Engineering a Two‐Component Hemostat for the Treatment of Internal Bleeding through Wound‐Targeted Crosslinking

Abstract

Primary hemostasis (platelet plug formation) and secondary hemostasis (fibrin clot formation) are intertwined processes that occur upon vascular injury. Researchers have sought to target wounds by leveraging cues specific to these processes, such as using peptides that bind activated platelets or fibrin. While these materials have shown success in various injury models, they are commonly designed for the purpose of treating solely primary or secondary hemostasis. In this work, a two‐component system consisting of a targeting component (azide/GRGDS PEG‐PLGA nanoparticles) and a crosslinking component (multifunctional DBCO) is developed to treat internal bleeding. The system leverages increased injury accumulation to achieve crosslinking above a critical concentration, addressing both primary and secondary hemostasis by amplifying platelet recruitment and mitigating plasminolysis for greater clot stability. Nanoparticle aggregation is measured to validate concentration‐dependent crosslinking, while a 1:3 azide/GRGDS ratio is found to increase platelet recruitment, decrease clot degradation in hemodiluted environments, and decrease complement activation. Finally, this approach significantly increases survival relative to the particle‐only control in a liver resection model. In light of prior successes with the particle‐only system, these results emphasize the potential of this technology in aiding hemostasis and the importance of a holistic approach in engineering new treatments for hemorrhage.

Spatiotemporally Controlled Release of Etamsylate from Bioinspired Peptide-Functionalized Nanoparticles Arrests Bleeding Rapidly and Improves Clot Stability in a Rabbit Internal Hemorrhage Model

“…In the physiological coagulation process, a minimum sequence in fibrinogen known as Gly-Arg-Gly-Asp-Ser (GRGDS) recognizes and binds to the glycoprotein IIb/IIIa (GPIIa/IIIb) receptor at the time of platelet aggregation. Such derivatives, immobilized on the surfaces of polymers or grafted on biomaterials, have been exploited for hemostatic application. , For example, a photochemically grafted Gly-Arg-Gly-Asp (GRGD) peptide onto the surface of polyethylene glycol-modified polyurethane has been observed to improve endothelial cell adherence, and the improvement efficiency was found to be closely related to the GRGD content . In another instance, Lin et al conjugated RGD-containing peptides to a polyurethane graft backbone, promoting cell adhesion and spreading, based on the cell-adhesive regions of fibronectin (Arg-Gly-Asp-Ser) and vitronectin (Arg-Gly-Asp-Val) .…”