Haemostatic material

Abstract

The present invention relates to a haemostatic material comprising a natural cellulose fibrous material and at least one Factor XII clotting activator, and to a method of manufacturing a haemostatic material comprising the steps of contacting a natural cellulose fibrous material with at least one Factor XII clotting activator.

Description

[0001] HAEMOSTATIC MATERIAL

[0002] Technical Field of the Invention

[0003] The present invention relates to a haemostatic material comprising a natural cellulose fibrous material and at least one Factor XII clotting activator, and methods of making said haemostatic material.

[0004] Background to the Invention

[0005] There are many circumstances where injury or wounding results in bleeding. Traditionally, the primary technique adopted for stemming blood flow from a wound is the application of continuous pressure to the wound. This enables clotting factors to collect at the wound site and form a congealed blood mass to stem blood flow. However, this technique is not suitable for severe wounds and wounds with multiple bleed points. Consequently, exsanguination continues to be a major cause of death.

[0006] Bleeding can also be a problem during surgical procedures. Bleeding is sometimes addressed by suturing or stapling an incision or an internally bleeding area, as well as using gauze, sponge, or other material to exert pressure against the bleed site or absorb the blood. However, when the bleeding becomes excessive, these measures may not be sufficient to stop the blood flow as quickly as necessary.

[0007] The requirement to control bleeding in both surgical and trauma scenarios relies on different factors that are all interlinked for successful patient outcome. These factors include time to initiate the clotting cascade, final clot formation, compression required, and whether the product requires direct contact with bleed site and / or conformability.

[0008] It is generally considered that speed is the overriding factor of success through quicker clot initiation and clot formation, with compression and conformability also impacting the speed of successful treatment.

[0009] However, clot strength is also another factor which can play a critical part in the success of a patient’s outcome in both surgical and trauma scenarios. A technology which can work as fast as (or faster than) the current devices on the market, but generate a stronger clot profile, decreases the risk of rebleeding. This is true for surgical procedures, where the patient is closed up and so any rebleeding would require furthersurgery, and is also true for trauma scenarios, where movement of the patient could result in a rebleed, or the patient requires the current device to be removed to view any further complications.

[0010] Clot strength therefore minimises the risk of rebleeding in surgery and minimises the risk of rebleeding during patient evacuation. Improved clot strength also allows the medic to remove the device earlier, if required, to further assess the wound area for further treatment. However, to offer full benefit, an improvement in clot strength cannot impact the speed of clot formation.

[0011] By measuring the elastic modulus (G’) of the clot being formed, it is possible to determine the clots resistance to being deformed elastically when a stress is applied to it. This may help understand how to develop products which can increase the G’ value and minimise the risk of deformation during movement or stress, thereby causing rebleeds.

[0012] Historically, this area has been served by products containing minerals such as zeolite or kaolin marketed under the brand name quick clot. The minerals contained within these products are known to activate factor XII of the intrinsic blood clotting process expediting formation of a clot and consequently haemostasis.

[0013] Typically, these materials are delivered to the site of bleeding bound to a fibrous fabric carrier. This carrier may often be defined as any fibrous material, with no demonstratable benefit for any specific fibres being shown.

[0014] However, the inventors have surprisingly discovered that this is not the case and that the type of fibre may substantially affect the clot strength and / or one or more of the above factors highlighted for successful patient outcomes.

[0015] As such, it is an aim of the present invention to provide a device comprising a natural cellulose fibre material and at least one Factor XII clotting activator which is able to provide an improved blood clot strength and / or an improvement in one or more of the aforementioned factors highlighted for successful patient outcomes.

[0016] Moreover, it is an aim of the present invention to provide a haemostatic material with improved haemostatic properties, such as reduced clotting time; increased clot strength; and / or improved conformability.It is also an aim of the present invention to provide a haemostatic material and / or a method of producing a haemostatic material that addresses at least one disadvantage of the prior art or to provide an alternative to existing haemostatic materials and / or existing methods of producing haemostatic materials.

[0017] It is therefore an aim of embodiments of the invention to overcome or mitigate at least one problem of the prior art, whether disclosed herein or not.

[0018] Summary of the Invention

[0019] According to a first aspect of the invention there is provided a haemostatic material comprising a natural cellulose fibrous material and at least one Factor XII clotting activator.

[0020] The inventors found that the administration of a haemostatic material comprising a natural cellulose fibrous material and at least one Factor XII clotting activator was surprisingly seen to result in a much improved clot strength and reduced clotting time when compared to the administration of a synthetic or semi-synthetic fibrous material comprising a Factor XII clotting activator.

[0021] By the term “natural cellulose fibre” it is meant herein a fibre derived directly from naturally occurring cellulose sources. The fibres are obtained through mechanical, thermal, or chemical processes that do not fundamentally alter the cellulose structure or composition into a regenerated or synthetic form. The term excludes semi -synthetic fibres such as viscose, rayon, and other chemically regenerated cellulose materials.

[0022] The natural cellulose fibrous material may comprise one or more fibres selected from the group consisting of cotton, flax, hemp, jute, sisal, coir, abaca, ramie, kapok, kenaf, bamboo-derived cellulose fibres (excluding chemically regenerated forms), wood-derived cellulose fibres (excluding chemically regenerated forms), and combinations thereof.

[0023] Preferably, the fibrous material substantially consists of fibres selected from the group consisting of cotton, flax, hemp, jute, sisal, coir, abaca, ramie, kapok, kenaf, bamboo-derived cellulose fibres (excluding chemically regenerated forms), wood-derived cellulose fibres (excluding chemically regenerated forms), and combinations thereof.Most preferably, the fibrous material consists of fibres selected from the group consisting of cotton, flax, hemp, jute, sisal, coir, abaca, ramie, kapok, kenaf, bamboo-derived cellulose fibres (excluding chemically regenerated forms), wood-derived cellulose fibres (excluding chemically regenerated forms), and combinations thereof.

[0024] Preferably, the fibrous material comprises or consists of one or more fibres selected from the group consisting of cotton, hemp, jute, flax, and combinations thereof.

[0025] Beneficially, a haemostatic material comprising one or more fibres selected from the above was able to provide an improved clot strength and reduced clotting time when combined with a Factor XII clotting agent in comparison to a similar haemostatic material comprising a synthetic or semi-synthetic fibre.

[0026] Most preferably, the natural cellulose fibre is cotton.

[0027] The fibrous material may be present in an amount of at least 80wt.%, 81wt.%, 82wt.%, 83wt.%, 84wt.%, 85wt.%, 86wt.%, 87wt.%, 88wt.%, 89wt.%, 90wt.%, 91wt.%, 92wt.%, 93wt.%, 94wt.%, 95wt.%, 96wt.%, 97wt.%, 98wt.%, 99wt.%, 99.05wt.%, 99.1wt.%, 99.15wt.%, 99.2wt.%, 99.25wt.%, 99.3wt.%, 99.35wt.%, 99.4wt.%, 99.45wt.%, 99.5wt.%, 99.55wt.%, 99.6wt.%, 99.65wt.%, 99.7wt.%, or at least 99.75wt.% by weight of the haemostatic material.

[0028] The fibrous material may be present in an amount of no more than 99.9wt.%, 99.8wt.%, 99.7wt.%, 99.6wt.%, 99.5wt.%, 99.4wt.%, 99.3wt.%, 99.2wt.%, 99.1wt.%, 99wt.%, 98wt.%, 97wt.%, 96wt.%, 95wt.%, 94wt.%, 93wt.%, 92wt.%, 91wt.%, 90wt.%, 89wt.%, 88wt.%, 87wt.%, 86wt.%, or no more than 85wt.% by weight of the haemostatic material.

[0029] The fibrous material may be present in an amount of from 80 - 99.9 wt.%, 80 - 99.8 wt.%, 80 - 99.6 wt.%, 80 - 99.5 wt.%, 80 - 99.25 wt.%, 80 - 99 wt.%, 80 - 98 wt.%, 80 - 97 wt.%, 80 - 96 wt.%, 82 - 99.9 wt.%, 82 - 99.8 wt.%, 82 - 99.6 wt.%, 82 - 99.5 wt.%, 82 - 99.25 wt.%, 82 - 99 wt.%, 82 - 98 wt.%, 82 - 97 wt.%, 82 - 96 wt.%, 84 - 99.9 wt.%, 84 - 99.8 wt.%, 84 - 99.6 wt.%, 84 - 99.5 wt.%, 84 - 99.25 wt.%, 84 - 99 wt.%, 84 - 98 wt.%, 84 - 97 wt.%, 84 - 96 wt.%, 86 - 99.9 wt.%, 86 - 99.8 wt.%, 86 -99.6 wt.%, 86 - 99.5 wt.%, 86 - 99.25 wt.%, 86 - 99 wt.%, 86 - 98 wt.%, 86 - 97 wt.%, 86 - 96 wt.%, 88 - 99.9 wt.%, 88 - 99.8 wt.%, 88 - 99.6 wt.%, 88 - 99.5 wt.%, 88 - 99.25wt.%, 88 - 99 wt.%, 88 - 98 wt.%, 88 - 97 wt.%, 88 - 96 wt.%, 90 - 99.9 wt.%, 90 - 99.8 wt.%, 90 - 99.6 wt.%, 90 - 99.5 wt.%, 90 - 99.25 wt.%, 90 - 99 wt.%, 90 - 98 wt.%, 90 - 97 wt.%, 90 - 96 wt.%, 92 - 99.9 wt.%, 92 - 99.8 wt.%, 92 - 99.6 wt.%, 92 - 99.5 wt.%, 92 - 99.25 wt.%, 92 - 99 wt.%, 92 - 98 wt.%, 92 - 97 wt.%, 92 - 96 wt.%, 94 - 99.9 wt.%, 94 - 99.8 wt.%, 94 - 99.6 wt.%, 94 - 99.5 wt.%, 94 - 99.25 wt.%, 94 - 99 wt.%, 94 - 98 wt.%, 94 - 97 wt.%, 94 - 96 wt.%, 95 - 99.9 wt.%, 95 - 99.8 wt.%, 95 - 99.6 wt.%, 95 - 99.5 wt.%, 95 - 99.25 wt.%, 95 - 99 wt.%, 95 - 98 wt.%, 95 - 97 wt.%, 95 -96 wt.% by weight of the haemostatic material.

[0030] Most preferably, the fibrous material may be present in an amount of from 80 -99.9 wt.%, 85 - 99.9 wt.%, 90 - 99.9 wt.%, 95 - 99.9 wt.%, 96 - 99.9 wt.%, 97 - 99.9 wt.%, 98 - 99.9 wt.%, or from 99 - 99.9 wt.% by weight of the haemostatic material.

[0031] In one embodiment, the fibrous material may comprise a blend of fibres.

[0032] In such an embodiment, the blend may comprise at least one natural cellulose fibre and at least one other fibre.

[0033] The at least one other fibre may be a synthetic or semi-synthetic fibre.

[0034] The synthetic fibre may be selected from the group consisting of polypropylene, polyethylene, Nylon, and one or more combinations thereof.

[0035] The semi synthetic fibre may be selected from the group consisting of chitosan, chitosan derivatives, viscose, rayon, lyocell, acetate and combination thereof.

[0036] In embodiments, wherein the fibrous material may comprise a blend of fibres, the natural cellulose fibres may be present in an amount of at least 50wt.%, 51 wt.%, 52wt.%, 53wt.%, 54wt.%, 55wt.%, 56wt.%, 57wt.%, 58wt.%, 59wt.%, 60wt.%, 61 wt.%, 62wt.%, 63 wt.%, 64wt.%, 65wt.%, 66wt.%, 67wt.%, 68wt.%, 69wt.%, 70wt.%, 71 wt.%, 72wt.%, 73 wt.%, 74wt.%, 75wt.%, 76wt.%, 77wt.%, 78wt.%, 79wt.%, 80wt.%, 81 wt.%, 82wt.%, 83 wt.%, 84wt.%, 85wt.%, 86wt.%, 87wt.%, 88wt.%, 89wt.%, 90wt.%, 91 wt.%, 92wt.%, 93 wt.%, 94wt.%, 95wt.%, 96wt.%, 97wt.%, 98wt.%, or at least 99wt.% by weight of the fibrous material.

[0037] The natural cellulose fibres may be present in an amount of no more than 99wt.%, 98wt.%, 97wt.%, 96wt.%, 95wt.%, 94wt.%, 93 wt.%, 92wt.%, 91 wt.%,90wt.%, 89wt.%, 88wt.%, 87wt.%, 86wt.%, 85wt.%, 84wt.%, 83wt.%, 82wt.%, 81wt.%, 80wt.%, 79wt.%, 78wt.%, 77wt.%, 76wt.%, 75wt.%, 74wt.%, 73wt.%, 72wt.%, 71wt.%, 70wt.%, 69wt.%, 68wt.%, 67wt.%, 66wt.%, 65wt.%, 64wt.%, 63 wt.%, 62wt.%, 61 wt.%, or no more than 60wt.% by weight of the fibrous material.

[0038] The natural cellulose fibre may be present in an amount of from 50 - 99.9 wt.%, 50 - 99 wt.%, 50 - 98 wt.%, 50 - 97 wt.%, 50 - 96 wt.%, 50 - 95 wt.%, 50 - 94 wt.%, 50 - 92 wt.%, 50 - 90 wt.%, 55 - 99.9 wt.%, 55 - 99 wt.%, 55 - 98 wt.%, 55 - 97 wt.%, 55 - 96 wt.%, 55 - 95 wt.%, 55 - 94 wt.%, 55 - 92 wt.%, 55 - 90 wt.%, 60 - 99.9 wt.%, 60 - 99 wt.%, 60 - 98 wt.%, 60 - 97 wt.%, 60 - 96 wt.%, 60 - 95 wt.%, 60 - 94 wt.%, 60 -92 wt.%, 60 - 90 wt.%, 65 - 99.9 wt.%, 65 - 99 wt.%, 65 - 98 wt.%, 65 - 97 wt.%, 65 -96 wt.%, 65 - 95 wt.%, 65 - 94 wt.%, 65 - 92 wt.%, 65 - 90 wt.%, 70 - 99.9 wt.%, 70 -99 wt.%, 70 - 98 wt.%, 70 - 97 wt.%, 70 - 96 wt.%, 70 - 95 wt.%, 70 - 94 wt.%, 70 - 92 wt.%, 70 - 90 wt.%, 75 - 99.9 wt.%, 75 - 99 wt.%, 75 - 98 wt.%, 75 - 97 wt.%, 75 - 96 wt.%, 75 - 95 wt.%, 75 - 94 wt.%, 75 - 92 wt.%, 75 - 90 wt.%, 80 - 99.9 wt.%, 80 - 99 wt.%, 80 - 98 wt.%, 80 - 97 wt.%, 80 - 96 wt.%, 80 - 95 wt.%, 80 - 94 wt.%, 80 - 92 wt.%, or from 80 - 90 wt.% by weight of the fibrous material.

[0039] The fibrous material may be woven or non-woven.

[0040] Preferably, the fibrous material is non-woven.

[0041] In such embodiments, the fibrous material may be formed into a cotton wool like material.

[0042] The fibrous material may be manufactured using any suitable manufacturing technique known in the art. The cotton wool like material may be formed into sheets, pads, balls and / or buds for use.

[0043] In some embodiments, the fibrous material may be manufactured using weaving, knitting, needle punching, spunbonding and / or meltblowing.

[0044] In one embodiment, the fibrous material can be formed into a textile fabric or a pad for use. In such embodiments, the fibrous material may be woven and / or nonwoven.

[0045] In such embodiments, the fibrous material may be woven or knitted into a fabric.The fabric may be used to create any suitable textile material. Suitable textile materials may be selected from the group consisting of bags, wound dressings, clothing, bandages, cloths, towels, and one or more combinations thereof.

[0046] The fibrous material may be of any desired diameter or length.

[0047] In one embodiment, the length of the fibres can be up to about 100 mm, and is typically from about 20-75 mm, more typically from about 32-51 mm.

[0048] The Factor XII clotting activator may be any substance that directly facilitates the activation of Factor XII into Factor Xlla, thereby initiating the intrinsic pathway of blood coagulation.

[0049] In one embodiment, the Factor XII clotting activator may be selected from the group consisting of kaolin, silica, glass particles (such as volcanic glasses including obsidian, pumice and / or perlite), zeolites, titanium dioxide, polyphosphates, collagen, chitosan, derivatives of chitosan, chitin, derivatives of chitin, oxidized cellulose, heparan sulphate, haemostatic polyphenol (such as ellagic acid), ceramics, and combinations thereof.

[0050] The chitin derivative may be any chemically related non-gelling compound derived from chitin following one or more chemical reactions or modifications. The one or more chemical reactions or modifications may involve substitution of one or more of the amino or hydroxyl protons in chitin or partial deacetylation of chitin. For example, a chitin derivative may include a partially deacetylated chitin, which may have different percentages of deacetylation, as desired. Typically, the partially deacetylated chitin suitable for use in the present invention has a deacetylation degree above about 50%, more typically above about 75%, and most typically above about 85%. Also included within the term ‘chitin derivatives’ are reaction products of chitin with other compounds. Such reaction products include, but are not limited to, carboxymethyl chitin, hydroxyl butyl chitin, N-acyl chitin, O-acyl chitin, N-alkyl chitin, O-alkyl chitin, N-alkylidene chitin, O-sulfonyl chitin, sulphated chitin, phosphorylated chitin, nitrated chitin, alkalichitin, or metal chelates with chitin, etc.

[0051] The chitosan derivative may be any chemically related compound that can be obtained from chitosan by one or more chemical reactions and / or structuralmodifications. The one or more chemical reactions or modifications may involve substitution of one or more of the amino or hydroxyl protons in chitosan. Also included within the terms ‘chitosan or chitin derivatives’ are reaction products of chitosan or chitin with other compounds. Such reaction products include, but are not limited to, chitosan salts (such as chitosan acetate, chitosan lactate, chitosan succinate, chitosan malate, chitosan sulphate or chitosan acrylate), carboxymethyl chitosan, hydroxyl butyl chitin, N-acyl chitosan (such as N acetyl chitosan), O-acyl chitosan, N-alkyl chitosan (N-trimethyl chitosan), O-alkyl chitosan (such as hydroxypropyl chitosan), N-alkylidene chitosan, O-sulfonyl chitosan, sulphated chitosan (such as chitosan sulphate), phosphorylated chitosan, hydroxyl butyl chitosan, quaternized chitosan, nitrated chitosan, chitosan-PEG (polyethylene glycol) conjugates, alkalichitin, alkalichitosan, or metal chelates with chitosan, etc.

[0052] Preferably, the Factor XII clotting activator may be selected from the group consisting of kaolin, ellagic acid, ceramics, silica particulates, volcanic glasses (such as perlite) and combinations thereof.

[0053] The Factor XII clotting activator may be in any suitable form for application to a fibrous material. For example, the Factor XII clotting activator may be in a form selected from the group consisting of a dry powder, solution, foam, fibre, gel and combinations thereof.

[0054] Preferably, the Factor XII clotting activator is in solid form=

[0055] The Factor XII clotting activator may be present in an amount of at least 0.1wt.%, 0.2wt.%, 0.3wt.%, 0.4wt.%, 0.5wt.%, 0.6wt.%, 0.7wt.%, 0.8wt.%, 0.9wt.%, lwt.%, 2wt.%, 3wt.%, 4wt.%, 5wt.%, 6wt.%, 7wt.%, 8wt.%, 9wt.%, 10wt.%, llwt.%, 12wt.%, 13wt.%, 14wt.%, 15wt.%, 16wt.%, 17wt.%, 18wt.%, 19wt.%, or at least 20wt.% by weight of the haemostatic material.

[0056] The Factor XII clotting activator may be present in an amount of no more than 50wt.%, 45wt%, 40wt.%, 35wt.%, 30wt.%, 25wt%, 20wt.%, 15wt.%, 10wt.%, 9wt.%, 8wt.%, 7wt.%, 6wt.%, 5wt.%, 4wt.%, 3wt.%, 2wt.%, lwt.%, 0.9wt.%, 0.8wt.%, 0.7wt.%, 0.6wt.%, 0.5wt.%, 0.4wt.%, 0.3wt.%, 0.2wt.%, or no more than 0.1wt.%by weight of the haemostatic material.The Factor XII clotting activator may be present in an amount of from 0.1 - 20 wt.%, 0.1 - 15 wt.%, 0.1 - 10 wt.%, 0.1 - 5 wt.%, 0.1 - 1 wt.%, 0.1 - 0.75 wt.%, 0.1 -0.5 wt.%, 0.1 - 0.4 wt.%, 0.2 - 20 wt.%, 0.2 - 15 wt.%, 0.2 - 10 wt.%, 0.2 - 5 wt.%, 0.2 - 1 wt.%, 0.2 - 0.75 wt.%, 0.2 - 0.5 wt.%, 0.2 - 0.4 wt.%, 0.3 - 20 wt.%, 0.3 - 15 wt.%, 0.3 - 10 wt.%, 0.3 - 5 wt.%, 0.3 - 1 wt.%, 0.3 - 0.75 wt.%, 0.3 - 0.5 wt.%, 0.3 - 0.4 wt.%, 0.35 - 20 wt.%, 0.35 - 15 wt.%, 0.35 - 10 wt.%, 0.35 - 5 wt.%, 0.35 - 1 wt.%, 0.35 -0.75 wt.%, 0.35 - 0.5 wt.%, or from 0.35 - 0.4 wt.% by weight of the haemostatic material.

[0057] Preferably, the Factor XII clotting activator may be present in an amount of from 0.1 - 10 wt.%, 0.1 - 5 wt.%, 0.1 - 1 wt.%, 0.1 - 0.9 wt.%, 0.1 - 0.5 wt.%, 0.2 - 0.5 wt.%, 0.3 - 0.5 wt.%, 0.3 - 0.4 wt.% by weight of the haemostatic material.

[0058] The Factor XII clotting activator may be applied to the fibrous material in any suitable way. For example, the Factor XII clotting activator may be bonded to the fibrous material using an adhesive; applied to the fibrous material as a solution comprising the clotting activator; coated onto the fibrous material as a solution comprising the clotting activator and drying the solution; or by heat bonding. The additional component may also be incorporated into the fibrous material during the processing of the fibrous material.

[0059] In one embodiment, the Factor XII clotting activator may interact and / or be attached to the fibrous material.

[0060] The interaction and / or attachment may be a physical and / or chemical interaction and / or attachment.

[0061] In one embodiment, the interaction and / or attachment may be selected from the group consisting of covalent bond formation, crosslinking, adsorption, complex formation, hydrogen bonding, hydrophobic interactions, crosslinking, encapsulation, coating, and one or more combinations thereof.

[0062] The interaction may be reversible and / or irreversible.

[0063] In one embodiment, the irreversible interaction may be in the form of covalent bond formation.In such an embodiment, the Factor XII clotting activator may form one or more covalent bonds with one or more functional groups present within the fibrous material. These functional groups may be a hydroxyl, carboxyl, and / or amino group.

[0064] In one embodiment, the interaction is reversible.

[0065] In such embodiment, the Factor XII clotting activator may be adsorbed onto and / or into the fibrous material or form one or more crosslinks with the fibrous material.

[0066] In one particularly preferred embodiment, the Factor XII clotting activator is ellagic acid.

[0067] In such an embodiment, the ellagic acid is irreversibly bound to the fibrous material.

[0068] The irreversible interaction of the ellagic acid with the fibrous material ensures that the ellagic acid is not substantially shed from the fibrous material such that the ellagic acid may substantially enter the bloodstream. Beneficially, this ensures a high concentration of ellagic acid at the wound site thereby increasing the haemostatic abilities of the ellagic acid.

[0069] Preferably, the ellagic acid is adsorbed onto the surface of the fibrous material. In such embodiments, the ellagic acid may form one or more hydrogen bonds and / or hydrophobic interactions with the fibrous material.

[0070] In such an embodiment wherein the clotting activator is ellagic acid, the haemostatic material may also comprise a metal ion.

[0071] The metal ion may be any metal ion suitable for application to a wound.

[0072] In one embodiment, the metal ion may be selected from the group consisting of alkaline earth metals, transition metals, actinides, lanthanides, post transition metals, and one or more combinations thereof.

[0073] Preferably, the metal ion is selected from the group consisting of a silver metal ion (Ag+), divalent (2+) metal ion, trivalent (3+) metal ion, and combinations thereof.

[0074] In such embodiments, the metal ion may be selected from the group consisting of silver (Ag+), calcium (Ca2+), magnesium (Mg2+), copper (Cu2+), zinc (Zn2+), iron (Fe2+), manganese (Mn2+), cobalt (Co2+), nickel (Ni2+), barium (Ba2+), and lead (Pb2+),iron (Fe3+), aluminium (Al3+), chromium (Cr3+), manganese (Mn3+), cobalt (Co3+), gold (Au3+), gallium (Ga3+), scandium (Sc3+), and rhodium (Rh3+), and one or more combinations thereof.

[0075] Most preferably, the metal ion is selected from the group consisting of copper (Cu2+), zinc (Zn2+), iron (Fe2+), iron (Fe3+), and one or more combinations thereof.

[0076] Preferably, the metal ion is a non-toxic metal ion.

[0077] In a preferred embodiment, the metal ion is provided from a salt.

[0078] In such embodiments, the haemostatic material comprises a metal ion salt. The metal ion salt may be a salt of one or more of the metal ions described herein above.

[0079] Preferably, the metal ion salt is an aqueous soluble metal ion salt.

[0080] In such embodiments, the metal ion salt may be selected from the group consisting of silver nitrate (AgNCh), silver chloride (AgCl), calcium chloride (CaCb), calcium sulphate (CaSCh), magnesium sulphate (MgSO4), magnesium chloride (MgCb), copper(II) sulphate (CuSCh), copper(II) chloride (CuCb), zinc sulphate (ZnSCb), zinc oxide (ZnO), iron(II) sulphate (FeSCb), iron(II) chloride (FeCh), iron(III) chloride (FeCh), aluminium chloride (A1CE), aluminium sulphate (Ab(SO4)s), chromium(III) chloride (CrCh), chromium(III) sulphate (C fSChh), cobalt(II) sulphate (CoSO4), and nickel chloride (NiCb).

[0081] The metal ion salt may be applied to the fibrous material in any suitable way known in the art. Examples of such methods include coating of the metal ion salt using methods such as dipping, spraying, or brushing; soaking of the fibrous material with a solution of the metal ion salt; chemical grafting of the metal salt to the surface of the fibrous material; and / or electrochemical deposition of the metal ion salt.

[0082] Beneficially, the inventors found that the presence of a metal ion in the fibrous material results in complexation with ellagic acid, thereby creating a multiway complex with the fibrous material and ellagic acid. This enhances the association of the ellagic acid with the fibrous material.

[0083] The metal ion may be present in an amount of at least 0.005wt.%, 0.01wt.%, 0.015wt.%, 0.02wt.%, 0.025wt.%, 0.03wt.%, 0.035wt.%, 0.04wt.%, 0.045wt.%,0.05wt.%, 0.055wt.%, 0.06wt.%, 0.065wt.%, 0.07wt.%, 0.075wt.%, or at least 0.08wt.% by weight of the fibrous material.

[0084] The metal ion may be present in an amount of no more than 0.2wt.%, 0.19wt.%, 0.18wt.%, 0.17wt.%, 0.16wt.%, 0.15wt.%, 0.14wt.%, 0.13wt.%, 0.12wt.%, 0.11wt.%, 0.1wt.%, 0.09wt.%, 0.08wt.%,by weight of the fibrous material.

[0085] The metal ion may be present in an amount of from 0.01 - 0.2 wt.%, 0.01 - 0.18 wt.%, 0.01 - 0.16 wt.%, 0.01 - 0.14 wt.%, 0.01 - 0.12 wt.%, 0.01 - 0.1 wt.%, 0.01 - 0.08 wt.%, 0.02 - 0.2 wt.%, 0.02 - 0.18 wt.%, 0.02 - 0.16 wt.%, 0.02 - 0.14 wt.%, 0.02 - 0.12 wt.%, 0.02 - 0.1 wt.%, 0.02 - 0.08 wt.%, 0.03 - 0.2 wt.%, 0.03 - 0.18 wt.%, 0.03 - 0.16 wt.%, 0.03 - 0.14 wt.%, 0.03 - 0.12 wt.%, 0.03 - 0.1 wt.%, 0.03 - 0.08 wt.%, 0.04 - 0.2 wt.%, 0.04 - 0.18 wt.%, 0.04 - 0.16 wt.%, 0.04 - 0.14 wt.%, 0.04 - 0.12 wt.%, 0.04 - 0.1 wt.%, 0.04 - 0.08 wt.%, 0.05 - 0.2 wt.%, 0.05 - 0.18 wt.%, 0.05 - 0.16 wt.%, 0.05 - 0.14 wt.%, 0.05 - 0.12 wt.%, 0.05 - 0.1 wt.%, 0.05 - 0.08 wt.%, 0.06 - 0.2 wt.%, 0.06 - 0.18 wt.%, 0.06 - 0.16 wt.%, 0.06 - 0.14 wt.%, 0.06 - 0.12 wt.%, 0.06 - 0.1 wt.%, 0.06 - 0.08 wt.%, 0.07 - 0.2 wt.%, 0.07 - 0.18 wt.%, 0.07 - 0.16 wt.%, 0.07 - 0.14 wt.%, 0.07 - 0.12 wt.%, 0.07 - 0.1 wt.%, 0.07 - 0.08 wt.% by weight of the fibrous material.

[0086] The haemostatic material may comprise one or more additional ingredients. The additional ingredient may be any ingredient commonly used in the medical field.

[0087] Such additional components may include, but are not limited to pharmaceutical agents, medical surfactants, wetting agents such as surfactants, growth factors, cytokines, agents which absorb agents which delay healing such as MMP’s (matrix metalloproteinases) and elastase, and / or another wound dressing component, such as calcium, vitamin K, fibrinogen, thrombin, factor VII, factor VIII, clays such as kaolin, oxidised regenerated cellulose, gelatin, or collagen, antifibrinolytic agents etc.

[0088] By “antifibrinolytic agent”, it is meant a natural or synthetic substance which inhibits fibrinolysis. Fibrinolysis is a process that prevents blood clots from growing. This process has two types: primary fibrinolysis and secondary fibrinolysis. The primary type is a normal body process, whereas secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other cause.Therefore, antifibrinolytic agents prevents the breakdown of blood clots, which should be stronger and last longer than if the antifibrinolytic agent was not present.

[0089] The antifibrinolytic agent may comprise a plasminogen activator inhibitor, such as a serine protease inhibitor. Non-limiting examples of such serine protease inhibitors include plasminogen activator inhibitor-1 (PAI-1), which is also known as endothelial plasminogen activator inhibitor or serpin El, or aprotinin. PAI-1 is a serine protease inhibitor that functions as the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and hence fibrinolysis. Aprotinin is a competitive inhibitor of several serine proteases, specifically trypsin, chymotrypsin and plasmin at a concentration of about 125,000 lU / ml, and kallikrein at 300,000 lU / ml. Its action on kallikrein leads to the inhibition of the formation of factor Xlla. As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis.

[0090] The antifibrinolytic agent may comprise a glycoprotein, such as fibrinogen; or tranexamic acid.

[0091] The antifibrinolytic agent may comprise a C2-C12 aminocarboxylic acid, a C4-C8 aminocarboxylic acid, or a C5-C7 aminocarboxylic acid, such as a C6 aminocarboxylic acid, e.g. aminocaproic acid or epsilon-aminocaproic acid.

[0092] The antifibrinolytic agent may comprise an aminobenzoic acid, such as aminomethylbenzoic acid.

[0093] Any one or more of these antifibrinolytic agents, or derivatives thereof, may be used either alone or in combination.

[0094] The term ‘derivative’ in relation to the antifibrinolytic agents is used herein to refer to any compounds which are directly derived or derivable from any of the abovelisted compounds and which also exhibit antifibrinolytic behaviour.

[0095] The haemostat material may further comprise a medical surfactant. By "medical surfactant" it is meant any surfactant that is pharmaceutically acceptable for contact with or administration to a human or animal body and does not cause any significant detrimental effects to the human or animal body. Exemplary medical surfactants for use in the present invention include any of the following either alone or in combination:block copolymers based on ethylene oxide and propylene oxide (e.g. BASF Pluronics®), glycerol, polyethylene glycol, propylene glycol, fatty acids such as lauric acid, oleic acid, other fatty acids and fatty acid salts, silicone-based surfactants and emulsifiers. Typically, the medical surfactants include lauric acid and oleic acid.

[0096] The additional component may be present in an amount of at least 0.1wt.%, 0.2wt.%, 0.3wt.%, 0.4wt.%, 0.5wt.%, 0.6wt.%, 0.7wt.%, 0.8wt.%, 0.9wt.%, lwt.%, 1.5wt.%, 2wt%, 2.5wt.%, 3wt.%, 3.5wt.%, 4wt.%, 4.5wt.%, 5wt.%, 5.5wt.%, 6wt.%, 6.5wt.%, 7wt.%, 7.5wt.%, 8wt.%, 8.5wt.%, 9wt.%, 9.5wt.%, or at least 10wt.% wt.% by weight of the haemostatic material.

[0097] The additional component may be present in an amount of no more than 10wt.%, 9wt.%, 8wt.%, 7wt.%, 6wt.%, 5wt.%, 4wt.%, 3wt.%, 2wt.%, lwt.%, 0.9wt.%, 0.8wt.%, 0.7wt.%, 0.6wt.%, 0.5wt.%, 0.4wt.%, 0.3wt.%, 0.2wt.%, or no more than 0. lwt.%by weight of the haemostatic material.

[0098] The additional component may be present in an amount of from 0.2 - 10 wt.%, 0.2 - 9 wt.%, 0.2 - 8 wt.%, 0.2 - 7 wt.%, 0.2 - 6 wt.%, 0.2 - 5 wt.%, 0.2 - 4 wt.%, 0.2 -3 wt.%, 0.2 - 2 wt.%, 0.3 - 10 wt.%, 0.3 - 9 wt.%, 0.3 - 8 wt.%, 0.3 - 7 wt.%, 0.3 - 6 wt.%, 0.3 - 5 wt.%, 0.3 - 4 wt.%, 0.3 - 3 wt.%, 0.3 - 2 wt.%, 0.4 - 10 wt.%, 0.4 - 9 wt.%, 0.4 - 8 wt.%, 0.4 - 7 wt.%, 0.4 - 6 wt.%, 0.4 - 5 wt.%, 0.4 - 4 wt.%, 0.4 - 3 wt.%, 0.4 -2 wt.%, 0.5 - 10 wt.%, 0.5 - 9 wt.%, 0.5 - 8 wt.%, 0.5 - 7 wt.%, 0.5 - 6 wt.%, 0.5 - 5 wt.%, 0.5 - 4 wt.%, 0.5 - 3 wt.%, 0.5 - 2 wt.%, 0.6 - 10 wt.%, 0.6 - 9 wt.%, 0.6 - 8 wt.%, 0.6 - 7 wt.%, 0.6 - 6 wt.%, 0.6 - 5 wt.%, 0.6 - 4 wt.%, 0.6 - 3 wt.%, 0.6 - 2 wt.%, 0.7 -10 wt.%, 0.7 - 9 wt.%, 0.7 - 8 wt.%, 0.7 - 7 wt.%, 0.7 - 6 wt.%, 0.7 - 5 wt.%, 0.7 - 4 wt.%, 0.7 - 3 wt.%, 0.7 - 2 wt.%, 0.8 - 10 wt.%, 0.8 - 9 wt.%, 0.8 - 8 wt.%, 0.8 - 7 wt.%, 0.8 - 6 wt.%, 0.8 - 5 wt.%, 0.8 - 4 wt.%, 0.8 - 3 wt.%, 0.8 - 2 wt.%, 0.9 - 10 wt.%, 0.9 - 9 wt.%, 0.9 - 8 wt.%, 0.9 - 7 wt.%, 0.9 - 6 wt.%, 0.9 - 5 wt.%, 0.9 - 4 wt.%, 0.9 - 3 wt.%, 0.9 - 2 wt.%, 1 - 10 wt.%, 1 - 9 wt.%, 1 - 8 wt.%, 1 - 7 wt.%, 1 - 6 wt.%, 1 - 5 wt.%, 1 - 4 wt.%, 1 - 3 wt.%, or from 1 - 2 wt.% by weight of the haemostatic material.

[0099] The one or more additional components may be in any suitable form for application to a fibrous material. For example, the additional component may be in the form of a dry powder, solution, foam, fibre or gel.The one or more additional components may be applied to the haemostatic material in any suitable way.

[0100] The additional component may be applied to the fibrous material by a variety of methods. These include bonding the additional component to the fibrous material using an adhesive; applying a solution containing the additional component to the fibrous material, coating the fibrous material and drying the solution; or by heat bonding. The additional component may also be incorporated into the fibrous material during the processing of the fibrous material.

[0101] The fibrous material may be provided in a sterile or non-sterile form. Where the material is provided in a sterile form, sterilisation may be carried out using any of the conventionally known methods, such as gamma irradiation, electron beam treatment, heat treatment, ethylene oxide (EtO) sterilization etc. A material in a non-sterile form may be provided in combination with one or more preservatives or antimicrobial agent, such as silver and its salts.

[0102] In a second aspect of the present invention, there is provided an article comprising a haemostatic material of the first aspect of the invention.

[0103] The article may be any material capable of comprising a fibrous material. For example, any suitable textile material. Suitable textile materials may be selected from the group consisting of bags, swabs, lap-pads (laparotomy sponge), gauze, clothing, wound dressings, bandages, cloths, towels, and one or more combinations thereof.

[0104] In a preferred embodiment, the article may be a wound dressing, swab, gauze or lap-pad (laparotomy sponge).

[0105] In one preferred embodiment, the article may be a wound dressing.

[0106] In such an embodiment, the one or more layers of the wound dressing may comprise or consist of the haemostatic material of the first aspect of the invention.

[0107] Preferably, the haemostatic material of the first aspect of the invention is a wound contact layer of the wound dressing.In some embodiments, the wound dressing is substantially the shape of a circle, a regular polygon, an irregular polygon, a geometric shape, or an irregular (organic shape). The shape of the wound dressing depends on its intended use and to which anatomical area it is to be applied.

[0108] In addition to the haemostatic material of the present invention the wound dressing may comprise one or more further materials.

[0109] One or more of the further materials may be an absorbent material. Absorbent material is used herein to refer to a physiologically acceptable material that is capable of absorbing liquid, such as wound exudate, and which is capable of absorbing liquid to greater than about 500% by weight of the absorbent material, and with a liquid retention of greater than about 40%.

[0110] The absorbent material may comprise a fibrous, foam, non-woven or woven material.

[0111] The absorbent material may be in the form of fibres. Typically, the absorbent material may be in the form of non-woven fibres.

[0112] The absorbent material may be a superabsorbent material.

[0113] The superabsorbent material may be selected from polymeric materials such as poly(vinyl alcohol) (PVA), poly(ethylene oxide) (PEO) and poly(acrylic acid).

[0114] The superabsorbent material may be chemically modified. For example, the superabsorbent material may be a polymeric material obtained by graft polymerisation of acrylic acid onto a chain of carboxymethyl cellulose.

[0115] The superabsorbent material may comprise a chemically modified material selected from starch, cellulose and polymeric materials such as poly(vinyl alcohol) (PVA), poly(ethylene oxide) (PEO), and poly(acrylic acid).

[0116] The poly(acrylic acid) may be a partially neutralised, lightly cross-linked poly(acrylic acid).

[0117] The superabsorbent material may be in the form of fibres. Typically, the superabsorbent material is in the form of non-woven fibres.The superabsorbent material may comprise or consist of an air laid nonwoven fibre. By air laid nonwoven fibre, it is meant a continuous web formed by a mixture of short fibres and / or 100% pulped fibres. The absorbent material may comprise a chemical pulp made from long fibre softwoods. Preferably, the absorbent material may be a fluff pulp. By the term “fluff pulp”, it is meant a chemical pulp made of cellulose fibres obtained from long softwoods.

[0118] In preferred embodiments, the absorbent materials may comprise a superabsorbent material and fluff pulp. Preferably, the absorbent material of the present invention comprises a poly(acrylic acid) and fluff pulp fibre blend.

[0119] In some embodiments, the absorbent material may consist of or comprise a gelling or semi -gelling material.

[0120] The gelling or semi-gelling material may be in any available form, such as for example, fibres, granules, powder, flakes, sheet, foam, freeze dried foam, compressed foam, film, perforated film, beads, and combinations of two or more of the aforesaid.

[0121] The gelling or semi-gelling material may be selected from carboxymethylcellulose, alginate, chitosan salt or a chitosan salt derivative.

[0122] Typically, the gelling or semi gelling material is in the form of fibres. The fibres can be of any desired diameter or length and can be formed into a textile fabric or a pad for use. The fibres may be woven or non-woven. Preferably, the fibres are non-woven.

[0123] The wound dressing may be a single layer. The wound dressing may comprise more than one layer. The wound dressing may comprise two, three, four, five, six, seven, eight, nine, ten, or more than ten layers. The wound dressing may comprise a plurality of layers.

[0124] In such an embodiment, at least one of the layers comprises a haemostatic material according to a first aspect of the invention.

[0125] In some embodiments at least one of the wound dressing may be fenestrated. The wound dressing may comprise decoupled layers.

[0126] Alternatively, the wound dressing may have a laminate structure.The layers of the wound dressing may be bonded together using an adhesive between the layers. The surfaces of the wound dressing which are to be bonded may be fully or partially coated with an adhesive.

[0127] The adhesive may be any suitable physiologically acceptable adhesive known in the art. The adhesive may be any suitable skin-contact adhesive known in the art.

[0128] The adhesive may be a silicone adhesive (such as a polydimethylsiloxane adhesive), an acrylic adhesive, a polyurethane adhesive, a hydrogel adhesive, or any combinations thereof.

[0129] The adhesive may be in the form of a powder, a liquid, a web or a net. The web may be an acrylic web.

[0130] The adhesive may comprise a meltable adhesive and / or a pressure sensitive adhesive, or the like. The meltable adhesive may be a heat -bonding adhesive or a heat-activated adhesive. The pressure sensitive adhesive may be acrylic based.

[0131] The adhesive may be a thermal adhesive. The adhesive may comprise any suitable thermal adhesive known in the art. For example, the thermal adhesive may be a thermoplastic adhesive, such as polycaprolactone.

[0132] The adhesive may be a powder. The powder may be scattered onto either or both surfaces of the wound dressing to be attached and then passed through a heat tunnel to laminate the layers of the wound dressing.

[0133] In a third aspect of the present invention, there is provided a method of manufacturing a haemostatic material according to the first aspect of the present invention comprising the steps of contacting a natural cellulose fibrous material with at least one Factor XII clotting activator.

[0134] The fibrous material and Factor XII clotting activator may be as described in the first aspect of the invention.

[0135] In one embodiment, the step of contacting the Factor XII clotting activator may comprise applying the Factor XII clotting activator to the fibrous material.

[0136] In one embodiment, the method may comprise bonding the Factor XII clotting activator to the fibrous material using an adhesive.Additionally or alternatively, the Factor XII clotting activator may be applied to the fibrous material by heat bonding.

[0137] In a further embodiment, the method may comprise applying a solution comprising the Factor XII clotting activator to the fibrous material.

[0138] In such embodiment, the step may comprise coating the fibrous material by applying a solution comprising the Factor XII clotting activator to the fibrous material and drying the solution.

[0139] In some embodiment, the Factor XII clotting activator be incorporated into the fibrous material during the processing of the fibrous material.

[0140] In some embodiments, the method may further comprise contacting the fibrous material with a solution comprising a metal ion. The metal ion may be as described in the first aspect of the invention.

[0141] The step of contacting the fibrous material with a solution comprising a metal ion may be performed before or after the step of contacting the fibrous material with the Factor XII clotting activator.

[0142] Preferably, the step of contacting the fibrous material with a solution comprising a metal ion is performed before the step of contacting the fibrous material with the Factor XII clotting activator.

[0143] In an alternative embodiment, the step of contacting a fibrous material with a Factor XII clotting activator may comprise reacting the Factor XII clotting activator with the fibrous material in a transesterification or esterification reaction.

[0144] In such an embodiment, the method may further comprise the addition of a catalyst.

[0145] The catalyst may be any catalyst known in the art suitable for use in a transesterification or esterification reaction.

[0146] In one embodiment, the catalyst may be selected from the group consisting of a strong base, strong acid, lewis acid and one or more combinations thereof.By the term “strong base” it is meant herein basic substance that is able to dissociate completely in an aqueous solution. For example, the strong acid may have a dissociation constant (kb)of greater than 1.

[0147] The strong base may be selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium methoxide (NaOCHs), sodium ethoxide (NaOC^Hs), and one or more combinations thereof.

[0148] By the term “strong acid” it is meant herein an acidic substance that is able to dissociate completely in an aqueous solution. For example, the strong acid may have a dissociation constant (Ka) of greater than 1.

[0149] The strong acid may be selected from the group consisting of sulfuric acid (H2SO4), hydrochloric acid (HC1), nitric acid (HNO3), phosphoric acid (H3PO4), p-toluenesulfonic acid (TsOH), trifluoroacetic acid (TFA), and one or more combinations thereof.

[0150] The term “Lewis acid” is used herein in accordance with its commonly accepted meaning in the chemical field, i.e. a molecule or ion which combines with a second molecule or ion by forming a covalent bond with two electrons from the latter.

[0151] The Lewis acid may be selected from the group consisting of boron trifluoride (BF3), aluminium chloride (A1CL), iron (III) chloride (FeCL), titanium tetrachloride (TiCL), zinc chloride (ZnCL), and one or more combinations thereof.

[0152] In either embodiment, the method may further comprise a step of washing and / or rinsing the fibrous material.

[0153] The washing and / or rinsing step may be performed after the step of contacting the fibrous material with the Factor XII clotting activator.

[0154] Beneficially, washing ensures that all Factor XII clotting activator and / or metal ions not associated with the fibrous material are removed from the surface of the material. This reduces the shed of any particulates when the material is applied to a physiological target site, such as a wound.

[0155] The step of washing the fibrous material may comprise contacting the fibrous material with water. Preferably, distilled water.The washing step is configured to remove any unreacted or excess substances left over from the step of contacting the fibrous material with the Factor XII clotting activator.

[0156] The method may further comprise a step of drying the fibrous material.

[0157] The step of drying the fibrous material may be carried out after one or more the preceding steps described herein. Preferably, the step of drying the fibrous material is be carried out after all of the preceding steps described herein

[0158] In some embodiments, the method may further comprise the step of contacting the fibrous material with an additional ingredient. The additional material may be as described in the first aspect of the invention.

[0159] In a fourth aspect of the invention there is provided a method of manufacturing an article according to the second aspect of the present invention.

[0160] The method of manufacturing an article may comprise the steps of forming the haemostatic material into an article according to the second aspect of the invention.

[0161] The method of forming the haemostatic material into the article may comprise the step of attaching the haemostatic material to a further material and / or second haemostatic material according to the first aspect of the invention.

[0162] The haemostatic material may be adhered to the further material and / or second haemostatic material using an adhesive as described herein.

[0163] Additionally or alternatively, the haemostatic material may be attached to a further material and / or second haemostatic material through any method of textile bonding, such as sewing.

[0164] The further material may comprise a woven material, or a non-woven material. The further material may be any of the materials described in relation to the second aspect of the invention.

[0165] The method may further comprise a step of cutting and shaping the article as desired or as appropriate.1

[0166] According to a fifth aspect of the present invention, there is provided a method of absorbing fluid (e.g. wound exudate) discharged from a physiological target site of a human or animal body, or of stemming a flow of a fluid discharged from a physiological target site of a human or animal body, comprising applying to the physiological target site a haemostatic material according to the first aspect of the invention or an article according to the second aspect of the invention.

[0167] According to a sixth aspect of the present invention, there is provided a haemostatic material according to a first aspect of the invention, or an article according to a second aspect of the invention, for use in stemming blood flow from a physiological target site.

[0168] Preferably, the physiological target site may be a wound.

[0169] The further aspects of the present invention may incorporate any of the features of the other aspects of the invention described herein as desired or as appropriate. Detailed Description of the Invention

[0170] In order that the invention may be more clearly understood one or more embodiments thereof will now be described, by way of example only.

[0171] Reference Example 1

[0172] A haemostatic material not according to the present invention comprising a semi -synthetic and synthetic fibre blend fibrous material was prepared as a Reference Example 1.

[0173] Kaolin was slurried in a solution of sodium alginate and applied to a viscose / polyolefin blend fibrous material to coat the viscose / polyolefin fibrous material blend with Kaolin. The coated material was then dipped into a calcium chloride solution to crosslink the alginate before drying.

[0174] Example 2

[0175] A haemostatic material according to the present invention comprising a natural cellulose fibrous material was prepared as an Example 2.Kaolin was slurried in a solution of sodium alginate and applied to a cotton fibrous material to coat the cotton fibrous material with Kaolin. The coated material was then dipped into a calcium chloride solution to crosslink the alginate before drying.

[0176] Reference Example 3

[0177] A further haemostatic material not according to the present invention comprising a semi -synthetic and synthetic fibre blend fibrous material was prepared as a Reference Example 3.

[0178] A viscose / polyolefin blend fibrous material was immersed in a 0.08wt.% solution of ferrous chloride hexahydrate, a source of Iron (Fe2+) ions, for a period of 1 minute. A 0.32wt.% solution of ellagic acid was then added to the mixture and the mixture was left for a period of 5 minutes. The pH of the mixture was then raised to approximately pH 8 and the fibrous material was left in the mixture for a period of 1 hour. The mixture was then removed from the solution and dried.

[0179] Example 4

[0180] A haemostatic material according to the present invention comprising a natural cellulose fibrous material was prepared as an Example 4.

[0181] A cotton fibrous material was immersed in a 0.08wt.% solution of ferrous chloride hexahydrate, a source of Iron (Fe2+) ions, for a period of 1 minute. A 0.32wt.% solution of ellagic acid was then added to the mixture and the mixture was left for a period of 5 minutes. The pH of the mixture was then raised to approximately pH 8 and the fibrous material was left in the mixture for a period of 1 hour. The mixture was then removed from the solution and dried.

[0182] Example 5

[0183] A haemostatic material according to the present invention comprising a natural cellulose fibrous material was prepared as an Example 5.

[0184] A flax fibrous material was immersed in a 0.08wt.% solution of ferrous chloride hexahydrate, a source of Iron (Fe2+) ions, for a period of 1 minute. A 0.32wt.% solution of ellagic acid was then added to the mixture and the mixture was left for a period of 5 minutes. The pH of the mixture was then raised to approximately pH 8 and the fibrousmaterial was left in the mixture for a period of 1 hour. The mixture was then removed from the solution and dried.

[0185] Example 6

[0186] A haemostatic material according to the present invention comprising a natural cellulose fibrous material was prepared as an Example 6.

[0187] A hemp fibrous material was immersed in a 0.08wt.% solution of ferrous chloride hexahydrate, a source of Iron (Fe2+) ions, for a period of 1 minute. A 0.32wt.% solution of ellagic acid was then added to the mixture and the mixture was left for a period of 5 minutes. The pH of the mixture was then raised to approximately pH 8 and the fibrous material was left in the mixture for a period of 1 hour. The mixture was then removed from the solution and dried.

[0188] Clot Strength and Clot Formation Testing

[0189] In order to assess the clot strength, the above referenced haemostatic materials were applied to blood and the G’ of the resulting clot was measured to determine the clots resistance to being deformed elastically when a stress is applied to it.

[0190] The clot strength testing was performed using an ElastoSens™ Bio device under controlled conditions. Anti coagulated blood (ACD) was prepared by gently inverting the collection tube 10 times to ensure thorough mixing without vigorous shaking. The blood was then warmed to 37°C in an oven for 30-40 minutes to reach physiological temperature.

[0191] The ElastoSens™ Bio chamber temperature was set to 37°C. An empty sample holder was placed into the chamber, and initialization was performed using the "soft" mode. Following this, 4.975 mL of pre-warmed blood was added to the sample holder. To initiate clotting, 25 pL of 5M CaCE solution was added to the blood sample and gently mixed by pipetting up and down four times using a 1000 pL pipette.

[0192] After mixing, the sample was carefully placed in the holder, and silicone oil was added to the top of the sample to minimize evaporation and maintain optimal testing conditions. The chamber lid was securely closed, and the test was programmed to runfor 30 minutes, with measurements taken every 20 seconds. This process ensured consistent and accurate analysis of clot strength.

[0193] The results of this testing are shown in Tables 1-4 below.

[0194]

[0195] Table 1 : A table showing clot strength G’ (Pa) at various time points in the clotting process for Reference Example 1 and Example 2.

[0196]

[0197] Table 2: A table showing clot strength G’ (Pa) at various time points in the clotting process for Reference Example 3 and Example 4.

[0198]

[0199]

[0200] Table 3 : A table showing clot strength G’ (Pa) at various time points in the clotting process for Reference Example 3 and Example 5.

[0201]

[0202] Table 4: A table showing clot strength G’ (Pa) at various time points in the clotting process for Reference Example 3 and Example 6.

[0203] As can be seen in the above tables, the haemostatic materials of the present invention demonstrate much greater improved clot strength when compared with similarly produced haemostatic materials comprising a semis-synthetic / synthetic fibrous material.

[0204] In practice, the provision of a haemostatic material which is able to provide a stronger clot profile, decreases the risk of rebleeding, which is a critical factor in obtaining a successful patient outcome in both surgery and trauma situations.

[0205] In addition to the clot strength, the inventors also measured the clotting time of the above examples. The results of this testing are shown in Table 5 below.

[0206]

[0207]

[0208] Table 5: A table showing clotting times (minutes). Clotting time has been defined as starting when G’>1 Pa and ending when dG' / dt <0.1 Pa / s.

[0209] As shown in Table 5, the haemostatic materials of the present invention also demonstrated significantly reduced clotting time when compared with similarly produced haemostatic materials comprising a semis-synthetic / synthetic fibrous material.

[0210] This reduced clotting time is a further critical factor in providing a successful patient outcome, through ensuring quicker clot initiation and clot formation.

[0211] Consequently, as shown above, it can be seen that the haemostatic materials of the present invention demonstrate much improved haemostatic properties, such as improved clot firmness and reduced clotting time when compared with similarly produced haemostatic materials comprising semi -synthetic and / or synthetic fibrous materials.

[0212] The one or more embodiments are described above by way of example only. Many variations are possible without departing from the scope of protection afforded by the appended claims.

Claims

CLAIMS1. A haemostatic material comprising a natural cellulose fibrous material and at least one Factor XII clotting activator.

2. A haemostatic material according to claim 1, wherein the fibrous material comprise one or more fibres selected from the group consisting of cotton, flax, hemp, jute, sisal, coir, abaca, ramie, kapok, kenaf, bamboo-derived cellulose fibres (excluding chemically regenerated forms), wood-derived cellulose fibres (excluding chemically regenerated forms), and combinations thereof.

3. A haemostatic material according to claim 2, wherein the fibrous material consists of one or more fibres selected from the group consisting of cotton, flax, hemp, jute, sisal, coir, abaca, ramie, kapok, kenaf, bamboo-derived cellulose fibres (excluding chemically regenerated forms), wood-derived cellulose fibres (excluding chemically regenerated forms), and combinations thereof.

4. A haemostatic material according to claim 1, wherein the fibrous material comprises one or more fibres selected from the group consisting of cotton, hemp, jute, flax, and combinations thereof5. A haemostatic material according to claim 1, wherein the fibrous material consists of one or more fibres selected from the group consisting of cotton, hemp, jute, flax, and combinations thereof.

6. A haemostatic material according to any preceding claim, wherein the fibrous material is present in an amount of at least 90wt.% by weight of the haemostatic material.

7. A haemostatic material according to any preceding claim, wherein the Factor XII clotting activator is selected from the group consisting of kaolin, silica, glass particles (such as volcanic glasses including obsidian, pumice and / or perlite), zeolites, titanium dioxide, polyphosphates, collagen, chitosan, derivatives of chitosan, chitin, derivatives of chitin, oxidized cellulose, heparan sulphate, haemostatic polyphenol (such as ellagic acid), ceramics and combinations thereof.

8. A haemostatic material according to claim 7, wherein the Factor XII clotting activator is selected from the group consisting of kaolin, ellagic acid, ceramics, silica particulates, volcanic glasses (such as perlite), and combinations thereof.

9. A haemostatic material according to any preceding claim, wherein the Factor XII clotting activator is in a form selected from the group consisting of a dry powder, solution, foam, fibre, gel, and combinations thereof.

10. A haemostatic material according to any preceding claim, wherein the Factor XII clotting activator is present in an amount of from 0.1-10 wt.% by weight of the haemostatic material.

11. A haemostatic material according to any preceding claim, wherein the Factor XII clotting activator is ellagic acid.

12. A haemostatic material according to claim 11, wherein the haemostatic material further comprises a metal ion.

13. A haemostatic material according to claim 12, wherein the metal ion is selected from the group consisting of copper (Cu2+), zinc (Zn2+), iron (Fe2+), iron (Fe3+), and one or more combinations thereof.

14. A haemostatic material according to any preceding claim, wherein the haemostatic material comprises one or more additional ingredients selected from the group consisting of pharmaceutical agents, medical surfactants, wetting agents such as surfactants, growth factors, cytokines, agents which absorb agents which delay healing such as MMP’s (matrix metalloproteinases) and elastase, and / or another wound dressing component, such as calcium, vitamin K, fibrinogen, thrombin, factor VII, factor VIII, clays such as kaolin, oxidised regenerated cellulose, gelatin, or collagen, antifibrinolytic agents, and combinations thereof.

15. An article comprising a haemostatic material according to any one of claims 1- 14.

16. An article according to claim 15, wherein the article is selected from the group consisting of a wound dressing, swab, gauze or lap-pad (laparotomy sponge), and combinations thereof.

17. A method of manufacturing a haemostatic material according to any one of claims 1-14 comprising the steps of contacting a natural cellulose fibrous material with at least one Factor XII clotting activator.

18. A method of manufacturing an article according to any one of claims 15-16, wherein the method comprises the step of attaching the haemostatic material to a further material and / or a second haemostatic material according to any one of claims 1-14.

19. A haemostatic material according to any one of claims 1-14, for use in stemming blood flow from a physiological target site20. An article according to any one of claims 15-16, for use in stemming blood flow from a physiological target site.

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