Polymeric nanoparticle hemostats have been demonstrated to be an attractive technology to halt bleeding through extensive testing in animal models. While the results of these in vivo experiments have been well documented, the details of particle-target interactions in vitro and their predictive capabilities for in vivo performance has yet to be fully explored. In this work, the size of GRGDS-conjugated PEG-b-PLGA nanoparticles was tuned and its effect on platelet binding, particle adherence to wound-mimetic surfaces, aggregation capability, biodistribution, and circulation lifetime were systematically assessed using various in vitro and in vivo experiments. Smaller and intermediate-sized nanoparticles were all found to specifically bind a larger number of activated platelets when compared to larger (>250 nm) particles, while incubation of these larger particles on collagen and activated platelet-coated surfaces led to a higher total mass of polymer bound. Intermediate particle diameters led to the greatest number of platelets aggregated on a surface relative to agonist-only positive controls. Finally, larger particles experienced faster clearance and higher pulmonary accumulation per organ mass in an uninjured murine model, whereas smaller particles exhibited longer circulation and retention times and increased accumulation in the liver.
To assess hemostatic efficacy, these three distinct sizes were challenged with a lethal inferior vena cava (IVC) puncture model. The intermediate nanoparticle size was observed to result in the most significant increase in survival over the course of two hours (P = 0.0060, 84.6% survival relative to 26.7% in saline controls), as well as the greatest accumulation at the injury site relative to uninjured vessel controls. These results indicate that tuning particle size provides a key handle for engineering the performance of particle-based hemostat systems, and may influence its efficacy in treating various types of lethal internal hemorrhage.

Dr. Paula T. Hammond

Institute Professor and Department Head, Dept. of Chemical Engineering, MIT and Koch Institute of Integrative Cancer Research

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