Peptide valency plays an important role in the activity of a synthetic fibrin-crosslinking polymer. (July 2017)

• Record Type: Journal Article
• Authors: Lamm, Robert J.; Lim, Esther B.; Weigandt, Katie M.; Pozzo, Lilo D.; White, Nathan J.; Pun, Suzie H.
• Is Part Of: Biomaterials. Volume 132(2017)
• Page Start: 96
• Page End: 104
• Publication Date: 2017-07
• Subjects: Peptide-polymer conjugate -- Synthetic injectable hemostat -- Fibrin-binding polymer -- Ligand density; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2017.04.002
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Therapeutic polymers have the potential to improve the standard of care for hemorrhage, or uncontrolled bleeding, as synthetic hemostats. PolySTAT, a fibrin-crosslinking peptide-polymer conjugate, has the capacity to rescue fibrin clot formation and improve survival in a model of acute traumatic bleeding. PolySTAT consists of a synthetic polymer backbone to which targeting fibrin-binding peptides are linked. For translation of PolySTAT, the optimal valency of peptides must be determined. Grafting of fibrin-binding peptides to the poly(hydroxyethyl methacrylate)-based backbone was controlled to produce peptide valencies ranging from 0 to 10 peptides per polymer. PolySTATs with valencies of ≈4 or greater resulted in increased clot firmness, kinetics, and decreased breakdown as measured by thromboelastometry. A valency of ≈4 increased clot firmness 57% and decreased clot breakdown 69% compared to phosphate-buffered saline. This trend was characterized by neutron scattering, which probed the structure of clots formed in the presence of PolySTAT. Finally, PolySTAT with valencies of 4 (100% survival; p = 0.013) and 8 (80% survival; p = 0.063) improved survival compared to an albumin control in a femoral artery injury model (20% survival). This work demonstrates tunability of hemostatic polymers and the ability of in vitro assays to predict in vivo efficacy. Graphical abstract: Highlights: PolySTAT is a material developed to treat hemorrhage by systemic administration. PolySTAT with 4 peptides/polymer, or greater, was effective in strengthening clots. Neutron scattering suggests PolySTAT enhances clots by altering fibrin fiber radius. In vitro assays predicted valencies that were effective in a traumatic injury model.