Ultrasoft platelet-like particles stop bleeding in rodent and porcine models of trauma

纤维蛋白 血小板 凝块形成 血小板活化 间隙 生物物理学 凝结 医学 生物医学工程 化学 细胞生物学 免疫学 生物 内科学 泌尿科
作者
Kimberly Nellenbach,Emily Mihalko,Seema Nandi,Drew W. Koch,Jagathpala Shetty,Leandro Moretti,Jennifer Sollinger,Nina Moiseiwitsch,Ana Sheridan,Sanika Pandit,Maureane Hoffman,Lauren V. Schnabel,L. Andrew Lyon,Thomas H. Barker,Ashley C. Brown
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science]
卷期号:16 (742) 被引量:8
标识
DOI:10.1126/scitranslmed.adi4490
摘要

Uncontrolled bleeding after trauma represents a substantial clinical problem. The current standard of care to treat bleeding after trauma is transfusion of blood products including platelets; however, donated platelets have a short shelf life, are in limited supply, and carry immunogenicity and contamination risks. Consequently, there is a critical need to develop hemostatic platelet alternatives. To this end, we developed synthetic platelet-like particles (PLPs), formulated by functionalizing highly deformable microgel particles composed of ultralow cross-linked poly ( N -isopropylacrylamide) with fibrin-binding ligands. The fibrin-binding ligand was designed to target to wound sites, and the cross-linking of fibrin polymers was designed to enhance clot formation. The ultralow cross-linking of the microgels allows the particles to undergo large shape changes that mimic platelet shape change after activation; when coupled to fibrin-binding ligands, this shape change facilitates clot retraction, which in turn can enhance clot stability and contribute to healing. Given these features, we hypothesized that synthetic PLPs could enhance clotting in trauma models and promote healing after clotting. We first assessed PLP activity in vitro and found that PLPs selectively bound fibrin and enhanced clot formation. In murine and porcine models of traumatic injury, PLPs reduced bleeding and facilitated healing of injured tissue in both prophylactic and immediate treatment settings. We determined through biodistribution experiments that PLPs were renally cleared, possibly enabled by ultrasoft particle properties. The performance of synthetic PLPs in the preclinical studies shown here supports future translational investigation of these hemostatic therapeutics in a trauma setting.
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