Transdural Drug Release for Treatment of Central Nervous System Injury

Abstract

Traumatic spinal cord and brain injuries may lead to a devastating loss of neurological function. After the traumatic, primary insult, a secondary injury phase ensues, which significantly increases the extent of the injury. Inflammation is a dominant component of secondary injury, which includes the immune response in which free radicals and proinflammatory cytokines are released that induce the death of surrounding neurons. Dexamethasone, a corticosteroid, produces neuroprotective effects by inhibiting inflammation and reducing cytokine release. However, the clinical application of large systemic doses of steroids is limited by side effects, such as sepsis and pneumonia. There is a need to develop a localized delivery method that minimizes these side effects and improves efficacy by delivering directly at the injury site. In this thesis, we present a delivery method that utilizes clinically used collagen dural substitutes as a vehicle to provide dexamethasone directly to the location of injury without introducing new surgical procedures or devices. This thesis will also explore multiple methods of delivery, such as controlled release from a polymer matrix in a microneedle format as well as coating the dural substitute. We quantified dexamethasone concentrations using high-performance liquid chromatography (HPLC) coupled mass spectrometry (MS). We conducted in-vitro studies using a customized trans-well insert that allowed for the simulation of transdural delivery into activated BV-2 microglia cells. After 24 hours of treatment, we used biological assays to determine nitric oxide, IL-1b, IL-6, TNF-a, and MCP-1 concentrations. With both systems, we were able to achieve sustained release for up to 24 hours. In-vitro, we achieved a significant reduction in nitric oxide concentrations using a polymer-coated dural substitute.