Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Adv Healthc Mater. 2023 Aug;12(20):e2202756. doi: 10.1002/adhm.202202756. Epub 2023 Apr 23.
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.
原发性止血（血小板栓形成）和继发性止血（纤维蛋白凝块形成）是血管损伤时相互交织的过程。研究人员一直试图通过利用这些过程特有的信号来靶向伤口，例如使用与激活的血小板或纤维蛋白结合的肽。虽然这些材料在各种损伤模型中取得了成功，但它们通常是专门为治疗原发性或继发性止血而设计的。在这项工作中，开发了一种由靶向成分（叠氮化物/GRGDS PEG-PLGA 纳米颗粒）和交联成分（多功能 DBCO）组成的两亲性体系，用于治疗内出血。该系统利用增加的损伤积累来实现临界浓度以上的交联，通过放大血小板募集和减轻纤维蛋白溶解来增强血栓稳定性，从而同时治疗原发性和继发性止血。通过测量纳米颗粒聚集来验证浓度依赖性交联，而发现 1:3 的叠氮化物/GRGDS 比例可增加血小板募集、减少血液稀释环境中的血栓降解，并减少补体激活。最后，这种方法在肝切除模型中与仅用颗粒的对照组相比，显著提高了存活率。鉴于仅用颗粒的系统取得的先前成功，这些结果强调了该技术在辅助止血方面的潜力，以及在开发新的出血治疗方法中采用整体方法的重要性。
