Efficacy of a novel polyoxazoline-based hemostatic patch in liver and spleen surgery

Abstract

Background A new hemostatic sealant based on a N-hydroxy-succinimide polyoxazoline (NHS-POx) polymer was evaluated to determine hemostatic efficacy and long-term wound healing and adverse effects in a large animal model of parenchymal organ surgical bleeds. Methods Experiment 1 included 20 pigs that were treated with two NHS-POx patch prototypes [a gelatin fibrous carrier (GFC) with NHS-POx and an oxidized regenerated cellulose (ORC) with poly(lactic-co-glycolic acid)-NHS-POx:NU-POx (nucleophilically activated polyoxazoline)], a blank gelatin patch (GFC Blank), TachoSil® and Veriset™ to stop moderate liver and spleen punch bleedings. After various survival periods (1–6 weeks), pigs were re-operated to evaluate patch degradation and parenchymal healing. During the re-operation, experiment 2 was performed: partial liver and spleen resections with severe bleeding, and hemostatic efficacy was evaluated under normal and heparinized conditions of the two previous prototypes and one additional NHS-POx patch. In the third experiment an improved NHS-POx patch (GATT-Patch; GFC-NHS-POx and added 20% as nucleophilically activated polyoxazoline; NU-POx) was compared with TachoSil®, Veriset™ and GFC Blank on punch bleedings and partial liver and spleen resections for rapid (10s) hemostatic efficacy. Results NHS-POx-based patches showed better (GFC-NHS-POx 83.1%, ORC-PLGA-NHS-POx: NU-POx 98.3%) hemostatic efficacy compared to TachoSil® (25.0%) and GFC Blank (43.3%), and comparable efficacy with Veriset™ (96.7%) on moderate standardized punch bleedings on liver and spleen. All patches demonstrated gradual degradation over 6 weeks with a reduced local inflammation rate and an improved wound healing. For severe bleedings under non-heparinized conditions, hemostasis was achieved in 100% for Veriset™, 40% for TachoSil and 80–100% for the three NHS-POx prototypes; similar differences between patches remained for heparinized conditions. In experiment 3, GATT-Patch, Veriset™, TachoSil and GFC Blank reached hemostasis after 10s in 100%, 42.8%, 7.1% and 14.3%, respectively, and at 3 min in 100%, 100%, 14.3% and 35.7%, respectively, on all liver and spleen punctures and resections. Conclusions NHS-POx-based patches, and particularly the GATT-Patch, are fast in achieving effective hemostatic sealing on standardized moderate and severe bleedings without apparent long-term adverse events.

Self-Nanoformulating Poly(2-oxazoline) and Poly(2-oxazine) Copolymers Based Amorphous Solid Dispersions as Microneedle Patch: A Formulation Study

“…Very recently, a POx based hemostatic patch was approved for clinical use. [32] This slow progression can likely be attributed to the historical commercial unavailability of these polymers with high quality and narrow dispersity, coupled with the dominant presence of poly(ethylene glycol) (PEG)-based materials in the market.…”

Thionation of poly(2-ethyl-2-oxazoline) and its effect on solubility and cloud point

“…[15][16][17][18][19][20] Recently, a POx-based polymer-drug conjugate successfully completed phase I clinical trials, 21 and a POx-based hemostatic patch was approved for clinical use. 22,23 The water solubility of POx homopolymers mainly depends on the length of the alkyl groups of the sidechain. While poly(2methyl-2-oxazoline) is completely soluble in water, poly(2-ethyl-2-oxazoline), poly(2-n-propyl-2oxazoline), poly(2-iso-propyl-2-oxazoline) and poly(2-cyclo-propyl-2-oxazoline) show thermoresponsive behavior with LCST.…”

Proof-of-principle of a lung sealant based on functionalized polyoxazolines: experiments in an ovine acute aerostasis model

“…Polyoxazolines are a novel group of polymers that hold promise as a lung sealant due to their strong adhesive and cohesive characteristics [ 10–13 ]. A specific formulation containing amine-functionalized and N -hydroxysuccinimide ester functionalized poly(2-oxazoline)s (NHS-POx, GATT Technologies BV, Nijmegen, The Netherlands) was a highly effective haemostat when impregnated in a porcine gelatin carrier [ 10 , 11 , 13 ]. NHS-POx reacts with proteins on tissue and blood within the patch to form covalent bonds, creating a strong sealing hydrogel within minutes [ 10 ].…”