Hemostatic nanoparticles increase survival, mitigate neuropathology and alleviate anxiety in a rodent blast trauma model

W Brad Hubbard,Shaylen Greenberg,Carly Norris,Pamela Vandevord,Joseph Eck,Margaret Lashof-Sullivan,Erin Lavik

doi:10.1038/s41598-018-28848-2

Abstract

Explosions account for 79% of combat related injuries and often lead to polytrauma, a majority of which include blast-induced traumatic brain injuries (bTBI). These injuries lead to internal bleeding in multiple organs and, in the case of bTBI, long term neurological deficits. Currently, there are no treatments for internal bleeding beyond fluid resuscitation and surgery. There is also a dearth of treatments for TBI. We have developed a novel approach using hemostatic nanoparticles that encapsulate an anti-inflammatory, dexamethasone, to stop the bleeding and reduce inflammation after injury. We hypothesize that this will improve not only survival but long term functional outcomes after blast polytrauma. Poly(lactic-co-glycolic acid) hemostatic nanoparticles encapsulating dexamethasone (hDNPs) were fabricated and tested following injury along with appropriate controls. Rats were exposed to a single blast wave using an Advanced Blast Simulator, inducing primary blast lung and bTBI. Survival was elevated in the hDNPs group compared to controls. Elevated anxiety parameters were found in the controls, compared to hDNPs. Histological analysis indicated that apoptosis and blood-brain barrier disruption in the amygdala were significantly increased in the controls compared to the hDNPs and sham groups. Immediate intervention is crucial to mitigate injury mechanisms that contribute to emotional deficits.

Highlights

Traumatic injury is the leading cause of death for both men and women between the ages of 5 and 44 worldwide[1], and blood loss is the primary cause of death at acute time points post injury[2,3]
primary blast lung injury (PBLI) is a highly lethal injury associated with mortality levels ranging from of 11% to 55% according to some reports, with this variance likely due to differences in severity[27,28]
Survival percentage was significantly lower (p < 0.05) in the control groups: IO (Injury Only), LR (Lactated Ringer’s), control nanoparticles, and control dexamethasone-loaded nanoparticles groups compared to the shams

Summary

Introduction

Traumatic injury is the leading cause of death for both men and women between the ages of 5 and 44 worldwide[1], and blood loss is the primary cause of death at acute time points post injury[2,3]. Following whole body blast exposure, the primary concern is to increase acute survival Chronic outcomes, such as mental health impairment, can be mitigated early if treatment addresses acute neuropathology[8]. We hypothesized that nanoparticles that could reduce bleeding as well as deliver an anti-inflammatory to the injured tissues might improve systemic outcomes. To this end, we devised hNPs that deliver dexamethasone[19]. We expect that intravenous administration of hemostatic nanoparticles delivering dexamethasone (hDNPs) would reduce bleeding and inflammation and improve survival after blast trauma. Administration of hDNPs resulted in reduced anxiety-like behavior and greater neural preservation following blast injury and promote further research to advance this viable treatment option

Methods

Results

Conclusion