Modulating Nanoparticle Size to Understand Factors Affecting Hemostatic Efficacy and Maximize Survival in a Lethal Inferior Vena Cava Injury Model.

Abstract

Intravenous nanoparticle hemostats offer a potentially attractive approach to promote hemostasis, in particular for inaccessible wounds such as noncompressible torso hemorrhage (NCTH). In this work, particle size was tuned over a range of <100-500 nm, and its effect on nanoparticle-platelet interactions was systematically assessed using <i>in vitro</i> and <i>in vivo</i> experiments. Smaller particles bound a larger percentage of platelets per mass of particle delivered, while larger particles resulted in higher particle accumulation on a surface of platelets and collagen. Intermediate particles led to the greatest platelet content in platelet-nanoparticle aggregates, indicating that they may be able to recruit more platelets to the wound. In biodistribution studies, smaller and intermediate nanoparticles exhibited longer circulation lifetimes, while larger nanoparticles resulted in higher pulmonary accumulation. The particles were then challenged in a 2 h lethal inferior vena cava (IVC) puncture model, where intermediate nanoparticles significantly increased both survival and injury-specific targeting relative to saline and unfunctionalized particle controls. An increase in survival in the second hour was likewise observed in the smaller nanoparticles relative to saline controls, though no significant increase in survival was observed in the larger nanoparticle size. In conjunction with prior <i>in vitro</i> and <i>in vivo</i> experiments, these results suggest that platelet content in aggregates and extended nanoparticle circulation lifetimes are instrumental to enhancing hemostasis. Ultimately, this study elucidates the role of particle size in platelet-particle interactions, which can be a useful tool for engineering the performance of particulate hemostats and improving the design of these materials.