WO2001058452A1

WO2001058452A1 - Thermal ablation of tissue

Info

Publication number: WO2001058452A1
Application number: PCT/GB2001/000465
Authority: WO
Inventors: David Fortune; Patrick Trotter; Douglas Stewart; Kevin Webb
Original assignee: Tissuemed Limited
Priority date: 2000-02-08
Filing date: 2001-02-07
Publication date: 2001-08-16
Also published as: AU2001231998A1; GB0002719D0

Abstract

A method for the controlled thermal ablation of tissue comprises applying to the tissue a composition comprising a biocompatible material and a chromophore, and irradiating the composition with light of a wavelength which is absorbed by the chromophore. The absorbed light energy is converted to thermal energy, leading to a rise in temperature and destruction of the tissue.

Description

Title Thermal Ablation of Tissue

This invention relates to materials and methods for the selective destruction of biological tissue using light energy The invention is particularly suitable for treating conditions such as localised microbiological infections, tumours, corns calluses, polyps, warts and skin blemishes In addition the invention may be used for removal of the lining of the womb in the treatment of heavy periods, the transurethral ablation of benign prostatic hyperplasia, the removal of cataracts from lens tissue and in the treatment of chronic bladder syndrome

The use of light to destroy tumours has until recently been focussed on the development of photodynamic therapy (PDT) PDT uses a photosensitizing dye that produces cytotoxic materials, such as singlet oxygen, from benign precursors, when irradiated in the presence of oxygen The effectiveness of PDT is limited by many factors These include

1) The ability of the dye to localise at the treatment site as opposed to surrounding tissue,

2) The short life-time of activated oxygen means that it is unlikely to escape from the cell in which it is produced Its cytotoxicity is therefore likely to be restricted to the cell in which it is produced, resulting in the need for multiple treatments, and

3) Because oxygen is rapidly used up during the activation process a pulsed activation source must therefore be used Expensive optical systems such as diode lasers are therefore required for activation of the benign precursors

In response to the problems associated with conventional PDT, and the toxicity and unwanted side effects of other methods of treatment, new methods of treating such pathologies are under development These could potentially be used as an alternative to, or in combination with, existing methods of treatment One such method designed to destroy localised pathologies is the use of elevated temperatures For example, the use of electric currents (GB2288163), the use of heat via micro heat exchangers inserted into the body (DE361 1971 and US 5534021 ), and techniques involving the input of energy by the application of radiation have all been proposed The last of these involves the use of sound, microwaves ([1] and US 5843144) and radiation of the visible wavelength

Recently, researchers have used lasers to irradiate various types of tumour The absorption of energy causes an increase in temperature of the tumour, and its subsequent destruction by hypothermia (the destruction of blood vessels supplying the tissue), coagulation or vapourisation

This non-PDT use of lasers has been used to treat hepatic tumours [2], breast cancer [3], colorectal villous tumour [4], gynaecological [5] and cerebral tumors [6] and for benign prostatic hyperplasia (US 5312392)

As with PDT, methods that rely on the elevation of temperature also suffer from distinct disadvantages For example, the application of energy is not specific to the diseased tissue, and it is often unclear when sufficient energy has been delivered to destroy the diseased tissue Consequently, the zone of destruction is often difficult to control Some recent inventions have tried to address these problems by the use of techniques to monitor tumour size during the irradiation process In this way the dose can be progressively increased until the tumour is destroyed (see WO99/26696) Other methods of trying to control the amount of tissue destroyed involved the use of lasers of specific wavelengths, designed to target only the diseased tissue, eg a laser 'tuned' to a specific wavelength targeting incident light to specific organ regions, eg the lymph node (see DE 4235841 ), thereby protecting healthy tissue These techniques are time consuming, difficult to control, or have limited utility A light source and a dye have also recently been used to peel off the lining of the womb, preventing heavy bleeding and therefore reducing the need for hysterectomies

The use of tissue bonding material to bond tissues together after surgery, or to repair wounds (see, for example, WO 96/22797) is also known Such materials commonly comprise a proteinaceous material and a low concentration of a chromophore The material is applied to the tissue to be joined and then subjected to curing by the action of light This causes the material to become crosshnked to itself and to the tissue, thereby creating a bond

We have now found that the application of material of the same general type as such tissue bonding material to tumours, corns, calluses, polyps, warts, cataracts, or to any other unwanted tissue (such as in benign prostatic hyperplasia prostatic or chronic bladder syndrome) will result in the specific destruction and removal of the undesirable tissue following irradiation with light

Thus, according to the first aspect of the invention, there is provided a composition comprising a biocompatible material and a chromophore and being suitable for therapeutic use by topical application, said chromophore being present in sufficient concentration to cause absorption of sufficient energy to bring about selective destruction of tissue to which said composition is applied

The biocompatible material is most preferably a cross-linkable proteinaceous or polypeptide material The material may be selected from natural and synthetic peptides, enzymatically cleaved or shortened variants and crosshnked derivatives thereof, as well as mixtures of any of the above Included among the peptides are structural proteins and serum proteins Examples of proteins are albumin, α-globuhns, β-globulins, γ-globulιns, transthyretin, collagen, elastin and fibronectin, and coagulation factors including fibπnogen, fibrin and thrombin The currently preferred material contains albumin

It is particularly preferred that the biocompatible material should comprise albumin in admixture with the chromophore and one or more further components Mammalian albumin, especially porcine albumin, is especially preferred Glycerol is a particularly preferred additional component

Such materials are generally similar to materials known for use as tissue adhesives though it will be appreciated that adhesive properties are not necessarily required for the performance of the present invention Following irradiation with light of an appropriate wavelength, the chromophore in the composition absorbs incident photons, and converts the incident energy to heat, which destroys the abnormal tissue. It is particularly preferred for the chromophore used in the composition to change colour when sufficient energy has been applied to kill the tumour cells or other tissue to be destroyed. Following this colour change, no further absorption of light at this wavelength by the chromophore will occur, therefore limiting the amount of heat energy generated (WO 96/22797 describes such 'colour change' chromophores used in this way). The presence of the chromophore within the composition thus serves as a "molecular switch", controlling the amount of light energy absorbed, and thus also, the amount of heat energy generated. This 'molecular switch' ensures that the correct, final ablation temperatures are obtained, and not exceeded. This minimises thermal damage to the treatment site, and protects the surrounding healthy tissue , thereby making the procedure specific to the targeted tissue. The colour change of the chromophore within the composition also provides a visual end point for the user, indicating when sufficient energy has been applied.

Examples of suitable chromophores which may be incorporated into the composition are basic fuchsin, phloxin, erythrosin, eosin and, particularly, methylene blue.

The amount of chromophore in the material can be adjusted to control the number of photons that are absorbed prior to the colour change. In this way different materials can be formulated to reach different desired temperatures.

The preferred choice of chromophore, particularly where it is desirable to minimise damage to healthy tissue, is methylene blue. Methylene blue has previously been used for destroying tumours. In photodynamic therapy methylene blue and indeed chemically modified variations of methylene blue have been used [7-9].

However, it is important to note that when methylene blue is used in photodynamic therapy it works by a photochemical rather than the photothermal mode of action described in this invention. During photodynamic therapy methylene blue must first find its way inside the cell to be destroyed. It then reacts with oxygen, following irradiation, producing oxygen free radicals. It is this generation of free oxygen that is cytotoxic and destroys the cancerous cells.

The present invention is distinct from the use of methylene blue in PDT, since the invention does not require the dye to be internalised into the cells, and works by elevation of tissue temperature.

In general, the concentration of chromophore in the composition will be rather higher than is the case for compositions intended for use as tissue adhesives. Typically, the concentration of chromophore, particularly in the preferred case of methylene blue, will be 0.25% w/w or greater, more preferably 0.3% w/w or greater, particularly 0.5% or greater. The upper limit on the concentration of chromophore may be several per cent, eg 10%, 5% or 2% w/w.

By modifying the amount of chromophore included in the formulation, the amount of heat energy generated by the composition, following irradiation, can be varied. This is shown, even for low methylene blue concentrations, in Table 1. This enables the tailoring of a composition to produce a localised temperature increase that is specific to the required application. For example, the destruction of a deep tumour may require a high temperature to be achieved - a material containing a high concentration of chromophore may be required in such a case. In contrast, a shallow tumour, or a tumour that is in close proximity to sensitive tissue (e.g. nervous tissue in the brain or spinal cord, or in the bowel/ bladder where perforation is a particular risk), may require a lower concentration of chromophore to limit the final temperature rise obtained. It should therefore be possible to destroy unwanted tissue with little damage to normal tissue. In addition, varying the concentration of the chromophore will allow one to design material that can be used to destroy a tumour by low temperatures (via hypothermia), intermediate temperatures (via coagulation) and high temperatures (via vapourisation). Tablel shows the effect of the concentration of chromophore, in this case methylene blue (MB) on the heat energy generated (measured as temperature by two different methods) following irradiation with visible light.

Table 1

MB concentration Temp (IR camera) Temp (temp, strips) / %w/w / °C / °C

0.05 61 54-60

0.1 83 82-88

0.15 74 66-82

0.2 1 15 93-99

0.24 98 88-93

0.27 Not done 99-104

0.30 Not done 104-1 10

0.33 Not done 104-121

The composition according to the invention may take any one of several different physical forms. The composition may be liquid, a viscous liquid, a semi-solid formulation such as a gel or paste, or in solid form (eg in the form of a sheet).

In addition to the chromophore, the composition preferably also contains other components or excipients, the function of which is to modify the physical properties of the composition, in order to optimise tissue contact, and retention of the composition at the locus to which it is applied. For example a plasticiser may be incorporated to ensure that the composition has sufficient flexibility, even after cross-linking or polymerization. Suitable plasticisers include polyalcohols, eg glycerol, sorbitol etc.

A viscosity-modifying agent may be included in a liquid or gel-like composition to aid with retention of the composition at the site of application. Examples of components that may be incorporated into the composition for this purpose are hyaluronic acid and the salts thereof such as sodium hyaluronate, hydroxypropylmethylcellulose, polyethylglycol, polyvinyl alcohol, polyvinyl pyrollidone, dextrans, honey, sodium chondroitin sulphate and mixtures thereof. In an approach intended to improve the adhesive properties of the composition, a synthetic polymer having bioadhesive properties may also be incorporated The bioadhesive polymer component may be any polymer with suitable bioadhesive properties, i e any polymer which confers on the composition a sufficient degree of adhesion to the tissue to which it is applied Preferred groups of such polymers are polycarboxylic acid derivatives, a particularly preferred class of such polymers being copolymers of methyl vinyl ether and maleic anhydride, in the form of the anhydride, ester, acid or metal salt Such polymers are supplied by International Specialty Products under the trade mark Gantrez

A relatively small proportion of surfactant, most preferably a non-ionic surfactant, will generally be incorporated into the composition, though normally to facilitate manufacture (i e prevention of foaming) rather than to confer any beneficial property on the finished product Suitable surfactants include block copolymers of ethylene oxide, such has those sold under the trade mark Pluronic^® by BASF

In one preferred embodiment, the composition is an aqueous liquid formulation, to allow precise application and optimal tissue contact, particularly on undulating surfaces

In an alternative embodiment, when the resulting composition is of relatively high viscosity, due to inclusion of aforementioned excipients, it may be more appropriately described as a gel, rather than a liquid

This liquid or gel composition most preferably comprises the following proportions of individual components The composition may be manufactured by combining the individual following components in aqueous solution (all amounts are percentage weight of the component in the final composition)

a) cross-linkable material - from about 2% to 45% by weight, more preferably 20% to 40%, and most preferably 25% to 35%,

b) chromophore - from about 0 125% to 5% by weight, more preferably 0 25% to 3%, and most preferably 0.5% to 2%;

c) surfactant - from about 0.001 % to 10% by weight, more preferably 0.01 % to 5%, and most preferably 0.05% to 1 %;

d) plasticiser / viscosity modifying agent- from about 0.01 % to 10%, more preferably 0.1 % to 5%, and most preferably 0.5% to 3%;

If bioadhesion required for the composition, also: e) bioadhesive - from about 0.001 % to 2%, more preferably 0.01 % to 1 %, and most preferably 0.1 % to 0.5%.

In another preferred embodiment, the composition may be provided in the form of a solid matrix or sheet, one example of the formation of which is described in our co-pending International Patent Application number PCT/GB99/02717. The sheet form is particularly advantageous in that it may enhance anchorage of the device at its intended site. For most applications the sheet may be 20 - 200 μm in thickness, and typically approximately 100 μm in thickness.

In addition to the aforementioned components, the sheet form preferably also incorporates a synthetic structural polymer to confer strength and elasticity on the solid matrix.

Suitable such polymers include water-soluble thermoplastic polymers, in particular selected from the group consisting of poly(vinyl alcohol), poly(ethylene glycol), poly(vinyl pyrrolidone), poly(acrylic acid), poly(acrylamide) and similar materials.

The matrix in the form of a sheet, patch or film may be homogeneous or heterogeneous in composition, and may be of continuous or discontinuous structure. One or both major surfaces may have adhesive properties.

The solid composition according to the invention most preferably comprises the following proportions of the individual components (all amounts are percentage weight of the component in the final composition): a) polymerisable and/or cross-linkable material - from about 2% to 80% by weight, more preferably 10% to 60%, and most preferably 30% to 50%;

b) structural polymer - from about 0.01 % to 20% by weight, more preferably 1 % to 15%, and more preferably 2% to 10%;

c) surfactant - from about 0.001 % to 10% more preferably 0.01 % to 5%, and most preferably 0.05% to 1 %;

d) plasticiser - from about 0.01 % to 50%, more preferably 10% to 40%, and most preferably 20% to 40%:

e) chromophore - from about 0.125% to 5% by weight, more preferably 0.25% to 3%, and most preferably 0.5% to 2%;

If bioadhesive properties required, also:

f) bioadhesive polymer - from about 0.01 % to 40%, more preferably 0.1 % to 30%, and most preferably 1 % to 30%.

The non-bioadhesive composition in the form of a solid matrix may be manufactured by combining the individual components a) to e) in solution, and then casting this solution into a suitable non-stick mould (e.g. of PTFE), and allowing the solid matrix to form through evaporation of water.

In an alternative, preferred embodiment, where one surface only, or a selected part thereof, is bioadhesive, the matrix may be prepared by preparing the components as two separate solutions, as follows (all amounts are percentage weight of the component in the respective solution):

a) Solution A: i) polymerisable and/or cross-linkable material: from about 5% to 50%, more preferably 10% to 40 %, and most preferably 20% to 30%; ii) structural polymer: from about 0.01 % to 20%, more preferably 1 % to 10% , and most preferably 2% to 8%; iii) surfactant: from about 0.001 % to 10%, more preferably 0.01 % to 5%, and most preferably 0.1 % to 1 %; iv) plasticiser: from about 0.01 % to 60%, more preferably 1 % to 50%, and most preferably 10% to 40%; v) chromophore: from about 0.125% to 5% by weight, more preferably 0.25% to 3%, and most preferably 0.5% to 2%.

b) Solution B: i) bioadhesive polymer: from about 0.01 % to 40%, more preferably 0.1 % to

30%, and most preferably 1 % to 20%; ii) plasticiser : from about 0.01 % to 40%, more preferably 0.1 % to 30%, and most preferably 1 % to 20%; iii) chromophore: from about 0.125% to 5% by weight, more preferably 0.25% to 3%, and most preferably 0.5% to 2%.

Solution A is cast into a suitable non-stick mould (e.g. of PTFE), and allowed to set through evaporation. Onto this is then cast Solution B, which is also allowed to set. During this process, the second solution penetrates into, and chemically binds to, the matrix formed by the first solution, so that the final matrix is composed of a single sheet with concentration gradients of the various components.

Alternatively, the matrix may be prepared from a single solution comprising all the components, or by combination of multiple solutions to create multi-lamellar matrices (e.g. bioadhesive - polymeric matrix - bioadhesive).

The casting process used to achieve the desired thickness of either the adhesive or non-adhesive sheet may involve pouring, manual spreading or spraying of the component solutions. For use in accordance with the invention, the sheet may have a surface area of only a few square millimetres, extending to several tens of centimetres

The solid matrix will typically contain between 10% and 60% water by weight, and most preferably between 20% and 40% The matrix may be partially or totally hydrated with a suitable aqueous medium at or following implantation (e g a body fluid or saline solution)

For some uses, it may be desirable to modify the stability of the sheet - such that the half-life of the product is extended or reduced This may be particularly applicable where it is desirable to impart a localised pharmaceutical effect following ablation treatment - for example, inhibition of regrowth of tumour tissue by a drug incorporated into the solid matrix This modification of stability can be effected by controlling the extent of formation of covalent bonds between molecules in the matrix (e g formation of disulphide bonds between protein molecules) If an increase in patch stability is desired, the matrix can be pre- treated to induce the formation of intermolecular covalent bonds

Pre-treatment methods that can be used to modify the stability of the matrix are

1) Heat Temperatures from 30-70°C will promote an unravelling of the polypeptide chains, which may reduce water solubility of the protein Exposure of the matrix to temperatures between 70°C and 120°C will promote formation of covalent bonds between albumin molecules This will increase the stability of the sheets, the degree of stability achieved being dependent on the precise time, and temperature of this pre-treatment

2) Irradiation Electromagnetic radiation (including visible and UV light, and gamma irradiation) can promote cross-linking of albumin molecules This is a potential method by which large sheets could pre-treated in such a way as to increase their stability

Further benefits of the composition of the invention are that it is biodegradable and may reduce post-surgical adhesions Preferred materials for use in the invention are activated and cross-linked by irradiation with light The cross-linked material forms a protective layer over the wound and will prevent the formation of undesired connective tissue following surgery This is particularly important during the removal of localised areas of tissue from internal organs (e g liver, bladder or stomach), and will reduce the likelihood of post-surgical complications arising In addition the composition will allow cell infiltration, and the normal healing process, to occur This is important for cosmetic purposes, and means that the material of the invention is particularly suited to the removal of unwanted tissue from skin The material may remain at the treatment site for a considerable time, eg 30 days or more, supporting the natural healing process and reducing complications such as post-surgical adhesion formation

Another beneficial feature of the invention is that the light energy required for the composition to be effective is supplied by a low power polychromatic light source, rather than by an expensive laser This means that each treatment is inexpensive and can be carried out quickly in hospitals, outpatient clinics and even in a general practitioner's surgery for use in routine surgical procedures such as the removal of warts, corns and calluses

According to the invention there is further provided a method for the selective destruction of biological tissue, which method comprises a) applying to the tissue which is to be destroyed a biocompatible material incorporating a chromophore, and (b) irradiating said biocompatible material with light of a wavelength which is absorbed by the chromophore and converted to heat energy by which the tissue is destroyed

The light energy is absorbed by the chromophore and is converted to thermal energy which destroys the adjacent tissue No thermal energy is absorbed directly onto the untreated, surrounding tissue, thus minimising unwanted thermal damage The invention can be used in the treatment of many conditions including tumours, corns, calluses, polyps, warts, skin blemishes, in the removal of the lining of the womb the removal of cataracts from lens tissue and the ablation of benign prostatic hyperplasia Such tissues are destroyed by elevated temperatures while causing minimal damage to the surrounding healthy tissue The invention may also be used to seal or repair bleeding following the removal of unwanted tissue, or to prevent bleeding from lesions such as ulcers, haemangiomas and capillary tears

In addition, the materials used are biodegradable, allow natural healing to occur, and reduce the formation of post-surgical adhesions

It will be appreciated that for many applications, eg the removal of warts or skin blemishes, the method of the invention will have a primarily cosmetic, rather than therapeutic, purpose

In another aspect of the invention there is provided the use of biocompatible material containing a chromophore in the selective destruction of biological tissue by thermal ablation by irradiation with light and conversion of light energy absorbed by the chromophore to thermal energy

The invention also provides the use of a chromophore in the manufacture of material for use in the thermal ablation of biological tissue by irradiation with light and conversion of light energy absorbed by the chromophore to thermal energy

The invention will now be described in more specific detail, by way of example only, with reference to the following Examples

Example 1 Liquid formulation

0 82g of porcine albumin (Sigma A2764), 0 02ml of glycerol and 0 9 ml of a 1 % w/v solution of methylene blue were dissolved in 0 34 ml of water for injection, and mixed together This produced a viscous blue solution The final concentration of methylene blue in this composition was 0 49% w/w

A volume of 10 μl of the composition formed above was dispensed onto a temperature sensitive colourimetric indicator strip, and spread to form a thin layer (analogous to its method of application on tissue). The composition was then irradiated with a polychromatic light source, delivering light energy in the wavelength range 570nm to 730nm. A power of 200mW was used, at a distance of approximately 1 to 2 mm. Irradiation was performed until the blue colour was seen to fade, and then stopped. Data from the temperature strip showed that the peak temperature reached was between 104 ° and 121 °C.

Example 2: Solid formulation 3.05g of porcine albumin, 0.5g of 80% hydrolysed polyvinyl alcohol (m.w. 9,000 kD), 3g glycerol, 0.02g Pluronic 25R2 were dissolved in 3.5g of 3% (w/v) methylene blue solution. 0.1 ml of this solution was poured onto a level PTFE surface, and spread manually to achieve a thickness of approximately 50 μm. The solution was heated at 100 °C for 10 minutes to evaporate off water and cross-link the albumin, thereby forming the solid matrix.

Example 3: Solid self-adhesive formulation

3.05g of porcine albumin, 0.5g of 80% hydrolysed polyvinyl alcohol (m.w. 9,000 kD), 3g glycerol, 0.02g Pluronic 25R2 were dissolved in 3.5g of 3% (w/v) methylene blue to form a first solution. 0.1 ml of this solution was poured onto a level PTFE surface, and spread manually to a thickness of approximately 50 μm. The cast solution was heated at 100°C for 10 minutes to evaporate off water and cross-link the albumin, thereby forming a solid matrix. This was allowed to cool.

5.01 g of Gantrez MS-955 and 8.5g of glycerol were dissolved in 36 ml of a 2% (w/v) solution of methylene blue to form a second solution. A volume of 0.1 ml of this was cast on to the solid matrix formed from the first solution. The matrix was heated further to 70 °C for 15 minutes, to polymerise the second solution.

References

1. Brunaud, J.M., Mordon, S., Maurioury, V and Beacco, C. "Non PDT uses of lasers in oncology" Lasers in Medical Science (1995) ,10, 3-8. 2. Hesterrkamp, J., van Hillegerberg, R.. Vzermany, J.N.M "Interstitial laser coagulation for hepatic tumours" British Journal of Surgery (1999), 86, 293-304.

3. Ismail, M..S. Philipp, G., Torsten, V. Wetzel, H., Berlien, H.P. "Laser induced-thermotherapy (LITT) for treatment of locally addressed recurrence of breast cancer" Lasers in Medical Science (1999), 14, 136-142

4. Aubert, A. Meduri, B, Fritsch, J. Dime. F., Baylin, D.C., Barbagelada, B. "Colorectal Villous tumour-treatment by electroresection and laser coagulation in 134 cases" Presse Medicale (1992) ,42, 2046-20049.

5. Wallwiener, D., Rimbach, S., Kaufman. M., Schmid, H., Pollmann, D., Sohn, C, Vonfournier, D. and Bastert, G. "Palliative laser treatment in Gynaecological oncology" Geburtshilfe Frauenheilkd (1992) 52, 191-194.

6. Derty, R., Pelissouguyotal, I., Mooltolase, C, Amat, D. "Routine use of the CO2-laser technique for resection of cerebral tumours" Acta Neurocherurgical (1993) 123, 43-45.

7. Orth, K., Russ, D. Beck, G., Ruck, A, Beger, H.G. "Photochemotherapy of experimental colonic tumours with intra-tumorally applied methylene blue" Langerbecks Archives of Surgery (1998) 383. 276-281.

8. Wainwright, M., Phoenix, D.A., Rice, L. Burrow, S.M., Waring, J. "Increased cytoxicity and photoxicity in the methylene blue series via chromophore methylation" Journal of Photochemistry and Photobiology B (1997) 40, 233-239.

9. Orth, K. Ruck, A, Beck, G., Stanescu. A, Beger, H.G. "Photodynamic therapy of small adenocarcinoms with methylene blue" Lancet (1995) 345, 519- 520.

Claims

1. A composition comprising a biocompatible material and a chromophore and being suitable for therapeutic use by topical application, said chromophore being present in sufficient concentration to cause absorption of sufficient energy to bring about selective destruction of tissue to which said composition is applied.

2. A composition according to Claim 1 , wherein the biocompatible material is a cross-linkable proteinaceous or polypeptide material.

3. A composition according to Claim 2, wherein the biocompatible material is selected from natural and synthetic peptides, enzymatically cleaved or shortened variants and crosshnked derivatives thereof, and mixtures of any thereof.

4. A composition as claimed in any preceding claim, wherein the biocompatible material comprises albumin in admixture with the chromophore and one or more further components.

5. A composition as claimed in Claim 4, wherein the albumin is a mammalian albumin.

6. A composition as claimed in Claim 5, wherein the mammalian albumin is porcine albumin.

7. A composition as claimed in any preceding claim, further comprising glycerol.

8. A composition as claimed in any preceding claim, wherein the chromophore changes colour when sufficient energy has been applied to kill cells to which the composition has been applied.

9. A composition according to any preceding claim, wherein the chromophore is selected from the group consisting of basic fuchsin, phloxin, erythrosin, eosin and methylene blue.

10. A composition according to any preceding claim, wherein the chromophore is methylene blue.

11. A composition according to any preceding claim, wherein the concentration of chromophore is 0.25% w/w or greater

12. A composition according to any preceding claim, wherein the concentration of chromophore is 0.3% w/w or greater

13. A composition according to any preceding claim, wherein the concentration of chromophore is 0.5% or greater.

14. A composition according to any preceding claim, wherein the concentration of chromophore is 10% w/w or less.

15. A composition according to any preceding claim, wherein the concentration of chromophore is 5% w/w or less.

16. A composition according to any preceding claim, wherein the concentration of chromophore is 2% w/w or less.

17. A composition according to any preceding claim, further comprising a synthetic polymer having bioadhesive properties.

18. A composition according to Claim 17, wherein the synthetic polymer having bioadhesive properties is a copolymer of methyl vinyl ether and maleic anhydride, in the form of the anhydride, ester, acid or metal salt.

19. A composition as claimed in any preceding claim, which is in the form of an aqueous liquid formulation.

20 A composition according to Claim 19, which contains a viscosity-enhancing agent and is in the form of a gel

21 A composition according to Claim 19 or Claim 20, which comprises a) cross-linkable material - from about 2% to 45% by weight, more preferably 20% to 40%, and most preferably 25% to 35%, b) chromophore - from about 0 125% to 5% by weight, more preferably 0 25% to 3%, and most preferably 0 5% to 2%, c) surfactant - from about 0 001 % to 10% by weight, more preferably 0 01 % to 5%, and most preferably 0 05% to 1 %, d) plasticiser / viscosity modifying agent- from about 0 01 % to 10%, more preferably 0 1 % to 5%, and most preferably 0 5% to 3%, and, optionally, e) bioadhesive - from about 0 001 % to 2%, more preferably 0 01 % to 1 %, and most preferably 0 1 % to 0 5%

22 A composition according to any one of Claims 1 to 18, which is in the form of a solid matrix or sheet

23 A composition according to Claim 22, wherein the sheet is 20-200μm in thickness

24 A composition according to Claim 22 or Claim 23, further comprising synthetic structural polymer to confer strength and elasticity on the solid matrix

25 A composition according to Claim 24, wherein said synthetic structural polymer is selected from the group consisting of poly(vιnyl alcohol), poly(ethylene glycol), poly(vιnyl pyrrohdone), poly(acryhc acid), poly(acrylamιde) and similar materials

26 A composition according to any one of Claims 22 to 25, which comprises a) polymerisable and/or cross-linkable material - from about 2% to 80% by weight, more preferably 10% to 60%, and most preferably 30% to 50%, b) structural polymer - from about 0 01 % to 20% by weight, more preferably 1 % to 15%, and more preferably 2% to 10%; c) surfactant - from about 0.001 % to 10% more preferably 0.01 % to 5%, and most preferably 0.05% to 1 %; d) plasticiser - from about 0.01 % to 50%, more preferably 10% to 40%, and most preferably 20% to 40%; e) chromophore - from about 0.125% to 5% by weight, more preferably 0.25% to 3%, and most preferably 0.5% to 2%; and, optionally, f) bioadhesive polymer - from about 0.01 % to 40%, more preferably 0.1 % to 30%, and most preferably 1 % to 30%.

27. A composition according to any one of Claims 22 to 26, which contains between 10% and 60% water by weight, and most preferably between 20% and 40%.

28. A method for the selective destruction of biological tissue, which method comprises a) applying to the tissue which is to be destroyed a composition as claimed in any preceding claim, said composition including a chromophore; and b) irradiating said composition with light of a wavelength which is absorbed by the chromophore and converted to heat energy by which the tissue is destroyed.

29. A method according to Claim 28, wherein the chromophore is methylene blue.

30. A method according to Claim 28 or Claim 29, wherein the composition is applied to a tumour, corn, callus, polyp, wart, skin blemish, the lining of the womb, a cataract or benign prostatic hyperplasia.

31. A method according to any one of Claims 28 to 30, which is wholly or primarily a cosmetic method.

32. The use of biocompatible material containing a chromophore in the selective destruction of biological tissue by thermal ablation by irradiation with light and conversion of light energy absorbed by the chromophore to thermal energy.

33. The use of a chromophore in the manufacture of material for use in the thermal ablation of biological tissue by by irradiation with light and conversion of light energy absorbed by the chromophore to thermal energy.