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.

中文翻译：

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超软血小板样颗粒可在啮齿动物和猪的创伤模型中止血

创伤后不受控制的出血是一个严重的临床问题。目前治疗创伤后出血的护理标准是输注包括血小板在内的血液制品；然而，捐赠的血小板保质期短、供应有限，并且具有免疫原性和污染风险。因此，迫切需要开发止血血小板替代品。为此，我们开发了合成血小板状颗粒（PLP），该颗粒是通过对由超低交联聚（氮-异丙基丙烯酰胺）与纤维蛋白结合配体。纤维蛋白结合配体旨在靶向伤口部位，纤维蛋白聚合物的交联旨在增强凝块形成。微凝胶的超低交联度使颗粒能够发生较大的形状变化，模拟活化后血小板形状的变化；当与纤维蛋白结合配体偶联时，这种形状变化有利于凝块收缩，从而增强凝块稳定性并有助于愈合。鉴于这些特征，我们假设合成 PLP 可以增强创伤模型中的凝血并促进凝血后的愈合。我们首先在体外评估了 PLP 活性，发现 PLP 选择性结合纤维蛋白并增强血栓形成。在小鼠和猪的创伤性损伤模型中，PLP 可以在预防性和立即治疗环境中减少出血并促进受伤组织的愈合。我们通过生物分布实验确定 PLP 可以通过肾脏清除，这可能是由超软颗粒特性实现的。这里显示的临床前研究中合成 PLP 的性能支持未来在创伤环境中对这些止血疗法进行转化研究。