro model of TBI comprised of oxidatively stressed neurons and activated astrocytes, given our central hypothesis that neuroinflammation and neurodegeneration need to be addressed concomitantly to improve therapeutic efficacy. This system mimics multiple aspects of TBI, such as oxidative stress, glutamate excitotoxicity, and upregulation of pro-inflammatory cytokines and chemokines. We used this system to evaluate the therapeutic efficacy of a BDNF/dex co-treatment. Our results support not only the need for a multi-modal approach for enhanced therapeutic efficacy, but a screening model must include multiple cell types, considering the complexity of TBI.