WO2013050428A1

WO2013050428A1 - Compressible dressing

Info

Publication number: WO2013050428A1
Application number: PCT/EP2012/069550
Authority: WO
Inventors: Peter Iddon; Michael Raxworthy; Lorenzo Pio Serino
Original assignee: Neotherix Limited
Priority date: 2011-10-07
Filing date: 2012-10-03
Publication date: 2013-04-11
Also published as: GB201117295D0

Abstract

A medical wound dressing, a method of manufacturing the dressing, and a method of treating wounds using such a dressing. The dressing comprises compression means with a wound-facing face, and at least one compressible wound contact integer which in use lies in contact with the wound bed, characterised in that the wound contact integer comprises a biodegradable porous scaffold which in use lies in contact with the wound bed, and the volume of the integer in an uncompressed state is greater than the volume of the wound void in a rest state, and the dressing comprises compression means for securing the dressing over the wound such that positive pressure (relative to atmospheric pressure) is applied to the porous scaffold and the wound bed, and the scaffold is pressed into intimate contact with the wound bed.

Description

Compressible Dressing

The present invention relates to a medical wound dressing, a method of manufacturing the dressing, and a method of treating wounds using such a dressing. It relates in particular to such a wound dressing and method that can be easily applied to a variety of acute wounds, and in particular surgical wounds, to promote tissue regeneration and repair.

When used herein:

The term "natural" refers to any material that is naturally occurring, for example, silk, collagen-based materials, chitosan, hyaluronic acid and alginate.

The term "synthetic" means any material that is not found in nature, even if made from naturally occurring biomaterials. Examples include, but are not limited to aliphatic polyesters, poly(amino acids), copoly(etheresters), polyalkylenes, oxalates, polyamides, tyrosine derived polycarbonates, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, polyoxaesters containing amino groups, poly(anhydrides), polyphosphazenes and combinations thereof.

The term "biocompatible" refers to any material which when in contact with the cells, tissues or body fluid of an organism does not induce adverse effects such as immunological reactions and/or rejections and the like. The term "biodegradable" refers to any material which can be degraded, for example by proteases or by hydrolysis, in, and bioresorbed into, the physiological environment. Examples of biodegradable materials include collagen, fibrin, hyaluronic acid, alginate, chitosan or mixtures thereof. Examples of such biodegradable materials also include poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(D/L-lactic acid) (PDLLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), trimethylene carbonate (TMC), poly(ethylene glycol) (PEG), and mixtures thereof. The term "scaffold" refers to a synthetic or natural porous structure used in the treatment of acute or chronic wounds, tissue engineering, regenerative medicine, or cell culture. A scaffold is any such structure that supports cell attachment, migration and/or proliferation in two or three dimensions, resulting in the formation or healing of tissue. It may inter alia be a porous body such as one comprising a foam, usually an open-cell foam to promote cell migration, or one that comprises fibres, such as nanofibres or microfibres, with interstices between the fibres. It may be in a form comprising at least one layer or sheet of porous material optionally bonded to each other and/or to a backing layer membrane, for example with an adhesive or thermally.

A scaffold may be biodegradable or non-degradable, and may comprise fluids, such as gases, liquids and gels, and cells in its interstices, and nutrients, and synthetic or natural biological or chemical agents, in its interstices and/or its structural members.

The term "nanofibres" in relation to a fibrous scaffold means that the majority of fibre diameters in the scaffold are less than 100 nanometres.

The term "microfibres" in relation to a fibrous scaffold means that the majority of fibre diameters in the scaffold are less than 100 micrometres. The term "wound" in relation to the present invention means any tissue with compromised integrity, such tissue including soft tissue, such as skin, muscle and viscera. Such wounds include acute wounds, such as gunshot, puncture, bite, surgical and infectious disease wounds; chronic wounds, such as diabetic ulcers or venous leg ulcers; and burns; and superficial, deep and cavity wounds, crush wounds, cuts, lacerations, abrasions, avulsions and velocity wounds.

Scaffold technologies are known for use in dermal regeneration in chronic and acute wounds. It is known, in a method of repair treatment of wounds, in particular those of relatively large area and/or depth, to apply a scaffold in contact with the wound bed (between the wound and the wound contact layer of a medical dressing) to create a favourable environment for tissue repair. Such scaffolds for use in wounds may be natural scaffolds or synthetic scaffolds, and may be biodegradable (and can remain within a wound) or nonbiodegradable (and need to be removed). The material and structure of such scaffolds are usually flexible and, since they are porous, such scaffolds are usually compressible. This is desirable for patient comfort.

The scaffold which in use lies in contact with the wound bed may underlie a dressing, and it may be separate from a dressing which it underlies, or may form an integral part of the wound-facing face of the dressing.

The intention of such scaffolds is that the scaffold which in use lies in contact with the wound bed stimulates infiltration by granulation tissue and cells from the wound bed into the scaffold, thereby facilitating tissue regeneration and repair. We have found, however, that scaffolds used in this way in conventional wound therapy suffer from the disadvantage that the degree and rate of infiltration, and hence the degree and rate of tissue regeneration and repair over the wound bed tends to be less than optimal. It is also known, in another method of repair treatment of wounds, to apply a therapeutic technique known as negative pressure wound therapy (NPWT), in particular to wounds of relatively large area and/or depth.

A wound filler, which may be a conformable porous body, such as a foam, for example an open-cell foam, is applied in contact with the wound bed and between the wound, and an occlusive film is applied over the wound and the tissue surrounding the wound to form a fluid-tight seal or closure over the wound.

A negative pressure (relative to atmospheric pressure) is applied by means of a vacuum pump to the volume between the wound bed and the occlusive film, and hence to the wound and the tissue surrounding the wound under the film, in order to draw out fluid from the wound bed and to increase blood flow to the area of the wound.

In one form, the assembly comprises a wound filler which is a conformable porous scaffold, for example a microfibre scaffold of a biodegradable material, such as poly(L-lactic acid), all as defined hereinbefore, applied in contact with the wound bed and between the wound and the film. Relatively hard and incompressible tubing or tubing ports running under the fluid- tight seal or closure over the wound are often used to connect the vacuum pump to the volume between the wound bed and the occlusive film. The application of sub-atmospheric pressure to such a sealed occlusive NPWT dressing by means of a vacuum pump coincidentally draws the film and the wound and the porous scaffold and any wound filler, which is typically present in the dressing, together thus generating a positive pressure (relative to atmospheric pressure) between the porous scaffold and the wound bed. However, in such NPWT systems, the wound and the tissue surrounding the wound under the film must overall be under a negative pressure (relative to atmospheric pressure) in order to draw out fluid from the wound bed and to increase blood flow to the area of the wound. Such NPWT systems suffer from several disadvantages that make them less than optimal, including the following:

The negative pressure generated in the volume between the wound bed and the occlusive film renders such NPWT systems unsuitable for use with many types of wound. In particular, serious complications are associated with negative pressure wound therapy systems, and they are contraindicated for certain wound types, such as those containing exposed vasculature, organs, nerves or anastomotic sites, especially in deeper wounds. There is an increased risk of blood loss for wounds that are actively bleeding or which already have an increased risk of haemorrhage.

A complete seal must be maintained around the perimeter of the wound, and the risk of pressure ulcers in adjacent tissue is increased owing to increased localised pressure between the relatively hard and incompressible tubing or tubing ports running under the fluid-tight seal or closure over the wound that are often used to connect the volume between the wound bed and the occlusive film to the vacuum pump.

The occlusive film that must be used and the complete seal that must be maintained around the perimeter of the wound increases the risk of maceration of tissue surrounding the wound to which it is attached. A gas-permeable wound dressing in contrast allows moisture to escape from the tissue surrounding the wound to which it is attached.

It would be desirable to provide a dressing which avoids these disadvantages of known wound therapy scaffolds and can be easily applied to a wide variety of wounds, but in particular acute, for example surgical, wounds, to promote tissue regeneration and repair

We have surprisingly found that this may be achieved by a wound therapy dressing which applies positive pressure (relative to atmospheric pressure) to a compressible scaffold that is, or is the underside of, a wound contact integer in such a dressing, and through it to the wound bed, and the scaffold is pressed into intimate contact with the wound bed. This is the more surprising since a scaffold having fibres of a small diameter will generally also be characterised by a small pore size, and foam scaffolds will generally also have a small pore size. Applying pressure to a compressible scaffold will tend to reduce the pore size, and it is believed in the art that this will have a negative effect on the degree and rate of migration of the cells into the scaffold, potentially leading to a restricted regeneration of replacement tissue around the periphery of the scaffold, with the core of the scaffold being substantially acellular.

Accordingly, in a first aspect of the present invention there is provided a conformable wound dressing that comprises at least one compressible wound contact integer which in use lies in contact with the wound bed, characterised in that

the wound contact integer comprises a biodegradable porous scaffold which in use lies in contact with the wound bed, and the volume of the integer in an uncompressed state is greater than the volume of the wound void in a rest state, and

the dressing comprises compression means for securing the dressing over the wound such that positive pressure (relative to atmospheric pressure) is applied to the porous scaffold and the wound bed, and the scaffold is pressed into intimate contact with the wound bed. Such means will be known to those skilled in the art, but for example include a wound dressing backing layer. Such a backing layer preferably comprises an elastic (for example elastomeric) gas-permeable barrier layer which is capable of forming a relatively liquid-tight seal or closure over a wound. The dressing is applied over the wound and secured to the body of the patient, generally to the skin by the backing layer, which may bear at least one layer of pressure sensitive adhesive for the purpose.

Alternatively, (but less preferably) the means may for example comprise an elastic woven or knitted textile bandage, known in the art as a crepe bandage. This is applied over the wound and the scaffold in the wound, taken around the relevant limb, head or torso, and secured to itself and hence to the body of the patient, for example by pinning, by adhesion or by Velcro hook and eye strips (when the bandage may bear at least one layer of pressure sensitive adhesive or at least a pair of strips for the respective purpose).

In one embodiment of the first aspect of the invention, the wound contact integer consists essentially of the porous scaffold. In one embodiment of the first aspect of the invention, the wound contact integer is separate from the rest of the dressing before the dressing is assembled in situ on the wound.

In another embodiment of the first aspect of the invention, the porous scaffold is separate from the rest of the dressing before the dressing is assembled in situ on the wound.

In a further embodiment of the first aspect of the invention, the porous scaffold and/or the wound contact integer form part of the dressing before its application to the wound.

In use, the scaffold, optionally as part of the wound contact integer of the dressing, is applied to the wound bed. Where the wound contact integer and/or the scaffold is separate from the rest of the dressing before the dressing is assembled in situ on the wound, the rest of the dressing (including the compression means, for example a backing layer) is then applied over the wound and secured to the body of the patient.

Alternatively, where the scaffold and/or the wound contact integer form part of the dressing before its application to the wound, the dressing as a whole is applied to the wound and then secured to the body of the patient, again by the compression means, for example a backing layer which may bear at least one layer of pressure sensitive adhesive for the purpose.

The wound contact integer of the dressing (and/or the scaffold within it) is compressible, and the volume of the integer in an uncompressed state before its application to the wound bed is greater than the volume of the wound void at rest.

By securing the dressing over the wound positive pressure is applied to the compressible integer to press the scaffold onto and into intimate contact with the wound bed until the positive pressure is relieved by removing the dressing from over the wound area. This results in a higher degree and rate of tissue infiltration, and hence of the degree and rate of tissue regeneration and repair over the wound bed. Securing the dressing over the wound also applies positive pressure (relative to atmospheric pressure) to the tissue under the wound bed. Unlike the application of sub-atmospheric pressure by NPWT, the present dressing does not require a fluid-tight occlusive film seal or closure over the wound and relatively hard and incompressible tubing or tubing ports running under it to connect the vacuum pump to the volume over the wound bed. Where any backing layer or bandage is gas-permeable, this allows moisture to escape from the tissue surrounding the wound to which it is attached.

The present dressing thus avoids the disadvantages of known NPWT wound therapy dressings with scaffolds, whilst also advantageously being optimal for cell adhesion, proliferation, migration and degree and rate of cell infiltration, and having dimensional stability. The dressing can be easily applied to promote tissue regeneration and repair for treating a wide variety of dermal conditions of an animal, including both humans and non-human animals. The dermal condition may be a wound, but in particular an acute wound, for example a surgical wound or a burn on the animal's skin. The medical dressing may be used to treat a wound that extends to at least the epidermis of the animal's skin. The medical dressing may also be used to treat a wound that extends to the dermis or the subcutaneous fat region of the animal's skin. In particular for shallower wounds, the wound contact integer which comprises the scaffold which in use is pressed into contact with the wound bed may typically be or consist essentially of the scaffold .

Alternatively, a more suitable wound contact integer, in particular for deeper wounds when therapy is applied in this way, comprises a conformable wound filler under the compression means, for example a backing layer, with a wound- facing face which in use lies in contact with the scaffold.

The scaffold and the wound-facing face of the filler may be essentially coterminous, or the wound-facing face of the filler may be smaller, preferably slightly smaller, than the opposing face of the scaffold, so that in use the scaffold at least partly surrounds the wound contact integer edges, and the scaffold lies in contact with the wound bed to its periphery. Such a wound filler as a component of the wound contact integer may be equally, less or more compressible as or than the scaffold.

It may preferably be more compressible, so that in use there is less compression of the scaffold, but the latter is still pressed into intimate contact with the wound bed.

Where (less preferably) the wound filler is less compressible than the scaffold, it may comprise a non-woven, woven or knitted textile fabric, as at least one cloth, layer or sheet, such as a gauze; at least one polymer film, layer sheet or membrane; or a at least one layer of a mesh, lattice, net or web; optionally bonded to each other and/or to the compression means, for example a backing layer membrane, with an adhesive or thermally. Where more suitably and preferably the wound filler is more compressible than the scaffold, the preferred type of wound filler may comprise at least one conformable porous body, such as a foam. Such a wound filler may be present as at least one layer or sheet, optionally bonded to each other and/or to the compression means, for example a backing layer membrane, with an adhesive or thermally. The or each foam may be in a range of various forms, including closed- and open-cell foams.

It will be seen that the conformable wound filler under the compression means, for example a backing layer, whether more or less compressible than the scaffold, may comprise at least one conformable absorbent body. The body may be, for examples a porous body, such as an open-cell foam, or a non-woven, woven or knitted textile fabric. Such a wound filler may absorb wound exudate in use through the scaffold or (less often) directly from the wound bed, if in contact with the latter, and will often expand as a result of such absorption, and further press the scaffold into intimate contact with the wound bed. Alternatively or additionally, a liquid, such as isotonic saline, may be deliberately added to the filler around or through the compression means, for example a backing layer for that purpose.

In all embodiments of the first aspect of the present invention, the compression means, for example a backing layer, all components of any wound filler, and the scaffold are all preferably mutually separate before application of the dressing over a wound. The wound filler then preferably comprises more than one component cloth, layer, sheet, film or membrane so than the wound filler may be adjustably shimmed to the desired thickness, and more preferably comprises at least two foam layers or sheets. The volume, and in practice the thickness, of the integer and/or scaffold is largely determined by the volume of the wound void at rest, and in practice by the depth of the wound; by the compressibility of the wound contact integer or scaffold, in turn determined by the structure of the scaffold and/or the wound contact integer; and by whether it is intended to allow an absorbent wound filler to swell with wound exudate or added fluid. Broadly, the scaffold or filler should preferably protrude above the surface of the tissue surrounding the wound, for example the skin, either immediately following application of the scaffold or filler to the wound or after the absorbent wound filler has swelled with wound exudate or added fluid.

For the suitable and preferred materials and structures of the scaffold and/or wound contact integer as so described hereinafter, examples of suitable depths of the scaffold and/or wound integer as a percentage of the depth of the wound are in the range of 100 to 1000 %, for example 100 to 500 %, and 100 to 200 %. The volume of the wound void at rest (in practice the area and/or depth of the wound) used to determine the thickness of the scaffold and/or the wound contact integer required may be determined by conventional invasive techniques. Such techniques include tracing the wound or a photograph thereof, and using a depth-gauge in the wound. However, non-invasive techniques, such as analysis of 3-D virtual photogrammetric images, such as in the Wound Measurement System™ from Eykona ®, are preferred.

As regards suitable and preferred materials for the scaffold, in a preferred embodiment, the scaffold is a biodegradable scaffold. A number of such tissue scaffold technologies exploit the biological properties of relatively pure natural polymers. Examples of these include collagen, fibrin, silk, alginate, chitosan and hyaluronate extracted from animal or plant tissue, and mixtures thereof. Others are based upon processed extracellular matrix (decellularised) materials which contain multiple natural macromolecules. An example of such a scaffold is Oasis® (Healthpoint Limited), a biologically derived extracellular matrix-based wound product comprised of porcine-derived acellular small intestine submucosa which contains type I collagen, glycosaminoglycans and some growth factors.

However, there are concerns over the use of natural polymers because of the potential pathogen transmission, immune reactions, poor handling, mechanical properties and less controlled biodegradability. Accordingly, synthetic polymeric materials are preferred for use in the scaffolds of the dressings of the first aspect of the present invention. It is widely accepted within the scientific community that fibrous scaffolds having fibres of a small diameter result in the greatest biological response, as evidenced by measuring cell adhesion and proliferation. This is considered to be as a result of the fibres providing a large surface area to which the cells can adhere and subsequently proliferate. Thus, the scaffold of the present invention is favourably a fibrous scaffold, which more favourably comprises biodegradable nanofibres or microfibres. Scaffolds of biodegradable polymer nanofibres or microfibres may be formed by the technique of electrospinning.

The technique of electrospinning was first introduced in the early 1930s to fabricate industrial or household non-woven fabric products.

In recent years, electrospinning has been utilised to form scaffolds of polymer fibres for use in tissue engineering. The technique involves forcing a natural or synthetic polymer solution through a capillary, forming a drop of the polymer solution at the tip and applying a large potential difference between the tip and a collection target. When the electric field overcomes the surface tension of the droplet, a polymer solution jet is initiated and accelerated towards the collection target. As the jet travels through the air, the solvent evaporates and a non- woven polymer fabric is formed on the target.

Such fibrous fabrics, having an average fibre diameter in the micrometre or nanometre scale, have been used to fabricate complex three-dimensional scaffolds for use in tissue engineering applications. Accordingly, electrospun synthetic polymeric materials are preferred for use in the scaffolds of the dressings of the first aspect of the present invention.

We have identified preferred scaffolds having an architecture and compressibility allowing them to be pressed against a wound bed, which is optimal for cell adhesion, proliferation and migration whilst also demonstrating dimensional stability (with less or negligible scaffold shrinkage, loss of initial porous architecture and reduction in initial pore size) over the time required for these initial cellular processes.

Examples of suitable biodegradable materials for the scaffold within or as the dressing wound contact integer include biodegradable materials, such as naturally occurring materials, for example keratin, laminin, elastin, collagen and extracellular matrix proteins, and

synthetic materials, for example aliphatic polyesters, in particular poly(hydroxyalkanoic acids), such as poly(L-lactic acid), poly(D-lactic acid), poly(D/L-lactic acid), poly(glycolic acid), poly(glycolic acid-co-lactic acid), polydioxanones, polycaprolactone, and blends and co-polymers thereof.

In preferred embodiments of the invention the fibre comprises a copolymer of a glycolide and/or a lactide and/or other suitable hydroxy acids and/or internal esters. Examples of suitable copolymers include poly(lactic acid-co-glycolic acid) (PLGA), a copolymer with lactic acid; poly(glycolide-co-caprolactone) (PGACL), a copolymer with [epsilon]-caprolactone and poly(glycolide-co- trimethylene carbonate) (PGATMC), a co-polymer with trimethylene carbonate. In preferred embodiments of the invention the copolymer is poly(lactic acid-co- glycolic acid) (PLGA), wherein the ratio of GA:LA is about 85:15, or about 85.25:14.75, or about 85.50:14.50, or about 85.75:14.25; or about 90:10, or about 90.25:9.75; or about 90.50:9.50; or about 90.75:9.25; or about 91 :9; or about 92:8; or about 93:7; or about 94:6; or about 95:5; or about 96:4; or about 97:3; or about 98:2; or about 99:1 .

In other preferred embodiments of the invention the fibre comprises polycaprolactone (PCL) and copolymers thereof with other hydroxyalkanoic acids and/or internal esters.

The invention further covers blends of PGA and a polyester. Examples of suitable blends include poly(glycolic acid) blended with poly(lactic acid) (PGA PLA) and also polydioxanone blended with poly(glycolic acid) (PDO/PGA). It is envisaged that the blends may comprise at least one copolymer.

All stereoisomeric forms of the polymers fall within the scope of the present invention.

In some embodiments of the invention the scaffold is a non-woven fabric. Non- woven fabrics are those which are neither woven nor knit and which are typically manufactured by putting small fibres together to form a sheet or web, and then binding them. Binding may be effected mechanically (as in the case of felt, by interlocking them with serrated needles such that the inter-fibre friction results in a stronger fabric), with an adhesive, or thermally (by applying binder (in the form of powder, paste, or polymer melt) and melting the binder onto the web by increasing temperature). In further embodiments of the invention the scaffold is manufactured by electrospinning (either solution or melt electrospinning), phase separation, melt- blowing, spinning or self-assembly. Electrospinning is the preferred method of manufacture because it readily allows scale-up to industrial levels of production, particularly in terms of appropriately sized scaffolds for use in medical applications.

The above suitable and preferred materials for the scaffold may be solvent spun using appropriate solvents, such as dimethylformamide, methylene chloride, chloroform, dichloromethane, acetonitrile, methanol, N-methylpyrolidone, hexafluoroisopropanol and dimethyl sulphoxide.

Such solvents may contain appropriate additives, such as sodium chloride, sodium acetate, magnesium chloride, potassium dihydrogen phosphate, potassium iodide, potassium phosphate, calcium carbonate, calcium phosphate and calcium lactate, in solution form or in nanoparticulate forms, and any other additives, solvents, polymers, bioactives, pharmaceutical agents, metals, metal oxides or cells or cellular components known to one skilled in the art, that can be integrated into an spun format.

Where the wound integer comprises a wound filler, the materials may be deposited onto and/or attached to the surface of the wound filler by any means known to those skilled in the art. They may be spun, for example electrospun, onto the wound filler.

In some embodiments of the invention the mean fibre diameter in the fibrous scaffold is between from about 50 nanometres to 50 microns, particularly of from about 0.1 to 10 microns and more particularly of from about 1 .2 to 4.0 microns.

In preferred embodiments of the invention the scaffold comprises electrospun fibres, typically having a fibre diameter of from about 1 .2 to 4.0 microns, particularly of from about 1 .5 to 3.5 microns and more particularly of from about 1 .9 to 2.8 microns.

The fibres may be continuous, semi-continuous or staple fibres. In some embodiments of the invention the fibrous scaffold may have a pore size of 1 to 50 microns, preferably between 3 and 35 microns, more preferably between 4 and 25 microns, and more preferably between 5 and 20 microns, with a preferred porosity of 60 to 98%, more preferably with a porosity of 70 to 95%.

The wound contact integer, and in particular the scaffold (but including other components of the wound contact integer), may comprise other substances, which may increase the bioaffinity and recognition of the cells proliferating and/or migrating through the scaffold and/or promote tissue regeneration and repair to increase the therapeutic potential of the scaffold, provided that at least the scaffold within the wound contact integer of the dressing is still compressible. In such cases, the wound contact integer may comprise a conformable tissue growth medium gel or other similar material, such as an alginate, a therapeutic agent, such as an antimicrobial agent, such as silver, iodine or chlorhexidine, or an agent that improves scar resolution and/or prevents scar formation, for example: insulin, vitamin B, hyaluronic acid, mitomycin C, growth factors (TGF[beta]), cytokines, corticosteroids and/or agents that promote re- epithelialisation.

Where appropriate, the substance can be provided within a scaffold polymer spinning solution prior to fibre formation. Additionally or alternatively the substance may be associated with the fibre post-formation.

According to a preferred embodiment of the invention there is provided a dressing with a scaffold comprising fibres having a mean fibre diameter of between from about 1 .2 to 4.0 microns, and wherein said fibres comprise a polymer comprising glycolide residues.

In some forms of this embodiment of the invention the polymer content of the fibre comprises over 85% glycolide, over 90% glycolide, over 95% glycolide, or consists of 100% glycolide residues. The polymer may also comprise lactide residues. Poly(glycolic acid) (PGA), also referred to as polyglycolide, and copolymers of glycolic acid (GA) with other hydroxyalkanoic acids or internal esters, such as lactic acid (LA) or caprolactone (CL), are biodegradable, thermoplastic polymers. PGA may be prepared from GA by means of polycondensation or ring-opening polymerisation of glycolide. Copolymers of GA with other hydroxyalkanoic acids or internal esters may be prepared from glycolic acid (GA) and the other acid by polycocondensation and/or ring-opening copolymerisation.

PGA and GA copolymers are characterised by hydrolytic instability owning to the presence of the ester linkage in the backbone, and thus when exposed to physiological conditions, they are degraded by hydrolysis. The degradation products, glycolic acid and/or the hydroxyalkanoic acids or internal ester are non-toxic and can enter the tricarboxylic acid cycle after which they are excreted as water and carbon dioxide. The polymers have been shown to be completely resorbed by an organism in a time frame of four weeks to six months.

According to a another preferred embodiment of the invention there is provided a dressing with a scaffold comprising fibres having a mean fibre diameter of between from about 1 .2 to 4.0 microns, and wherein said fibres comprise a polymer comprising caprolactone residues.

Polycaprolactone (PCL) and copolymers of caprolactone (CL) with other hydroxyalkanoic acids or internal esters are also biodegradable, thermoplastic polymers. PCL may be prepared from CL by means of ring-opening polymerisation. Copolymers of GA with other hydroxyalkanoic acids or internal esters may be prepared from CL and the other acid by polycocondensation and/or ring-opening copolymerisation.

Copolymers containing CL and GA are also characterised by hydrolytic instability owning to the presence of the ester linkage in the backbone, and thus when exposed to physiological conditions, they are also degraded by hydrolysis. The degradation products, CL and/or the hydroxyalkanoic acids or internal ester are non-toxic and can enter the tricarboxylic acid cycle after which they are excreted as water and carbon dioxide. As noted above, the compression means in the present wound dressing is preferably a backing layer which comprises a gas-permeable barrier layer which is capable of forming a relatively liquid-tight seal or closure over a wound. In the dressing, such a dressing backing layer will prevent excessive water vapour loss or retention from the area of the wound. The porous scaffold will encourage epithelial cell migration and proliferation and so will encourage re- epithelialisation and wound closure.

In some embodiments of the invention such a dressing backing layer is composed of biological, synthetic or blended materials. Suitable materials include polymers, for example: polycellulose, polyurethane, polystyrene, polyimides, polyamides, resins, nylon, silicone, polyester, polyolefin for example polyethylene, polypropylene and polybutylene, copolymers and mixtures thereof. Silicone dressing backing layers can be classified according to their permeability to vapour and air. Occlusive silicone dressing backing layers are impermeable to vapour and air. Perforated silicone dressing backing layers allow free vapour and air exchange through the perforations whilst permeable silicone dressing backing layers are vapour and air transmissible. In specific embodiments of the invention the silicone dressing backing layer is a silicone-based film, for example Cica-Care® (Smith & Nephew PLC).

As noted above, in one embodiment of the first aspect of the invention, the wound contact integer is separate from the rest of the dressing before the dressing is assembled in situ on the wound.

In another embodiment of the first aspect of the invention, the scaffold is separate from the rest of the dressing before the dressing is assembled in situ on the wound.

In a third embodiment of the first aspect of the invention, the scaffold and/or the wound contact integer form part of the dressing before its application to the wound. In use, the scaffold, optionally as part of the wound contact integer of the dressing, is applied to the wound bed. Where the wound contact integer and/or the scaffold is separate from the rest of the dressing before the dressing is assembled in situ on the wound, the rest of the dressing is then applied over the wound and secured to the body of the patient. Alternatively, where the scaffold and/or the wound contact integer form part of the dressing before its application to the wound, the dressing is then secured to the body of the patient.

In the third embodiment of the first aspect of the invention, where the scaffold and/or the wound contact integer forms part of the dressing before its application to the wound, the dressing compression means may be removably attached to the scaffold or the rest of the wound contact integer using a suitable adhesive. When re-epithelialisation is complete in the wound healing process, the compression means is peeled away from the scaffold and/or the wound contact integer. Where it is peeled away from the scaffold, the resorbable scaffold fibres remain in the wound bed, degrading over time into harmless breakdown products.

Alternatively, where the scaffold and/or the wound contact integer form part of the dressing before its application to the wound, the dressing compression means, in particular when it is a backing layer, may be irremovably attached to the scaffold or the rest of the wound contact integer using a suitable adhesive, or other means of bonding.

In all the foregoing, once the wound dressing of the first aspect of the invention has been applied to the patient with the scaffold in contact with the wound, a secondary dressing, for example consisting of gauze pads secured with surgical netting and adhesive tape, may be applied over the compressible scaffold dressing in order to protect it.

A second aspect of the present invention provides a method of manufacturing a wound dressing of the first aspect of the invention, where the scaffold and/or the wound contact integer forms part of the dressing before its application to the wound, which method comprises attaching the wound contact integer removably or irremovably to the compression means. The wound contact integer may be or comprise the scaffold, and the compression means may in particular be a backing layer.

The compression means may be removably or irremovably attached to the scaffold or the rest of the wound contact integer using a suitable adhesive, or other means of bonding.

Where appropriate, the scaffold may be spun, in particular electrospun, directly onto the dressing compression means or the rest of wound contact integer. This provides a relatively low cost means to manufacture the dressing.

Temporary or permanent adhesion of the spun scaffold may be effected by spinning, in particular electrospinning, the scaffold onto a layer of appropriate adhesive on the appropriate substrate.

Alternatively, depending on the choice of materials for the scaffold, any spinning solvent and the appropriate substrate, the scaffold may be deposited by spinning, in particular electrospinning, and self-adhered removably or irremovably onto the surface of the substrate.

According to one embodiment of the second aspect of the invention there is provided a method of manufacturing a dressing in which the scaffold comprises a glycolide and wherein the mean fibre diameter is between from about 1 .2 to 4.0 microns, comprising electrospinning fibres which form the scaffold onto the appropriate target. In some embodiments of this embodiment of the second aspect of the invention the glycolide is PGA.

The manufacture of the dressing can be performed within a laboratory or a manufacturing plant.

Where the fibrous scaffold and/or the wound contact integer forms part of the dressing before its application to the wound, the scaffold can be spun onto the appropriate target, packaged and sterilised. Alternatively, where the fibrous scaffold does not form part of the dressing before its application to the wound, the method can be performed in situ, for example, at the site of the wound. The electrospun scaffold is directly spun into the wound bed, optionally using a hand-held electrospinning device. The compression means, optionally having the rest of the wound facing integer, such as a wound filler, attached removably or irremovably to it, is then applied over the wound and secured to the body of the patient.

In all the foregoing, the wound contact integer of the dressing (and/or the scaffold within it) is compressible, and the volume of the integer in an uncompressed state before its application to the wound bed is greater than the volume of the wound void at rest.

By securing the dressing over the wound positive pressure is applied to the compressible integer to press the scaffold onto and into intimate contact with the wound bed until the positive pressure is relieved by removing the dressing from over the wound area.

According to a third aspect of the present invention there is provided a method of treating a wound to promote tissue regeneration and repair and wound healing using the dressing of the first aspect of the invention, in which such a dressing is applied to the wound.

In such method, the scaffold, optionally as part of the wound contact integer of the dressing, is applied to the wound bed.

Where the wound contact integer and/or the scaffold is separate from the rest of the dressing before the dressing is assembled in situ on the wound, the rest of the dressing is then applied over the wound and secured to the body of the patient. Alternatively, where the scaffold and/or the wound contact integer form part of the dressing before its application to the wound, the dressing is then secured to the body of the patient.

The wound contact integer of the dressing (and/or the scaffold within it) is compressible, and the volume of the integer in an uncompressed state before its application to the wound bed is greater than the volume of the wound void at rest. In all the foregoing, once the wound dressing of the first aspect of the invention has been applied to the patient with the scaffold in contact with the wound, a secondary dressing, for example consisting of gauze pads secured with surgical netting and adhesive tape, may be applied over the compressible scaffold dressing in order to protect it.

By securing the dressing over the wound positive pressure is applied to the compressible integer to press the scaffold onto and into intimate contact with the wound bed until the positive pressure is relieved by removing the dressing from over the wound area. This results in a higher degree and rate of infiltration, and hence the degree and rate of tissue regeneration and repair over the wound bed.

The positive pressure can be maintained for the minimum duration required in order to initiate the integration of the scaffold into the new tissue, or the positive pressure can be maintained until wound healing is essentially complete.

The dressing can be easily applied to promote tissue regeneration and repair for treating a wide variety of dermal conditions of an animal, including both humans and non-human animals. The dermal condition may be a wound, and in particular an acute wound, for example a surgical wound or a burn on the animal's skin. The dressing may be used to treat a wound that extends to at least the epidermis of the animal's skin . The medical dressing may also be used to treat a wound that extends to the dermis or the subcutaneous fat region of the animal's skin.

In one embodiment of the third aspect of the invention, the dressing comprises a scaffold including fibres having a mean fibre diameter of between from about 1 .2 to 4.0 microns, and wherein said fibres comprise a polymer comprising glycolide residues.

In another embodiment of the third aspect of the invention there is provided a dressing with a scaffold comprising fibres having a mean fibre diameter of between from about 1 .2 to 4.0 microns, and wherein said fibres comprise a polymer comprising caprolactone residues.

The present invention is illustrated by the following figures and examples: Figure 1 : A scanning electron micrograph (SEM) image of an electrospun biodegradable scaffold integer of the first aspect of the invention.

Figures 2a & 2b: Isometric cross-sections respectively through a wound contact integer and through a wound dressing of the first aspect of the invention in situ in a wound. Figures 3a & 3b: Photographs of full-thickness excisional porcine wounds, 7 days after wounding and treatment with a biodegradable scaffold, with and without a compressible wound filler, as described in Example 3. Figures 4a & 4b: Histology images of full-thickness excisional porcine wounds,

10 days after wounding and treatment with a biodegradable scaffold, with and without a compressible wound filler, as described in Example 3.

Referring to Figure 1 , this shows a magnified image of a poly(glycolic (PGA) scaffold, the preparation of which is described in Example 1 .

Referring to Figure 2b, the conformable wound dressing 1 comprises a wound contact integer comprising a biodegradable scaffold 2, here an electrospun PGA scaffold and a foam wound filler layer 3, and a self-adhesive backing layer, here a gas-permeable barrier film 4. The biodegradable scaffold 2 lies in contact with the wound bed of a full thickness skin wound. A full thickness wound is characterised in that it extends through the epidermis 5 and the dermis 6, leaving the subcutaneous tissue 7 exposed.

As shown in Figure 2a, prior to application of the self-adhesive gas-permeable barrier film 4 over the wound contact integer, the foam wound filler 3 protrudes above the surface of the surrounding uninjured skin 8. As shown in Figure 2b, following application of the self-adhesive barrier film 4 to the upper surface 9 of the foam wound filler layer 3, adhesion of the barrier film 4 to the surrounding skin surface 8 compresses the foam filler layer 3. This creates a distal positive pressure which pushes the scaffold 2 into close contact with the wound bed.

Referring to Figures 3a and 3b, these show photographs of full-thickness excisional porcine wounds, 7 days after wounding and treatment with a biodegradable scaffold, with and without a compressible wound filler, as described in Example 3. Both wounds received an electrospun PGA scaffold at day 0. The wound in Figure 3a also received a compressible foam wound filler in addition to the scaffold, which remained in place for the 7 days. The control wound in Figure 3b did not receive a wound filler.

Referring to Figures 4a and 4b, these show histology images photographs of full- thickness excisional porcine wounds, 10 days after wounding and treatment with a biodegradable scaffold, with and without a compressible wound filler, as described in Example 3. Both wounds received an electrospun PGA scaffold at day 0.

The wound in Figure 4a also received a compressible foam wound filler in addition to the scaffold, which remained in place for the first 7 days. The control wound in Figure 4b did not receive a wound filler.

Example 1 : Preparation of an electrospun fibrous scaffold as a separate integer from the rest of the dressing. PGA was used to prepare a 1 1 .3 w/w % solution in 1 ,1 ,1 ,3,3,3-hexafluoropropan- 2-ol (HFIP). PGA and HFIP were weighed into a glass vial and left until dissolved. Prior to electrospinning, the solution of PGA in HFIP was filtered through a 1 0 pm polypropylene filter into a polypropylene syringe. The resulting clear pale yellow solution was then loaded into a syringe pump.

The syringe exit was connected to a HFIP-resistant flexible plastic tube, which then split into two tubes. These tubes connected to two flat-ended 21 gauge steel needles, which were supported in a needle arm which could be made to traverse by means of a motor. The pair of needles was aligned perpendicularly with respect to the rotational axis of an earthed 1 50 mm diameter, 200 mm long steel mandrel and the needle tip to mandrel separation distance was set to 150 mm. The syringe pump was set to dispense polymer solution at 0.04 mLmin^"1 per needle.

The mandrel was completely covered in a sheet of non-stick release paper and rotated at 50 rpm for the duration of the collection process by means of a motor. The preparation was conducted at 21 ±1 °C.

When the needles were charged to a potential difference of 1 1 kV relative to the mandrel, electrospun fibres were formed from the solution of PGA delivered to the needle tips, which collected on the paper-covered mandrel to form a non- woven scaffold material. After sufficient scaffold had collected, the voltage generator was switched off and the scaffold sheet was removed from the mandrel and dried overnight in a vacuum oven at room temperature to remove any residual solvent.

The thickness of the fibrous scaffold sheet was measured to be 1 10 m by callipers. The mean fibre diameter of the PGA fibres in the scaffold was measured from SEM images to be 2.49 μιη with a standard deviation of 0.39 pm. Capillary flow porometry was used to measure the median and modal pore diameters, which were 7.71 μιτι and 7.26 μιη, respectively.

Example 2: Use of the scaffold of Example 1 in a compressible scaffold dressing to treat porcine full thickness excisional wounds.

On day 0, full-thickness excisional 2.5x2.5 cm wounds were created on the dorsal flanks of a large white pig. For each wound, a 2x2 cm gamma-irradiated piece of the scaffold of Example 1 was applied to the base of the wound. A compressible foam wound filler composed of two 2.5x2.5 cm layers cut from ActivHeal® non-adhesive foam dressing (a porous polyurethane foam wound contact layer with a vapour permeable polyurethane film backing layer), was placed on the top of the scaffold with the wound-facing face of the filler in contact with the scaffold, to form a wound contact integer together with the scaffold. The wound, containing the wound contact integer, was then additionally dressed with Tielle® Max non-adhesive dressing, a standard absorbent wound dressing used to control moisture levels in the wounds.

The final layer of the primary compressible scaffold dressing which was applied over the wound contact integer consisted essentially of Bioclusive® self- adhesive gas-permeable barrier film, in which an approximate 3 <3 cm central window had been cut to facilitate the evaporation of wound exudates absorbed by the other dressing layers. Adhesion of this film layer to the surrounding skin was used to maintain the wound filler in a compressed state, thereby creating a downward positive pressure on the biodegradable scaffold into close contact with the wound bed. Finally a secondary dressing consisting of gauze pads secured with surgical netting and adhesive tape was applied in order to protect the assembled compressible scaffold dressing.

On post-wounding day 3, the compressible wound filler foam, Tielle® Max dressing and Bioclusive® layers were removed, taking care not to disturb the scaffold. The wounds were digitally photographed and visually examined to determine the degree of integration of the scaffold into the wound bed. The wound filler foam, Tielle® Max and Bioclusive® layers were then replaced. On this occasion, however, only one 2.5x2.5 cm layer of ActivHeal® non-adhesive foam was used due to the level of tissue infill reducing the depth of the wound. A secondary dressing was then applied in the same manner as for day 0.

On post-wounding day 7, the compressible wound filler foam, Tielle® Max dressing and Bioclusive® layers were removed, taking care not to disturb the scaffold implanted on day 0. The wounds were digitally photographed and visually examined to determine the degree of integration of the scaffold into the wound bed. Since the scaffold was observed to have integrated into the wound bed to an acceptable level, the use of the compressible wound filler was therefore discontinued and only the Tielle® Max dressing and Bioclusive® layers were replaced. A secondary dressing was then applied in the same manner as for day 0. On post-wounding day 10, all dressing layers were removed, taking care not to disturb the scaffold implanted on day 0. The wounds were digitally photographed and assessed. After assessment and photography, the animal was euthanised and wound tissues harvested and processed for histological analysis.

Example 3: Comparison of porcine full thickness excisional wounds treated with compressed and non-compressed scaffold dressings.

The procedures of Example 2 were carried out and compared to control wounds on the same animal in which a compressible wound filler was not used. Apart from the absence of a foam wound filler cut from ActivHeal® non-adhesive foam dressing, the wound treatment protocol for the control wounds was identical to the wounds described in Example 2.

At the post-wounding day 3 assessment time point, the visual examination of the wounds treated with the compressible scaffold dressings versus the control wounds showed that all the scaffolds had begun to integrate into the wound bed to some degree. In the wounds treated with the compressible scaffold dressings the upper surfaces of the scaffolds were clearly visible, and the scaffolds appeared to be highly adherent to the wound surface and covered in a thin film of fibrin . Areas of high vascular activity were observed within the scaffolds of these wounds. However, in the control wounds the upper surface of the scaffold was not clearly visible due to the presence of noticeably more fibrin.

At the post-wounding day 7 assessment time point, the visual examination of the wounds treated with the compressible scaffold dressings showed that the scaffolds in these wounds were only partially visible on the wound surface, and appeared to be highly integrated into the wound surface and well vascularised.

A photograph of a representative example of one such wound is shown in figure

3a. In the control wounds some material that had the outline size and shape of the applied scaffold material was still apparent on the surface of the wounds and lay on the surface of those wounds. A photograph of a representative example of one such wound in shown in Figure 3b. At the post-wounding day 10 assessment time point, in the wounds treated with compressible scaffold dressings, no clearly identifiable scaffold material was observed on the surface of any of these wounds.

However, on removal of the Tielle® Max moisture control dressing from the control wounds, some non-integrated scaffold material was observed on the surface of those wounds, which detached from the wound during gentle cleaning with saline solution. Histology analysis showed that scaffold presence, level, distribution and integration into the wound were found to vary between the control wounds and the wounds treated with compressible scaffold dressings. Figure 4a is a histology image of a representative example of a wound treated with the compressible scaffold dressing at day 10. It shows that scaffold material was present in the form of corrugated sheets fully integrated into the newly-formed wound tissue. Scaffold material tended to be located in the central region (with respect to the vertical axis) of those wounds and not at the surface.

The level of scaffold integration into the newly-formed wound tissue observed in those wounds was greater than that observed in the control wounds, where the scaffold material was present more in the form of individual fibres or small patches and tended to be located in the upper region of those wounds. Overall there are fewer cells visible within the boundary of the volume occupied by the scaffold. A histology image of a representative example of a control wound is shown in Figure 4b.

The visual examinations during the live phase of the porcine study showed that the application of the compressible scaffold dressing promoted the integration of the scaffolds in a full-thickness excisional porcine wound model, compared to a control dressing which did not contain a compressible wound filler. This conclusion was confirmed by histological analysis of the post-wounding day 10 wound tissue.

In practice, an improved integration of the scaffold into the healing wound translates into a full colonisation of the scaffold by the cells involved in wound healing. This leads to enhanced tissue regeneration, thereby increasing the therapeutic potential of the scaffold.

Claims

1 . A conformable wound dressing that comprises at least one compressible wound contact integer which in use lies in contact with the wound bed, characterised in that

the dressing comprises compression means for securing the dressing over the wound such that positive pressure (relative to atmospheric pressure) is applied to the porous scaffold and the wound bed, and the scaffold is pressed into intimate contact with the wound bed.

2. A dressing according to claim 1 , wherein the compression means layer comprises a backing layer.

3. A dressing according to claim 2, wherein the backing layer comprises a gas- permeable barrier layer which is capable of forming a relatively liquid-tight seal or closure over a wound.

4. A dressing according to claim 1 , wherein the wound contact integer consists essentially of the porous scaffold.

5. A dressing according to claim 1 , wherein the wound contact integer comprises a conformable wound filler under the compression means with a wound-facing face which in use lies in contact with the scaffold.

6. A dressing according to claim 1 , wherein the wound contact integer or the porous scaffold is separate from the rest of the dressing before the dressing is assembled in situ on the wound.

7. A dressing according to claim 1 , wherein the porous scaffold and/or the wound contact integer form part of the dressing before its application to the wound.

8. A dressing according to claim 1 , wherein the scaffold is fibrous

9. A dressing according to claim 8, wherein the scaffold comprises poly(L-lactic acid), poly(D-lactic acid), poly(D/L-lactic acid), poly(glycolic acid), poly(glycolic acid-co-lactic acid), a polydioxanone or polycaprolactone, or a blend or co-polymer thereof.

10. A dressing according to claim 8, wherein the scaffold comprises poly(glycolic acid).

1 1 . A dressing according to claim 8, wherein, wherein the scaffold comprises electrospun fibres and the mean fibre diameter of the scaffold is between from about 1 .2 to 4.0 microns.

12. A dressing according to claim 1 , wherein the depth of the scaffold or filler immediately following application of the scaffold or filler to the wound and/or wound integer as a percentage of the depth of the wound is in the range of 100 to 200 %.

13. A method of manufacturing a dressing according to claim 1 in which the scaffold and/or the wound contact integer forms part of the dressing before its application to the wound, which method comprises attaching the wound contact integer removably or irremovably to the compression means.

14. A method according to claim 13, wherein the scaffold is spun directly onto a substrate comprising the dressing compression means or the rest of wound contact integer.

15. A method according to claim 14, wherein temporary or permanent adhesion of the spun scaffold is effected by spinning the scaffold to be self-adhered onto the surface of the substrate.

16. A method according to claim 14 or 15, wherein the scaffold is electrospun

17. A method of use of a dressing according to claim 1 , characterised in that the scaffold, optionally as part of the wound contact integer of the dressing, is applied to the wound bed, and the rest of the dressing is then applied over the wound and secured to the body of the patient by the compression means, optionally by way of at least one layer of pressure sensitive adhesive on the compression means layer.

18. A method according to claim 17, wherein the wound contact integer and/or the scaffold is applied separately before from the rest of the dressing.

19. A method according to claim 18, wherein scaffold is directly electrospun into the wound bed.