Engineering Nano-Delivery for Diagnosis and Restoration of Disrupted Brain Endothelium Post Blast-Induced Traumatic Brain Injury (TBI)

Traumatic brain injury (TBI) associated with explosive blasts is a serious concern among military personnel, potentially causing neurological sequelae. Although disruption of the blood-brain barrier has long been suspected, the coupling mechanisms are yet to be elucidated. Our previous studies have shown that a blast can generate highly pressurized micron-size bubbles, and the microbubbles subsequently collapse and produce a secondary shock pressure (i.e., microjet). Using tissue engineering approaches, we recently demonstrated that the microjet can cause disruption of brain endothelium (BE) tight junctions. High expression of E-Selectins is typically indicative of inflammation and injury to endothelial cells (ECs). Upregulation of this protein following an injury can be exploited for diagnosis and potential therapy through targeted delivery. We hypothesized that BE disrupted by microject could be targeted, diagnosed, and treated for repair and restoration. To test this hypothesis, we engineered nanoparticles (NPs) to encapsulate therapeutic reagents and decorated the NPs with peptides to specifically bind to the damaged BCs.

Poly (lactic-co-glycolic acid; PLGA) nanoparticles (NPs) were successfully fabricated and characterized. The PLGA NPs were functionalized with the ligands (CD162) to target E-Selectins expressed on the damaged ECs. Damaged cells exhibited a high affinity to conjugated NPs compared to unconjugated control NPs. Such cellular uptakes are quantified by measuring the accumulation of intracellular NPs. The cellular repair was quantified by measuring the rate of proliferation of brain ECs to restore the injury site. Targeted delivery of non-biologics as potential therapeutic reagents is developed and tested to repair and restore the BE.

Exploiting the tunable properties of PLGA, a targeted drug delivery strategy was developed for targeted treatment of injured brain ECs. Because the current approach combines the specificity of ligand/receptor interaction with therapeutic reagents, it provides a potential theragnostic approach for treatment of TBI.