Bio-Inspired In Situ Injectable Hemostatic Agent with Covalent-Ionic Hybrid Network for Non-Compressible Hemorrhage

Non-compressible hemorrhage is an arduous clinical challenge that primarily occurs at thoracic/abdominal solid organ injuries, deep arterial ruptures, and major vascular trauma, and cannot be stopped by compressing the hemorrhage site. Currently available commercial hemostatic materials for non-compressible hemorrhage are plagued by issues such as poor sealing ability and insufficient hemostatic performance. In the current work, tetra-PEG-succinimidyl glutarate (TPEG-SG), carboxymethyl chitosan (CMCS), and the coagulation factor Ca^{2 +} were used as the primary ingredients to create a covalent-ionic hybrid crosslinked hemostatic agent TPEG-SG/CMCS/Ca^{2 +}. The optimal formula of hemostatic agent was screened by using response surface methodology. The obtained hemostatic agent TPEG-SG/CMCS/Ca^{2 +} could achieve rapid and ultra-high sealing ability, with a burst pressure of 354 mmHg. It also demonstrated excellent hemostatic ability in vivo, outperforming the commercial fibrin glue in hemostasis including mouse liver and inferior vena cava hemorrhage models, rabbit renal incision, partial hepatectomy, femoral artery puncture, and lethal rabbit carotid artery puncture hemorrhage models, showing great potential in non-compressible hemorrhage hemostasis. In addition, in the mouse full-thickness skin incision model, the hemostatic agent was superior to fibrin glue in wound closure and repair. Overall, the TPEG-SG/CMCS/Ca^{2 +} hemostatic agent showed promising clinical application potential in the management of non-compressible hemorrhage.