Topical brachytherapy device and method of treatment of malignant cancer cells

Abstract

To provide a flexible brachytherapy device for application on a wound site in a body, and a method for producing the device.SOLUTION: A flexible brachytherapy device 1 comprises a bioresorbable carrier matrix structure 2 comprising a plurality of radio-isotope particles 3 and having opposite first surface and second surfaces. The bioresorbable carrier matrix structure degrades, when implanted at a wound site, at a rate substantially longer than a half-life of the plurality of radio-isotope particles. A hydrophilic substrate 4 located adjacent to the first surface of the bioresorbable carrier matrix structure degrades, 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. A hydrogel substrate 5 located adjacent to the second surface of the bioresorbable carrier matrix structure shields radioactivity and degrades at a rate longer than the half-life of the plurality of radio-isotope particles.SELECTED DRAWING: Figure 1

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Australian Provisional Patent Application No. 2018900745, filed March 7, 2018, the contents of which are incorporated herein by reference in their entirety. [Technical field]

[0002] The present invention relates to a flexible brachytherapy device for application to a wound site in the body. In some instances, the device may be used to treat cancer in the body. [Background technology]

[0003] Cancer is a cellular disease that affects multiple body organs and affects a large number of people worldwide. When the normal mechanisms for regulating cell growth in the body are disrupted, cells can begin to grow in an uncontrolled manner. Cancer develops when normal cells in the body begin to develop abnormal growth patterns and do not go through the normal cell cycle, including cell death. Rapid uncontrolled growth and invasion of normal tissues by abnormal cells is the definition of malignant cancer. Cancer cells can undergo metastasis, whereby they break off from their primary site and travel to other parts of the body where they begin to grow new tumor deposits.

[0004] Treatment for cancer can include surgery, chemotherapy, and radiation therapy or a combination thereof. Surgery is the treatment of choice for most cancers, usually when the cancer appears to be localized to an organ, and is the initial workup of the patient to determine if the tumor can be removed by surgical means. Some cancers are amenable to surgical resection of metastatic deposits, such as colorectal, melanoma, and neuroendocrine tumors.

[0005] In the surgical removal of cancerous tumors, it is important to completely remove or destroy all malignant cells. Surgical removal of cancer involves cutting out the tumour or tumours, including a margin of normal tissue surrounding the cancer to ensure that the entire disease is excised. This includes removal of lymph nodes through which the primary tumor can spread. Generally, pathological examination of the margins of the removed tissue is employed during surgery to ensure that the tumor has been completely removed.

[0006] One of the most feared complications of major cancer surgery is incomplete resection or the presence of microscopic tumor cells at the resection margins. The likelihood of such occurrence is reduced but not eliminated by frozen section histology, which has a greatly reduced accuracy without the ability of immunohistochemistry to identify tumor cells. Secondly, many cancers invade along lymphatics or follow perineural lymphatics that are impossible to detect at the time of surgery.

[0007] Tumor cells may be left behind during cancer surgery because they have invaded vital structures that cannot be safely resected or reconstructed in the individual patient. In many cases, the index procedure is physically and metabolically intrusive to the patient's physiology, and reoperation or further resection is simply not possible. In these cases, the survival rate of individual patients with positive margins is significantly and significantly reduced from comparable patients with clear margins.

[0008] The current process of managing close or positive margins is chemotherapy with or without adjuvant radiation therapy to the surgical bed. This treatment is often ineffective in preventing local recurrence and is highly toxic. The dose of radiation delivered to the tumor cells is severely limited due to the presence of surrounding radiosensitive structures such as the bowel, and the need to wait for reconstructed structures (such as anastomoses) to heal before chemotherapy is initiated.

[0009] This results in ineffective radiation doses to the surgical bed for tumor control, and delays of up to 8-10 weeks, often before chemotherapy is initiated, at which time the immunological / inflammatory insults of major surgery reduce the body's ability to fight tumor cells, and cells at positive margins are left untreated, often resulting in local recurrence and then metastasis throughout the body.

[0010] Recently, the usefulness of high dose rate brachytherapy devices for managing inoperable tumors has been increasingly recognized. Radioisotopes conceived from intra-arterially injected beta-emitting particles have shown potential for managing inoperable liver tumors, and beta emitters suspended in silica diluents have shown early potential for injection or direct placement into inoperable pancreatic tumors through special applicators inserted into body cavities or tissues. However, there is currently no suitable device for the routine management of the risk to patients of positive margins after surgery, and current devices based on the prior art are not useful as routine surgical adjuncts. Barriers to the creation of such routine surgical devices include high cost, moderate flexibility, non-bioresorbable radioisotope sources, and lack of absorbable unidirectionality.

[0011] Any discussion of documents, acts, materials, devices, articles or the like which has been included in this specification should not be construed as an admission that any or all of such matters form part of the prior art or were common general knowledge in the field relevant to this disclosure as they existed prior to the priority date of each claim of this application.

[0012] It will be understood that throughout this specification the word "comprise", or variations such as "comprises" or "comprising", 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. Summary of the Invention

[0013] Prior art brachytherapy devices are often non-flexible and not fully bioabsorbable and bioresorbable by the body. This is due to the use of non-bioabsorbable / bioresorbable radioisotope sources or metallic shields used to make the device unidirectional. This in turn does not allow for accurate imaging of the site after resection. Prior art non-flexible brachytherapy devices are also not suitable for adjunctive approaches to surgery, as they cannot fully fit into the operating bed and provide a uniform dose to all tissues. Prior art devices promote the creation of separate metallic sealed sources that can be connected together by flexible membranes. They are limited in fit, in dose distribution, and by being non-absorbable in the body. Foreign bodies that are permanently implanted in the body (especially in surgical fields potentially contaminated with microorganisms), such as prior art brachytherapy seeds, have a very high risk of chronic infection and severe morbidity for the patient. If there is any long-term residual material in the brachytherapy seeds, this risk is not mitigated with partially absorbable devices. It is therefore desirable for brachytherapy devices to be flexible, unidirectional (so that surgeons and operating room personnel have minimal exposure to radiation), and completely bioresorbable in the body so that no foreign or metallic material remains for long periods of time.

[0014] A flexible brachytherapy device for application to a wound site in a body, the device comprising: a bioresorbable carrier matrix structure containing a plurality of radioisotope particles, the bioresorbable carrier matrix structure configured to degrade at a rate substantially longer than a half-life of the plurality of radioisotope particles when implanted at the wound site such that activity from the plurality of radioisotope particles is localized to the wound site, the bioresorbable carrier matrix structure having opposed first and second surfaces; and a first substrate of the bioresorbable carrier matrix structure. a hydrophilic matrix positioned adjacent to one surface of the bioresorbable carrier matrix structure, the hydrophilic matrix being configured such that when the hydrophilic matrix adheres to the wound site and is implanted at the wound site, the hydrophilic matrix degrades at a rate shorter than the bioresorbable carrier matrix structure so as to prevent migration of the device during the half-life of the plurality of radioisotope particles; and a hydrogel matrix positioned adjacent to a second surface of the bioresorbable carrier matrix structure, the hydrogel matrix being configured to shield radioactivity and degrade at a rate longer than the half-life of the plurality of radioisotope particles.

[0015] The bioresorbable carrier matrix may be formed by adsorbing or dispersing an aqueous solution of the radioisotope onto a hydrophobic material. The bioresorbable carrier matrix may further be formed by precipitating the radioisotope to form a plurality of insoluble radioisotope particles in the bioresorbable carrier matrix structure.

[0016] The hydrophobic material may include a hydrophilic surface to form a bioresorbable carrier matrix structure.The aqueous solution may include radioactive ions.

[0017] The radioactive ions are derived from one or more of monosodium phosphate, disodium phosphate, potassium phosphate, dipotassium phosphate, orthophosphate, or tetrasodium pyrophosphate, or iodide-containing soluble compounds.

[0018] The bioresorbable carrier matrix structure may be composed of a material(s) degradable by enzymatic processes. The bioresorbable carrier matrix structure may be composed of a material(s) degradable by pyrophosphatase.

[0019] The bioresorbable carrier matrix structure may be provided by adsorbing or dispersing an aqueous solution of the radioisotope onto an amorphous or semi-crystalline hydrophobic material to provide the bioresorbable carrier matrix structure. The amorphous or semi-crystalline hydrophobic material may include a hydrophilic surface.

[0020] The plurality of radioisotope particles can include elements in a calcium phosphate complex molecule, which can include one or more of calcium pyrophosphate, monocalcium phosphate, dicalcium phosphate, octacalcium phosphate, tricalcium phosphate, hydroxyapatite, fluoroapatite, or tetracalcium phosphate.

[0021] The precipitating agent may include an aqueous solution of calcium ions. The precipitating agent may include one or more of calcium chloride, calcium hydroxide, calcium nitrate, or calcium bromide.

[0022] The bioresorbable carrier matrix can be amorphous or semi-crystalline in nature. The bioresorbable carrier matrix can be partially semi-crystalline such that the degradation rate of the device is based on the half-life of the multiple radioisotope particles and through modification of the crystallinity.

[0023] In the device, the hydrogel matrix is ​​cross-linked with citric acid, and the percentage of citric acid is selected to specify the rate at which the hydrogel matrix degrades while maintaining its structural integrity and shielding ability. The percentage can be between 2.5% and 10%. The citric acid cross-linking can be catalyzed by titanium dioxide.

[0024] The device may further include an inactive adhesive layer positioned adjacent to a surface of the hydrogel matrix, the inactive adhesive layer configured to adhere to the wound site.

[0025] The device may further include a removable film located adjacent to the unactivated adhesive layer, the removable film being removable from the unactivated adhesive layer to expose a surface of the unactivated adhesive layer to the wound site.

[0026] A method of manufacturing a flexible brachytherapy device for application to a wound site in a body, the method comprising forming a bioresorbable carrier matrix structure containing a plurality of radioisotope particles, the bioresorbable carrier matrix structure configured to degrade at a rate substantially longer than a half-life of the plurality of radioisotope particles such that activity from the plurality of radioisotope particles is localized to the wound site, the biodegradable carrier matrix structure having opposed first and second surfaces; and forming a hydrophilic substrate adjacent to the first surface of the bioresorbable carrier matrix structure. forming a hydrophilic matrix configured to adhere to the wound site and to degrade at a rate shorter than the bioresorbable carrier matrix structure when implanted at the wound site, such that the hydrophilic matrix prevents migration of the device during the half-life of the plurality of radioisotope particles; and forming a hydrogel matrix located adjacent a second surface of the bioresorbable carrier matrix structure, such that the hydrogel matrix is ​​configured to shield radioactivity and to degrade at a rate longer than the half-life of the plurality of radioisotope particles.

[0027] In the method, the bioresorbable carrier matrix may be formed by adsorbing or dispersing an aqueous solution of the radioisotope onto a hydrophobic material. The bioresorbable carrier matrix structure may be formed by precipitating the radioisotope to form a plurality of insoluble radioisotope particles in the bioresorbable carrier matrix structure. The hydrophobic material may include a hydrophilic surface.

[0028] The aqueous solution may contain radioactive ions.

[0029] In the method, the bioresorbable carrier matrix structure may be formed by adsorbing or dispersing an aqueous solution of the radioisotope onto an amorphous or semi-crystalline hydrophobic material to provide a bioresorbable carrier matrix structure. The amorphous or semi-crystalline hydrophobic material may include a hydrophilic surface.

[0030] A bioresorbable carrier matrix structure comprising a plurality of radioisotope particles, the bioresorbable carrier matrix structure being formed by adsorbing or dispersing an aqueous solution of the radioisotope onto a hydrophobic material to produce the bioresorbable carrier matrix structure. The bioresorbable carrier matrix structure may be formed by precipitating the radioisotope to form a plurality of insoluble radioisotope particles in the bioresorbable carrier matrix structure. The hydrophobic material may include a hydrophilic surface.

[0031] The aqueous solution may contain radioactive ions.

[0032] The bioresorbable carrier matrix structure may be formed by adsorbing or dispersing a plurality of insoluble radioisotope particles onto an amorphous or semi-crystalline hydrophobic material to provide a bioresorbable carrier matrix structure. The amorphous or semi-crystalline hydrophobic material may include a hydrophilic surface.

[0033] The bioresorbable carrier matrix structure can be amorphous or semi-crystalline in nature.

[0034] The bioresorbable carrier matrix structure can be configured, when implanted at a wound site, to degrade at a rate substantially longer than the half-life of the multiple insoluble radioisotope particles such that activity from the multiple radioisotope particles is localized to the wound site.

[0035] The bioresorbable carrier matrix may be configured for use in a brachytherapy device for application to a wound site, the device including a hydrophilic substrate positioned adjacent to a first surface of the bioresorbable carrier matrix structure, the hydrophilic substrate being configured to adhere to the wound site and, upon implantation at the wound site, the hydrophilic substrate degrades at a faster rate than the bioresorbable carrier matrix structure so as to prevent migration of the device during the half-life of a plurality of radioisotope particles.

[0036] It may be configured for use in a brachytherapy device for application to a wound site, the device including a hydrogel matrix positioned adjacent to a second surface of the bioresorbable carrier matrix structure, the hydrogel matrix configured to shield radioactivity and to degrade at a rate longer than the half-life of the plurality of radioisotope particles.

[0037] A method for producing a bioresorbable carrier matrix containing a plurality of radioisotope particles, the method comprising adsorbing or dispersing an aqueous solution of the radioisotope onto a hydrophobic material. The bioresorbable carrier matrix may be formed by precipitating the radioisotope to form a plurality of insoluble radioisotope particles in the bioresorbable carrier matrix structure. The hydrophobic material may comprise a hydrophilic surface.

[0038] The aqueous solution may contain radioactive ions.

[0039] An applicator device for application of a brachytherapy device to a wound site in the body, the applicator device including an upper housing having a recess for receiving the brachytherapy device, and a removable base attached to the upper housing, where when attached, the removable base and the upper housing shield radiation from the brachytherapy device, the removable base being removable from the upper housing to expose a first surface of the brachytherapy device to the wound site.

[0040] The removable base is slidably attached to and slidably removable from the upper housing.

[0041] The upper housing may further include an inlet port fluidly connected to the recess for allowing introduction of a fluid through the inlet port to the brachytherapy device in the recess.

[0042] The applicator device may further include a soluble adhesive for additionally securing the upper housing and the removable base, the soluble adhesive being dissolvable by a liquid introduced into the recess to enable the removable base to be slidably removed from the upper housing.

[0043] The upper housing may include a material that is transparent, semi-transparent, or translucent to block beta radiation. The upper housing may be formed from an acrylate polymer.

[0044] The applicator device may further include a handle on the upper housing to assist in placement of the applicator device and the brachytherapy device at the wound site.

[0045] A brachytherapy system comprising an applicator device as described above and a brachytherapy device as described above, wherein the hydrogel matrix is ​​hydrated to an equilibrium water content by an inlet port of the applicator device.

[0046] Examples of the present disclosure will be described with reference to the following figures. [Brief description of the drawings]

[0047] [Figure 1] 1 shows a schematic diagram of a brachytherapy device. [Diagram 2] 1 shows a further schematic diagram of a brachytherapy device following absorption of a hydrophilic substrate. [Diagram 3]1 shows a cross-sectional schematic diagram of a brachytherapy device. [Figure 4] 1 shows a further cross-sectional schematic diagram of a brachytherapy device following absorption of a hydrophilic matrix. [Diagram 5] 13 shows a further cross-sectional schematic of the brachytherapy device following further absorption of the hydrophilic matrix, degradation of the hydrogel, and decay of the radioisotope. [Figure 6] 1 shows a schematic diagram of an applicator device. [Figure 7] 1 shows a further schematic diagram of the applicator device; [Figure 8] 1 shows a further schematic diagram of a brachytherapy device; [Figure 9] 9 shows a schematic cross-sectional view of the device in FIG. 8. [Figure 10] 1 shows a further schematic diagram of a brachytherapy device; [Figure 11] SUMMARY OF THE DISCLOSURE A method for manufacturing a brachytherapy device is presented. [Figure 12] 1 shows a further schematic diagram of the applicator device; [Figure 13] 1 shows a further schematic diagram of the applicator device; [Figure 14] 1 shows a further schematic diagram of the applicator device; DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] overview An example of a brachytherapy device is shown in FIG. 1. The device 1 may be used on a wound site in the body, for example during a surgical procedure. The device 1 includes a bioresorbable carrier matrix structure 2 containing a plurality of radioisotope particles 3. The bioresorbable carrier matrix structure 2 is configured to degrade at a rate substantially longer than the half-life of the plurality of radioisotope particles 2 when implanted at the wound site. In this way, activity from the plurality of radioisotope particles 2 is localized to the wound site. The bioresorbable carrier matrix structure 2 has opposed first and second surfaces 21, 22.

[0049] The device 1 further includes a hydrophilic matrix 4 located adjacent the first surface 21 of the bioresorbable carrier matrix structure 2. The hydrophilic matrix 4 adheres to the wound site. The hydrophilic matrix is ​​configured to degrade at a faster rate than the bioresorbable carrier matrix structure when implanted at the wound site to prevent migration of the device during the half-life of the plurality of radioisotope particles 3.

[0050] The device 1 further includes a hydrogel matrix 5 located adjacent the second surface 22 of the bioresorbable carrier matrix structure 2. In some examples, the hydrogel matrix 5 is adhesive to and integral with the hydrophilic substrate 4. The hydrogel matrix 5 is configured to shield radioactivity and to degrade at a rate greater than the substantial activity of the plurality of radioisotope particles 3, e.g., greater than the half-life of the plurality of radioisotope particles 3. In this manner, the hydrogel matrix 5 shields radioactivity until radioactive decay renders the bioresorbable carrier matrix structure 2 substantially inactive (of radioactivity) and safe.

[0051] The device 1 may be suitable for minimizing and / or controlling local recurrence of malignant cancers and seromas following cancer surgery. The device 1 may also be suitable for minimizing and / or controlling uncontrolled proliferation of microscopic tumor cells at the margins of surgical resection.

[0052] It is an advantage that the device 1 is configured to be completely bioabsorbable and / or bioresorbable in the body. In this way, the device can be completely degraded / replaced "in vivo". Additionally, the device 1 has the advantage of being a completely sealed source (while still being significantly radioactive). In some examples, the device 1 is constructed such that it can withstand immersion in water, phosphate buffered saline, or other physiologically compatible fluids at room temperature for 24 hours without significant loss of radioisotope.

[0053] It is a further advantage that the plurality of radioisotope particles 3 are maintained in place at the wound site until such time as they are no longer substantially radioactive.

[0054] It is a further advantage that the brachytherapy device 1 is configured to be flexible and to conform to the wound site.

[0055] Next, details of the exemplary brachytherapy device 1 will be described in detail.

[0056] Bioresorbable carrier matrix 2 As described above, the device 1 includes a bioresorbable carrier matrix structure 2 that includes a plurality of radioisotope particles 3. In some examples, the bioresorbable carrier matrix 2 is formed by adsorbing or dispersing an aqueous solution of a radioisotope onto a hydrophobic material. The bioresorbable carrier matrix may further be formed by precipitating the radioisotope to form a plurality of insoluble radioisotope particles in the bioresorbable carrier matrix structure 2. In this example, the aqueous solution may include radioactive ions. The radioactive ions may include one or more of monosodium phosphate, disodium phosphate, potassium phosphate, dipotassium phosphate, orthophosphate, or tetrasodium pyrophosphate, or a soluble compound containing iodide.

[0057] The multiple radioisotope particles 3 can include a beta emitter. In other examples, the multiple radioisotope particles 3 can include a gamma emitter or a mixed gamma / beta emitter. In some examples, the multiple radioisotope particles 3 can be an element in a family of calcium phosphate compounds. In one example, the multiple radioisotope particles 3 can include an element in a calcium pyrophosphate complex molecule. This can include calcium phosphate, monocalcium phosphate, dicalcium phosphate, octacalcium phosphate, tricalcium phosphate, hydroxyapatite, fluoroapatite, or tetracalcium phosphate complex molecules. In some examples, the multiple radioisotope particles 3 can include complex molecules in hydrated or anhydrous form.

[0058] In other examples, the multiple radioisotope particles 3 can include one or more of yttrium-90, iridium-192, palladium-103, cesium-137, 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 radioisotopes as the multiple radioisotope particles 3 reduces incidental radiation exposure from handling compared to P32 alone. In this description, it should be understood that the radioisotope particles 3 can include compounds containing radioisotopes.

[0059] The bioresorbable carrier matrix structure 2 is configured such that, when implanted at the wound site, it degrades at a rate substantially longer than the half-life of the plurality of radioisotope particles 3. In this manner, activity from the plurality of radioisotope particles is localized to the wound site.

[0060] 5 shows a cross-sectional view of the device 1 after significant decay of the plurality of radioisotope particles 3. As shown, the bioresorbable carrier matrix structure 2 remains in place after degradation of the hydrophilic substrate 4, hydrogel 5, and decay of the plurality of radioisotope particles 3. Having a bioresorbable carrier matrix that outlives the substantial radioactivity of the radioisotope (such as beyond the half-life of the radioisotope) ensures that the radioactivity is localized to the wound site 100 of the surgical margin wound bed 7.

[0061] The rate of delivery of radiation from the plurality of radioisotope particles 3 may be determined by the characteristics of the bioresorbable carrier matrix structure 2 and / or the hydrophilic substrate 4 .

[0062] In some examples, the plurality of radioisotope particles 3 can include particles with intermediate half-lives (less than 30 days), thus allowing the bioresorbable carrier matrix structure 2 to degrade at a rate substantially greater than 30 days.

[0063] The bioresorbable carrier matrix structure 2 may be formed by adsorbing or dispersing a plurality of insoluble radioisotope particles onto a hydrophobic material having a hydrophilic surface. The hydrophobic material may be microporous or macroporous.

[0064] In some examples, the hydrophobic material can include a hydrophilic surface. In this way, as described below, a solution containing radioactive ions can be drawn up into the microporous hydrophobic material by capillary action. Without a hydrophilic surface, the radioactive ions cannot be so distributed. Alternatively, in examples of hydrophobic materials that do not have a hydrophilic surface, the radioactive particles can be hot pressed / imprinted onto the hydrophobic material.

[0065] In one example, a microporous hydrophobic material with a hydrophilic surface is prepared as follows: A hydrophobic biodegradable polymer, such as polycaprolactone (PCL), is rendered hydrophilic by the addition of a surfactant. In one example, the surfactant can include a polyethylene glycol-polypropylene glycol block monomer (Pluronic P123). In another example, other hydrophobic base biopolymers can 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.

[0066] In further examples, hydrophilic copolymers can be added to improve hydrophilicity and available sites for crosslinking. Examples of hydrophilic copolymers can include collagen, alginate, carboxymethylcellulose and other forms of cellulose, polyethylene glycol, or any of a large series of copolymers of polyethylene glycol. In some examples, partially amorphous polymers such as PDLLA, or biodegradable elastomers including but not limited to (poly)glycerol sebacate (or polyurethane-based biodegradable elastomers) can be added to increase the flexibility of PCL, reduce the percentage of crystallinity, and / or increase the hydrophilicity of the resulting blend.

[0067] The new slowly hydrolyzable polymer blend is then made microporous through the incorporation of highly soluble substances such as non-toxic solvent soluble salts (NaCl, MgCl, etc.), or soluble liquids (such as glycerol), or other soluble components. The soluble components can be leached out of the PCL blend by a combination of heat and / or solvent. This results in a microporous hydrophobic matrix with a hydrophilic surface. The matrix can be slowly absorbed.

[0068] In some examples, porosity of the hydrophobe / matrix can also be created by bubbling an inert gas during mixing of the polymers, such as in an extruder. The inert gas can include nitrogen, carbon dioxide, or argon. In other examples, porosity of the hydrophobe / matrix can be created with the inclusion of a "porogen" compound, such as sodium bicarbonate, in the formulation. In this way, the gas can be released upon exposure to heat.

[0069] In another example, a rapidly decaying radioisotope may be used for multiple radioisotope particles, which may facilitate the use of purely hydrophilic carrier matrices as the bioresorbable carrier matrix structure 2, including polyglycolide polymers or cross-linked hydrogels.

[0070] In another example, the hydrophobic and hydrophilic components can be thoroughly mixed in a batch mixer or extruder and compatibilized with an amphiphilic polymer or copolymer (such as polyethylene glycol or Pluronic P123) and then with the incorporated radioisotope component by using the low melting point of the biodegradable matrix by hot pressing, injection molding, or extrusion.

[0071] In some examples, the plurality of insoluble radioisotope particles 3 can be provided by adding a precipitating agent to the plurality of radioisotope particles. In one example, the plurality of radioisotope particles 3 can include ions, so that the precipitating agent is added to the plurality of radioisotope ions. In one example, the radioisotope ions can be suspended in solution to form an aqueous radioisotope solution and dispersed throughout the carrier matrix 2. This creates an insoluble form of the plurality of radioisotope particles 3. In one example, the aqueous radioisotope solution can be composed of the elements of the compound tetrasodium pyrophosphate. In other examples, any aqueous radioisotope solution that can be precipitated into a bioresorbable insoluble salt can be used. These include any aqueous solution containing 32P phosphate ions, while 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, cesium 137, etc.

[0072] In one example, the precipitant includes calcium chloride. In another example, the precipitant can include an additional aqueous solution of calcium ions, including hydroxide or nitrate forms. The precipitant can include one or more of calcium chloride, calcium hydroxide, calcium nitrate, or calcium bromide. In this manner, the plurality of insoluble radioisotope particles can be formed into a complex calcium pyrophosphate (Ca 2 P 2 O 7 ), anhydride, dihydrate (Ca 2 P 2 O 7 2H 2 O) or the element in its tetrahydrate (Ca2P2O7 4H2O).

[0073] The precipitating agent can also include any insoluble or poorly soluble salt that can be bioresorbed by the body. These include any type of calcium phosphate or forms of ammonium magnesium phosphate (Struvite). In one example, the functional groups of the absorbable polymer can be iodized using radioactive iodides 125 or 131, or crystalline iodide embedded / distributed throughout the bioresorbable carrier matrix. In yet another example, the precipitating agent can include another molecule containing calcium, magnesium, zinc, or iron.

[0074] In another example, multiple radioisotopes 3 can be adsorbed into an anion exchange resin and a precipitating agent can be applied after absorption. In this example, a precipitating agent such as magnesium ammonium phosphate (Struvite) can be used. In another example, a gamma source such as chromium 51 can be precipitated onto the anion exchange resin or into the resorbable radioactive molecule.

[0075] The microporous hydrophobic material with hydrophilic surface can then be tailored through the addition of copolymers to achieve partial crystallization (semi-crystalline). This is an advantage because it allows the device 1 to be flexible and malleable, conforming to the shape of the wound site. The semi-crystalline blend can modify the long hydrolysis time of pure PCL / polylactide. That is, the degradation rate of the device 1 can be determined by modifying the crystallinity of the bioresorbable carrier matrix structure 2. In some examples, the degradation rate of the device 1 can be through modification of the crystallinity based on the half-life of multiple radioisotopes 3. Thus, the device 1 is suitable for use in surgical procedures.

[0076] The bioresorbable carrier matrix structure 2 can then be completely biodegradable in the body. As mentioned above, this is an advantage of the device 1. It is also an additional advantage that the device 1 can prevent chronic infection when such a device 1 is utilized in a potentially contaminated area. In some examples, the bioresorbable carrier matrix structure 2 can be degraded by intracellular, extracellular, and enzymatic processes present in the body, such as pyrophosphatase or circulating osteocyte precursor cells and / or mature bone cells. In some examples, osteoclasts (or their circulating osteoclast precursor cells) can degrade the structure 2. Osteoclasts can degrade, resorb, modify, and / or replace any of the entire family of calcium phosphates. This can include any insoluble, bioresorbable complex molecule. In other examples, the bioresorbable carrier matrix structure 2 can be degraded by other enzymes present in the body.

[0077] In some examples, iodized compounds may be used as radioisotope particles 3. This may include iodinating one or more functional groups of an absorbable polymer using a radioactive iodide, such as iodine-131, iodine-125, or iodine-123. In other examples, crystalline iodide may be embedded in a bioabsorbable polymer.

[0078] In this way, over time, the initially insoluble phosphate compound in the multiple insoluble radioisotope particles can become aqueous through the body's enzymatic processes. The initially insoluble phosphate compound present in the multiple insoluble radioisotope particles can be required for safe surgical handling as a sealed source of brachytherapy. The radioisotope particles / ions can then diffuse from the bioresorbable carrier matrix structure 2 toward the wound site 100 and be absorbed into the cells. The radioisotope particles / ions can then be incorporated into the cancer cell DNA to increase apoptosis.

[0079] In some examples, the bioresorbable carrier matrix structure 2 can be pressed, extruded, or injection molded into a desired shape, such as a flat sheet. The bioresorbable carrier matrix structure 2 can have a thin mesh surface interface.

[0080] The bioresorbable carrier matrix structure 2 includes opposed first and second surfaces 21,22.

[0081] In some examples, the plurality of radioisotope particles 3 may be impregnated in the space between the bioresorbable carrier matrix structure 2 and the hydrophilic substrate 4. For example, there may be a receptacle formed by at least two layers to receive the plurality of radioisotope particles 3. In this example, a sealed source of radiotherapy may be obtained through stacking of radioactive particles with a hydrophobic or partially hydrophobic layer. In this way, the stacked radioactive particles can be completely or mostly bioresorbed by the processes of the body in which the device 1 is placed. In other examples, insoluble radioisotope particles, or a microporous matrix (such as an ion exchange resin) containing insoluble radioisotope particles, may be imprinted in the surface of the bioresorbable carrier matrix structure 2.

[0082] A further advantage of the device is that multiple radioisotope particles 3 are embedded within the bioresorbable carrier matrix 2, allowing safe removal of the device 1 (and therefore the radioisotope source) whilst maintaining unidirectional shielding should a return to the operating theatre be required.

[0083] Hydrophilic substrate 4 As noted above, the device 1 further includes a hydrophilic substrate 4 located adjacent to the first surface 21 of the bioresorbable carrier matrix structure. The hydrophilic substrate 4 faces the wound site and adheres to the wound site 100. In this manner, the hydrophilic substrate 4 provides integration or bridging of the device 1 to the wound site. In some instances, the hydrophilic substrate 4 is at and across the first surface 21 of the bioresorbable carrier matrix structure. This is shown in FIG.

[0084] In one example, the hydrophilic matrix 4 is supplied fully hydrated, with an equilibrium water content similar to that of the hydrogel matrix 5. In this manner, the fully hydrated hydrophilic matrix 4 may be less likely to undergo dramatic size and / or shape changes upon implantation and crosslinking into tissue at the wound site 100. In another example, the hydrophilic matrix 4 may include a portion of the material required to create amide bonds and / or hydrogen-hydrogen interactions between the device and tissue at the wound site 100 in the body. In this manner, added materials such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dopa, or other crosslinking agents can activate crosslinking between the device and tissue.

[0085] In some other examples, the hydrophilic substrate 4 absorbs moisture from the wound site, allowing the hydrophilic substrate 4 to wet and gel to conform to the wound site. The hydrophilic substrate 4 can be selected to be relatively quickly absorbent, allowing for placement of the device 1 in close proximity to the wound site. In other examples, the hydrophilic substrate 4 can be configured to be absorbed at the wound site within 3-5 days.

[0086] The hydrophilic matrix 4 is configured to degrade at a faster rate than the bioresorbable carrier matrix structure 2 when implanted at the wound site 100 to prevent migration of the device during the half-life of the plurality of radioisotope particles 3. This ensures that the device 1 does not migrate from the wound site 100. That is, the hydrophilic matrix 4 is configured to absorb at a faster rate than the bioresorbable carrier matrix structure 2. This allows the plurality of radioisotope particles 3 to be maintained in place at the wound site until it is no longer substantially active 4. In some examples, the time to substantial inactivation of the radioisotope may be 9 to 28 days.

[0087] 2 shows an example of a device 1 demonstrating faster absorption of the hydrophilic matrix 4. As shown, the hydrophilic matrix 4 is completely absorbed. The hydrogel matrix 5, bioresorbable carrier matrix structure 2, and plurality of radioisotope particles 3 remain in place at the wound site.

[0088] 4 shows a cross-sectional view showing the hydrophilic matrix 4 being absorbed into a wound site. In this example, the hydrogel matrix 5, the bioresorbable carrier matrix structure 2, and the plurality of radioisotope particles 3 remain in place at the wound site 100.

[0089] The hydrophilic substrate 4 may be composed of a cross-linked polymer. In some examples, the hydrophilic substrate 4 includes starch (of any type), carboxymethylcellulose, glycerol, xylitol, or citric acid, or any type of one or more thereof. In other examples, the hydrophilic substrate 4 may include other surgical adhesives, such as carbodiimide cross-links, dopa-lysine interactions, or citric acid cross-links.

[0090] In other examples, the hydrophilic substrate 4 can include a thin layer of a biocompatible resin, gel, or flexible biopolymer to rapidly absorb water and conform to the surgical bed. Other polymers derived from cellulose can also be used.

[0091] The hydrophilic matrix 4 may also include a radiosensitizer, such as gemcitabine or capecitabine. The radiosensitizer may be suspended in the hydrophilic matrix 4 by solvent casting techniques, solution immersion, or melt extrusion techniques. In this manner, the radiosensitizer may be released as the wound site absorbs the hydrophilic matrix 4. This may have the effect of making tumor cells in or adjacent to the wound site more susceptible to radiation from the multiple radioisotope particles 3.

[0092] When the hydrophilic matrix 4 is applied to a wound site, it hydrates to form a surface film that conforms to the wound site. As shown in Figure 3, the hydrophilic matrix 4 can extend beyond the edges of the bioresorbable carrier matrix structure 2.

[0093] In some examples, the hydrophilic matrix 4 provides a hemostatic effect to the wound site and prevents a hematoma that may lift the device 1 from the wound site. In this example, the hydrophilic matrix 4 may further include a coating or suspension of a hemostatic agent, such as thrombin, fibrin, fibrinogen, or other hemostatic agent, to enhance the hemostatic properties of the hydrophilic matrix 4.

[0094] Hydrogel Substrate 5 The device 1 further includes a hydrogel matrix 5 located adjacent to the second surface 22 of the bioresorbable carrier matrix structure 2. The hydrogel matrix 5 allows for conformability, flexibility, and the ability to allow for surgical implantation of the device 1. The hydrogel matrix 5 is configured to shield radiation and to degrade at a rate greater than the half-life of the plurality of radioisotope particles. The hydrogel matrix 5 may also be configured to completely hydrolyze at a rate greater than the half-life of the plurality of radioisotope particles. In this manner, the hydrogel matrix 5 is configured to absorb any emitted radiation to protect the surrounding tissue of the patient and, in some circumstances, the operator of the device 1, such as a surgeon. This is an advantage of the device 1, since unlike prior art devices such as those described above, the shielding provided by the hydrogel matrix 5 helps the device to be unidirectional.

[0095] In one example, the hydrogel substrate 5 is attached to the second surface 22 of the bioresorbable carrier matrix structure 2 so that the hydrogel substrate 5 is adhered to and consolidated in a hydrated state using phosphate buffered saline (or other biocompatible solution). A hydrated state can mean that the hydrogel substrate 5 is at or close to its equilibrium water content (EWC). This is an advantage of the device 1 because, unlike prior art devices, it is convenient and safe for application during surgery. That is, the device can be safely handled as one-way out of the packaging and does not require additional assembly by the operator of the device.

[0096] In some instances, the hydrogel matrix 5 limits the penetration of the plurality of radioisotope particles 3 to a few millimeters. As shown in Figures 3 and 4, the hydrogel matrix 5 faces away from the wound site 100. Additionally, in some instances, the hydrogel matrix is ​​at and across the second surface 22 of the bioresorbable carrier matrix structure. In a further instance, as shown in Figures 1-4, the hydrogel matrix 5 extends beyond the perimeter of the bioresorbable carrier matrix structure 2. This provides additional shielding to tissue near the surrounding area. As shown in Figure 3, the hydrogel matrix 5 near the perimeter can be in contact with the hydrophilic matrix 4. Thus, in some instances, the bioresorbable carrier matrix structure is encapsulated by the hydrogel matrix 5 and the hydrophilic matrix 4 when the device 1 is initially implanted.

[0097] The hydrogel substrate 5 may be combined with the bioresorbable carrier matrix structure 2 by at least one of mechanical integration, chemical crosslinking, or enzymatic crosslinking. In some instances, a combination of mechanical integration and chemical crosslinking using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and / or N-hydroxysuccinimide (NHS) carbodiimide chemistry may be used. In this instance, surface modification may be required, for example, by means of plasma treatment and / or surface hydrolysis.

[0098] The hydrogel matrix 5 may be comprised of a hydrophilic polymer interpenetrating multipolymeric hydrogel. This may include polyvinyl alcohol, carboxymethylcellulose, partially hydrolyzed collagen, and xylitol cross-linked with citric acid. The hydrogel matrix 5 may also include a blend of copolymers using polyethylene glycol. In some instances, a catalyst such as titanium dioxide may be present for citric acid cross-linking. In still other instances, other hydrophilic resorbable polymers or sugar alcohols may be used, including but not limited to sodium alginate, starch, chitosan, cellulose forms, varieties or collagen, polyethylene glycol, glycerol, sorbitol, and the like.

[0099] As mentioned above, the hydrogel matrix can at least partially comprise citric acid. The percentage of citric acid can be selected to specify the rate at which the hydrogel matrix 5 degrades and maintains its structural integrity and shielding ability. In some examples, the percentage of citric acid can be 2.5% to 10%. In this way, the citric acid ensures that the hydrogel matrix 5 continues to shield radiation for the duration of time after implantation at the wound site. This can be useful, for example, if a patient with such a device 1 needs to return to the operating room at a time point after implantation. In other examples, chemical crosslinking can be performed using agents such as glutaraldehyde, or crosslinking can be performed using gamma irradiation, UV exposure, or through a freeze-thaw method.

[0100] The hydrogel matrix 5 can have a thickness of at least 3 mm, and preferably closer to 3.5 mm. In other examples, gamma radiation sources may be used that require an increased thickness of the hydrogel matrix 5 to provide effective unidirectional shielding. As shown in FIG. 3, the hydrogel matrix 5 can be configured with a central recessed portion for receiving the bioresorbable carrier matrix structure 2 therein.

[0101] The hydrogel matrix 5 can also act to prevent damage or undesired adhesion and adhesion of surrounding tissues and structures to the device. As shown in Figure 3, the hydrogel matrix 5 can be attached at the edge portions of the hydrophilic substrate 4. In this manner, the hydrogel matrix 5 can extend beyond the edges of the first and second surfaces 21, 22 of the biocompatible carrier matrix structure 2.

[0102] Method for manufacturing a flexible brachytherapy device 200 As shown in FIG. 11, a method 200 of manufacturing a flexible brachytherapy device for application to a wound site in the body is also provided. The method 200 includes forming 202 a bioresorbable carrier matrix structure 2 including a plurality of radioisotope particles 3. In the method 200, the bioresorbable carrier matrix structure 2 is provided by adsorbing a plurality of insoluble radioisotope particles to a hydrophobic material having a microporous hydrophilic surface 4 to provide the bioresorbable carrier matrix structure 2 as described above. In some examples, the bioresorbable carrier matrix structure 2 may be formed using a thermoplastic process, such as a combination of extrusion and / or heated batch mixing. In other examples, injection molding or hot pressing may be used. In some examples, the plurality of insoluble radioisotope particles is provided by adding a precipitating agent to the plurality of radioisotope particles.

[0103] The bioresorbable carrier matrix structure 2 is configured to degrade at a rate substantially longer than the half-life of the multiple radioisotope particles 3 so that activity from the multiple radioisotope particles 3 is localized to the wound site, and the bioresorbable carrier matrix structure 2 has opposing first and second surfaces 21, 22.

[0104] The method 200 includes forming 204 a hydrophilic matrix 4 adjacent to the first surface 21 of the bioresorbable carrier matrix structure 2, where the hydrophilic matrix 4 adheres to the wound site. The hydrophilic matrix 4 is configured to degrade at a faster rate than the bioresorbable carrier matrix structure 3 when implanted at the wound site to prevent migration of the device 1 during the half-life of the plurality of radioisotope particles 3. The hydrophilic matrix may be formed through extrusion, solvent casting, spray coating and / or dipping.

[0105] The method 200 further includes forming 206 a hydrogel matrix 5 adjacent the second surface 22 of the bioresorbable carrier matrix structure 2, the hydrogel matrix 5 configured to be radiation shielding and to degrade at a rate greater than the half-life of the plurality of radioisotope particles 3. In some examples, the hydrogel matrix 5 may be formed through a combination of multiple polymers prior to melt extrusion or solvent casting.

[0106] The hydrophilic substrate 4 and hydrogel substrate 5 may be attached to the device 1 through one or more of the following techniques: mechanical consolidation, hot pressing, molding, chemical and / or enzymatic cross-linking. This may include carbodiimide chemistry, GEM, transglutaminase, or other more traditional cross-linking methods (e.g., glutaraldehyde). In one example, a combination of mechanical consolidation and carbodiimide chemistry is used, utilizing amide-hydroxyl bonds between collagen molecules in the radioactive bioresorbable carrier matrix structure 2 and free amide and / or hydroxyl groups in the hydrophilic substrate 5 and hydrogel substrate 5.

[0107] Applicator Device 6 shows an example of an applicator device 66 for application of a brachytherapy device 1 to a wound site 100 in the body. The applicator device 66 provides for application of the brachytherapy device 1 to the wound site 100 while protecting an operator, such as a surgeon or nuclear medicine physician. The applicator device 66 also provides for safe distribution and storage of the device 1 as well as easy placement of the device 1 at the wound site 100. The applicator device 66, when used with the brachytherapy device 1 contained therein, keeps the brachytherapy device 1 dry and also shields any nearby personnel from radioactive radiation, minimizing incidental radiation exposure.

[0108] The applicator device 66 is configured to be placed inside the body so that the base 8 faces away from the operator and towards the wound site 100.

[0109] The applicator device 66 includes an upper housing 6 having a recess 67 for receiving the brachytherapy device 1. The upper housing 6 of the applicator device 66 can include a material that is transparent, semi-transparent, or translucent to allow the surgeon to accurately position the brachytherapy device while shielding the surgeon from beta radiation. In some examples, the upper housing 6 can be formed from an acrylate polymer, such as Perspex.

[0110] The applicator device 66 also includes a removable base 8 attached to the upper housing 6, and when attached, the removable base 8 and the upper housing 6 shield radiation from the brachytherapy device 1. In some examples, the removable base 8 is slidably attached to the upper housing 6. In this manner, the removable base 8 may be slidably removable from the upper housing 6. As shown in FIG. 12, in some examples, the upper housing 6 includes a rail 15 that is received and engaged in a groove 17 on the removable base 8. In some examples, this may include the rail 15 being formed in a dovetail with the groove 17. It should be understood that other sliding engagement arrangements may be used, such as inwardly facing opposing grooves that receive opposing edges of the base.

[0111] The removable base 8 can have a flat surface. The removable base 8 can be constructed of a material suitable for protection against bremsstrahlung radiation, such as acrylic. In another example, if a gamma emitter is used, lead vinyl, leaded glass, or leaded vinyl acrylic can be used for the removable base 8. The combination of the upper housing 6 and the removable base 8 provides for safe handling and delivery of the brachytherapy device 1 to the wound site 100 during and after placement during a surgical procedure.

[0112] The removable base 8 can be configured to face the first surface 21 of the brachytherapy device 1. In some examples, the removable base 8 can face the hydrophilic substrate 4 of the brachytherapy device 1 according to the examples above.

[0113] The removable base 8 is removable such that it is slidably removable from the upper housing 6 to expose the first surface 21 of the brachytherapy device 1 to the wound site 100. FIG. 13 illustrates a slidably removable base 8. The removable base 8 may also be removable by other means, such as a hinge associated with the applicator device 66. In some examples, the first surface 21 may include the hydrophilic substrate 4 of the brachytherapy device 1 as described above. This is illustrated in FIG. 14. In this manner, the removable base 8 is slidably removed during application and placement of the brachytherapy device 1 to the wound site 100 to expose the hydrophilic substrate 4 to the wound site 100.

[0114] The removable base 8 may also include tabs 14 to allow an operator, such as a surgeon, to apply a pulling or pushing force to slidably remove the base 8 from the upper housing 6, thus exposing the first surface 21 of the brachytherapy device 1 so that the device 1 can be adjacent to and conform to the wound site 100.

[0115] In some examples, the upper housing 6 further includes an inlet port 11 fluidly connected to the recess 67. The inlet port 11 allows for the introduction of fluid through the inlet port 11 to the brachytherapy device 1 in the recess 67. In some examples, the channel 12 is connected to the inlet port 11 such that the fluid flows from the inlet port 11 to the brachytherapy device 1 in the recess 67. This can include introducing a liquid to hydrate the hydrogel matrix 5.

[0116] In some examples, the inlet port 11 may be used to "activate" the adhesive components of the brachytherapy device 1, either by channelling the adhesive components to the attachment surface of the device 1 or to some components of a cross-linking solution, which upon attachment to the tissue of the wound site 100 provides cross-linking between the device 1 and the tissue of the wound site 100. Such agents may incorporate one component of carbodiimide chemistry (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) or promote dopa-lysine interactions with or without transglutaminase promotion.

[0117] The applicator device 66 may further include a soluble adhesive 9 to additionally secure the upper housing 6 and the removable base 8. In this manner, the soluble adhesive 9 provides additional security to shield the operator of the applicator device 66 from any activity from the brachytherapy device 1 contained therein. The soluble adhesive 9 may also provide a seal, such as a hermetic seal, for the applicator device 66.

[0118] The soluble adhesive 9 may be a water and / or heat soluble adhesive. The soluble adhesive 9 may be dissolvable by the liquid 13 introduced into the recess 67 to allow the removable base 8 to be slidably removed from the upper housing 6. In some examples, the upper housing 6 and the removable base 8 may be bonded by the soluble adhesive 9 around the periphery of the upper housing 6 and the removable base 8.

[0119] In some examples, water may be injected into the inlet port 11 of the upper housing 6. In this manner, the soluble adhesive 9 may be solubilized to such an extent that the removable base 8 may be removed to expose the first surface 21 (e.g., hydrophilic substrate 4) of the brachytherapy device 1 to the wound site 100.

[0120] In another example, heat in addition to liquid can be inserted into the inlet port 11 to the recess 67. For example, this can include warm water. In this manner, the soluble adhesive 9 can absorb the heated liquid, so that the soluble adhesive 9 is solubilized and removes the removable base 8, exposing the hydrophilic matrix 4 of the brachytherapy device 1 to the wound site 100. In a further example, the hydrogel matrix 5 of the brachytherapy device 1 can expand to absorb heat and / or liquid to fill. The hydrogel matrix 5 shields against radiation as described above.

[0121] In one example, after the applicator device 66 is positioned at the wound site 100, water and heat can be inserted into the inlet port 11 into the recess 67. The soluble adhesive 9 can absorb water and heat. The hydrophilic matrix 4 of the device 1 can also absorb water and heat. The hydrogel matrix 5 can also absorb water and heat. The bioresorbable carrier matrix structure 2 can also absorb water and heat. When the hydrogel matrix 5 is fully absorbed, the saturated hydrogel matrix 5 is easily removed from the upper housing 6 for application of the device 1 to the wound site 1. The device 1 then becomes flexible and can conform and adhere to a surface, such as the wound site 100. The device 1 can then deliver a radiation dose.

[0122] In a further example, a liquid or gas suitable for sterilization may be inserted into the inlet port 11. For example, ethylene oxide may be introduced to sterilize the device 1 and / or applicator device 66 at the manufacturing facility and / or prior to a surgical procedure.

[0123] The applicator device 66 may further include a handle 10 on the upper housing 6 to aid in placement of the applicator device 66 and the brachytherapy device 1 at the wound site 100. In some examples, the handle 10 may be longitudinal as shown in Figures 6 and 7. In other examples, the handle 10 may be of another configuration attached to the upper housing 6.

[0124] In some examples, the device 1 may be completely enclosed by the upper housing 6 and the removable base 8. That is, the hydrophilic matrix 4 and the bioresorbable carrier matrix 2 may be smaller in diameter than the removable base 8 and the hydrogel matrix 5. In one example, the hydrophilic matrix and the bioresorbable carrier matrix 2 may be flat and circular, 3 cm in diameter, and the removable base 8 and the hydrogel matrix 5 may be flat and circular, 4-4.5 cm in diameter.

[0125] Also provided is a brachytherapy system including the applicator device 66 and device 1 as described above. In some examples, the hydrogel matrix 5 of device 1 can be hydrated at equilibrium water content by the inlet port 11 of the applicator device 66. In this manner, the hydrogel matrix 5 can be fully formed, hydrated, and crosslinked with the device 1. Advantageously, the device 1 can then be handled from the applicator device 66 by the operator without additional assembly by the operator or fellow personnel. Also advantageously, the fully hydrated hydrogel matrix 5 shields radioactivity from the operator, thus making radiation from device 1 substantially unidirectional. Variations

[0126] In a further example, referring to Figures 8-10, a substantially flat local brachytherapy laminate structure 30 is shown including an outer film 37 made of a polycaprolactone-starch composite, an inert adhesive layer 38 including carboxymethylcellulose covering a portion of the outer film, and an active radioisotope film layer 39 including a predetermined ratio of 32P particles 40 and 33P particles 41 in a carboxymethylcellulose matrix. In this example, the inert adhesive layer 38 extends around the active radioisotope film layer 39 on or near the periphery of the outer film 37 and is adapted to contact the surface of the patient's skin to adhere the laminate structure to the desired location. In one embodiment, the radioisotope particles may be impregnated into the surface interface between layer 45 and layer 39.

[0127] As shown in FIG. 10, the inactive adhesive layer 38 may further include a peelable backing layer (removable film) 43 for storage that is peeled off to expose the inactive adhesive layer for adhesion to the desired treatment site. In this embodiment, the inactive adhesive is a pressure sensitive adhesive layer 8 with a removable backing film 43. The outer layer 37 may include a hydrogel layer adapted to absorb radiation to protect the surgeon and any other tissue while they finish the case and the radioisotope decays. In this embodiment, the hydrogel layer 37 may have a thickness of about 4-5 mm to absorb the radioactive particles.

[0128] Layers 45 and 39 are of a smaller diameter (eg, 3 cm flat circle) than layers 44 and 37 (eg, 4-4.5 cm flat circle) so that it is completely surrounded by radiation shielding.

[0129] In this example, the positive margins are concentrated in small locations on a two-dimensional (albeit irregular) surface. Thus, the example described by the laminate structure in Figures 8 and 9 is preferably a substantially flat composite sheet having multiple layers.

[0130] With reference to Figure 9, the laminate structure is shown positioned on the wound bed, represented by reference numeral 42, with the active radioisotope film layer 39 in direct contact with the wound bed. In Figure 10, the flat local brachytherapy laminate structure further includes a removable shielding sheet 44. In one example, the removable shielding sheet 44 may comprise a lead vinyl / acrylic composite that is present only for handling and delivery and is removed upon application.

[0131] The shielding sheet 44 is attached around the active radioisotope film layer 9 with a water and / or heat soluble adhesive for removal therefrom for attachment to the wound bed. As further shown in FIG. 10, a thin film 45 of a rapidly absorbing hydrocolloid such as cellulose may be sandwiched between the active radioisotope film layer 9 and the removable shielding sheet 44. In use, the thin film 45 of the local brachytherapy laminate is approximately 25-200 microns thick and is the first layer that contacts the wound surface. The thin film 45 further contains gemcitabine or other radio-sensitiser to sensitize tumor cells to radiation.

[0132] As water and heat are absorbed from the surgical or wound bed, the layers of the laminate become highly flexible and adhere to irregular surfaces to deliver a predetermined radiation dose.

[0133] Outwardly from the wound bed, the laminated structure includes a removable shielding sheet 44, e.g., lead vinyl and / or acrylic, that is present only for handling and delivery and is removed upon application. The removable shielding sheet 44 may be attached to the periphery of the outer layer 37 with a water and / or heat soluble adhesive for peeling off. The laminated structure further includes a thin film of fast absorbing hydrocolloid 45 (cellulose) that is the first layer that actually touches the wound surface. This contains gemcitabine or other radiosensitizers to sensitize tumor cells to radiation, which may be about 25-200 microns thick. The laminated structure further includes radioisotope particles impregnated at the surface interface between layer 44 and layer 39 forming a flat sheet or thin mesh layer 45.

[0134] The outer layer 37, which absorbs radiation to protect the surgeon and any other tissue while they complete the case and the radioisotope decays, can have a thickness of about 4-5 mm to efficiently absorb the particles.

[0135] Advantages of the system include that it offers an alternative treatment to manage close or positive margins to chemotherapy with or without adjuvant radiation therapy to the surgical bed, that it avoids exposure to the high toxicity of conventional treatments, that the dose of radiation can be more easily localized to the tissue margins, thus reducing the impact of the presence of surrounding radiosensitive structures such as the bowel, and that there is no need to wait for reconstructed structures (such as anastomoses) to heal before initiating treatment with a local device.

[0136] It will be understood by those skilled in the art that many variations and / or modifications may be made to the above-described embodiments without departing from the broad general scope of the present disclosure, and the present embodiments are therefore to be considered in all respects as illustrative and not restrictive.

Claims

1. 1. A flexible brachytherapy device for application to a wound site in a body, said device comprising: a bioresorbable carrier matrix structure comprising a plurality of radioisotope particles, the bioresorbable carrier matrix structure being configured to degrade at a rate substantially longer than a half-life of the plurality of radioisotope particles when implanted at the wound site such that activity from the plurality of radioisotope particles is localized to the wound site, the bioresorbable carrier matrix structure having opposed first and second surfaces; a hydrophilic matrix positioned adjacent the first surface of the bioresorbable carrier matrix structure, the hydrophilic matrix being configured to adhere to the wound site and degrade at a faster rate than the bioresorbable carrier matrix structure when implanted at the wound site such that the hydrophilic matrix prevents migration of the device during the half-life of the plurality of radioisotope particles; the flexible brachytherapy device comprising: a hydrogel matrix positioned adjacent to the second surface of the bioresorbable carrier matrix structure, the hydrogel matrix configured to shield radiation and to degrade at a rate longer than the half-life of the plurality of radioisotope particles.

2. The bioresorbable carrier matrix is 2. The method of claim 1, wherein the radioisotope is formed by adsorbing or dispersing an aqueous solution of the radioisotope onto a hydrophobic material.

3. The bioresorbable carrier matrix is 3. The method of claim 2, wherein the radioisotope is formed by precipitating the radioisotope to form a plurality of insoluble radioisotope particles in the bioresorbable carrier matrix structure.

4. The device of claim 2 or 3, wherein the hydrophobic material comprises a hydrophilic surface.

5. 5. The apparatus of claim 2, 3, or 4, wherein the aqueous solution comprises radioactive ions.

6. 6. The device of claim 5, wherein the radioactive ions are derived from one or more of the following compounds: monosodium phosphate, disodium phosphate, potassium phosphate, dipotassium phosphate, orthophosphate, or tetrasodium pyrophosphate, or a soluble compound containing iodide.

7. 10. A device according to any one of the preceding claims, wherein the bioresorbable carrier matrix structure is composed of material(s) that are degradable by enzymatic processes.

8. 10. A device according to any one of the preceding claims, wherein the bioresorbable carrier matrix structure is composed of a material(s) that is degradable by pyrophosphatase.

9. The bioresorbable carrier matrix structure comprises:

10. The device of claim 1, formed by adsorbing or dispersing an aqueous solution of a radioisotope onto an amorphous or semi-crystalline hydrophobic material to provide the bioresorbable carrier matrix structure.

10. The device of claim 9 , wherein the amorphous or semi-crystalline hydrophobic material comprises a hydrophilic surface.

11. 2. An apparatus according to any one of the preceding claims, wherein the plurality of radioisotope particles are elements in a calcium phosphate complex molecule.

12. 9. The device of claim 8, wherein the calcium phosphate complex molecules include one or more of calcium pyrophosphate, monocalcium phosphate, dicalcium phosphate, octacalcium phosphate, tricalcium phosphate, hydroxyapatite, fluoroapatite, and tetracalcium phosphate.

13. The device of any one of claims 4 to 9, wherein the precipitating agent comprises an aqueous solution of calcium ions.

14. 11. The apparatus of claim 10, wherein the precipitating agent comprises one or more of calcium chloride, calcium hydroxide, calcium nitrate, or calcium bromide.

15. The device of any one of claims 2 to 14, wherein the bioresorbable carrier matrix is ​​amorphous or semi-crystalline in nature.

16. 16. The device of claim 15, wherein the bioresorbable carrier matrix is ​​partially semi-crystalline such that the degradation rate of the device is based on the half-life of the plurality of radioisotope particles through modification of crystallinity.

17. 10. The device of any one of the preceding claims, wherein the hydrogel matrix is ​​cross-linked with citric acid, the percentage of citric acid being selected to specify a rate at which the hydrogel matrix degrades while maintaining its structural integrity and shielding ability.

18. 18. The apparatus of claim 17, wherein the percentage is between 2.5% and 10%.

19. 19. The device of claim 17 or 18, wherein the citrate cross-linking is catalyzed by titanium oxide.

20. 2. The device of any one of the preceding claims, further comprising an inactive adhesive layer positioned adjacent a surface of the hydrogel matrix, the inactive adhesive layer configured to adhere to the wound site.

21. 21. The device of claim 20, further comprising a removable film positioned adjacent to the unactivated adhesive layer, the removable film being removable from the unactivated adhesive layer to expose a surface of the unactivated adhesive layer to the wound site.

22. 1. A method of manufacturing a flexible brachytherapy device for application to a wound site in a body, the method comprising: forming a bioresorbable carrier matrix structure comprising a plurality of radioisotope particles, said bioresorbable carrier matrix structure configured to degrade at a rate substantially longer than a half-life of the radioisotope particles such that activity from the plurality of radioisotope particles is localized to the wound site, said bioresorbable carrier matrix structure having opposed first and second surfaces; forming a hydrophilic matrix adjacent the first surface of the bioresorbable carrier matrix structure, the hydrophilic matrix being configured to adhere to the wound site and degrade at a faster rate than the bioresorbable carrier matrix structure when implanted at the wound site such that the hydrophilic matrix prevents migration of the device during the half-life of the plurality of radioisotope particles; forming a hydrogel matrix adjacent to the second surface of the bioresorbable carrier matrix structure, the hydrogel matrix being configured to shield radioactivity and to degrade at a rate longer than the half-life of the plurality of radioisotope particles.

23. The bioresorbable carrier matrix structure comprises:

23. The method of claim 22, formed by adsorbing or dispersing an aqueous solution of the radioisotope onto a hydrophobic material.

24. The bioresorbable carrier matrix structure comprises:

23. The method of claim 22, wherein the radioisotope is formed by precipitating the radioisotope to form a plurality of insoluble radioisotope particles in the bioresorbable carrier matrix structure.

25. 25. The method of claim 23 or 24, wherein the hydrophobic material comprises a hydrophilic surface.

26. The method of any one of claims 22 to 25, wherein the aqueous solution comprises radioactive ions.

27. The bioresorbable carrier matrix structure comprises:

23. The method of claim 22, wherein the bioresorbable carrier matrix structure is formed by adsorbing or dispersing an aqueous solution of a radioisotope onto an amorphous or semi-crystalline hydrophobic material to provide said bioresorbable carrier matrix structure.

28. 28. The method of claim 27, wherein the amorphous or semi-crystalline hydrophobic material comprises a hydrophilic surface.

29. 1. A bioresorbable carrier matrix structure comprising a plurality of radioisotope particles, the bioresorbable carrier matrix structure comprising: The bioresorbable carrier matrix structure is formed by adsorbing or dispersing an aqueous solution of a radioisotope onto a hydrophobic material to produce the bioresorbable carrier matrix structure.

30. The bioresorbable carrier matrix structure comprises:

30. The bioresorbable carrier matrix structure of claim 29, formed by precipitating the radioisotope to form a plurality of insoluble radioisotope particles in the bioresorbable carrier matrix structure.

31. 31. A bioresorbable carrier matrix structure according to claim 29 or 30, wherein the hydrophobic material comprises a hydrophilic surface.

32. 32. The bioresorbable carrier matrix structure of claim 29, 30, or 31, wherein the aqueous solution comprises radioactive ions.

33. The bioresorbable carrier matrix structure comprises:

26. A bioresorbable carrier matrix structure according to claim 25, formed by adsorbing or dispersing an aqueous solution of a radioisotope onto an amorphous or semi-crystalline hydrophobic material to provide said bioresorbable carrier matrix structure.

34. 34. The bioresorbable carrier matrix structure of claim 33, wherein the amorphous or semi-crystalline hydrophobic material comprises a hydrophilic surface.

35. A bioresorbable carrier matrix structure according to any one of claims 29 to 34, wherein said bioresorbable carrier matrix is ​​amorphous or semi-crystalline in nature.

36. The bioresorbable carrier matrix structure of any one of claims 29 to 35, wherein the bioresorbable carrier matrix structure, when implanted at a wound site, is configured to degrade at a rate substantially longer than the half-life of the plurality of insoluble radioisotope particles such that activity from the plurality of radioisotope particles is localized to the wound site.

37. The bioresorbable carrier matrix structure is adapted for use in a brachytherapy device for application to a wound site, the device comprising: The bioresorbable carrier matrix structure of any one of claims 29 to 36, comprising a hydrophilic matrix positioned adjacent to a first surface of the bioresorbable carrier matrix structure, the hydrophilic matrix being configured to adhere to the wound site and degrade at a faster rate than the bioresorbable carrier matrix structure when implanted at the wound site, such that the hydrophilic matrix prevents migration of the device during the half-life of the plurality of radioisotope particles.

38. The bioresorbable carrier matrix structure is adapted for use in a brachytherapy device for application to a wound site, the device comprising: The bioresorbable carrier matrix structure of any one of claims 29 to 36, comprising a hydrogel matrix positioned adjacent to a second surface of the bioresorbable carrier matrix structure, the hydrogel matrix configured to shield radioactivity and to degrade at a rate longer than the half-life of the plurality of radioisotope particles.

39. 1. A method for producing a bioresorbable carrier matrix containing a plurality of radioisotope particles, the method comprising: The method comprises adsorbing or dispersing an aqueous solution of a radioisotope onto a hydrophobic material.

40. The bioresorbable carrier matrix structure comprises:

40. The method of claim 39, wherein the radioisotope is formed by precipitating the radioisotope to form a plurality of insoluble radioisotope particles in the bioresorbable carrier matrix structure.

41. 41. The method of claim 39 or 40, wherein the hydrophobic material comprises a hydrophilic surface.

42. The method of any one of claims 39 to 42, wherein the aqueous solution comprises radioactive ions.

43. 1. 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 for receiving the brachytherapy device; a removable base attached to the upper housing, the removable base and the upper housing, when attached, shielding from radiation from the brachytherapy device; The applicator device, wherein the removable base is removable from the upper housing to expose a first surface of the brachytherapy device to a wound site.

44. 44. The applicator device of claim 43, wherein the removable base is slidably attached to and slidably removable from the upper housing.

45. 45. The applicator device of claim 43 or 44, wherein the upper housing further comprises an inlet port fluidly connected to the recess for enabling introduction of a fluid through the inlet port to the brachytherapy device in the recess.

46. 46. ​​An applicator device as described in claim 43, 44, or 45, further comprising a soluble adhesive for additionally securing the upper housing and the removable base, the soluble adhesive being dissolvable by a liquid introduced into the recess to enable the removable base to be slidably removed from the upper housing.

47. The applicator device of any one of claims 43 to 46, wherein the upper housing comprises a material that is transparent, translucent, or semi-transparent for blocking beta radiation.

48. 48. The applicator device of claim 47, wherein the upper housing is formed from an acrylate polymer.

49. The applicator device of any one of claims 43 to 48, further comprising a handle on the upper housing to assist in placement of the applicator device and brachytherapy device at the wound site.

50. 1. A brachytherapy system comprising: An applicator device according to any one of claims 43 to 48; A brachytherapy device according to any one of claims 1 to 21, The brachytherapy system, wherein the hydrogel matrix is ​​hydrated to an equilibrium water content by the inlet port of the applicator device.

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