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Publication Number
US-9808553-B2
Publication Date
2017-11-07
Expiration Date
Abstract
Haemostatic wound dressings are described. The dressings comprise a non-colloidal porous dressing material, and a plurality of fibrinogen-binding peptides immobilised to the non-colloidal porous dressing material, wherein each fibrinogen-binding peptide comprises: an amino acid sequence Gly-Pro-Arg-Xaa (SEQ ID NO: 1) at an amino-terminal end of the peptide, wherein Xaa is any amino acid other than Val, preferably Pro, Sar, or Leu; or an amino acid sequence Gly-His-Arg-Xaa (SEQ ID NO: 2) at an amino-terminal end of the peptide, wherein Xaa is any amino acid other than Pro. The dressings are able to accelerate haemostasis without requiring enzymatic activity. In particular, the dressings to do not rely on the action of exogenous thrombin, and can be stored long-term at room temperature in solution. Methods of making the dressings, and use of the dressings to control bleeding are also described.
Core Innovation
The invention relates to haemostatic wound dressings that comprise a non-colloidal porous dressing material with fibrinogen-binding peptides immobilised thereon. The fibrinogen-binding peptides are presented with an amino-terminal motif of Gly-Pro-Arg-Xaa (SEQ ID NO: 1) where Xaa is any amino acid other than Val, or Gly-His-Arg-Xaa (SEQ ID NO: 2) where Xaa is any amino acid other than Pro.
The dressings are configured to accelerate haemostasis by forming a fibrinogen–peptide copolymer/clot-like structure without exogenous thrombin. The patent positions the fibrinogen-binding peptide-functionalised non-colloidal porous dressing material as a thrombin alternative, and describes covalent immobilisation of the fibrinogen-binding peptides to a plurality of carriers immobilised to the non-colloidal porous dressing material.
The non-colloidal porous dressing material is defined in formats including sheet, pad, sponge, foam, film, gauze, mesh, granules or beads, with a majority of granules or beads having a maximum dimension greater than 6 µm. The patent further describes non-peptide spacers, including hydrophilic polymers such as polyethylene glycol, dry and freeze-dried formats, and kits and agents for formation and administration of the haemostatic wound dressing to control bleeding.
Claims Coverage
The independent claims cover four inventive aspects: a haemostatic wound dressing with fibrinogen-binding peptides immobilized to a non-colloidal porous dressing material via carriers and covalent linkage; a kit for formation of such a dressing with a separately provided haemostatic agent; a haemostatic dressing with granules or beads and covalent immobilisation to the porous material; and a kit for formation where the haemostatic agent consists of fibrinogen-binding peptides covalently immobilized to a granules or beads non-colloidal porous dressing material. Two allowed amino-terminal peptide motifs and a majority particle-size threshold for granules or beads are specified.
Haemostatic wound dressing with non-colloidal porous material and covalently immobilized peptide carriers
A haemostatic wound dressing comprising a non-colloidal porous dressing material and a plurality of fibrinogen-binding peptides immobilized to the non-colloidal porous dressing material, wherein each fibrinogen-binding peptide comprises an amino-terminal Gly-Pro-Arg-Xaa (SEQ ID NO: 1) motif with Xaa any amino acid other than Val or an amino-terminal Gly-His-Arg-Xaa (SEQ ID NO: 2) motif with Xaa any amino acid other than Pro; wherein the non-colloidal porous dressing material comprises a sheet, pad, sponge, foam, film, gauze, mesh, granules or beads; wherein if granules or beads are present, a majority of the granules or beads have a maximum dimension greater than 6 µm; and wherein a plurality of carriers are immobilized to the non-colloidal porous dressing material, and the plurality fibrinogen binding peptides are covalently immobilized to each carrier.
Kit for formation with separately provided carriers and covalently immobilized peptide agent
A kit for formation of a haemostatic wound dressing comprising a non-colloidal porous dressing material and, separately, a haemostatic agent comprising a plurality of carriers and a plurality of fibrinogen-binding peptides immobilized to each carrier, wherein each fibrinogen-binding peptide comprises an amino terminal Gly-Pro-Arg-Xaa (SEQ ID NO: 1) motif with Xaa any amino acid other than Val or an amino-terminal Gly-His-Arg-Xaa (SEQ ID NO: 2) motif with Xaa any amino acid other than Pro; wherein the non-colloidal porous dressing material comprises a sheet, pad, sponge, foam, film, gauze, mesh, granules or beads; wherein if granules or beads are present, a majority have a maximum dimension greater than 6 µm; and wherein the plurality of carriers are immobilized to the non-colloidal porous dressing material, and the plurality fibrinogen binding peptides are covalently immobilized to each carrier.
Haemostatic wound dressing with granules or beads and covalent peptide immobilisation to the porous material
A haemostatic wound dressing comprising a non-colloidal porous dressing material and a plurality of fibrinogen-binding peptides immobilized to the non-colloidal porous dressing material, wherein each fibrinogen-binding peptide comprises an amino-terminal Gly-Pro-Arg-Xaa (SEQ ID NO: 1) motif with Xaa any amino acid other than Val or an amino-terminal Gly-His-Arg-Xaa (SEQ ID NO: 2) motif with Xaa any amino acid other than Pro; wherein the non-colloidal porous dressing material comprises granules or beads, wherein a majority of the granules or beads have a maximum dimension greater than 6 µm; and wherein the plurality of fibrinogen binding peptides are covalently immobilized to the non-colloidal porous dressing material.
Kit for formation with granules or beads and covalently immobilized peptide agent
A kit for formation of a haemostatic wound dressing comprising a non-colloidal porous dressing material and, separately, a haemostatic agent comprising a plurality of fibrinogen-binding peptides, wherein each fibrinogen-binding peptide comprises an amino terminal Gly-Pro-Arg-Xaa (SEQ ID NO: 1) motif with Xaa any amino acid other than Val or an amino-terminal Gly-His-Arg-Xaa (SEQ ID NO: 2) motif with Xaa any amino acid other than Pro; wherein the non-colloidal porous dressing material comprises granules or beads, wherein a majority of the granules or beads have a maximum dimension greater than 6 µm; and wherein the fibrinogen-binding peptides are covalently immobilized to the non-colloidal porous dressing material.
Across the independent claims, the inventive core is the use of fibrinogen-binding peptides defined by the Gly-Pro-Arg-Xaa and Gly-His-Arg-Xaa amino-terminal motifs immobilized to a non-colloidal porous dressing material, with covalent immobilisation via carriers in one claim set and directly to the porous material in another. Two independent claims further specify kit formats in which a non-colloidal porous dressing material is provided separately from a haemostatic agent bearing the covalently immobilized peptides.
Stated Advantages
Accelerates haemostasis by forming a fibrinogen–peptide copolymer/clot-like structure without exogenous thrombin.
Improved bleeding outcomes in an abrasion model versus saline or thrombin-soaked gelatin pads, as indicated by bleeding scores.
Retention of clotting activity after freeze-drying.
Improved blood impedance using peptide-functionalised gauze.
Stability of peptide-functionalised carriers in solution at 37°C for at least 6 months.
Documented Applications
Controlling bleeding by administering a haemostatic wound dressing to a wound.
Use of the haemostatic wound dressing in an abrasion bleeding model (rabbit liver abrasion model) with assessment of bleeding scores.
Use of peptide-functionalised porous dressings in formats such as dry and freeze-dried preparations, including retention of clotting activity after freeze-drying.
Use of peptide-functionalised gauze evaluated via blood impedance.
Use of peptide-functionalised carriers or gelatin pads/granules described in functional clotting and bleeding-related evaluations.
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