Device for topical brachytherapy

Abstract

Flexible brachytherapy device for application to a wound site in a body, the device comprising: a bioresorbable carrier matrix structure comprising a plurality of radioisotopic particles, wherein the bioresorbable carrier matrix structure is configured to degrade at such a rate when deployed at the wound site that the bioresorbable carrier matrix structure has a half-life longer than the half-life of the plurality of radioisotopic particles, so that the activity from the plurality of radioisotopic particles is localized at the wound site, wherein the bioresorbable carrier matrix structure has an opposing first surface and an opposing second surface; a hydrophilic substrate located adjacent to the first surface of the bioresorbable support matrix structure, wherein the hydrophilic substrate is configured to adhere to the wound site, and wherein the hydrophilic substrate is configured to degrade at a rate faster than that of the bioresorbable support matrix structure when deployed at the wound site in order to prevent migration of the device during the half-life of the multitude of radioisotope particles; and a hydrogel substrate adjacent to the second surface of the bioresorbable support matrix structure, wherein the hydrogel substrate is configured to shield radioactivity and degrade at such a rate that the hydrogel substrate has a half-life longer than the half-life of the multitude of radioisotope particles.

Description

Cross-reference to related applications

[0001] The present application claims priority over Australian provisional patent application No. 2018900745, which was filed on 7 March 2018 and the contents of which are incorporated in full into this document by reference. Technical field

[0002] The present disclosure relates to a brachytherapy device for application to a wound site in the body. The device can be used, in some examples, to treat cancers of the body. background

[0003] Cancer is a disease of cells that affects multiple organs and impacts a large number of people worldwide. When the normal mechanisms that regulate cell growth in the body are disrupted, cells can begin to grow uncontrollably. Cancer develops when normal cells in the body develop an abnormal growth pattern and do not follow the normal cell life cycle, including cell death. The uncontrolled, rapid growth and invasion of normal tissue by abnormal cells is the definition of malignant cancer. Cancer cells can metastasize, meaning they detach from their site of origin and travel to other parts of the body, where they form new tumors.

[0004] Cancer treatments include surgery, chemotherapy, and radiation therapy, or combinations thereof. Surgery is generally the treatment of choice for most cancers when the cancer appears to be confined to one organ and serves as the initial examination to determine if the tumor can be surgically removed. In some cancers, such as colorectal cancer, melanoma, and neuroendocrine tumors, surgical resection of metastases is possible.

[0005] When surgically removing a cancerous tumor, it is crucial to completely remove or destroy all malignant cells. Surgical cancer removal involves excising the tumor(s), including a margin of normal tissue around the cancer to ensure complete excision. Lymph nodes, to which the primary tumor may have spread, are often removed as well. Generally, a pathological examination of the resection margins is performed at the time of surgery to confirm that the tumor has been completely removed.

[0006] One of the most feared complications in major cancer surgeries is incomplete resection or the presence of microscopic tumor cells at the resection margin. While the use of frozen section histology reduces the likelihood of such an occurrence, it does not eliminate it entirely, as its accuracy is significantly reduced without the possibility of immunohistochemistry for tumor cell identification. Secondly, many cancers infiltrate along the lymphatic vessels or follow the perineural lymphatic system, where they may not be detected at the time of surgery.

[0007] Tumor cells can remain after cancer surgery because they have invaded a critical structure that cannot be safely resected or reconstructed in a single patient. In many cases, the initial surgery causes such a significant physical and metabolic impairment to the patient's physiology that further surgery and resection are simply not feasible. In these cases, the survival rate of the individual patient with positive margins is severely and significantly reduced compared to a similar patient with intact margins.

[0008] The current approach for managing narrow or positive margins is chemotherapy with or without adjuvant radiotherapy at the operating bed. This treatment is often ineffective in preventing local recurrence and is highly toxic. The radiation doses delivered to the tumor cells are severely limited because surrounding structures, such as the bowel, are radiosensitive, and the healing of reconstructed structures (e.g., anastomoses) must be awaited before chemotherapy can begin.

[0009] This results in an ineffective radiation dose to the surgical bed for tumor control and a delay of up to 8-10 weeks before chemotherapy is initiated. During this time, the immunological / inflammatory insult of the major surgery reduces the body's ability to fight tumor cells, and cells at the positive margin remain untreated, often leading to a local recurrence that can then metastasize throughout the body.

[0010] Recently, the benefits of high-dose-rate brachytherapy devices for treating inoperable tumors have been increasingly recognized. Radioisotopes from beta emitters injected intra-arterially have proven suitable for treating inoperable liver tumors, and beta emitters suspended in a silicon dioxide diluent were early on demonstrated suitability for injection or placement directly into inoperable pancreatic tumors via specialized applicators inserted into body cavities or tissues. However, no suitable device currently exists for the routine management of postoperative positive margin risk, and existing state-of-the-art devices are not suitable for routine surgical use.Obstacles to developing such a routine surgical device include high costs, low flexibility, non-bioresorbable radioisotope sources, and a lack of absorbable unidirectionality.

[0011] Any mention of documents, actions, materials, devices, articles or the like included in the present description shall not be construed as an admission that some or all of these things are prior art or were generally known in the field relevant to the present disclosure, as was the case before the priority date of the individual claims of this application.

[0012] In this description, the word "include" or variants such as "encompasses" or "containing" is understood to mean the inclusion of a particular element, integer, step, or group of elements, integers, or steps, but not the exclusion of another element, integer, step, or group of elements, integers, or steps. Brief description

[0013] State-of-the-art brachytherapy devices are often inflexible and not fully bioabsorbable or bioresorbable by the body. This is due to the use of non-bioabsorbable / non-bioresorbable radioisotope sources or metallic shielding, which makes the device unidirectional. This, in turn, prevents accurate imaging of the site after resection. The inflexible state-of-the-art brachytherapy devices are also unsuitable for an adjunctive approach to surgery, as they cannot fully conform to the surgical bed to deliver a uniform dose to each cell. State-of-the-art devices have enabled the fabrication of discrete, metallic, sealed sources that can be interconnected by a flexible membrane.Their adaptability and dose distribution are limited because they cannot be absorbed by the body. Foreign bodies such as state-of-the-art brachytherapy seeds, which are permanently implanted in the body (especially in a surgical area potentially contaminated with microorganisms), pose a very high risk of chronic infection and serious morbidity for the patient. This risk is not mitigated by a partially resorbable device if the brachytherapy seeds contain residual material in the long term. Therefore, it is desirable for a brachytherapy device to be flexible and unidirectional (so that the surgeon and operating room staff are exposed to minimal radiation) and completely bioresorbable in the body, leaving no foreign or metallic material behind in the long term.

[0014] A flexible brachytherapy device for application at a wound site in a body, the device comprising: a bioresorbable carrier matrix structure comprising a plurality of radioisotopic particles, wherein the bioresorbable carrier matrix structure, when implanted at the wound, is configured to degrade at a rate substantially longer than the half-life of the plurality of radioisotopic particles, such that the activity from the plurality of radioisotopic particles is limited to the wound site, wherein the bioresorbable carrier matrix structure has a first surface and a second surface facing each other;a hydrophilic substrate located adjacent to the first surface of the bioresorbable support matrix structure, wherein the hydrophilic substrate adheres to the wound site, and wherein, upon implantation at the wound, the hydrophilic substrate is configured to degrade at a rate shorter than that of the bioresorbable support matrix structure in order to prevent migration of the device during the half-life of the plurality of radioisotopic particles; and a hydrogel substrate adjacent to the second surface of the bioresorbable support matrix structure, wherein the hydrogel substrate is configured to shield radioactivity and degrade at a rate longer than the half-life of the plurality of radioisotopic particles.

[0015] The bioresorbable support matrix can be formed by adsorbing or dispersing an aqueous solution of a radioisotope onto a hydrophobic substance. Alternatively, the bioresorbable support matrix can be formed by precipitating the radioisotope to create a variety of insoluble radioisotope particles within the bioresorbable support matrix structure.

[0016] The hydrophobic substance may have a hydrophilic surface to form the bioresorbable support matrix structure. The aqueous solution may contain radioactive ions.

[0017] The radioactive ions are obtained from one or more of the following substances: monosodium phosphate, disodium phosphate, potassium phosphate, dipotassium phosphate, orthophosphoric acid or tetrasodium pyrophosphate or soluble iodide-containing compounds.

[0018] The bioresorbable support matrix structure can be configured with material(s) that are degradable by enzymatic processes. The bioresorbable support matrix structure can be configured with material(s) that are degradable by pyrophosphatase.

[0019] The bioresorbable support matrix structure can be provided by adsorbing or dispersing an aqueous solution of a radioisotope onto an amorphous or semi-crystalline hydrophobic substance. The amorphous or semi-crystalline hydrophobic substance may have a hydrophilic surface.

[0020] The multitude of radioisotopic particles can include elements in the compound molecules of calcium phosphate. The calcium phosphate compound molecules can comprise one or more of the following: calcium pyrophosphate, monocalcium phosphate, dicalcium phosphate, octacalcium phosphate, tricalcium phosphate, hydroxyapatite, fluorapatite, or tetracalcium phosphate.

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

[0022] The bioresorbable support matrix can be amorphous or semicrystalline by nature. The bioresorbable support matrix can be partially semicrystalline, so that the degradation rate of the device is based on the half-life of the multitude of radioisotopic particles and is determined by changes in crystallinity.

[0023] In the device, the hydrogel substrate can be crosslinked with citric acid, the percentage of which is selected to determine the rate of hydrogel substrate degradation in order to maintain structural integrity and shielding capacity. The percentage can range from 2.5% to 10%. The citric acid crosslinking can be catalyzed by titanium dioxide.

[0024] The device may further comprise an inert adhesive layer adjacent to a surface of the hydrogel substrate, wherein the inert adhesive layer is configured to adhere to the wound site.

[0025] The device may further comprise a removable film adjacent to the inert adhesive layer, wherein the removable film can be removed from the inert adhesive layer to expose a surface of the inert adhesive layer at the wound site.

[0026] Method for manufacturing a flexible brachytherapy device for application at a wound site in a body, the method comprising: forming a bioresorbable carrier matrix structure comprising a plurality of radioisotopic particles, wherein the bioresorbable carrier matrix structure is configured to degrade at a rate substantially longer than the half-life of the radioisotopic particles, such that the activity from the plurality of radioisotopic particles is confined to the wound site, wherein the bioresorbable carrier matrix structure has a first surface and a second surface facing each other;Forming a hydrophilic substrate adjacent to the first surface of the bioresorbable support matrix structure, wherein the hydrophilic substrate adheres to the wound site, the hydrophilic substrate being configured upon implantation at the wound to degrade at a rate shorter than that of the bioresorbable support matrix structure to prevent migration of the device during the half-life of the plurality of radioisotope particles; and forming a hydrogel substrate adjacent to the second surface of the bioresorbable support matrix structure, the hydrogel substrate being configured to shield radioactivity and degrade at a rate longer than the half-life of the plurality of radioisotope particles.

[0027] In this process, the bioresorbable support matrix structure can be formed by adsorbing or dispersing an aqueous solution of a radioisotope onto a hydrophobic substance. Alternatively, the bioresorbable support matrix structure can be formed by precipitation of the radioisotope, creating a variety of insoluble radioisotope particles within the bioresorbable support matrix. The hydrophobic substance may have a hydrophilic surface.

[0028] The aqueous solution may contain radioactive ions.

[0029] In this process, the bioresorbable support matrix structure can be formed by adsorbing or dispersing an aqueous solution of a radioisotope onto an amorphous or semi-crystalline hydrophobic substance to obtain the resorbable support matrix structure. The amorphous or semi-crystalline hydrophobic substance may have a hydrophilic surface.

[0030] A bioresorbable support matrix structure comprising a variety of radioisotopic particles, wherein the bioresorbable support matrix structure is formed by: adsorbing or dispersing an aqueous solution of a radioisotope onto a hydrophobic substance to produce the bioresorbable support matrix structure. The bioresorbable support matrix structure can be formed by precipitation of the radioisotope to form a variety of insoluble radioisotopic particles within the bioresorbable support matrix structure. The hydrophobic substance may have a hydrophilic surface.

[0031] The aqueous solution may contain radioactive ions.

[0032] The bioresorbable support matrix structure can be formed by adsorbing or dispersing a variety of insoluble radioisotope particles onto an amorphous or semi-crystalline hydrophobic substance. The amorphous or semi-crystalline hydrophobic substance may have a hydrophilic surface.

[0033] The structure of the bioresorbable carrier matrix can be amorphous or semicrystalline.

[0034] The bioresorbable carrier matrix structure can be configured, when implanted at the wound, to degrade at a rate significantly longer than the half-life of the multiple radioisotope particles, thus limiting the activity of the multitude of insoluble radioisotope particles to the wound site.

[0035] The bioresorbable carrier matrix can be configured for use in a brachytherapy device for application at a wound site, the device comprising: a hydrophilic substrate adjacent to a first surface of the bioresorbable carrier matrix structure, the hydrophilic substrate adhering to the wound site, the hydrophilic substrate being configured, upon implantation at the wound, to degrade at a rate shorter than that of the bioresorbable carrier matrix structure in order to prevent migration of the device during the half-life of the multitude of radioisotope particles.

[0036] The bioresorbable carrier matrix can be configured for use in a brachytherapy device for application at a wound site, the device comprising: a hydrogel substrate adjacent to a second surface of the bioresorbable carrier matrix structure, the hydrogel substrate being configured to shield radioactivity and degrade at a rate longer than the half-life of the plurality of radioisotopic particles.

[0037] A method for producing a bioresorbable support matrix comprising a variety of radioisotopic particles, wherein the method comprises: adsorbing or dispersing an aqueous solution of a radioisotope onto a hydrophobic substance. The bioresorbable support matrix can be formed by precipitation of the radioisotope to create a variety of insoluble radioisotopic particles within the bioresorbable support matrix structure. The hydrophobic substance may have a hydrophilic surface.

[0038] The aqueous solution may contain radioactive ions.

[0039] Applicator device for applying a brachytherapy device to a wound site in a body, the applicator device comprising: an upper housing with a recess for receiving a brachytherapy device; a removable base attached to the upper housing, wherein the removable base and the upper housing, when attached, 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 at a wound site.

[0040] The removable base can be attached to and removed from the upper housing by sliding.

[0041] The upper housing may further have an inlet opening which is in fluid communication with the recess to allow the introduction of a fluid through the inlet opening into the brachytherapy device in the recess.

[0042] The applicator device may further include a soluble adhesive to additionally secure the upper housing and the removable base, wherein the soluble adhesive is soluble by a liquid introduced into the recess so that the removable base can be slid away from the upper housing.

[0043] The upper casing can be made of a transparent, semi-transparent, or translucent material to shield against beta radiation. The upper casing can be made of an acrylate polymer.

[0044] The applicator device may also have a handle on the upper housing to assist in placing the applicator device and the brachytherapy device at a wound site.

[0045] Brachytherapy system comprising: the applicator device as described above, and the brachytherapy device as described above, wherein the hydrogel substrate is hydrated to an equilibrium water content through the inlet opening of the applicator device. Brief description of the drawings

[0046] Examples of the present revelation are described with reference to the figures below: Fig. Figure 1 illustrates a schematic representation of a brachytherapy device; Fig. Figure 2 illustrates a further schematic representation of a brachytherapy device after absorption of a hydrophilic substrate; Fig. Figure 3 illustrates a schematic cross-sectional view of a brachytherapy device; Fig. Figure 4 illustrates another schematic cross-sectional view of a brachytherapy device after absorption of a hydrophilic substrate; Fig. Figure 5 illustrates a further schematic cross-sectional view of a brachytherapy device after further absorption of the hydrophilic substrate, degradation of the hydrogel and decay of the radioisotope; Fig. Figure 6 illustrates a schematic representation of an applicator device; Fig. Figure 7 illustrates another schematic representation of an applicator device; Fig. Figure 8 illustrates another schematic representation of a brachytherapy device; Fig. Figure 9 illustrates a schematic cross-sectional view of the device in Fig. 8; Fig. Figure 10 illustrates another schematic representation of a brachytherapy device; Fig. 11 illustrates a method for manufacturing a brachytherapy device; Fig. Figure 12 illustrates another schematic representation of an applicator device; Fig. Figure 13 illustrates a further schematic representation of an applicator device; and Fig. Figure 14 illustrates another schematic representation of an applicator device. Description of the embodiments Overview

[0047] An example of a brachytherapy device is in Fig. Figure 1 illustrates this. The device 1 can be used at a wound site in the body, for example, during surgery. The device 1 comprises a bioresorbable carrier matrix structure 2, which contains a variety of radioisotopic particles 3. When implanted at the wound, the bioresorbable carrier matrix structure 2 is configured to degrade at a rate significantly longer than the half-life of the variety of radioisotopic particles 2. In this way, the activity of the variety of radioisotopic particles 2 is confined to the wound site. The bioresorbable carrier matrix structure 2 has a first and second surface 21, 22, which are opposite each other.

[0048] The device 1 further comprises a hydrophilic substrate 4 adjacent to the first surface 21 of the bioresorbable support matrix structure 2. The hydrophilic substrate 4 adheres to the wound site. Upon implantation at the wound, the hydrophilic substrate is configured to degrade at a faster rate than the bioresorbable support matrix structure in order to prevent migration of the device during the half-life of the multitude of radioisotope particles 3.

[0049] The device 1 further comprises a hydrogel substrate 5 adjacent to the second surface 22 of the bioresorbable support matrix structure 2. In some examples, the hydrogel substrate 5 adheres to and is bonded to the hydrophilic substrate 4. The hydrogel substrate 5 is configured to shield radioactivity and degrade at a rate longer than the substantial activity of the plurality of radioisotopic particles 3, for example, at a rate longer than the half-life of the plurality of radioisotopic particles 3. In this way, the hydrogel substrate 5 shields the radioactivity until the bioresorbable support matrix structure 2 is substantially inactive (with respect to radioactivity) and safe due to radioactive decay.

[0050] Device 1 may be suitable for minimizing and / or controlling the local recurrence of malignant cancer and seromas after cancer surgery. Device 1 may also be suitable for minimizing and / or controlling the uncontrolled growth of microscopic tumor cells at the resection margin of the surgery.

[0051] It is advantageous that 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." Furthermore, Device 1 has the advantage of being a completely closed source (although it is significantly radioactive). In some examples, Device 1 is designed to withstand immersion in water, phosphate-buffered saline, or another physiologically acceptable liquid at room temperature for 24 hours without significant loss of radioisotopes.

[0052] Another advantage is that the large number of radioisotope particles remain in the wound area until they are no longer significantly radioactive.

[0053] Another advantage is that the brachytherapy device 1 is flexible and adapts to the wound site.

[0054] Details of an exemplary brachytherapy device 1 will now be described in detail. Bioresorbable carrier matrix 2

[0055] As described above, the device 1 comprises a bioresorbable support matrix structure 2 containing a plurality of radioisotopic particles 3. In some examples, the bioresorbable support matrix 2 is formed by adsorbing or dispersing an aqueous solution of a radioisotope onto a hydrophobic substance. The bioresorbable support matrix can also be formed by precipitating the radioisotope to create a plurality of insoluble radioisotopic particles within the bioresorbable support matrix structure 2. In this example, the aqueous solution can include radioactive ions. The radioactive ions can include one or more of the following: monosodium phosphate, disodium phosphate, potassium phosphate, dipotassium phosphate, orthophosphoric acid, tetrasodium pyrophosphate, or soluble iodide-containing compounds.

[0056] The multitude of radioisotope particles 3 may include a beta emitter. In other examples, the multitude of radioisotope particles 3 may include a gamma emitter or a mixed gamma / beta emitter. In some examples, the multitude of radioisotope particles 3 may be elements from the calcium phosphate compound family. In one example, the multitude of radioisotope particles 3 may include elements in the calcium pyrophosphate compound molecule. This may include the following compound molecules: calcium phosphate, monocalcium phosphate, dicalcium phosphate, octacalcium phosphate, tricalcium phosphate, hydroxyapatite, fluorapatite, or tetracalcium phosphate. In some examples, the multitude of radioisotope particles 3 may include the compound molecules in a hydrated or anhydrous form.

[0057] In other examples, the multitude of radioisotope particles 3 may include one or more of the following: yttrium-90, iridium-192, palladium-103, cesium-137, iodine-131, iodine-125, iodine-123, phosphorus-33 (33P), phosphorus-32 (32P), or a ratio of phosphorus-33 to phosphorus-32, and / or compounds containing such isotopes. In some examples, using a ratio of phosphorus-33 to phosphorus-32 as the multitude of radioisotope particles 3 reduces the collateral radiation exposure during handling compared to phosphorus-32 alone. It is understood that in this description, the radioisotope particles 3 may include compounds containing radioisotopes.

[0058] The bioresorbable carrier matrix structure 2 is configured, upon implantation at the wound, to degrade at a rate significantly longer than the half-life of the multitude of radioisotope particles 3. In this way, the activity of the multitude of radioisotope particles is confined to the wound site.

[0059] Fig. Figure 5 shows a cross-sectional view of the device 1 after significant nuclear decay of the multiple radioisotope particles 3. As shown, the bioresorbable support matrix structure 2 is retained after the degradation of the hydrophilic substrate 4, the hydrogel 5, and the nuclear decay of the multiple radioisotope particles 3. The bioresorbable support matrix, which persists longer than the significant radioactivity of the radioisotope (e.g., over one half-life of the radioisotope), ensures that the radioactivity is confined to the wound site 100 at the surgical margin / wound bed 7.

[0060] The emission rate of the radiation from the multitude of radioisotope particles 3 can be determined by the properties of the bioresorbable support matrix structure 2 and / or the hydrophilic substrate 4.

[0061] In some examples, the multitude of radioisotope particles can include particles with a medium half-life (less than 30 days). In this way, the bioresorbable support matrix structure 2 can degrade at a rate significantly longer than 30 days.

[0062] The bioresorbable support matrix structure 2 can be formed by adsorption or dispersion of a variety of insoluble radioisotope particles on a hydrophobic substance with a hydrophilic surface. The hydrophobic substance can be microporous or macroporous.

[0063] In some examples, the hydrophobic substance may have a hydrophilic surface. In this way, as described below, a solution containing radioactive ions can be drawn into a microporous hydrophobic substance by capillary action. Without the hydrophilic surface, the radioactive ions cannot be distributed in this way. Alternatively, in an example of a hydrophobic substance without a hydrophilic surface, the radioactive particles can be hot-pressed / printed onto the hydrophobic substance.

[0064] 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 by the 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.

[0065] In other examples, a hydrophilic copolymer can be added to improve hydrophilicity and the available sites for crosslinking. Examples of hydrophilic copolymers include collagen, alginate, carboxymethylcellulose and other forms of cellulose, polyethylene glycol, or one of the numerous polyethylene glycol copolymers. 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), can be added to increase the flexibility of the PCL, reduce the percentage of crystallinity, and / or increase the hydrophilicity of the resulting mixture.

[0066] The new, slowly hydrolyzable polymer mixture is then made microporous by incorporating a highly soluble substance, such as a soluble salt (NaCl, MgCl, etc.) or a soluble liquid (like glycerol), or another soluble component in a non-toxic solvent. The soluble component can be leached from the PCL mixture by a combination of heat and / or a solvent. The result is a microporous, hydrophobic matrix with a hydrophilic surface. The matrix may be slowly absorbent.

[0067] In some examples, the porosity of the hydrophobic substance / matrix can also be created by injecting an inert gas during the mixing of the polymers, such as in an extruder. The inert gas can include nitrogen, carbon dioxide, or argon. In other examples, the porosity of the hydrophobic substance / matrix can be created by adding "porogenic" compounds, such as sodium bicarbonate, to the formulation. In this way, gas can be released upon application of heat.

[0068] In another example, a rapidly decaying radioisotope can be used for the multitude of radioisotopic particles. This can facilitate the use of a purely hydrophilic support matrix as a bioresorbable support matrix structure 2, including polymers made of polyglycolide or a cross-linked hydrogel.

[0069] In another example, the hydrophobic and hydrophilic components can be thoroughly mixed in a batch mixer or extruder, made compatible with an amphiphilic polymer or copolymer (such as polyethylene glycol or Pluron P123), and then the radioisotope component can be incorporated by hot pressing, injection molding, or extrusion, taking advantage of the low melting temperature of the biodegradable matrix.

[0070] In some examples, the multitude of insoluble radioisotope particles 3 can be provided by adding a precipitating agent to a multitude of radioisotope particles. In one example, the multitude of radioisotope particles 3 can comprise ions, so the precipitating agent is added to a multitude of radioisotope ions. In another example, the radioisotope ions can be suspended in a solution to form an aqueous radioisotope solution and distributed in the support matrix 2. This converts the multitude of radioisotope particles 3 into an insoluble form. In one example, the aqueous radioisotope solution can consist of elements of the compound tetrasodium pyrophosphate. In other examples, any aqueous radioisotope solution that can be precipitated to a bioresorbable insoluble salt can be used.This includes all aqueous solutions containing 32P-phosphate ions, but in other examples also radioactive calcium ions, radioactive chromium 51, radioactive iodine ions (I-131, I-125, I-123 etc.), palladium 103, cesium 137 etc.

[0071] In one example, the precipitating agent comprises calcium chloride. In other examples, the precipitating agent may comprise another aqueous solution of calcium ions, including the hydroxide or nitrate forms. The precipitating agent may contain one or more of calcium chloride, calcium hydroxide, calcium nitrate, or calcium bromide. In this way, the multitude of insoluble radioisotopic particles can be precipitated into the compound calcium pyrophosphate (CaPO₄). 227 ), anhydrous, dihydrate (Ca PO 227 -2 H2 O) or tetrahydrate (Ca2P2O7-4H2O).

[0072] The precipitating agent can also contain any insoluble or sparingly soluble salt that can be biologically absorbed in the body. This includes all types of calcium phosphate or a form of ammonium magnesium phosphate (struvite). In one example, the functional groups of absorbable polymers can be iodinated with radioactive iodide-125 or -131, or with crystalline iodide embedded / dispersed in a biologically absorbable support matrix. In still other examples, the precipitating agent can comprise a different molecule containing calcium, magnesium, zinc, or iron.

[0073] In other examples, a variety of radioisotopes can be adsorbed in an anion exchange resin, and the precipitating agent can be applied after adsorption. 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 in an anion exchange resin or in a resorbable radioactive molecule.

[0074] The microporous, hydrophobic substance with a hydrophilic surface can then be modified by adding copolymers to achieve partial crystallization (semicrystalline). This has the advantage that the device 1 is flexible and compliant, adapting to the shape of the wound site. The semicrystalline mixture can modify the long hydrolysis degradation time of pure PCL / polylactide. That is, the degradation rate of the device 1 can be determined by modifying the crystallinity of the bioresorbable support matrix structure 2. In some cases, the degradation rate of the device 1 can be determined based on the half-life of a variety of radioisotopic particles 3 and by modifying the crystallinity. Therefore, the device 1 is suitable for use in surgery.

[0075] The bioresorbable support matrix structure 2 can then be completely biodegradable in the body. As described above, this is an advantage of Device 1. Another advantage is that Device 1, when used in a potentially contaminated area, can prevent chronic infections. In some examples, the bioresorbable support matrix structure 2 is degradable in the body by intracellular, extracellular, and enzymatic processes, such as by pyrophosphatase or circulating osteocyte precursors and / or mature osteocytes. In some examples, osteoclast cells (or their circulating osteoclast precursors) can degrade Structure 2. The osteoclast cells can degrade, resorb, modify, and / or replace the entire family of calcium phosphates. This can include any insoluble and bioresorbable compound molecule.In other examples, the bioresorbable carrier matrix structure 2 is degradable by other enzymes present in the body.

[0076] In some examples, iodinated compounds can be used as radioisotope particles. This can involve the iodination of one or more functional groups of bioabsorbable polymers with radioactive iodide, such as Iodine-131, Iodine-125, or Iodine-123. In other examples, crystalline iodide can be implanted into bioabsorbable polymers.

[0077] In this way, the initially insoluble phosphate compounds in the multitude of insoluble radioisotope particles can be hydrated over time by the body's enzymatic processes. These initially insoluble phosphate compounds, present in the multitude of insoluble radioisotope particles, may be necessary for safe surgical handling as a sealed source for brachytherapy. The radioisotope particles / ions can then diffuse from the bioresorbable carrier matrix structure 2 to the wound site 100 for intracellular absorption. The radioisotope particles / ions can then be incorporated into the DNA of cancer cells to enhance apoptosis.

[0078] 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 structure.

[0079] The bioresorbable carrier matrix structure 2 comprises a first and second surface 21, 22, which are opposite each other.

[0080] In some examples, the multitude of radioisotopic particles 3 can be impregnated in a space between the bioresorbable support matrix structure 2 and the hydrophilic substrate 4. For example, a vessel consisting of at least two layers can be provided to hold the radioisotopic particles 3. In this example, a closed radiation source can be obtained by laminating radioactive particles with hydrophobic or partially hydrophobic layers. In this way, the laminated radioactive particles can be completely or largely biologically absorbed by the processes of the body in which the device 1 is placed. In other examples, insoluble radioisotopic particles or a microporous matrix (such as an ion-exchange resin) containing insoluble radioisotopic particles can be imprinted on the surface of the bioresorbable support matrix structure 2.

[0081] Another advantage of the device is that the multitude of radioisotope particles 3 are embedded in the bioresorbable carrier matrix 2, so that safe removal of the device 1 (and thus the radioisotope source) is possible while maintaining unidirectional shielding when return to the operating room for treatment is required. Hydrophilic substrate 4

[0082] As described above, the device 1 further comprises a hydrophilic substrate 4 adjacent to the first surface 21 of the bioresorbable support matrix structure. The hydrophilic substrate 4 faces the wound site and also adheres to the wound site 100. In this way, the hydrophilic substrate 4 ensures the integration or cross-linking of the device 1 with the wound site. In some examples, the hydrophilic substrate 4 is located on and above the first surface 21 of the bioresorbable support matrix structure. This is shown in Fig. 3 illustrated.

[0083] In one example, the hydrophilic substrate 4 is supplied in a fully hydrated state, with a similar equilibrium water content to the hydrogel substrate 5. In this way, the fully hydrated hydrophilic substrate 4 is unlikely to undergo any dramatic changes in size and / or shape after implantation and cross-linking with the tissue of the wound site 100. In another example, the hydrophilic substrate 4 can include some of the substances required to establish amide bonds and / or hydrogen-hydrogen interactions between the device and the tissues of the wound site 100 in the body. In this way, an additive can activate the cross-linking between the device and the tissues, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), DOPA, or another cross-linking agent.

[0084] In some other examples, the hydrophilic substrate 4 absorbs moisture from the wound site to allow wetting and gelation of the hydrophilic substrate 4, enabling it to conform to the wound. The hydrophilic substrate 4 can be selected for relatively rapid absorption, allowing the device 1 to closely conform to the wound site. In other examples, the hydrophilic substrate 4 can be configured to be absorbed at the wound site within three to five days.

[0085] The hydrophilic substrate 4, when implanted at the wound site 100, is configured to degrade faster than the bioresorbable carrier matrix structure to prevent device migration during the half-life of the multitude of radioisotope particles 3. This ensures that the device 1 does not migrate away from the wound site 100. That is, the hydrophilic substrate 4 is configured to absorb faster than the bioresorbable carrier matrix structure 2. This allows the multitude of radioisotope particles 3 to remain at the wound site until they are no longer substantially active 4. In some examples, the time until substantial radioisotope inactivity can range from 9 to 28 days.

[0086] Fig. Figure 2 illustrates an example of the device 1, demonstrating faster absorption of the hydrophilic substrate 4. As shown, the hydrophilic substrate 4 is completely absorbed. The hydrogel substrate 5, the bioresorbable support matrix structure 2, and the multitude of radioisotopic particles 3 remain at the wound site.

[0087] Fig. Figure 4 illustrates a cross-sectional view showing the absorption of the hydrophilic substrate 4 at the wound site. In this example, the hydrogel substrate 5, the bioresorbable support matrix structure 2, and the multitude of radioisotope particles 3 remain at the wound site 100.

[0088] The hydrophilic substrate 4 can consist of a cross-linked polymer. In some examples, the hydrophilic substrate 4 also includes one or more of the following: any type of starch, carboxymethylcellulose, glycerol, xylitol, or citric acid, or any type thereof. In other examples, the hydrophilic substrate 4 can include other surgical adhesives, such as carbodiimide cross-linking, dopa-lysine interactions, or citric acid cross-linking.

[0089] In other examples, the hydrophilic substrate 4 can comprise a thin layer of a biocompatible resin, gel, or flexible biopolymer, allowing it to rapidly absorb water and conform to the surgical bed. Other cellulose-derived polymers can also be used.

[0090] The hydrophilic substrate 4 can also contain a radiosensitizer, such as gemcitabine or capecitabine. The radiosensitizer can be suspended in the hydrophilic substrate 4 by solvent casting, immersion in a solution, or melt extrusion. In this way, the radioactive sensitizer can be released when the wound site absorbs the hydrophilic substrate 4. This can cause tumor cells located in or near the wound site to become susceptible to radiation from the multitude of radioisotopic particles 3.

[0091] The hydrophilic substrate 4 hydrates after application to the wound site and forms a surface film that adapts to the wound area. As in Fig. As illustrated in Figure 3, the hydrophilic substrate 4 can extend beyond the edges of the bioresorbable support matrix structure 2.

[0092] In some examples, the hydrophilic substrate 4 provides a simultaneous hemostatic effect on the wound site, thus preventing a hematoma that could lift the device 1 from the wound site. In this example, the hydrophilic substrate 4 may further comprise a coating or suspension of a hemostatic agent, such as thrombin, fibrin, fibrinogen, or other hemostatic agents, to enhance the hemostatic properties of the hydrophilic substrate 4. Hydrogel substrate 5

[0093] The device 1 further comprises a hydrogel substrate 5 adjacent to the second surface 22 of the bioresorbable support matrix structure 2. The hydrogel substrate 5 provides adaptability, flexibility, and the ability to permit surgical implantation of the device 1. The hydrogel substrate 5 is configured to shield radioactivity and degrade at a rate longer than the half-life of the multitude of radioisotopic particles. The hydrogel substrate 5 can also be configured to be completely hydrolyzed at a rate longer than the half-life of the multitude of radioisotopic particles. In this way, the hydrogel substrate 5 is configured to absorb any emitted radiation to protect the surrounding tissue of the patient and, if necessary, the operator of the device 1, such as a surgeon.This is an advantage of device 1, since the shielding by the hydrogel substrate 5 contributes to the fact that the device is unidirectional in contrast to the prior art devices described above.

[0094] In one example, the hydrogel substrate 5 is attached to the second surface 22 of the bioresorbable support matrix structure 2, such that the hydrogel substrate 5 adheres to and is integrated in a hydrated state using phosphate-buffered saline (or another biocompatible solution). The hydrated state can mean that the hydrogel substrate 5 is at or near its equilibrium water content (EWC). This is advantageous for the device because, unlike prior art devices, the device 1 can be used conveniently and safely during a surgical procedure. That is, the device can be safely handled unidirectionally from its packaging and requires no additional assembly by the operator.

[0095] In some examples, the hydrogel substrate 5 limits the penetration of the radioisotope particles 3 to a few millimeters. As in Fig. 3 and Fig. As illustrated in Figure 4, the hydrogel substrate 5 faces away from the wound site 100. Furthermore, in some examples, the hydrogel substrate is located on and above the second surface 22 of the bioresorbable support matrix structure. In other examples, as in Fig. As illustrated in Figures 1 to 4, the hydrogel substrate 5 extends beyond the perimeter of the bioresorbable support matrix structure 2. This provides additional tissue shielding near the perimeter. As shown in Fig. As illustrated in Figure 3, the hydrogel substrate 5 can be in contact with the hydrophilic substrate 4 near its circumference. Thus, in some examples, the bioresorbable support matrix structure is encapsulated by the hydrogel substrate 5 and the hydrophilic substrate 4 when the device 1 is first implanted.

[0096] The hydrogel substrate 5 can be combined with the bioresorbable support matrix structure 2 by at least one of the following: mechanical integration, chemical cross-linking, or enzymatic cross-linking. In some examples, a combination of mechanical integration and chemical cross-linking with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and / or N-hydroxysuccinimide (NHS)-carbodiimide chemistry can be used. In this example, surface modification may be required, such as by plasma treatment and / or surface hydrolysis.

[0097] The hydrogel substrate 5 can consist of a hydrophilic, interpenetrating multipolymer hydrogel. This may contain polyvinyl alcohol, carboxymethylcellulose, partially hydrolyzed collagen, and xylitol crosslinked with citric acid. The hydrogel substrate 5 may also comprise a mixture of copolymers with polyethylene glycol. In some examples, a catalyst such as titanium dioxide may be present for the citric acid crosslinking. In still other examples, other hydrophilic absorbable polymers or sugar alcohols may be used, including, but not limited to, sodium alginate, starch, chitosan, forms of cellulose, varieties of collagen, polyethylene glycol, glycerin, sorbitol, and the like.

[0098] As described above, the hydrogel substrate can contain at least some citric acid. The percentage of citric acid can be chosen to determine the rate at which the hydrogel substrate 5 degrades, thus maintaining its structural integrity and shielding capacity. In some examples, the percentage of citric acid can range from 2.5% to 10%. In this way, the citric acid ensures that the hydrogel substrate 5 continues to shield the wound site from radiation for a certain period of time after implantation. This can be useful, for example, if the patient needs to return to the operating room with such a device 1 after implantation. In other examples, chemical cross-linking can be achieved with an agent such as glutaraldehyde, or cross-linking can be achieved by gamma irradiation, UV irradiation, or a freeze-thaw process.

[0099] The hydrogel substrate 5 can have a thickness of at least 3 mm, preferably 3.5 mm. In other examples, a gamma source can be used, which may require a greater thickness of the hydrogel substrate 5 to ensure effective unidirectional shielding. As in Fig. As illustrated in Figure 3, the hydrogel substrate 5 can be configured to have a central recessed section for receiving the bioresorbable support matrix structure 2.

[0100] The hydrogel substrate 5 can also serve to prevent damage or unwanted adhesion of surrounding tissues and structures to the device. As described in Fig. As illustrated in Figure 3, the hydrogel substrate 5 can be connected to the hydrophilic substrate 4 at its edges. In this way, the hydrogel substrate 5 can extend beyond the edges of the first and second surfaces 21, 22 of the biocompatible support matrix structure 2. Method 200 for the manufacture of a flexible brachytherapy device

[0101] As in Fig. Figure 11 illustrates a method 200 for the fabrication of a flexible brachytherapy device for application at a wound site in the body. Method 200 comprises forming 202 a bioresorbable carrier matrix structure 2 comprising a variety of radioisotope particles 3. In method 200, the bioresorbable carrier matrix structure 2 can be provided by adsorbing a variety of insoluble radioisotope particles onto a microporous, hydrophobic substance with a hydrophilic surface 4, thus providing the bioresorbable carrier matrix structure 2 as described above. In some examples, the bioresorbable carrier matrix structure 2 can be fabricated by a thermoplastic process, such as a combination of extrusion and / or heated batch mixing. In other examples, injection molding or hot pressing can be used.In some examples, the multitude of insoluble radioisotope particles is provided by adding a precipitating agent to the multitude of radioisotope particles.

[0102] The bioresorbable carrier matrix structure 2 is configured to degrade at a rate significantly longer than the half-life of the radioisotope particles 3, so that the activity from the multitude of radioisotope particles 3 is limited to the wound site, wherein the biodegradable carrier matrix structure 2 has a first surface and a second surface 21, 22 that are opposite each other.

[0103] Method 200 further comprises forming 204 a hydrophilic substrate 4 adjacent to the first surface 21 of the bioresorbable support matrix structure 2, wherein the hydrophilic substrate 4 adheres to the wound site. Upon implantation at the wound, the hydrophilic substrate 4 is configured to degrade at a lower rate than the bioresorbable support matrix 3 in order to prevent migration of the device 1 during the half-life of the plurality of radioisotopic particles 3. The hydrophilic substrate can be produced by extrusion, solvent casting, spray coating, and / or dipping.

[0104] The process 200 further comprises forming 206 a hydrogel substrate 5 adjacent to the second surface 22 of the bioresorbable support matrix structure 2, wherein the hydrogel substrate 5 is configured to shield radiation and degrade at a rate longer than the half-life of the plurality of radioisotopic particles 3. In some examples, the hydrogel substrate 5 can be formed by a combination of several polymers prior to melt extrusion or solvent casting.

[0105] The hydrophilic substrate 4 and the hydrogel substrate 5 can be bonded to the device 1 by one or more of the techniques of mechanical integration, hot pressing, shaping, chemical and / or enzymatic crosslinking. This can include carbodiimide chemistry, GEM, transglutaminase, or other conventional crosslinking methods (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 support matrix structure 2 and free amide and / or hydroxyl groups in the hydrophilic substrate 5 and the hydrogel substrate 5. Applicator device

[0106] Fig. Figure 6 shows an example of an applicator device 66 for applying a brachytherapy device 1 to a wound site 100 in a body. The applicator device 66 enables the application of the brachytherapy device 1 to a wound site 100 while simultaneously protecting the operator, such as a surgeon or a nuclear medicine physician. The applicator device 66 also ensures the safe distribution and storage of the device 1, as well as its rapid positioning at the wound site 100. When used with the brachytherapy device 1 contained within it, the applicator device 66 keeps the brachytherapy device 1 dry and also shields nearby personnel from radioactive radiation. This minimizes collateral radiation exposure.

[0107] The applicator device 66 is configured to be placed inside the body so that the base 8 points away from the operator and towards the wound site 100.

[0108] The applicator device 66 comprises an upper housing 6 with a recess 67 for receiving a brachytherapy device 1. The upper housing 6 of the applicator device 66 can be made of a transparent, semi-transparent, or translucent material to allow the surgeon to precisely position the brachytherapy devices while being protected from beta radiation. In some examples, the upper housing 6 can be made of an acrylate polymer, such as acrylic (Perspex).

[0109] The applicator device 66 also includes a removable base 8 attached to the upper housing 6, wherein the removable base 8 and the upper housing 6, when attached, shield the radiation from the brachytherapy device 1. In some examples, the removable base 8 is slidably attached to the upper housing 6. In this way, the removable base 8 can be slidably removed from the upper housing 6. As in Fig. As illustrated in Figure 12, the upper housing 6 in some examples comprises rails 15 that are received by and engage in grooves 17 on the removable base 8. In some examples, the rails 15 may be shaped to engage in the grooves 17. It is understood that other sliding engagement arrangements may also be used, such as inwardly facing and opposing grooves that receive opposite edges of a base.

[0110] The removable base 8 can have a flat surface. The removable base 8 can be made of a material suitable for protection against bremsstrahlung, such as acrylic. Alternatively, the removable base 8 can be made of lead vinyl, leaded glass, or leaded vinyl acrylic if a gamma emitter was used. The combination of the upper housing 6 and the removable base 8 enables safe handling and delivery of the brachytherapy device 1 to the wound site 100 during and after placement during the operation.

[0111] The removable base 8 can be configured to face a first surface 21 of the brachytherapy device 1. In some examples, the removable base 8 can face a hydrophilic substrate 4 of the brachytherapy device 1, as described above.

[0112] The removable base 8 is removable from the upper housing 6, such as by sliding, to expose a first surface 21 of the brachytherapy device 1 at a wound site 100. Fig. Figure 13 shows a slidingly removable base 8. The removable base 8 can also be removable in other ways, e.g., by a hinge connected to the applicator device 66. In some examples, the first surface 21 can consist of a hydrophilic substrate 4 of the brachytherapy device 1, as described above. This is shown in Fig. Figure 14 shows that the removable base 8 is slid away during the application and positioning of the brachytherapy device 1 at the wound site 100 to expose the hydrophilic substrate 4 at the wound site 100.

[0113] The removable base 8 may also have a tab 14 which allows an operator, such as a surgeon, to apply a pulling or pushing force to slide the base 8 away from the upper housing 6, thus exposing a first surface 21 of the brachytherapy device 1 so that the device 1 can adjoin and adapt to the wound site 100.

[0114] In some examples, the upper housing 6 further includes an inlet opening 11 connected to the recess 67. The inlet opening 11 allows a fluid to be introduced through the inlet opening 11 into the brachytherapy device 1 in the recess 67. In some examples, a channel 12 is connected to the inlet opening 11 so that the fluid can flow from the inlet opening 11 to the brachytherapy device 1 in the recess 67. This may include the introduction of a fluid for hydrating the hydrogel substrate 5.

[0115] In some examples, the inlet opening 11 can be used to “activate” an adhesive component of the brachytherapy device 1 by either introducing an adhesive substance onto a mounting surface of the device 1 or a component of a crosslinking solution that, upon application to the tissue of the wound site 100, causes crosslinking between the device 1 and the tissue of the wound site 100. Such agents may contain a component of carbodiimide chemistry (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) or facilitate dopa-lysine interactions with or without the assistance of transglutaminase.

[0116] 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 way, the soluble adhesive 9 provides additional security to protect the operator of the applicator device 66 from any activity of the brachytherapy device 1 contained therein. The soluble adhesive 9 may also form a seal, such as a hermetic seal, for the applicator device 66.

[0117] The soluble adhesive 9 can be water-soluble and / or heat-soluble. The soluble adhesive 9 can be dissolved by a liquid 13 introduced into the recess 67, allowing the removable base 8 to slide away from the upper housing 6. In some examples, the upper housing 6 and the removable base 8 can be bonded to the circumferential sections of the upper housing 6 and the removable base 8 by the soluble adhesive 9.

[0118] In some examples, water can be injected into the inlet opening 11 of the upper housing 6. In this way, the soluble adhesive 9 can be dissolved sufficiently to allow the removable base 8 to be removed, thus exposing the first surface 21 (e.g., the hydrophilic substrate 4) of the brachytherapy device 1 at the wound site 100.

[0119] In other examples, heat, in addition to a liquid, can be introduced into the inlet opening 11 of the recess 67. This could be, for example, warm water. In this way, the soluble adhesive 9 can absorb the heated liquid, dissolving it to remove the detachable base 8 and expose the hydrophilic substrate 4 of the brachytherapy device 1 at the wound site 100. In another example, a hydrogel substrate 5 of the brachytherapy device 1 can also absorb the heat and / or liquid to fill and expand. The hydrogel substrate 5 shields the radioactivity as described above.

[0120] In one example, after the applicator device 66 has been placed at the wound site 100, water and heat can be introduced into the inlet opening 11 of the recess 67. The soluble adhesive 9 can absorb the water and heat. The hydrophilic substrate 4 of the device 1 can also absorb water and heat. The hydrogel substrate 5 can also absorb water and heat. The bioresorbable support matrix structure 2 can also absorb water and heat. When the hydrogel substrate 5 is completely absorbed, the saturated hydrogel substrate 5 can be easily detached from the upper housing 6 to apply the device 1 to the wound site 1. The device 1 can then become flexible and conform to and adhere to a surface such as the wound site 100. The device 1 can then deliver a radiation dose.

[0121] In other examples, a liquid or gas suitable for sterilization can be introduced into the inlet opening 11. For example, ethylene oxide can be introduced to sterilize the device 1 and / or the applicator device 66 in a production facility and / or before an operation.

[0122] The applicator device 66 may further include a handle 10 on the upper housing 6 to assist in the placement of the applicator device 66 and the brachytherapy device 1 at the wound site 100. In some examples, the handle 10 may extend longitudinally, as in Fig. 6 and Fig. Figure 7 illustrates this. In other examples, the handle 10 may be attached to the upper housing 6 in a different configuration.

[0123] In some examples, the device 1 can be completely enclosed by the upper housing 6 and the removable base 8. That is, the hydrophilic substrate 4 and the bioresorbable support matrix 2 can have a smaller diameter than the removable base 8 and the hydrogel substrate 5. In one example, the hydrophilic substrate and the bioresorbable support matrix 2 can have a flat circular diameter of 3 cm, while the removable base 8 and the hydrogel substrate 5 can have a flat circular diameter of 4 to 4.5 cm.

[0124] A brachytherapy system is also provided, comprising the applicator device 66 and the device 1 as described above. In some examples, the hydrogel substrate 5 of the device 1 can be hydrated through the inlet opening 11 of the applicator device 66 at a uniform water content. In this way, the hydrogel substrate 5 can be fully formed, hydrated, and crosslinked with the device 1. It is advantageous that the device 1 can then be handled by the operator from the applicator device 66 without requiring any additional assembly by the operator or associated personnel. Another advantage is that the fully hydrated hydrogel substrate 5 shields the operator from radioactivity, making the radiation from the device 1 essentially unidirectional. Variations

[0125] In another example, referring to Fig. Figures 8 to 10 show an essentially planar topical brachytherapy laminate structure 30 comprising an outer film 37 made of a polycaprolactone-starch composite, an inert adhesive layer 38 comprising carboxymethylcellulose overlying a portion of the outer film, and an active radioisotope film layer 39 comprising 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 adjacent to the periphery of the outer film 37 and is designed to come into contact with a patient's skin surface to adhere the laminate structure to a desired location. In one aspect, the radioisotope particles can be impregnated into the surface interface between layer 45 and layer 39.

[0126] As in Fig. As shown in Figure 10, the inert adhesive layer 38 can further include a peelable backing layer (removable film) 43 for storage, which is peeled off to expose the inert adhesive layer for bonding to a desired treatment site. In this embodiment, the inert adhesive is a pressure-sensitive adhesive layer 8 with a peelable backing film 43. The outer layer 37 can comprise a hydrogel layer designed to absorb radiation to protect the surgeon and any other tissues while they complete the procedure and the radioisotope decays. In this embodiment, the hydrogel layer 37 can have a thickness of about 4 to 5 mm to absorb the radioactive particles.

[0127] Layers 45 and 39 have a smaller diameter (e.g., 3 cm flat circle) than layers 44 and 37 (e.g., 4 to 4.5 cm flat circle), so they are completely surrounded by the radioactive shielding.

[0128] In this example, the positive margin is concentrated at a small point on a two-dimensional (albeit irregular) surface. Therefore, it is preferable that the laminate structure in Fig. 8 and Fig. The example described in point 9 is an essentially flat composite film with several layers.

[0129] In Fig. Figure 9 shows the laminate structure on a wound bed represented by reference numeral 42, with the active radioisotope film layer 39 in direct contact with the wound bed. Fig. 10 The planar topical brachytherapy laminate structure further includes a removable shielding film 44. In one example, the removable shielding film 44 can comprise a lead vinyl / acrylic composite material that is present only for handling and delivery and is removed during application.

[0130] The shielding foil 44 is attached to the active radioisotope film layer 9 around its circumference with a water- and / or heat-soluble adhesive and can be peeled off for application to the wound bed. As in Fig. As further shown in Figure 10, a thin film 45 of rapidly absorbing hydrocolloid, such as cellulose, can be inserted between the active radioisotope film layer 9 and the removable shielding foil 44. When in use, the thin film 45 of the topical brachytherapy laminate structure, which is between approximately 25 and 200 micrometers thick, is the first layer to come into contact with the wound surface. The thin layer 45 also contains gemcitabine or another radiosensitizer to make the tumor cells susceptible to the radiation.

[0131] When water and heat are absorbed from the surgical or wound bed, the layers of the laminate structure become very flexible and adhere to the irregular surface, emitting the predetermined radiation dose.

[0132] From the wound bed outwards, the laminate structure comprises the following: a removable shielding film 44, such as lead vinyl and / or acrylic, which is present only for handling and delivery and is removed during application. The removable cover film 44 may be attached to the perimeter of the outer layer 37 with a water- and / or heat-soluble adhesive that can be removed. The laminate structure further comprises a thin film of rapidly absorbing hydrocolloid 45 (cellulose), which is the first layer that actually contacts the wound surface. This contains gemcitabine or another radiosensitizer to make the tumor cells susceptible to radiation and may be between 25 and 200 micrometers thick. The laminate structure also comprises radioisotopic particles impregnated in the surface interface between layer 44 and layer 39, forming a flat film or a thin mesh layer 45.

[0133] The hydrogel layer 37, which absorbs the radiation to protect the surgeon and all other tissues while they complete the procedure and the radioisotope decays, can have a thickness of about 4 to 5 mm to effectively absorb the particles.

[0134] The advantages of the system include the following: it provides an alternative treatment for narrow or positive margins to chemotherapy with or without adjuvant radiotherapy at the operating bed; it avoids the high toxicity of conventional treatments; and radiation doses can be more easily confined to the tissue margins, thereby reducing the effects of the presence of radiosensitive surrounding structures such as the bowel, as it is not necessary to wait for reconstructed structures (such as anastomoses) to heal before starting treatment with the current device.

[0135] It will be apparent to those skilled in the art that numerous variations and / or modifications can be made to the embodiments described above without deviating from the broad general scope of this disclosure. The present embodiments are therefore to be regarded in every respect as illustrative and not as limiting. QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited patent literature

[0000] AU 2018900745

[0001]

Claims

[1] A flexible brachytherapy device for application to a wound site in a body, the device comprising: a bioresorbable carrier matrix structure comprising a plurality of radioisotope particles, the bioresorbable carrier matrix structure being configured to degrade, when deployed at the wound site, at a rate such that the bioresorbable carrier matrix structure has a half-life longer than a half-life of the plurality of radioisotope particles such that activity from the plurality of radioisotope particles is localized at the wound site, the bioresorbable carrier matrix structure having an opposing first surface and an opposing second surface; a hydrophilic substrate disposed adjacent to the first surface of the bioresorbable carrier matrix structure, the hydrophilic substrate configured to adhere to the wound site, the hydrophilic substrate configured to degrade at a rate faster than that of the bioresorbable carrier matrix structure when deployed to the wound site to prevent migration of the device during the half-life of the plurality of radioisotope particles; and a hydrogel substrate adjacent to the second surface of the bioresorbable support matrix structure, the hydrogel substrate configured to shield radioactivity and degrade at a rate such that the hydrogel substrate has a half-life longer than the half-life of the plurality of radioisotope particles. [2] The apparatus of claim 1, wherein the plurality of radioisotope particles comprises a beta emitter. [3] The device of claim 1 or 2, wherein the plurality of radioisotopic particles comprise one or more of the following: yttrium-90, iridium-192, palladium-103, cesium-131, iodine-131, iodine-125, iodine-123, 33-phosphorus, 32-phosphorus, a mixture of 33-phosphorus and 32-phosphorus, and compounds including such isotopes. [4] Device according to one of claims 1 to 3, wherein the bioresorbable carrier matrix is ​​formed by: Adsorbing or dispersing an aqueous solution of a radioisotope onto a hydrophobic substance. [5] Device according to one of claims 1 to 4, wherein the bioresorbable carrier matrix is ​​formed by: Precipitation of an aqueous solution of a radioisotope to form a plurality of insoluble radioisotope particles in the bioresorbable carrier matrix structure. [6] The device of claim 5, wherein the precipitation is achieved by a precipitating agent, and the precipitating agent comprises an insoluble or sparingly soluble salt that can be biologically reabsorbed in a body. [7] The device of claim 6, wherein the precipitating agent comprises an aqueous solution of calcium ions. [8] The device of claim 7, wherein the precipitating agent comprises one or more of the following elements: calcium chloride, calcium hydroxide, calcium nitrate or calcium bromide. [9] A device according to any one of claims 4 to 8, wherein the hydrophobic substance comprises a hydrophilic surface. [10] The device according to any one of claims 4 to 9, wherein the aqueous solution comprises radioactive ions. [11] A device according to claim 10, wherein the radioactive ions are derived from one or more of the following compounds: monosodium phosphate, disodium phosphate, potassium phosphate, dipotassium phosphate, orthophosphoric acid, tetrasodium pyrophosphate and soluble compounds including iodide. [12] A device according to any one of the preceding claims, wherein the plurality of radioisotope particles comprise radioactive elements in the linking molecules of the calcium phosphate. [13] The device of claim 12, wherein the linking molecules of calcium phosphate comprise one or more of the following: calcium pyrophosphate, monocalcium phosphate, dicalcium phosphate, octacalcium phosphate, tricalcium phosphate, hydroxyapatite, fluorapatite, tetracalcium phosphate. [14] A device according to any one of the preceding claims, wherein the hydrogel substrate is cross-linked with citric acid, the percentage of citric acid being selected to indicate the rate at which the hydrogel substrate degrades to maintain structural integrity and shielding capacity. [15] A device according to any one of the preceding claims, wherein the hydrophilic substrate comprises a coating or suspension of a hemostatic agent.

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