Journal
BIOMATERIALS
Volume 132, Issue -, Pages 96-104Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2017.04.002
Keywords
Peptide-polymer conjugate; Synthetic injectable hemostat; Fibrin-binding polymer; Ligand density
Funding
- NIH [R21EB018637]
- NSF Graduate Fellowship [2013163249]
- NIH Training Grant NIBIB [T32EB1650]
- National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH) [KL2 TR000421]
- National Science Foundation [DMR-1508249]
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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. Poly-STATs with valencies of approximate to 4 or greater resulted in increased clot firmness, kinetics, and decreased breakdown as measured by thromboelastometry. A valency of 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. (C) 2017 Elsevier Ltd. All rights reserved.
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