GB2474851A

GB2474851A - Wound dressing comprising anti-microbial honey encapsulated within biocompatible and biodegradable fibre, and the fibre's production

Info

Publication number: GB2474851A
Application number: GB0918841A
Authority: GB
Inventors: Saeed Hamzeh; Mohsen Miraftab
Original assignee: University of Bolton
Current assignee: University of Bolton
Priority date: 2009-10-27
Filing date: 2009-10-27
Publication date: 2011-05-04
Also published as: GB0918841D0

Abstract

A material 2 is encapsulated in a fibre 4. The fibre 4 is biocompatible and biodegrades upon contact with fluids emanating from a human or animal body. The material 2 is preferably encapsulated in discrete sections of the fibre or as a continuous core. The preferred encapsulated material 2 is honey obtained from the treeLeptospermumscopariumand has anti-microbial properties. Preferably the fibre 4 comprises chitosan, pectin, silk, polylactic acid or calcium alginate. The fibre is produced by co-extruding a water-soluble biocompatible material and the anti-microbial material 2, and then making the soluble filament 4 insoluble by means of ion exchange. The preferred soluble filament 4 comprises sodium alginate and the ion exchange bath contains a source of Ca ions. The fibres are used in wound dressings.

Description

Fibres for Infection Control The present invention relates to a fibre which is for use in the treatment of physiological target sites and which is able to impart an antimicrobial effect and aid in the control and treatment of infection in the physiological target sites, and to a method of production of the fibres.

In recent years, silver has enjoyed a major comeback as an active antimicrobial and healing promoter for infected wounds. However, the presence of silver in wound dressings not only increases the cost of treatment, but also could cause undesirable side effects, such as staining and allergic responses. There has thus been a need for an alternative potent yet safe, and simultaneously relatively cheap, antibacterial wound dressing component.

Amongst others, one such potential component is honey. Honey has had a prominent place in traditional medicine for centuries, and has been used for reducing potential clinical infection and for accelerating wound healing. Despite its widespread use in years gone by, many practitioners had been sceptical about its modem day potential benefits. However, many clinical and analytical studies in recent times have confirmed its multifunctional benefits and the successful outcomes of its use.

The antibacterial properties of honey were first identified by Van Ketel in 1892. Honey is a supersaturated sugar solution with a low water activity and high S...

:::. : osmolarity. This means that there is little water available to support the growth of bacteria and yeast. The high osmolarity is also considered to be a valuable tool in the *5** * treatment of established infections, because it prevents the growth of bacteria and *5*** * . encourages healing. S... * * . * . S. S S * S S 55

The antibacterial action of some honey is linked to the production of hydrogen peroxide on dilution of the honey with wound exudate. Hydrogen peroxide is a well-.

known antimicrobial agent, initially praised for its effective antibacterial and cleansing properties when it was first introduced into clinical practice. In more recent times however, it has been frowned upon because of inflammation and damage it can cause to tissues. However, the hydrogen peroxide concentration produced in honey activated by dilution is typically around 1 mmol/l, about 1000 times less than in the 3 per cent solution commonly used as an antiseptic. The harmful effects of hydrogen peroxide are further reduced because honey isolates and inactivates the free iron which catalyses the formation of oxygen free radicals produced by hydrogen peroxide, and its antioxidant components help to mop up oxygen free radicals.

C5H1206 + H20 + 02 -÷ C6H1207 + H202 (1) (glucose) (gluconic acid) When honey is used topically (for example, as a wound dressing), hydrogen peroxide is produced by dilution with body fluids, as illustrated by equation (1) above. As a result, hydrogen peroxide is released slowly, and in safe concentrations, and acts as an antiseptic. S... S. *

* : 20 In recent years, honey from different sources has been studied and a few have been identified as having particularly high antibacterial activity. For example, 5SS * Manuka honey gathered from the Manuka tree Leptospermum scoparium, native to New Zealand, has an exceptionally high antibacterial activity for the treatment of infected wounds. There are two types of Manuka Honey: ordinary Manuka honey with only the hydrogen peroxide antibacterial property common to most honeys and UMF Manuka honey which has the natural hydrogen peroxide antibacterial property in addition to its own natural UMF antibacterial property. This gives it a still further increased antibacterial potency. Such specialty honey is identified by the name UMF (Unique Manuka Factor).

"Inhibine number" is another method of expressing honey's antibacterial properties. The inhibine number is the degree of dilution to which a honey will retain its antibacterial activity, representing sequential dilutions of honey in steps of 5% from 25% to 5%. One reason why Manuka honey is recommended is because antibacterial factors within it are unaffected by enzymes in the body that destroy hydrogen peroxide components.

The higher the UMF rating, the greater the level of antibacterial activity which is observed. Medical professionals in New Zealand use active Manuka honey with a rating of UMF 10 or higher. As it is important that a sterilised, laboratory-tested honey is used for medicinal purposes, UMF graded honey is also sterilised by gamma irradiation without any loss of antibacterial activity.

Clinical observations suggest that Manuka honey holds significant promise, particularly in the management of non-healing wounds, and when applied topically on wounds will accelerate the healing processes. It is also known for enhancing wound *.S* : contraction in fresh wounds, which is one of the key features of wound healing. * *

Research has also indicated that Manuka honey may possess anti-inflammatory activity which stimulates immune responses within a wound, and the ability to * * S... * S

I *S * * S I I **

modulate production and quenching of free radicals may contribute to the ability of some honeys to help in resolving the state of inflammation typifying chronic wounds.

Recent studies on the medical use of Manuka honey as wound dressings, particularly in patients susceptible to MRSA and other infections involving antibiotic-resistant strains of bacteria, has proved to be positive. Manuka honey has been used to treat infections in a wide range of wound types including diabetic foot ulcers, leg ulcers, pressure sores, boils, burns, abscesses, surgical wounds, necrotising faciitis and neonatal post-operative wound infections. It has also been successful in healing wounds that do not respond to traditional treatment methods.

Honey creates a moist healing environment that allows for the regeneration of new skin growth across a healing wound, flush with the surface of the skin. This prevents scarring and deformity of the skin. If a dry scab forms on a wound, the skin cells can only grow across the wound, deep down where it is moist. However, Manuka honey causes scabs and dead skin cells to lift off the surface of the wound, leaving a clean and healthy wound bed in which re-growth of tissue can occur.

Manuka honey stimulates the formation of new blood capillaries and the growth of fibroblasts that replace the connective tissue of the deeper layer of the skin and produces the collagen fibres that give strength to the repair. In addition, honey stimulates the growth of epithelial cells that form the new skin cover over a healed :::. . 20 wound. As a result, the honey prevents scarring and keloid formation, eliminating the *.S.

need for skin grafting. **.. * *

* Manuka honey also has an anti-inflammatory action which reduces the *:::: swelling around a wound. This improves circulation and hastens the healing process. ** * * S * * **

Its anti-inflammatory properties also reduce the pain generated by the wound. Manuka honey also reduces the amount of fluid exuding from the wound. Another factor is that its high sugar content draws lymph out of a wound which lifts dirt out of the Scientists also have reason to believe that Manuka honey even prevents the odour that is commonly associated with serious wounds and skin ulcers by clearing bacterial infection and more immediately, by providing sugar to any bacteria present.

In this environment, lactic acid is produced instead of the smelly by-products of the degradation of protein.

Even though the use of Manuka honey in the treatment of wounds has been found to have no negative medical side effects, the sticky mess of applying honey to the skin is somewhat undesirable. The amount of honey needed to treat a wound depends upon the amount of exudates; beneficial effects are reduced or lost if a small amount of honey is diluted by large amounts of exudates. The deeper the infection, the more honey will be needed to achieve an effective level of antibacterial activity diffusing deep into the wound tissues.

Typically, about 20 ml of honey (about 25-3 0 g) is used on a 10 cm-square dressing. Dressings are usually changed once a day, but with heavily exuding or *: : : . infected wounds they may initially need to be changed up to three times a day. The * 20 anti-inflammatory and antibacterial action of honey will reduce the amount of exudates, so within a few days the dressings would need to be changed less *.

: frequently. In some cases dressing changes may be reduced to every two to three days. S S * S **

Honey, Manuka or otherwise, is runny and sticky, which can make it a difficult medium to handle, but this is currently dealt with by soaking it into an absorbent wound-contact material, such as gauze and cotton tissue. However, the contact material is not ideal and suffers from incompatibility issues as well as associated problems with removal and post treatment disposals. In cases where a cavity is being treated, sticky raw honey is virtually poured in before dressing pads are applied. Secondary dressings are subsequently applied to keep the dressing in place.

To remedy the runny effect of honey, some honey-based creams have been produced for direct application, but this is not a satisfactory solution because it compromises honey's natural concentration and its consistency, hence affecting its potency and antimicrobial effectiveness.

Therefore, it is an object of the present invention to provide a means of applying an antimicrobial component, such as honey, to a physiological target site for the control and treatment of infection which is able to mask any stickiness and difficulty of application. The present invention is able to overcome one or more of these disadvantages.

According to the present invention there is provided a biocompatible fibre comprising a secondary material encapsulated therein wherein the fibre is * : 20 biodegradable upon contact with fluids from a human or animal body.

* The physiological target site(s) referred to herein may be any site(s) in or on *.S* * the body of an animal. The animal may be a human or a non-human animal. The ***.*.

* physiological target site may be a wound or it may be an opening in a body caused * S S SS * S. * * S* * S. during a medical procedure, for example during surgery. Hereinafter, the physiological target site is generally referred to as a wound for convenience and illustrative purposes only.

According to one embodiment of the invention, the secondary material used in the invention is typically an antimicrobial material. More typically, the antimicrobial material is honey, and even more typically it is UMF Manuka honey.

According to another embodiment, the secondary material may be a pharmaceutically active component such as a drug or another form of medication.

According to one embodiment of the invention, the secondary material may be trapped or encapsulated within a continuous length of fibre such that the secondary material is held within discrete sections of the fibre. This results in bead-like fibres which can subsequently be made into nonwovens or any other textile-based structures with maximum diversity in form, shape and ease of application. Techniques for the inclusion of one medium into another as a continuous bicomponent fibre are known, but the technology involved in encapsulating the medium in segmented quantities is not.

The segmentation is achieved by causing deliberate intermittent feeding of the core material during manufacture, thus allowing the sheath fibre to open and close at the beginning and the end of each segment. The advantage of such an elaborate action and hence the resulting fibre is that whenever and wherever the fibre is cut, only a * S S tiny amount of the secondary material is exposed, and therefore the messiness is S...

avoided in processing and handling. Alternatively, the same effect maybe achieved as S...

* : * an after process, i.e. the secondary material is initially allowed to occupy the core but * . S. S *5 S * * S * I. then made into segmented capsules by a mechanical or physical process as an after treatment.

According to the invention, the fibre is biocompatible and biodegradable upon contact with fluids which are exuded from physiological target sites on a human or animal body, gradually dissolving upon such contact. It is this biodegradable property which enables the release of the secondary material from its encapsulated state in the fibres and thus delivery of the secondary material to the target site from the fibre and the subsequent treatment. It also means that the fibres do not need to be removed from the physiological target site after the treatment as they integrate and eventually dissolve harmlessly within the body.

By biocompatible', it is meant that the fibre does not cause any significant undesirable medical side effects to a human or animal as a result of its dissolution in the exudates from the physiological target site on a body.

Typically, the biocompatible fibre comprises a biocompatible polymer, typically a biocompatible polysaccharide. Amongst the range of available biocompatible polysaccharides, alginates have been developed most extensively for use in wound dressings and a vast number of alginate-based dressings are currently available. Of course, it will be appreciated that any other equally safe biomaterial with similar properties may be used. Other than alginate, the encapsulating or sheath * :. 20 material could be any other polysaccharide, protein or man-made fibre including, but :.: not limited to, chitosan, pectin, silk, polylactic acid (PLA), or other equally S...

* physiologically acceptable fibres.

* :* The term alginate relates to a polymer composed of mannuronate (Iv!) and :: guluronate (G) monomeric units. An alginate structure is exemplified below.

(RDH(at9inicackJ) \ R Na (sodium alginate) m = Ca (calcium alginate)/ a-L-guluronate / alginate 4)-a-L-GulpA-(i a. -.4}-D-ManpA-( I (atrangecl 1r a block fas1ion} Sodium alginate is soluble in water and only a small percent of the dry power forms a smooth dope after thorough mixing. The dope is then often extruded into a mild calcium chloride bath where sodium from the extruded dope exchanges ions with those of calcium. The rate and extent of the ion exchanges leads to an insoluble calcium alginate fibre. The production of calcium alginate is well documented and available in the literature. Dressings made from calcium alginate revert back to soluble sodium alginate upon exposure to wound exudates due to reverse ion exchanges, i.e. the calcium ions interchange with the sodium ions present in the exudates as sodium chloride salt, hence making the alginate soluble again.

To enable the encapsulation of the secondary material in the fibres of the invention, an alginate is typically used as the fibre material, and can be readily :::: prepared. An exemplary but non-limiting general description of the preparation of a S...

biocompatible according to the invention is given below. S... * S

An appropriate quantity of a water-soluble alginate, such as sodium alginate * . :: powder, is dissolved in deionised water (about 1-5% w/v) whilst stirring for a period of time, e.g. about 1-4 hours, and it is then allowed to degas overnight (i.e. about 12- 16 hours). The alginate dope and the secondary material are independently housed and fed separately into the extruder head such that sodium alginate is extruded as the sheath or cover material into calcium chloride bath and the secondary material as the core material. This extrusion setup is no different to the currently available bicomponent extrusion technique. However, to create the intermittent or discrete encapsulation of the secondary material, the feeding rate of the secondary material is pulsated at regular intervals such that the generated bicomponent fibre approaches a number of closing points in a "node:anti-node" configuration. This effect may also be generated as an after treatment if the secondary material is continuously run through the centre of the fibre. This may be achieved by physical or mechanical clipping or pinching of the fibre at regular intervals as an after treatment.

The distance and frequency of secondary material encapsulation can be controlled by varying the feed speed of the secondary material and the rate at which it is delivered to the sheath material as it passes through the extruder head.

Once made into a wound dressing as a nonwoven or any other type of textile structure, the dressing would typically operate in the following way.

Upon application to an exudating wound, the secondary material is gradually released as the calcium ions in the dressing begin to exchange ions with sodium present in the exudates. The dissolved or disintegrated dressing releases the secondary * S * material locally and the dissolved alginate is harmlessly absorbed by the body. Any fibrous excess could alternatively be easily washed off during dressing changes or *5*S *: post-treatment of the wound if necessary. *.** * ** S. S S. * * *. S.

The solubility properties of the fibre can be adjusted by using different concentrations of alginate or by manipulating the internal diameter of the sheath fibre.

By doing this, the rate of dissolution of the material comprising the sheath part of the fibre, and hence the rate of dispersal of the secondary material to the physiological target site, can be varied as desired.

It will be appreciated that the rate of dissolution of the material comprising the sheath part of the fibre may vary with the temperature at the physiological target site.

The fibre may be susceptible to dissolution or dispersal at temperatures of around 0 to around 100°C, such as around 45°C or below, more preferably around 41°C or below and most preferably around 37°C (i.e. around normal human body temperature) or below.

The invention will now be described further by way of example with reference to the following figures which are intended to be illustrative only and in no way limiting upon the scope of the invention.

Figure 1 shows a longitudinal profile of the fibre of the invention.

Figure 2 shows a shot through the cross sectional profile of the capsule within the fibre of the invention.

Figure 3 shows a representation of a design and functional operation of an extruder head used to make the fibre of the invention.

Figure 1 shows honey 2 encapsulated within a sheath fibre 4 of the invention. * * *

::..: The honey is encapsulated in several discrete sections of the fibre 4, which is shown ***.

in a node:anti-node' arrangement with the nodes 6 and anti-nodes 8 clearly **** * * S...

distinguishable. * S * . * ... * S* S* S S. * * S* S 55

H

Figure 2 shows the end-on cross sectional view of the fibre 4 with the honey 2 visible in the core of the fibre 4.

In Figure 3, the extruder head 10 which is used to manufacture the fibre of the invention is shown. This is a similar arrangement to those used in conventional bi-component extrusion techniques.

The raw material for the sheath fibre is injected into primary inlet 12 of the extruder head, while the core material, i.e. the honey, is injected into secondary inlet 14. If a continuous core of honey is desired as in conventional bicomponent fibre extrusion, the honey supply is constant to the sheath fibre material from the inlet 14.

This would then be treated mechanically or physically to impart discrete encapsulation. If discrete compartments of honey in the fibre are desired during manufacture, as is the more likely case, the honey is supplied in discrete pulses at regular intervals from the inlet 14 to the sheath fibre material as it passes through the bead 10, before being extruded out through needle 16.

A plurality of the fibres can be woven, knitted or nonwoven, and used to make a wound dressing material. The material may take any suitable form and may be provided in a range of different sizes, shapes and thicknesses necessary to deal with a wound, such as a square, rectangular, circular, elliptical, or even rope-like configuration. For example, the material may be a generally flat shape with little *::: : 20 height relative to its width/depth. Any regular or irregular shape may be employed. It * may be provided in large sheets which can be cut to the required size.

The thickness of the material may be varied between upper and lower limits as *.*.

* :.: desired. The upper limit of the thickness is typically about 2 cm, down to a few * * * ** * S. S S 5.

microns, such as 5-10 microns. It is however important that the material is flexible so that it can be curved to fit the contours of the body.

The material can be applied by a person with only basic medical training. It is simply a matter of applying the material to the physiological target site and maintaining its position there. The dressing made from the fibres of the invention will not be suitable for entirely dry wounds as presence of liquid/exudates is necessary to initiate the unlocking of the encapsulated secondary material.

According to another embodiment of the invention, the fibres may be made into nonwovens or any other textile-based structure intended for wound dressing.

According to a further aspect of the invention, there is provided a method of manufacturing a fibre comprising a secondary material encapsulated therein wherein the fibre is biodegradable upon contact with fluids from a human or animal body, comprising the steps of: i) co-extruding a water-soluble biocompatible material and a secondary material; and ii) contacting the co-extruded product with a substance able to exchange ions with the water-soluble material in order to render the water-soluble material substantially water insoluble.

* 20 Depending upon whether it is desired to have the secondary material, such as * honey, as a continuous core in the sheath fibre or encapsulated in discrete sections of **** the fibre, the secondary material may be supplied either continuously or intermittently **** * :.: into the fibre during the extrusion process. Alternatively, the segmented encapsulation **** * * * ** * ** * * * * * *.

effect may be achieved by using a mechanical or physical process as an after treatment.

Typically, the water-soluble fibre material is sodium alginate and the substance able to exchange ions with it contains a source of calcium ions, typically calcium chloride.

The present invention also provides a method of controlling or treating infection in a physiological target site, comprising the steps of applying to a physiological target site a plurality of fibres comprising a secondary material encapsulated therein wherein the fibre is biodegradable upon contact with fluids from a human or animal body.

More specifically, the secondary material is released from the fibres as a result of ion exchange processes which take place between the fibre and exudates from the physiological target site. The e.g. calcium ions in the fibre are exchanged for the sodium ions in the wound exudates, thus rendering the fibre soluble. The structure of the fibre disintegrates and releases the secondary material encapsulated inside. The now soluble fibre component, such as sodium alginate, is physiologically acceptable and can merge safely with the wound exudates.

The present invention also provides a use of a fibre comprising a secondary material encapsulated therein wherein the fibre is biodegradable upon contact with fluids from a human or animal body, in controlling or treating infection in a physiological target site. S...

It is of course to be understood that the present invention is not intended to be * *1 restricted to the foregoing examples which are described by way of example only. * . .

S S* S *S

Claims

Claims 1. A biocompatible fibre comprising a secondary material encapsulated therein wherein the fibre is biodegradable upon contact with fluids from a human or animal body.
2. A fibre according to claim 1, wherein the secondary material is encapsulated in discrete sections of the fibre.
3. A fibre according to claim 1, wherein the secondary material is encapsulated within the fibre as a continuous core.
4. A fibre according to claim 1 or claim 2, wherein the encapsulation of the secondary material in discrete sections of the fibre is achieved by an intermittent feeding of the honey into the fibre.
5. A fibre according to claim 4, wherein the distance and frequency of the discrete sections of the fibre containing the encapsulated honey can be controlled by varying the rate at which secondary material is delivered to the fibre. * * *
6. A fibre according to any preceding claim, wherein the biocompatible fibre is a **** * biocompatible polymer. *** *

** **.* * * * *** * * * ** S ** * * S I * I.
7. A fibre according to claim 6 wherein the biocompatible polymer comprises a polysaccharide, a polysaccharide, a protein, or a man-made fibre.
8. A fibre according to claim 7 wherein the fibre is selected from chitosan, pectin, silk, or polylactic acid.
9. A fibre according to claim 7 wherein the polysaccharide comprises an alginate.
10. A fibre according to claim 9 wherein the alginate is calcium alginate.
11. A fibre according to any preceding claim, wherein the secondary material is released from the fibre as a result of ion exchange processes taking place between the fibre and exudates from a physiological target site.
12. A fibre according to any preceding claim, wherein the secondary material is an antimicrobial material.
13. A fibre according to claim 12, wherein the antimicrobial material comprises honey. S. * S *SS S S... * S S.'.
14. A fibre according to claim 13 wherein the honey is Manuka honey obtained S...* :.: from the tree Leptospermum scoparium. I... * SS S* * *5 * S S* S 55
15. A fibre according to claim 14 wherein the Manuka honey has a UMF (Unique Manuka Factor) value of at least 10.
16. A fibre according to any preceding claim for use in the manufacture of a wound dressing.
17. A wound dressing comprising a biocompatible fibre according to any of claims 1-15.
18. A method of manufacturing a biocompatible fibre according to any of claims 1-15, comprising the steps of: i) co-extruding a water-soluble biocompatible material and a secondary material; and ii) contacting the co-extruded product with a substance able to exchange ions with the water-soluble material in order to render the water-soluble material substantially water insoluble.
19. A method according to claim 18 wherein the secondary material is supplied *::: e
20 either intermittently or continuously into the fibre during the extrusion. * ?*. * e S.. *

5.., 20. A method according to claim 18 or claim 19, wherein the water-soluble fibre *: material is sodium alginate and the substance able to exchange ions with it contains a source of calcium ions.

II S. I S. * * I I. 50
21. A method of controlling or treating infection in a physiological target site, comprising the steps of applying to a physiological target site a plurality of biocompatible fibres having a secondary material encapsulated therein wherein the fibre is biodegradable upon contact with fluids from a human or animal body.
22. A method according to claim 21, further comprising the secondary material being released from the fibres as a result of ion exchange processes taking place between the fibre and exudates from the physiological target site.
23. A method according to any of claims 18-22, wherein the secondary material is an antimicrobial material.
24. A method according to claim 23, wherein the antimicrobial material comprises honey.
25. Use of a biocompatible fibre according to any of claims 1-15 in controlling or treating infection in a physiological target site.SS * S *. S
26. A fibre, wound dressing, method or use substantially as described herein in the S. S** * .: description and drawings. * **. * . . S. * S. *S SI S *q