Engineering Intravenously Administered Nanoparticles to Reduce Infusion Reaction and Stop Bleeding in a Large Animal Model of Trauma

Abstract

Bleeding from traumatic injury is the leading cause of death for young people across the world, but interventions are lacking. While many agents have shown promise in small animal models, translating the work to large animal models has been exceptionally difficult in great part because of infusion-associated complement activation to nanomaterials that leads to cardiopulmonary complications. Unfortunately, this reaction is seen in at least 10% of the population. We developed intravenously infusible hemostatic nanoparticles that were effective in stopping bleeding and improving survival in rodent models of trauma. To translate this work, we developed a porcine liver injury model. Infusion of the first generation of hemostatic nanoparticles and controls 5 min after injury led to massive vasodilation and exsanguination even at extremely low doses. In naïve animals, the physiological changes were consistent with a complement-associated infusion reaction. By tailoring the zeta potential, we were able to engineer a second generation of hemostatic nanoparticles and controls that did not exhibit the complement response at low and moderate doses but did at the highest doses. These second-generation nanoparticles led to cessation of bleeding within 10 min of administration even though some signs of vasodilation were still seen. While the complement response is still a challenge, this work is extremely encouraging in that it demonstrates that when the infusion-associated complement response is managed, hemostatic nanoparticles are capable of rapidly stopping bleeding in a large animal model of trauma.

Systemically Administered Hemostatic Nanoparticles for Identification and Treatment of Internal Bleeding

“…35 While this complement response occurs in both rodents and larger animal models (such as dogs and pigs), it is significantly milder in small animals and frequently overlooked. 36 Consequently, testing in higher order species is a necessary next step.…”

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

“…Table 1 lists 30 experimental studies [15, which utilized the pig model to analyze the cardiopulmonary adverse effects of different nanoparticles (NPs) or other agents. Some of these studies highlighted the concordance of HSR symptoms in pigs and hypersensitive patients [25][26][27][28][29]32,33,[46][47][48], others addressed the mechanism of HSRs [15,[21][22][23][24][25][26][27][28][29][30][31][32][33]36,[41][42][43][44][45][46][47], and yet others focused on the prevention of HSRs by pharmacological intervention [15], or by optimizing the structure [24,44] or administration protocol [24,37,48] of NPs. Importantly, many of these studies were initiated mainly for preclinical safety evaluation of nanomedicines [15,22,23,30,31,35,…”

Temporal Progression: A case study in Porcine Survivability through Hemostatic Nanoparticles

“…As evident from the complexity of the reactions to hemostatic particles and variations possible by nanoparticles administered, it is imperative that we have a robust model to represent the changes to blood loss over time and identify similarities and dissimilarities between animals not just by treatment but also by the trends in their blood loss. In addition we also observe trends in the cytokine features that lead to reactions in the immune system that occur as a result of the trauma (including Il6, IL8, Neutrophils [8]). Understanding Cytokine reactions may also be useful in studying severe acute respiratory syndrome coronavirus [31,32].…”

“…Immediate intervention is key to survival [4], and yet there are no reliable and readily available treatments for internal bleeding. We developed an intravenously infusible hemostatic nanoparticle that effectively stopped internal bleeding in a number of rodent models of trauma [5][6][7], but we have encountered off target effects in large animal (porcine) models of trauma that mimic infusion reactions seen in some people [8]. We developed a novel version to avoid these infusion reactions, and while it did not exhibit signs of complement activation seen previously, off target effects including non-specific clots were seen in some animals.…”