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.

Polymeric Materials for Hemostatic Wound Healing

“…Lamm et al, have shown that the quadrivalent PolySTATs increased clot firmness values by 57% and decreased the breakdown values by 69% as compared to phosphate-buffered saline [133]. Furthermore, Lamm et al, also carried out an experiment with PolySTAT to optimize its yield and synthesis method, which could potentially capacitate mass production of PolySTAT and its clinical translation [134]. The primary purpose of the research was to increase the water solubility and yield without compromising the structure and hemostatic efficacy of PolySTAT.…”

“…The primary purpose of the research was to increase the water solubility and yield without compromising the structure and hemostatic efficacy of PolySTAT. From their study, they found that the substitution of hydroxyethyl methacrylate with glycerol monomethacrylate (GmMA) greatly increases the water solubility of PolySTAT without affecting its performance [134]. The hemostatic efficacy of the GmMA-based PolySTAT was verified by an in vivo study of a rat femoral artery bleeding model.…”

“…The hemostatic efficacy of the GmMA-based PolySTAT was verified by an in vivo study of a rat femoral artery bleeding model. Moreover, the ROTEM experiment suggested that the methacrylamide and methacrylate peptide monomer synthesized and polymerized via reversible additional fragmentation chain transfer greatly improved the PolySTAT yield [134]. Figure 4 represents the schematic of the PolySTAT synthesis mechanism and it's in vivo and in vitro hemostatic efficacy [134].…”

“…Moreover, the ROTEM experiment suggested that the methacrylamide and methacrylate peptide monomer synthesized and polymerized via reversible additional fragmentation chain transfer greatly improved the PolySTAT yield [134]. Figure 4 represents the schematic of the PolySTAT synthesis mechanism and it's in vivo and in vitro hemostatic efficacy [134]. The PolySTAT can also be used to increase the hemostatic efficacy of chitosan.…”

Solvent Remodeling in Single-Chain Amphiphilic Heteropolymer Systems

“…Methacrylate-based random heteropolymers (RHPs) are one such system, which self-assembles into nano-scale particles containing single or few chains in water, and offers an exciting avenue for protein stabilization and mimicry, nanofiltration, and other promising applications. [3][4][5][6][7] . Behavior of methacrylate-based designs in water have been studied most in depth, as many of their applications occur in aqueous environments.…”