Clotting factor replacement is the standard management of acute bleeding in congenital and acquired bleeding disorders. We present a synthetic approach to hemostasis using an engineered hemostatic polymer (PolySTAT) that circulates innocuously in the blood, identifies sites of vascular injury, and promotes clot formation to stop bleeding. PolySTAT induces hemostasis by crosslinking the fibrin matrix within clots, mimicking the function of the transglutaminase Factor XIII. Furthermore, synthetic PolySTAT binds specifically to fibrin monomers and is uniformly integrated into fibrin fibers during fibrin polymerization, resulting in a fortified, hybrid polymer network with enhanced resistance to enzymatic degradation. In vivo hemostatic activity was confirmed in a rat model of trauma and fluid resuscitation in which intravenous administration of PolySTAT improved survival by reducing blood loss and resuscitation fluid requirements. PolySTAT-induced fibrin crosslinking is a novel approach to hemostasis utilizing synthetic polymers for non-invasive modulation of clot architecture with potentially wide-ranging therapeutic applications.
A series of thermosensitive ABA type triblock poly(e-caprolactone)-bpoly(N-isopropylacrylamide)-b-poly(e-caprolactone) (PCL-PNIPAAm-PCL) copolymers with different molecular weights were synthesized by the combination of ring opening polymerization and reversible addition-fragmentation chain transfer (RAFT) polymerization. The critical micelle concentrations (CMCs) of the resulted four triblock copolymers in aqueous solution were determined to be 33. 8, 39.8, 35.5, and 41.7 mg/L, respectively, by fluorescence spectroscopy using pyrene as a fluorescence probe. Optical absorption measurements showed that the lower critical solution temperatures (LCSTs) of the copolymers were 35.8, 36.2, 35.2, and 36.2 8C, respectively, in distilled water, and 33.9, 34.2, 33.3, 34.6 8C, respectively, in PBS (pH ¼ 6.8, I ¼ 0.1). Transmission electron microscopy (TEM) showed that the self-assembled micelles exhibited a well-defined spherical shape with diameter of around 100 nm. The drug-loaded PCL-PNIPAAm-PCL micelles displayed thermosensitive controlled release behaviors. V V C 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: [3048][3049][3050][3051][3052][3053][3054][3055][3056][3057] 2008
Shell cross-linked (SCL) thermoresponsive hybrid micelles consisting of a cross-linked thermoresponsive hybrid hydrophilic shell and a hydrophobic core domain were synthesized from poly(N-isopropylacrylamide-co-3- (trimethoxysilyl)propyl methacrylate)-b-polymethyl methacrylate (P(NIPAAm-co-MPMA)-b-PMMA) amphiphilic block copolymers. Transmission electron microscopy (TEM) images showed that the SCL micelles formed regularly globular nanoparticles. The SCL micelles showed reversible dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PNIPAAm at around 33 degrees C, observed by turbidity measurements and dynamic light scattering (DLS). The drug loading and in vitro drug release properties of the SCL micelles bearing a silica-reinforced PNIPAAm shell were further studied, which showed that the SCL micelles exhibited a much improved entrapment efficiency (EE) as well as a slower release rate which allowed the entrapped molecules to be slowly released over a much longer period of time as compared with pure PNIPAAm-b-PMMA micelles.
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