Optimizing the Polymer Chemistry and Synthesis Method of PolySTAT, an Injectable Hemostat.

Abstract

There is a lack of prehospital hemostatic agents, especially for noncompressible hemorrhage. We previously reported PolySTAT, a unimeric, injectable hemostatic agent, that physically cross-links fibrin to strengthen clots. In this work, we sought to improve the water-solubility and synthesis yield of PolySTAT to increase the likelihood of clinical translation, reduce cost, and facilitate future mass production. First, we focused on side-chain engineering of the carrier polymer backbone to improve water-solubility. We found that substitution of the 2-hydroxyethyl methacrylate (HEMA) monomer with glycerol monomethacrylate (GmMA) significantly improved the water-solubility of PolySTAT without compromising efficacy. Both materials increased clot firmness and decreased lysis as measured by rotational thromboelastometry (ROTEM). Additionally, we confirmed the in vivo activity of GmMA-based PolySTAT by improving rat survival in a femoral artery bleed model. Second, to reduce waste, we evaluated PolySTAT synthesis via direct polymerization of peptide monomers. Methacrylamide and methacrylate peptide-monomers were synthesized and polymerized via reversible addition-fragmentation chain transfer (RAFT) polymerization. This approach markedly improved the yield of PolySTAT synthesis while maintaining its biological activity in ROTEM. This work demonstrates the flexibility of PolySTAT to a variety of comonomers and synthetic routes and establishes direct RAFT polymerization of peptide monomers as a potential route of mass production.