Topical brachytherapy device and method of treatment of malignant cancer

The present application claims priority from Australian Provisional Patent Application No 2018900745, filed 7 Mar. 2018, the contents of which are incorporated herein by reference in their entirety.

The present disclosure relates to a brachytherapy device for application on a wound site in a body. The device may, in some examples, be used to treat cancers of the body.

Cancer is a disease of the cells that impacts multiple body organs and affects a large number of people throughout the world. When normal mechanisms for regulating the growth of cells in the body are disturbed, cells can begin to grow in an uncontrolled fashion. A cancer develops when normal cells in the body begin to develop an abnormal growth pattern, and do not undergo the normal cell lifecycle including cell death. The uncontrolled rapid growth, and invasion of normal tissue by abnormal cells is the definition of malignant cancer. Cancer cells may undergo metastasis whereby they detach from their primary site and travel to other parts of the body where they begin to grow new tumor deposits.

Treatments for cancer can include surgery, chemotherapy, and radiation therapy or combinations thereof. Surgery is usually the treatment of choice for most cancers if the cancer appears localized to an organ, and initial work up of a patient to determine whether the tumor is removable by surgical means. Some cancers are amenable to surgical resection of metastatic deposits, such as colorectal, melanoma, and neuroendocrine tumors.

In surgical removal of a cancerous tumor, it is important to completely remove or destroy all the malignant cells. Surgical removal of cancer involves cutting out the tumor or tumors, including a margin of normal tissue around the cancer to ensure the entire disease is excised. This often includes removal of the lymph nodes to which the primary tumor may spread. Generally, a pathological examination of the resection margin of the tissue that is removed is employed at the time of surgery to ensure that the tumor has been completely removed.

One of the most feared complications of major cancer surgery is incomplete resection, or the presence of microscopic tumor cells at the resection margin. The likelihood of such an occurrence is reduced but not eliminated by the use of frozen section histology, which has a greatly reduced accuracy without the facility of immunohistochemistry to identify tumor cells. Secondly, many cancers infiltrate along lymphatic channels or follow perineal lymphatics where they are impossible to detect at the time of surgery.

Tumor cells can be left behind during cancer surgery because they have invaded into a critical structure that cannot be safely resected or reconstructed in an individual patient. In many cases, the index operation is such a physical and metabolic insult to the patient's physiology that re-operation and further resection is just not possible. In these cases, survival of the individual patient with positive margins is greatly and significantly reduced from an equivalent patient with clear margins.

The current process to manage close or positive margins is chemotherapy with or without adjuvant radiotherapy to the operative bed. This treatment is often ineffective at preventing local recurrence, and highly toxic. The doses of radiation achieved by the tumor cells are severely limited because of the presence of radiosensitive surrounding structures like the bowel, and the need to wait for reconstructed structures (like anastomoses) to heal before the commencement of chemotherapy.

This results in an ineffective radiation dose to the operative bed for tumor control, and a delay often up to 8-10 weeks before chemotherapy is instituted. In this time, the immunological/inflammatory insult of major surgery decreases the body's ability to fight tumor cells, and the cells at positive margin are left untreated, which results often in local recurrence, which can then metastasize throughout the body.

Recently the utility for high dose rate brachytherapy devices for managing inoperable tumors has increasingly been recognized. Radio-isotopes devised from beta emitting particles injected intra-arterially have shown potential in managing inoperable liver tumors, and beta-emitters suspended in a silica diluent has shown early potential for injection or positioning directly into inoperable pancreatic tumors through special applicators inserted into body cavities or tissues. There is however currently no suitable device for the routine management of the risk to the patient of positive margins post-surgery, and current devices based on the prior art are not useful as a routine surgical adjunct. Barriers to creation of such a routine surgical device include high cost, moderate inflexibility, non-bioresorbable radio-isotope sources, and a lack of absorbable unidirectionality.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application.

Throughout this specification the word “comprise,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Brachytherapy devices of the prior art are often inflexible and not fully bioabsorbable and bioresorbable by the body. This is because of the use of non-bioabsorbable/bioresorbable radio-isotope sources, or metallic shields used to make the device unidirectional. This in turn does not allow accurate imaging of the site after resection. Inflexible brachytherapy devices of the prior art are also not suitable for an adjunctive approach to surgery as they are not able to fully conform to the operative bed, providing a uniform dose to every cell. Devices of the prior art have facilitated the production of discrete metallic sealed sources, which may be connected together by a flexible membrane. They are limited in conformability, in dose distribution, and by being non-absorbable in the body. Foreign objects, like brachytherapy seeds of the prior art, which are permanently implanted in the body (particularly in a surgical field which is potentially contaminated with microorganisms) have a very high risk of chronic infection and severe morbidity for the patient. This risk is not mitigated with a partially absorbable device, if there is any long term residual material in the brachytherapy seeds. It is therefore desirable for a brachytherapy device to be flexible, unidirectional (so that the surgeon and operating theatre staff have minimal exposure to radiation) and fully bioresorbable in the body, such that no foreign or metallic material remains in the long term.

Disclosed herein, in various embodiments, is a flexible brachytherapy device for application on a wound site in a body, the device comprising: a bioresorbable carrier matrix structure comprising a plurality of radio-isotope particles, the bioresorbable carrier matrix structure configured to degrade, when implanted at the wound site, at a rate substantially longer than a half-life of the plurality of radio-isotope particles such that activity from the plurality of radio-isotope particles is localized to the wound site, wherein the bioresorbable carrier matrix structure has opposite first surface and second surfaces; a hydrophilic substrate located adjacent to the first surface of the bioresorbable carrier matrix structure, wherein the hydrophilic substrate adheres to the wound site, the hydrophilic substrate configured to degrade, when implanted at the wound site, at a rate shorter than the bioresorbable carrier matrix structure to prevent migration of the device during the half-life of the plurality of radio-isotope particles; and a hydrogel substrate located adjacent to the second surface of the bioresorbable carrier matrix structure, the hydrogel substrate configured to shield radioactivity and to degrade at a rate longer than the half-life of the plurality of radio-isotope particles.

The bioresorbable carrier matrix may be formed by adsorbing or dispersing an aqueous solution of a radio-isotope to a hydrophobic substance. The bioresorbable carrier matrix may be further formed by precipitating the radio-isotope to form a plurality of insoluble radio-isotope particles in the bioresorbable carrier matrix structure.

The hydrophobic substance may comprise a hydrophilic surface to form the bioresorbable carrier matrix structure. The aqueous solution may comprise radioactive ions.

The radioactive ions are derived from one or more of: monosodium phosphate, disodium phosphate, potassium phosphate, dipotassium phosphate, orthophosphoric acid or tetrasodium pyrophosphate or soluble compounds containing iodide.

The bioresorbable carrier matrix structure may be configured with material(s) degradable by enzymatic processes. The bioresorbable carrier matrix structure may be configured with material(s) degradable by pyrophosphatase.

The bioresorbable carrier matrix structure may be provided by adsorbing or dispersing an aqueous solution of a radio-isotope to an amorphous or semicrystalline hydrophobic substance to provide the bioresorbable carrier matrix structure. The amorphous or semicrystalline hydrophobic substance may comprise a hydrophilic surface.

The plurality of radio-isotope particles may comprise elements in the compound molecules of calcium phosphate. The compound molecules of calcium phosphate may comprise one or more of: calcium pyrophosphate, monocalcium phosphate, dicalcium phosphate, octacalcium phosphate, tricalcium phosphate, hydroxyapatite, fluoroapatite or tetracalcium phosphate.

The precipitant may comprise an aqueous solution of calcium ions. The precipitant may comprise one or more of calcium chloride, calcium hydroxide, calcium nitrate or calcium bromide.

The bioresorbable carrier matrix may be amorphous or semicrystalline in nature. The bioresorbable carrier matrix may be partially semicrystalline, such that the rate of degradation of the device is based on the half-life of the plurality of radio-isotope particles and through modification of crystallinity.

In the device, the hydrogel substrate may be crosslinked with citric acid, wherein a percentage of citric acid is selected to specify the rate that the hydrogel substrate degrades to maintain structural integrity and shielding capacity. The percentage may be between 2.5% and 10%. The citric acid crosslinking may be catalyzed by titanium oxide.

The device may further comprise an inert adhesive layer located adjacent to a surface of the hydrogel substrate, wherein the inert adhesive layer is configured to adhere to the wound site.

The device may further comprise a removable film located adjacent to the inert adhesive layer, wherein the removable film is removable from the inert adhesive layer to expose a surface of the inert adhesive layer to the wound site.

Also disclosed herein, in various embodiments, is a method of manufacturing a flexible brachytherapy device for application on a wound site in a body, the method comprising: forming a bioresorbable carrier matrix structure comprising a plurality of radio-isotope particles, wherein the bioresorbable carrier matrix structure is configured to degrade at a rate substantially longer than a half-life of the radio-isotope particles such that activity from the plurality of radio-isotope particles is localized to the wound site, wherein the biodegradable carrier matrix structure has opposite first surface and second surfaces; forming a hydrophilic substrate adjacent to the first surface of the bioresorbable carrier matrix structure, wherein the hydrophilic substrate adheres to the wound site, the hydrophilic substrate configured to degrade, when implanted at the wound site, at a rate shorter than the bioresorbable carrier matrix structure to prevent migration of the device during the half-life of the plurality of radio-isotope particles; and forming a hydrogel substrate adjacent to the second surface of the bioresorbable carrier matrix structure, the hydrogel substrate configured to shield radioactivity and to degrade at a rate longer than the half-life of the plurality of radio-isotope particles.

In the method, the bioresorbable carrier matrix structure may be formed by: adsorbing or dispersing an aqueous solution of a radio-isotope to a hydrophobic substance. The bioresorbable carrier matrix structure may be formed by precipitating the radio-isotope to form a plurality of insoluble radio-isotope particles in the bioresorbable carrier matrix structure. The hydrophobic substance may comprise a hydrophilic surface.

The aqueous solution may comprise radioactive ions.

In the method, the bioresorbable carrier matrix structure may be formed by: adsorbing or dispersing an aqueous solution of a radio-isotope to an amorphous or semicrystalline hydrophobic substance to provide the resorbable carrier matrix structure. The amorphous or semicrystalline hydrophobic substance may comprise a hydrophilic surface.

A bioresorbable carrier matrix structure comprising a plurality of radio-isotope particles, wherein the bioresorbable carrier matrix structure is formed by: adsorbing or dispersing an aqueous solution of a radio-isotope to a hydrophobic substance to produce the bioresorbable carrier matrix structure. The bioresorbable carrier matrix structure may be formed by precipitating the radio-isotope to form a plurality of insoluble radio-isotope particles in the bioresorbable carrier matrix structure. The hydrophobic substance may comprise a hydrophilic surface.

The aqueous solution may comprise radioactive ions.

The bioresorbable carrier matrix structure may be formed by: adsorbing or dispersing a plurality of insoluble radio-isotope particles to an amorphous or semicrystalline hydrophobic substance to provide the bioresorbable carrier matrix structure. The amorphous or semicrystalline hydrophobic substance may comprise a hydrophilic surface.

The bioresorbable carrier matrix structure may be amorphous or semicrystalline in nature.

The bioresorbable carrier matrix structure may be configured to degrade, when implanted at a wound site, at a rate substantially longer than a half-life of the plurality of radio-isotope particles such that activity from the plurality of insoluble radio-isotope particles is localized to the wound site.

The bioresorbable carrier matrix may be configured to be used in a brachytherapy device for application on a wound site, the device comprising: a hydrophilic substrate located adjacent to a first surface of the bioresorbable carrier matrix structure, wherein the hydrophilic substrate adheres to the wound site, the hydrophilic substrate configured to degrade, when implanted at the wound site, at a rate shorter than the bioresorbable carrier matrix structure to prevent migration of the device during the half-life of the plurality of radio-isotope particles.

The bioresorbable carrier matrix may be configured to be used in a brachytherapy device for application on a wound site, the device comprising: a hydrogel substrate located adjacent to a second surface of the bioresorbable carrier matrix structure, the hydrogel substrate configured to shield radioactivity and degrade at a rate longer than the half-life of the plurality of radio-isotope particles.

Further disclosed herein is a method for manufacturing a bioresorbable carrier matrix comprising a plurality of radio-isotope particles, the method comprising: adsorbing or dispersing an aqueous solution of a radio-isotope to a hydrophobic substance. The bioresorbable carrier matrix may be formed by precipitating the radio-isotope to form a plurality of insoluble radio-isotope particles in the bioresorbable carrier matrix structure. The hydrophobic substance may comprise a hydrophilic surface.

The aqueous solution may comprise radioactive ions.

Also disclosed herein is an applicator device for application of a brachytherapy device to a wound site in a body, the applicator device comprising: an upper housing having a recess to receive a brachytherapy device; a removable base attached with the upper housing, wherein when attached the removable base and upper housing shield radiation from the brachytherapy device; wherein the removable base is removable from the upper housing to expose a first surface of the brachytherapy device to a wound site.

The removable base may be slidably attached with the upper housing and slidably removable from the upper housing.

The upper housing may further comprise an inlet port fluidly connected to the recess, to allow introduction of a fluid through the inlet port to the brachytherapy device in the recess.

The applicator device may further comprise a soluble adhesive to additionally secure the upper housing and the removable base, wherein the soluble adhesive is dissolvable by a liquid introduced into the recess to allow the removable base to be slidably removed from the upper housing.

The upper housing may comprise a transparent, semi-transparent, or translucent material to shield beta radiation. The upper housing may be formed of an acrylate polymer.

The applicator device may further comprise a handle at the upper housing to assist placement of the applicator device and brachytherapy device to a wound site.

Further disclosed is a brachytherapy system comprising: the applicator device as described above, and the brachytherapy device as described above, wherein the hydrogel substrate is hydrated at equilibrium water content by the inlet port of the applicator device.

Overview

1 FIG. 1 1 2 3 2 2 2 2 21 22 An example of a brachytherapy device is illustrated in. The devicemay be used on a wound site in a body, for example during surgery. The devicecomprises a bioresorbable carrier matrix structurecomprising a plurality of radio-isotope particles. The bioresorbable carrier matrix structureis configured to degrade, when implanted at the wound site, at a rate substantially longer than a half-life of the plurality of radio-isotope particles. In this way, activity from the plurality of radio-isotope particlesis localized to the wound site. The bioresorbable carrier matrix structurehas opposite first surface and second surfaces,.

1 4 21 2 4 3 The devicefurther comprises a hydrophilic substratelocated adjacent to the first surfaceof the bioresorbable carrier matrix structure. The hydrophilic substrateadheres to the wound site. The hydrophilic substrate is configured to degrade, when implanted at the wound site, at a rate shorter than the bioresorbable carrier matrix structure to prevent migration of the device during the half-life of the plurality of radio-isotope particles.

1 5 22 2 5 4 5 3 3 5 2 The devicefurther comprises a hydrogel substratelocated adjacent to the second surfaceof the bioresorbable carrier matrix structure. In some examples, the hydrogel substrateis adherent to and integrated with the hydrophilic substrate. The hydrogel substrateis configured to shield radioactivity and to degrade at a rate longer than the substantial activity of the plurality of radio-isotope particles, for example at a rate longer than the half-life of the plurality of radio-isotope particles. In this way, the hydrogel substrateshields radioactivity until radioactive decays renders the bioresorbable carrier matrix structureto be substantially inactive (of radioactivity) and safe.

1 1 The devicemay be suitable for minimizing and/or controlling local recurrence of malignant cancer and seroma following cancer surgery. The devicemay also be suitable for minimizing and/or controlling uncontrolled growth of microscopic tumor cells at the resected margin of surgery.

1 1 1 It is an advantage that the deviceis configured to be completely bioabsorbable and/or bioresorbable in the body. In this way, the device may be completely degraded/replaced “in vivo.” Furthermore, the devicealso has the advantage of being a fully sealed source (while significantly radioactive). In some examples, the deviceis constructed such that it can withstand immersion in water. phosphate buffered saline or other physiological compatible fluid at room temperature for 24 hours without significant loss of radio-isotope.

3 It is a further advantage that the plurality of radio-isotope particlesare maintained in place in the wound site until the time they are no longer substantially radioactive.

1 It is yet a further advantage that the brachytherapy deviceis configured to be flexible and conform to the wound site.

1 Details of an exemplary brachytherapy devicewill now be described in detail.

2 Bioresorbable Carrier Matrix

1 2 3 2 2 As described above, the devicecomprises a bioresorbable carrier matrix structurecomprising a plurality of radio-isotope particles. In some examples, the bioresorbable carrier matrixis formed by adsorbing or dispersing an aqueous solution of a radio-isotope to a hydrophobic substance. The bioresorbable carrier matrix may further be formed by precipitating the radio-isotope to form a plurality of insoluble radio-isotope particles in the bioresorbable carrier matrix structure. In this example, the aqueous solution may comprise radioactive ions. The radioactive ions may comprise one or more of: monosodium phosphate, disodium phosphate, potassium phosphate, dipotassium phosphate, orthophosphoric acid or tetrasodium pyrophosphate or soluble compounds containing iodide.

3 3 3 3 3 The plurality of radio-isotope particlesmay comprise a beta-emitter. In other examples, the plurality of radio-particlesmay comprise a gamma emitter or a mixed gamma/beta emitter. In some examples, the plurality of radio-isotope particlesmay be elements in the family of calcium phosphate compounds. In one example, the plurality of radio-isotope particlesmay comprise elements in the compound molecule of calcium pyrophosphate. This may comprise the compound molecules of: calcium phosphate, monocalcium phosphate, dicalcium phosphate, octacalcium phosphate, tricalcium phosphate, hydroxyapatite, fluoroapatite or tetracalcium phosphate. In some examples, the plurality of radio-isotope particlesmay comprise the compound molecules in a hydrated or anhydrous form.

3 3 3 In other examples, the plurality of radio-isotope particlesmay comprise one or more of: Yttrium-90, Iridium-192, Palladium-103, Caesium-137131, Iodine-131, Iodine-125, Iodine-123, 33-phosphorus (33P), 32-phosphorus (32P) or a ratio of 33-phosphorus to 32-phosphorus and/or compounds containing such isotopes. In some examples, the use of a ratio of 33P to 32P radio-isotope as the plurality of radio-isotope particlesreduces the collateral radiation exposure from handling compared to P32 alone. It is to be appreciated that in this description, radio-isotope particlescan include compounds that contain radio-isotopes.

2 3 The bioresorbable carrier matrix structureis configured to degrade, when implanted at the wound site, at a rate substantially longer than a half-life of the plurality of radio-isotope particles. In this way, activity from the plurality of radio-isotope particles is localized to the wound site.

5 FIG. 1 3 4 5 3 2 100 7 illustrates a cross-sectional view of the deviceafter significant nuclear decay of the plurality of radio-isotope particles. As shown, after degradation of the hydrophilic substrate, hydrogeland nuclear decay of the plurality of radio-isotope particles, the bioresorbable carrier matrix structureremains in place. Having the bioresorbable carrier matrix that persists longer than the substantial radioactivity of the radio-isotope (such as over a half-life of the radio-isotope) ensures that radioactivity is localized to the wound siteat the operative margin-wound bed.

3 2 4 The rate of delivery of the radiation from the plurality of radio-isotope particlesmay be determined by characteristics of the bioresorbable carrier matrix structureand/or the hydrophilic substrate.

3 2 In some examples, the plurality of radio-isotope particlesmay comprise medium (under 30 days) half-life particles. In this way, the bioresorbable carrier matrix structuremay degrade at a rate substantially longer than 30 days.

2 The bioresorbable carrier matrix structuremay be formed by adsorbing or dispersing a plurality of insoluble radio-isotope particles to a hydrophobic substance with a hydrophilic surface. The hydrophobic substance may be microporous or macroporous.

In some examples, the hydrophobic substance may comprise a hydrophilic surface. In this way, as described below, a solution containing radioactive ions may be drawn up into a microporous hydrophobic substance by capillary action. Without the hydrophilic surface, the radioactive ions may not be distributed in that way. Alternatively, in an example of the hydrophobic substance without a hydrophilic surface, the radioactive particles may be hot pressed/imprinted onto the hydrophobic substance.

In one example, a microporous, hydrophobic substance with a hydrophilic surface is prepared as follows. A hydrophobic, biodegradable polymer such as polycaprolactone (PCL) is made hydrophilic with addition of a surfactant. In one example, the surfactant may comprise a polyethylene glycol-polypropylene glycol block monomer (Pluronic P123). In other examples, other hydrophobic base biopolymers may be used such as polylactide or racemers of polylactide such as poly-L Lactide, poly D-lactide, or Poly-DL lactide (PDLLA), or composites thereof.

In further examples, a hydrophilic copolymer may be added to improve hydrophilicity and available sites for crosslinking. Examples of a hydrophilic copolymer may comprise collagen, alginate, carboxymethylcellulose and other forms of cellulose, polyethylene glycol, or any of a large series of copolymers of polyethylene glycol. In some examples, a partially amorphous polymer such as PDLLA, or a biodegradable elastomer including but not limited to (poly)glycerol sebacate (or polyurethane based biodegradable elastomers) may be added to increase the flexibility of the PCL, reduce the percentage of crystallinity, and/or increase the hydrophilicity of the resultant blend.

The new slowly hydrolysable polymer blend is then made microporous through the incorporation of a very soluble substance, such as a soluble salt (NaCl, MgCl etc.) or soluble liquid (like glycerol) or other soluble component in a non-toxic solvent. The soluble component may be leached out of the PCL blend by a combination of heat and/or a solvent. This results in a microporous, hydrophobic matrix with a hydrophilic surface. The matrix may be slowly absorbing.

In some examples, the porosity of the hydrophobic substance/matrix may also be generated by bubbling of an inert gas during the mixing of polymers, such as in the extruder. The inert gas may comprise nitrogen, carbon dioxide or argon. In other examples, the porosity of the hydrophobic substance/matrix may be generated with the inclusion of ‘porogen’ compounds, such as sodium bicarbonate, in the formulation. In this way, gas may be released on exposure to heat.

2 In another example, a rapidly decaying radio-isotope may be used for the plurality of radio-isotope particles. This may facilitate the use of a purely hydrophilic carrier matrix as the bioresorbable carrier matrix structure, including polymers of polyglycolide or a crosslinked hydrogel.

In another example, the hydrophobic and hydrophilic components may be mixed thoroughly in a batch mixer or extruder, compatibilized with an amphiphilic polymer or copolymer (like polyethylene glycol or pluronic P123, and then the radioisotope component incorporated by using the low melting temperature of the biodegradable matrix, by hot press, injection molding or extrusion.

3 3 2 3 In some examples, the plurality of insoluble radio-isotope particlesmay be provided by adding a precipitant to a plurality of radio-isotope particles. In one example, the plurality of radio-isotope particlesmay comprise ions, so that the precipitant is added to a plurality of radio-isotope ions. In one example, the radio-isotope ions may be suspended in a solution to form a radio-isotope aqueous solution and disseminated throughout the carrier matrix. This makes the plurality of radio-isotope particlesin an insoluble form. In one example, the radio-isotope aqueous solution may be comprised of elements of the compound tetrasodium pyrophosphate. In other examples, any aqueous radio-isotope solution capable of being precipitated into a bioresorbable insoluble salt may be used. These include any aqueous solutions containing 32P phosphate ions, but other examples include but are not limited to radioactive calcium ions, radioactive chromium 51, radioactive Iodine ions (I-131, I-125, I-123 etc.), palladium 103, caesium137131, etc.

2 2 7 2 2 7 2 In one example, the precipitant comprises calcium chloride. In other examples, the precipitant may comprise a further aqueous solution of calcium ions, including the hydroxide or nitrate forms. The precipitant may comprise one or more of calcium chloride, calcium hydroxide, calcium nitrate or calcium bromide. In this way, the plurality of insoluble radio-isotope particles may be elements in the compound calcium pyrophosphate (CaPO), anhydrous, dihydrate (CaPO.2HO) or tetrahydrate (Ca2P2O7.4H2O).

125 131 The precipitant may also comprise any insoluble or poorly soluble salt capable of being bio-resorbed in the body. These include any variety of calcium phosphate or form of ammonium magnesium phosphate (Struvite). In one example, the functional groups of absorbable polymers may be iodinated using radioactive iodideor, or crystalline iodide embedded/distributed throughout a bio-absorbable carrier matrix. In yet other examples, the precipitant may comprise another molecule containing calcium, magnesium, zinc or iron.

3 In other examples, the plurality of radio-isotopesmay be adsorbed into an anion exchange resin, and the precipitant may be applied after adsorption. In this example, a precipitant such as magnesium ammonium phosphate (Struvite) may be used. In another example, a gamma source such as chromium 51 may be precipitated in an anion exchange resin or into a resorbable radioactive molecule.

1 1 2 1 3 1 The microporous, hydrophobic substance with a hydrophilic surface may then be tuned through the addition of copolymers to achieve partial crystallization (semicrystalline). This is an advantage as it enables the deviceto be flexible, compliant and conform to the shape of the wound site. The semicrystalline blend may modify the long hydrolysis degradation time of pure PCL/polylactide. That is, the rate of degradation of the devicemay be determined by modifying the crystallinity of the bioresorbable carrier matrix structure. In some examples, the rate of degradation of the devicemay be based on the half-life of the plurality of radio-isotope particlesand through modification of the crystallinity. Therefore the deviceis suitable for use in surgery.

2 1 1 1 2 2 2 The bioresorbable carrier matrix structuremay then be completely biodegradable within the body. As described above, this is an advantage of the device. It is also a further advantage that when such a deviceis utilized in a potentially contaminated field the devicemay prevent chronic infection. In some examples, the bioresorbable carrier matrix structureis degradable by intracellular, extracellular and enzymatic processes present in the body, such as pyrophosphatase or circulating osteocyte progenitors and/or mature osteocytes. In some examples, osteoclast cells (or their circulating osteoclast precursors) may degrade the structure. The osteoclast cells may degrade, resorb, modify and/or replace any of the entire family of calcium phosphate. This may include any insoluble and bioresorbable compound molecule. In other examples, the bioresorbable carrier matrix structureis degradable by other enzymes present in the body.

3 In some examples, iodinated compounds may be used as the radio-isotope particles. This may comprise iodinating one or more functional groups of absorbable polymers using radioactive iodide, such as Iodine-131, Iodine-125 or Iodine-123. In other examples, crystalline iodide may be implanted into bioabsorbable polymers.

2 100 In this way, over time, the initially insoluble phosphate compounds in the plurality of insoluble radio-isotope particles may be made aqueous through the enzymatic processes of the body. The initially insoluble phosphate compounds present in the plurality of insoluble radio-isotope particles may be required for safe surgical handling as a sealed source of brachytherapy. The radio-isotope particles/ions may then diffuse from the bioresorbable carrier matrix structuretowards the wound siteto be absorbed intra-cellularly. The radio-isotope particles/ions may then be taken up into cancer cell DNA to increase apoptosis.

2 2 In some examples, the bioresorbable carrier matrix structuremay be pressed, extruded or injection molded into a desired shape, such as a flat sheet. The bioresorbable carrier matrix structuremay have a thin mesh surface interface.

2 21 22 The bioresorbable carrier matrix structurecomprises opposite first surface and second surfaces,.

3 2 4 3 1 2 In some examples, the plurality of radio-isotope particlesmay be impregnated in a space between the bioresorbable carrier matrix structureand hydrophilic substrate. For example, there may be a receptacle formed by at least two layers to receive the plurality of radio-isotope particles. In this example, a sealed source of radiotherapy may be obtained through the lamination of radioactive particles with hydrophobic or partially hydrophobic layers. In this way, the laminated radioactive particles may be capable of being completely or mostly bio-resorbed by the processes of the body that the deviceis placed in. In other examples, insoluble radio-isotope particles, or a microporous matrix (like an ion exchange resin) containing insoluble radioisotope particles, may be imprinted into the surface of the bioresorbable carrier matrix structure.

3 2 1 A further advantage of the device is that since the plurality of radio-isotope particlesare embedded within the bioresorbable carrier matrix, safe removal of the device(and thus the source of radio-isotope) is possible whilst maintaining the unidirectional shield if a return to theatre is required for management.

4 Hydrophilic Substrate

1 4 21 4 100 4 1 4 21 3 FIG. As described above, the devicefurther comprises a hydrophilic substratelocated adjacent to the first surfaceof the bioresorbable carrier matrix structure. The hydrophilic substratefaces the wound site and also adheres to the wound site. In this way, the hydrophilic substrateprovides integration, or crosslinking, of the deviceto the wound site. In some examples, the hydrophilic substrateis at, and across, the first surfaceof the bioresorbable carrier matrix structure. This is illustrated in.

4 5 4 100 4 100 In one example, the hydrophilic substrateis supplied in a fully hydrated state, at a similar equilibrium water content to the hydrogel substrate. In this way, the fully hydrated hydrophilic substratemay be unlikely to undergo a dramatic change in size and/or modification in shape upon implantation and crosslinking to the tissues of the wound site. In another example, the hydrophilic substratemay comprise a portion of substances required to create amide bonds and/or hydrogen-hydrogen interactions between the device and tissues of the wound sitein the body. In this way, an additive substance may activate the crosslinking between the device and the tissues, such as 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), dopa, or other crosslinking agent.

4 4 4 1 4 In some other examples, the hydrophilic substrateabsorbs moisture from the wound site to allow wetting and gelation of the hydrophilic substrateto conform to the wound site. The hydrophilic substratemay be selected to be relatively rapidly absorptive, allowing close conformation of the deviceto the wound site. In other examples, the hydrophilic substratemay be configured to be absorbed at the wound site within three to five days.

4 100 3 1 100 4 2 3 4 The hydrophilic substrateis configured to degrade, when implanted at the wound site, at a rate shorter than the bioresorbable carrier matrix structure to prevent migration of the device during the half-life of the plurality of radio-isotope particles. This ensures that the devicedoes not move from the wound surface. That is, the hydrophilic substrateis configured to absorb at a faster rate than the bioresorbable carrier matrix structure. This allows the plurality of radio-isotope particlesto be maintained in place at the wound site until it is no longer substantially active. In some examples, the time to substantial inactivity of the radio-isotopes may be between 9 to 28 days.

2 FIG. 1 4 4 5 2 3 illustrates an example of deviceshowing faster absorption of the hydrophilic substrate. As shown, the hydrophilic substratehas completely absorbed. The hydrogel substrate, bioresorbable carrier matrix structureand the plurality of radio-isotope particlesremain in place at the wound site.

4 FIG. 4 5 2 3 100 illustrates a cross-sectional view showing the hydrophilic substratebeing absorbed into the wound site. In this example, the hydrogel substrate, bioresorbable carrier matrix structureand the plurality of radio-isotope particlesremain in place at the wound site.

4 4 4 The hydrophilic substratemay be comprised of a crosslinked polymer. In some examples, the hydrophilic substratealso comprises one or more of: any variety of) starch, carboxymethyl cellulose, glycerol, xylitol, or citric acid, or any variety thereof. In other examples, the hydrophilic substratemay comprise other surgical adhesive substances, such as carbodiimide crosslinking, dopa-lysine interactions, or citric acid crosslinking.

4 In other examples, the hydrophilic substratemay comprise a thin layer of bio-compatible resin, gel, or flexible biopolymer such that it absorbs water rapidly to conform with the operative bed. Other polymers derived from cellulose may also be used.

4 4 4 3 The hydrophilic substratemay also comprise a radio-sensitizing agent, such as gemcitabine or capecitabine. The radio-sensitizing agent may be suspended in the hydrophilic substrateby a solvent casting technique, solution immersion, or melt extrusion technique. In this way, when the wound site absorbs the hydrophilic substratethe radio-sensitizing agent may release. This may have the effect of making tumor cells that are in or close to the wound site susceptible to radiation from the plurality of radio-isotope particles.

4 4 2 3 FIG. The hydrophilic substratehydrates once applied to the wound site to form a surface film which conforms to the wound site. As illustrated inthe hydrophilic substratemay extend beyond the edges of the bioresorbable carrier matrix structure.

4 1 4 4 In some examples, the hydrophilic substrateprovides a concomitant haemostatic effect on the wound site, preventing haematoma which may lift the deviceaway from the wound site. In this example, the hydrophilic substratemay further comprise a coating or suspension of a haemostatic agent, such as thrombin, fibrin, fibrinogen or other haemostatic agents to augment the haemostatic properties of the hydrophilic substrate.

5 Hydrogel Substrate

1 5 22 2 5 1 5 5 5 1 1 5 The devicefurther comprises a hydrogel substratelocated adjacent to the second surfaceof the bioresorbable carrier matrix structure. The hydrogel substrateenables conformability, flexibility and the ability to allow surgical implantation of the device. The hydrogel substrateis configured to shield radioactivity and to degrade at a rate longer than the half-life of the plurality of radio-isotope particles. The hydrogel substratemay also be configured to fully hydrolyze at a rate longer than the half-life of the plurality of radio-isotope particles. In this way, the hydrogel substrateis configured to absorb any emitted radiation to protect surround tissues of the patient and, in some circumstances the operator of the device, such as a surgeon. This is an advantage of the deviceas the shield provided by the hydrogel substrateassists in the device being unidirectional, unlike devices of the prior art as described above.

5 22 2 5 5 1 In one example, the hydrogel substrateis attached to the second surfaceof the bioresorbable carrier matrix structureso that the hydrogel substrateis adherent to and integrated in a hydrated state using phosphate buffered saline (or other biocompatible solution). The hydrated state may mean that the hydrogel substrateis at or close to its equilibrium water content (EWC). This is an advantage to the device because the deviceis convenient and safe for application during surgery, unlike devices of the prior art. That is, the device may be safely handled from its packaging as unidirectional and does not require additional assembly by the operator of the device.

5 3 5 100 22 5 2 5 4 5 4 1 3 4 FIGS.and 1 4 FIGS.to 3 FIG. In some examples, the hydrogel substratelimits penetration of the plurality of radio-isotope particlesto a few millimeters. As illustrated inthe hydrogel substratefaces away from the wound site. Furthermore, in some examples, the hydrogel substrate is at, and across the second surfaceof the bioresorbable carrier matrix structure. In further examples, as illustrated in, the hydrogel substrateextends beyond a perimeter of the bioresorbable carrier matrix structure. This provides additional shielding to tissue near the perimeter regions. As illustrated in, the hydrogel substrate, near the perimeter, may be in contact with the hydrophilic substrate. Thus, in some examples, the bioresorbable carrier matrix structure is encapsulated by the hydrogel substrateand the hydrophilic substratewhen the deviceis first implanted.

5 2 The hydrogel substratemay be combined with the bioresorbable carrier matrix structureby at least one of: mechanical integration, chemical crosslinking or enzymatic crosslinking. In some examples, a combination of mechanical integration and chemical crosslinking with 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and/or N-Hydroxysuccinimide (NHS) carbodiimide chemistry may be used. In this example, surface modification may be required for example by way of plasma treatment and/or surface hydrolysis.

5 5 The hydrogel substratemay be composed of a hydrophilic polymer interpenetrating multi-polymeric hydrogel. This may contain polyvinyl alcohol, carboxymethylcellulose, partially hydrolyzed collagen and xylitol, crosslinked with citric acid. The hydrogel substratemay also comprise a blend of copolymer using polyethylene glycol. In some examples, a catalyst such as titanium dioxide may be present for the citric acid crosslinking. In yet other examples, other hydrophilic resorbable polymers or sugar alcohols may be used, including but not limited to sodium alginate, starch, chitosan, forms of cellulose, varieties or collagen, polyethylene glycol, glycerol, sorbitol and the like.

5 5 1 As described above, the hydrogel substrate may comprise, at least in part, citric acid. A percentage of citric acid may be selected to specify the rate that the hydrogel substratedegrades to maintain structural integrity and shielding capacity. In some examples, the percentage of the citric acid may be between 2.5% and 10%. In this way, the citric acid ensures that the hydrogel substratecontinues to shield radiation for a duration of time after implantation at the wound site. This may be useful, for example, if the patient with such a deviceis required to return to theatre at a time after implantation. In other examples, chemical crosslinking may be performed with an agent such as glutaraldehyde, or crosslinked with gamma irradiation, UV exposure or through a freeze-thaw method.

5 5 5 2 3 FIG. The hydrogel substratemay have a thickness of at least 3 mm, and preferably closer to 3.5 mm. In other examples, a gamma source may be used which may necessitate an increased thickness of the hydrogel substrateto provide an effective unidirectional shield. As illustrated in, the hydrogel substratemay be configured to have a central recessed portion for receiving the bioresorbable carrier matrix structurewithin.

5 5 4 5 21 22 2 3 FIG. The hydrogel substratemay also act to prevent damage or undesired attachment and adhesions of surrounding tissues and structures to the device. As illustrated in, the hydrogel substratemay be attached at edge portions to the hydrophilic substrate. In this way, the hydrogel substratemay extend beyond edges of the first and second surfaces,of the biocompatible carrier matrix structure.

200 Methodof Manufacturing a Flexible Brachytherapy Device

11 FIG. 200 200 202 2 3 200 2 4 2 2 As illustrated inthere is also provided a methodof manufacturing a flexible brachytherapy device for application on a wound site in a body. The methodcomprises forminga bioresorbable carrier matrix structurecomprising a plurality of radio-isotope particles. In the method, the bioresorbable carrier matrix structuremay be provided by adsorbing a plurality of insoluble radio-isotope particles to a microporous, hydrophobic substance with a hydrophilic surfaceto provide the bioresorbable carrier matrix structureas described above. In some examples, the bioresorbable carrier matrix structuremay be formed using a thermoplastic process, such as a combination of extrusion and/or heated batch mixing. In other examples, injection molding or hot press may be used. In some examples, the plurality of insoluble radio-isotope particles is provided by adding a precipitant to the plurality of radio-isotope particles.

2 3 3 2 21 22 The bioresorbable carrier matrix structureis configured to degrade at a rate substantially longer than a half-life of the radio-isotope particlessuch that activity from the plurality of radio-isotope particlesis localized to the wound site, wherein the biodegradable carrier matrix structurehas opposite first surface and second surfaces,.

200 204 4 21 2 4 4 3 1 3 The methodfurther comprises forminga hydrophilic substrateadjacent to the first surfaceof the bioresorbable carrier matrix structure, wherein the hydrophilic substrateadheres to the wound site. The hydrophilic substrateis configured to degrade, when implanted at the wound site, at a rate shorter than the bioresorbable carrier matrixto prevent migration of the deviceduring the half-life of the plurality of radio-isotope particles. The hydrophilic substrate may be formed through extrusion, solvent casting, spray coating and/or dipping.

200 206 5 22 2 5 3 5 The methodfurther comprises forminga hydrogel substrateadjacent to the second surfaceof the bioresorbable carrier matrix structure, the hydrogel substrateconfigured to shield radiation and to degrade at a rate longer than the half-life of the plurality of radio-isotope particles. In some examples, the hydrogel substratemay be formed through a combination of multiple polymers prior to melt extrusion or solvent casting.

4 5 1 2 5 5 The hydrophilic substrateand hydrogel substratemay be adhered to the devicethrough one or more of the techniques of mechanical integration, hot press, mold, chemical and/or enzymatic crosslinking. This may comprise carbodiimide chemistry, GEM, transglutaminase, or other more traditional method of crosslinking (e.g., Gluteraldehyde). In one example, a combination of mechanical integration and carbodiimide chemistry is used, utilizing amide-hydroxyl bonds between the collagen molecules in the radioactive bioresorbable carrier matrix structureand free amide and/or hydroxyl groups in the hydrophilic substrateand hydrogel substrate.

Applicator Device

6 FIG. 66 1 100 66 1 100 66 1 1 100 66 1 1 illustrates an example of an applicator devicefor application of a brachytherapy deviceto a wound sitein a body. The applicator deviceprovides for application of the brachytherapy deviceto a wound sitewhile protecting the operator, such as a surgeon, or nuclear medicine physician. The applicator devicealso provides for safe distribution and storage of the device, as well as for ready location of the deviceat the wound site. The applicator device, when used together with the brachytherapy devicecontained therein, keeps the brachytherapy devicedry and also shields any nearby personnel from radioactive radiation. This minimizes collateral radiation exposure.

66 8 100 The applicator deviceis configured to be placed inside the body so that the basefaces away from the operator and towards the wound site.

66 6 67 1 6 66 6 The applicator devicecomprises an upper housinghaving a recessto receive a brachytherapy device. The upper housingof the applicator devicemay comprise a transparent, semi-transparent, or translucent material to allow the surgeon to accurately place the brachytherapy devices whilst shielding the surgeon from beta radiation. In some examples, the upper housingmay be formed of an acrylate polymer, such as acrylic (Perspex).

66 8 6 8 6 1 8 6 8 6 6 15 17 8 15 17 12 FIG. The applicator devicealso comprises a removable baseattached with the upper housing, wherein when attached the removable baseand upper housingshield radiation from the brachytherapy device. In some examples, the removable baseis slidably attached with the upper housing. In this way, the removable basemay be slidably removable from the upper housing. As illustrated in, in some examples, the upper housingcomprises railsthat are received by, and engage with, grooveson the removable base. In some examples, this may include railsthat are shaped to dovetail with the grooves. It is to be appreciated that other sliding engagement arrangements may be used, such as inwardly facing and opposing grooves that receive opposing edges of a base.

8 8 8 6 8 1 100 The removable basemay have a planar surface. The removable basemay be comprised of a material suitable for protection against Bremsstrahlung radiation, such as acrylic. In another example, if a gamma emitter was used, lead vinyl, lead containing glass or lead containing vinyl-acrylic may be employed in the removable base. The combination of the upper housingand removable baseprovides safe handling and delivery of the brachytherapy deviceto the wound siteduring and after placement during surgery.

8 21 1 8 4 1 The removable basemay be configured to face a first surfaceof the brachytherapy device. In some examples, the removable basemay face a hydrophilic substrateof the brachytherapy devicein accordance with the examples described above.

8 6 21 1 100 8 8 66 21 4 1 8 1 100 4 100 13 FIG. 14 FIG. The removable baseis removable, such as slidably removable, from the upper housingto expose a first surfaceof the brachytherapy deviceto a wound site.illustrates a slidably removable base. The removable basemay also be removable by other means such as a hinge associated with the applicator device. In some examples, the first surfacemay comprise a hydrophilic substrateof the brachytherapy deviceas described above. This is illustrated in. In this way, the removable baseis slidably removed during application and location of the brachytherapy deviceto the wound siteto expose the hydrophilic substrateto the wound site.

8 14 8 6 21 1 1 100 The removable basemay also comprise a tabto allow an operator, such as the surgeon, to apply a pulling or pushing force to slidably remove the basefrom the upper housingand to therefore expose a first surfaceof the brachytherapy deviceso that the devicemay be adjacent to and conform to the wound site.

6 11 67 11 11 1 67 12 11 11 1 67 5 In some examples, the upper housingfurther comprises an inlet portfluidly connected to the recess. The inlet portallows introduction of a fluid through the inlet portto the brachytherapy devicein the recess. In some examples, a channelis connected to the inlet portfor the fluid to flow from the inlet portto the brachytherapy devicein the recess. This may include introducing a liquid to hydrate the hydrogel substrate.

11 1 1 100 1 100 In some examples, the inlet portmay be used to ‘activate’ an adhesive component of the brachytherapy device, either by channeling an adhesive substance to an attachment surface of the device, or some component of a crosslinking solution, which on attachment to the tissues of the wound siteprovides crosslinking between the deviceand the tissues of the wound site. Such agents may incorporate one component of carbodiimide chemistry (e.g., 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)), or facilitate dopa-lysine interactions with or without the facilitation of transglutaminase.

66 9 6 8 9 66 1 9 66 The applicator devicemay further comprise a soluble adhesiveto additionally secure the upper housingand the removable base. In this way the soluble adhesiveprovides an additional security against shielding the operator of the applicator devicefrom any activity from the brachytherapy devicecontained therein. The soluble adhesivemay also provide a seal, such as a hermetic seal, for the applicator device.

9 9 13 67 8 6 6 8 9 6 8 The soluble adhesivemay be a water and/or heat soluble glue. The soluble adhesivemay be dissolvable by a liquidintroduced into the recessto allow the removable baseto be slidably removed from the upper housing. In some examples, the upper housingand removable basemay be adhered by the soluble adhesiveabout the periphery portions of the upper housingand removable base.

11 6 9 8 21 4 1 100 In some examples, water may be injected into the inlet portof the upper housing. In this way the soluble adhesivemay be solubilized to an extent so that the removable basemay be removed to expose the first surface(such as the hydrophilic substrate) of the brachytherapy deviceto the wound site.

11 67 9 9 8 4 1 100 5 1 5 In other examples, heat in addition to a liquid may be inserted in the inlet portto the recess. For example, this may comprise warm water. In this way the soluble adhesivemay absorb the heated liquid so that the soluble adhesiveis solubilized to remove the removable baseto expose the hydrophilic substrateof the brachytherapy deviceto the wound site. In a further example, a hydrogel substrateof the brachytherapy devicemay also absorb the heat and/or liquid to fill and expand. The hydrogel substrateshields radioactivity as described above.

66 100 11 67 9 4 1 5 2 5 5 6 1 1 1 100 1 In one example, after the applicator deviceis located at the wound sitewater and heat may be inserted in the inlet portto the recess. The soluble adhesivemay absorb the water and heat. The hydrophilic substrateof the devicemay also absorb the water and heat. The hydrogel substratemay also absorb the water and heat. The bioresorbable carrier matrix structuremay also absorb the water and heat. When the hydrogel substrateis fully absorbed, the saturated hydrogel substrateis readily detached from the upper housingfor application of the deviceto the wound site. The devicemay then become flexible and conform and adhere to a surface such as the wound site. The devicemay then deliver radiation dosage.

11 1 66 In further examples, a liquid or gas suitable for sterilization may be inserted into the inlet port. For example, ethylene oxide may be introduced to sterilize the deviceand/or applicator deviceat a manufacturing facility and/or before surgery.

66 10 6 66 1 100 10 10 6 6 7 FIGS.and The applicator devicemay further comprise a handleat the upper housingto assist placement of the applicator deviceand brachytherapy deviceto the wound site. In some examples, the handlemay be longitudinal as illustrated in. In other examples, the handlemay be in another configuration attached to the upper housing.

1 6 8 4 2 8 5 2 8 5 In some examples, the devicemay be completely surrounded by the upper housingand removable base. That is, the hydrophilic substrateand bioresorbable carrier matrixmay be smaller in diameter than the removable baseand the hydrogel substrate. In one example, the hydrophilic substrate and bioresorbable carrier matrixmay be 3 cm in diameter flat circular, and the removable baseand hydrogel substratemay be 4 to 4.5 cm in diameter flat circular.

66 1 5 1 11 66 5 1 1 66 5 1 There is also provided a brachytherapy system comprising the applicator deviceand deviceas described above. In some examples, the hydrogel substrateof the devicemay be hydrated at equilibrium water content by the inlet portof the applicator device. In this way, the hydrogel substratemay be fully formed, hydrated and crosslinked with the device. It is an advantage that the devicemay then be handled from the applicator deviceby the operator without any additional assembly by the operator or associated staff. It is also an advantage that the fully hydrated hydrogel substrateshields radioactivity from the operator, thus rendering the radiation from the devicesubstantially unidirectional.

Variations

8 10 FIGS.to 30 37 38 39 40 41 38 39 37 45 39 In a further example referring to, there is shown a substantially planar topical brachytherapy laminate structurecomprising an outer filmmade from a polycaprolactone-starch composite, an inert adhesive layercomprising carboxymethylcellulose overlaying a part of the outer film, and an active radioisotope film layercomprising a predetermined ratio of 32P particlesand 33P particles, in a carboxymethylcellulose matrix. In this example, the inert adhesive layerextends about the active radioisotope film layeron or adjacent the peripheral edge of the outer filmand is adapted to contact a surface of a patient's skin to adhere the laminate structure to a desired location. In one aspect, the radioisotope particles may be impregnated in the surface interface between layerand layer.

10 FIG. 38 43 8 43 37 37 As shown in, the inert adhesive layermay further include a peelable backing layer (removable film)for storage which is peeled away to expose the inert adhesion layer for adhesion to a desired treatment site. In this embodiment the inert adhesive is a pressure sensitive adhesive layerhaving removable backing film. The outer layermay comprise a hydrogel layer adapted to absorb radiation to protect the surgeon and any other tissues while they finish the case and the radioisotope decays. In this embodiment the hydrogel layermay have a thickness of between about 4 to 5 mm in order to absorb the radioactive particles.

45 39 44 37 Layersandare a smaller diameter (for example, 3 cm flat circle) than layersand(for example, 4 to 4.5 cm flat circle), so that it is completely surrounded by radioactive shielding.

8 9 FIGS.and In this example, the positive margin is focused in a small location, on a two-dimensional (albeit irregular) surface. Hence it is preferred that the example described by the laminate structure inis a substantially flat composite sheet with multiple layers.

9 FIG. 10 FIG. 42 39 44 44 Referring to, the laminate structure is shown located on a wound bed represented by reference numeralwith the active radioisotope film layerdirectly contacting the wound bed. In, the planar topical brachytherapy laminate structure further includes a removable shielding sheet. In one example, the removable shielding sheetmay comprise a lead vinyl/acrylic composite that is present only for handling and delivery and removed on application.

44 9 45 9 44 45 45 10 FIG. The shielding sheetis attached peripherally to the active radioisotope film layerwith water and/or heat soluble glue for peeling away therefrom for attachment to the wound bed. As further shown in, a thin filmof quick absorbing hydrocolloid such as cellulose may be sandwiched between the active radioisotope film layerand removable shielding sheet. In use, the thin filmof the topical brachytherapy laminate structure, which is between about 25 to 200 microns thick, is the first layer that contacts the wound surface. The thin filmfurther contains gemcitabine or other radio-sensitizer to make the tumor cells susceptible to radiation.

When water and heat is absorbed from the operative bed or wound bed, layers of the laminate structure become very flexible and stick to the irregular surface and deliver the predetermined radiation dose.

44 44 37 45 44 39 45 From the wound bed and heading outwards, the laminate structure comprises: a removable shielding sheet, for example lead vinyl and/or acrylic that is present only for handling and delivery, removed on application. The removable shielding sheetmay be attached peripherally to outer layerwith water and/or heat soluble glue for peeling away. The laminate structure further comprises a thin film of quick absorbing hydrocolloid(cellulose) which is the first layer that actually touches the wound surface. This contains gemcitabine or other radio-sensitizer to make the tumor cells susceptible to radiation—can be between about 25 to 200 microns thick. The laminate structure further comprises radioisotope particles impregnated in the surface interface between layerand layerforming a flat sheet or thin mesh layer.

37 The hydrogel layer, which absorbs radiation to protect the surgeon and any other tissues while they finish the case and the radioisotope decays, may have a thickness of between about 4 to 5 mm thick to effectively absorb the particles.

Benefits of the system include that: it provides an alternative treatment to manage close or positive margins to chemotherapy with or without adjuvant radiotherapy to the operative bed; it avoids the exposure to high toxicity of conventional treatments; and the doses of radiation can be localized to the tissue margins more readily hence decrease the effect of the presence of radiosensitive surrounding structures like the bowel, no need to wait for reconstructed structures (like anastomoses) to heal before the commencement of treatment with the topical device.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

The various embodiments described above can be combined to provide further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.