Polyphosphate‐conjugated Silica Nanoparticles (polyP‐SNPs) Attenuate Bleeding After Tail Amputation

Hemorrhage control is a major focus in treating critically injured trauma patients. Uncontrolled blood loss accounts for 25–30% of civilian deaths and the vast majority of all battlefield deaths. Acute traumatic coagulopathy (ATC) occurs in 25–40% of patients nearly immediately after injury and is associated with worsened bleeding, increased need for transfusion, and a 4‐fold increase in mortality. Stopping bleeding and correcting coagulopathy remain the key goals in trauma treatment. Unfortunately, there are few current treatments, and the ones that exist are inadequate due to ineffectiveness, side effects, steep cost per dose, and need for refrigeration. Biomaterials can bridge the critical time between injury and treatment to begin treatment quicker and improve the condition of trauma patients upon hospital arrival. One such potential solution is created by coating a silica nanoparticle (SNP) with a heterogeneous 70‐mer polymer polyphosphate (polyP) chain to form polyP‐SNP. In response to vessel injury, short‐chain polyP binds to thrombin at the injury site. After binding to thrombin, polyP enhances back‐activation of FXI and FV, ultimately leading to an increase in the production of thrombin, the integral factor for clotting. Increased production of thrombin quickly leads to the formation of the physical clot which seals the wound and limits blood loss. However, short‐chain polyP is a poor activator of FXII, which makes it a potentially ideal agent for enhancing the body's ability to clot at injury sites without inducing clots in otherwise healthy vessels. Among its many benefits, the long term stability of polyP‐SNP at ambient conditions has the potential to minimize this time between injury and treatment. Preliminary animal trials suggests that a 5 mg/kg dose of polyP‐SNPs after a tail cut reduced blood loss by roughly 25 % (Fig. 2, p = 0.011) and led to 100 % survival. Earlier tests conducted to determine the circulation time of polyP‐SNPs using blood drawn from an uninjured rat after a lower dose (2 mg/kg) injection. In the presence of injury, these tests showed that the polyP‐SNP particles are active in the bloodstream for roughly 2 hours after injection (Fig. 3). Post‐euthanasia histopathology studies showed that polyP‐SNPs were not thrombotically active in uninjured vessels during the same time period. This suggests that the polyP‐SNP system is both safe and effective for intravenous use in an animal model of trauma. PolyP‐SNP's ability to quickly grow clots, and its stability at ambient conditions enables quicker intervention to prevent or attenuate shock and the onset of ATC. Initial in vivo studies have shown that the use of polyP‐SNP quickly after injury significantly reduces blood loss. This system has been shown to be effective at reducing blood loss in a traumatic injury without unwanted clotting, while also reducing clot time in simulated trauma. PolyP‐SNPs have the potential to be at the vanguard of biomaterials that save lives by safely and effectively enabling prehospital treatment for trauma patients. Support or Funding Information U.S Congressionally Directed Medical Research Programs (CDMRP) under Contact Number W911NF‐10‐2‐0114 and the Institute for Collaborative Biotechnologies (ICB). The MRL Shared Experimental Facilities are supported by the MRSEC Program of the National Science Foundation under award NSF DMR 1121053; a member of the NSF‐funded Materials Research Facilities Network. Conflict‐of‐interest disclosure: D.K and G.S. are co‐inventors on patent applications covering potential medical uses of polyP‐SNP. D.K., K.P., S.H., T.K., and G.S. declare financial interest in the medical uses of polyP‐SNP.