MULTILAYERED BIOLOGIC MESH AND METHODS OF USE THEREOF

Abstract

Systems and methods for using surgical meshes to deliver chemotherapeutic agents and radioactive elements are presented herein. The surgical mesh may comprise multiple layers, with an inner or outer layer comprising the radioactive element, and an inner or outer layer comprising the chemotherapeutic layer. Upon exposure to physiological conditions, the surgical mesh along with pellets or powdered elements embedded therein biodegrades.

Claims

1. A surgical multilayer mesh for the treatment of cancer comprising: a bioabsorbable material; a chemotherapeutic agent; and a radioactive element.

2. The surgical mesh of claim 1, wherein the surgical mesh comprises: one or more inner or outer layers comprising the radioactive element; and one or more inner or outer layers comprising the chemotherapeutic agent.

3. The surgical mesh of claim 1, comprising: two or more layers comprising the radioactive element and the chemotherapeutic agent in the same layer.

4. The surgical mesh of claim 1, wherein the surgical mesh comprises a pore size ranging from 50 um to 5 mm.

5. The surgical mesh of claim 1, wherein the radioactive element is provided in the form of a pellet.

6. The surgical mesh of claim 1, wherein the chemotherapeutic agent is provided in the form of a pellet.

7. The surgical mesh of claim 2, wherein the radioactive element is provided in the form of a pellet embedded in the one or more inner layers.

8. The surgical mesh of claim 2, wherein the chemotherapeutic agent is provided in the form of a pellet embedded in the one or more outer layers.

9. The surgical mesh of claim 2, wherein the radioactive element is provided in the form of a pellet embedded in the one or more inner layers, and the chemotherapeutic agent is provided in the form of a pellet embedded in the one or more outer layers.

10. The surgical mesh of claim 1, wherein the radioactive element and the chemotherapeutic agent together are provided in the form of a pellet, wherein the pellet is embedded in the surgical mesh, and wherein the radioactive element and the chemotherapeutic agent are dispersed throughout a same layer of the pellet.

11. The surgical mesh of claim 1, wherein the radioactive element and the chemotherapeutic agent together are provided in the form of a pellet, wherein the pellet is embedded in the surgical mesh, and wherein the radioactive element is dispersed throughout an inner layer of the pellet, and the chemotherapeutic agent is dispersed throughout an outer layer of the pellet.

12. The surgical mesh of claim 1, wherein the mesh comprises a biodegradable biosynthetic material.

13. The surgical mesh of claim 1, wherein the mesh comprises a material derived from a human.

14. The surgical mesh of claim 1, wherein the mesh comprises a material that is porcine urinary bladder.

15. The surgical mesh of claim 1, wherein the mesh biodegrades when exposed to physiological conditions.

16. The surgical mesh of claim 15, wherein the physiological conditions comprise one or more of: (a) an aqueous environment; or (b) a temperature of 21 C. to 37 C.

17. A radioactive pellet for the treatment of cancer, wherein the pellet is fully biodegradable and comprises an inner layer comprising one or more radioactive elements.

18. The radioactive pellet of claim 17, wherein the inner layer additionally comprises one or more chemotherapeutic agents.

19. A method of treating a patient comprising implanting the surgical multilayer mesh of claim 1 within the patient.

20. A method of manufacturing a surgical multilayer mesh or a biodegradable pellet comprising: a bioabsorbable material; a chemotherapeutic agent; and a radioactive element.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] FIGS. 1A-ID are illustrations showing layers of an example surgical multilayer mesh, according to embodiments presented herein.

[0042] FIGS. 2A-2B are illustrations showing layers of another example surgical multilayer mesh, according to embodiments presented herein.

[0043] FIGS. 3A-3C are illustrations showing example surgical multilayer meshes with differing pore sizes or no pores, according to embodiments presented herein.

[0044] FIGS. 4A-4D are illustrations showing layers of example pellets that may be embedded in the multilayer mesh, according to embodiments presented herein.

[0045] FIGS. 5A-5B are illustrations showing an example mesh with pellets embedded therein, according to embodiments presented herein.

[0046] FIGS. 6A-6C are illustrations showing additional examples of meshes with pellets embedded therein, according to embodiments presented herein.

[0047] The examples presented herein are not intended to be limiting. It is understood that many different variations of these examples are disclosed within the application, and that all such embodiments fall within the scope of present invention embodiments.

DETAILED DESCRIPTION

[0048] Present invention embodiments are directed towards a multilayered biologic mesh comprising one or more radioactive elements and one or more chemotherapeutic agents embedded therein. It is understood that the meshes may be formed of any number of layers, and the examples presented herein are intended to be non-limiting. For example, an inner layer may comprise one or more layers, though a single layer may be shown in reference to a figure. Similarly, an outer layer may comprise one or more layers, though a single layer may be shown in reference to a figure.

[0049] FIGS. 1A-1B are example illustrations of a multilayered mesh 100. In FIG. 1A, three layers of mesh are formed, for example, two outer layers 110 and an inner layer 120. The layers undergo bonding or compression, e.g., using high compression technology, to form a multilayered mesh 100, as shown in FIG. 1B. In this example, the outer layers 110 contain one or more chemotherapeutic agents dispersed throughout, while the inner layers contain a radioactive element dispersed throughout. The thickness and number of layers determine the rate of bioabsorbability.

[0050] In this example, the radioactive element may be combined with (e.g., by immersing the layer in a solution comprising the therapeutic, by applying a coating of the therapeutic to the layer, by applying a powder or gel comprising the therapeutic to the layer, etc.) the biodegradable material used to form a layer of the mesh, allowing a homogenous or substantially homogeneous distribution of the radioactive element throughout the mesh. Similarly, the chemotherapeutic agent may be mixed with the biodegradable material used to form a layer of the mesh, allowing a homogenous or substantially homogeneous distribution of the chemotherapeutic agent throughout the mesh.

[0051] Manufacturing processes utilizing bonding may use adhesives to join individual layers of the mesh together, while compression may use compressive force to join individual layers of the mesh together.

[0052] FIGS. 1C-1D are example illustrations of another multilayered mesh 105. In FIG. 1C, three layers of mesh are formed, for example, two outer layers 120 and an inner layer 110. The layers undergo bonding or compression, e.g., using high compression technology or adhesive forces, to form a multilayered mesh 105, as shown in FIG. 1D. In this example, the outer layers 120 contain one or more radioactive agents or pellets dispersed throughout, while the inner layers contain one or more chemotherapeutic agents dispersed throughout. The thickness and number of layers determine the rate of bioabsorbability.

[0053] FIGS. 2A-2B are illustrations of another example of a multilayer mesh 200. In FIG. 2A, three layers of mesh 210 are formed. In this example, the three layers of mesh each comprise both one or more chemotherapeutic agents and one or more radioactive elements. The layers may undergo bonding or compression, e.g., using high compression technology, to form multilayered mesh 200, as shown in FIG. 2B. In this example, each layer 210 contains a chemotherapeutic agent dispersed throughout and a radioactive element dispersed throughout.

[0054] In this example, the radioactive element and the chemotherapeutic agent may be combined with (e.g., by immersing the layer in a solution comprising the therapeutic, by applying a coating of the therapeutic to the layer, by applying a powder or gel comprising the therapeutic to the layer, etc.) the biodegradable material used to form layers of the mesh, allowing homogenous or substantially homogeneous distribution of the chemotherapeutic agent and the radioactive element throughout the mesh.

[0055] In some embodiments, layer 110 comprising one or more chemotherapeutic agents may be combined with layer 210 comprising one or more radioactive agents (dispersed or as pellets) and one or more chemotherapeutic agents. In other embodiments, layer 120 comprising one or more radioactive agents (dispersed or as pellets) may be combined with layer 210 comprising one or more radioactive agents (dispersed or as pellets) and one or more chemotherapeutic agents. In this example, layer 110 may be an inner or an outer layer, layer 120 may be an inner or an outer layer, and layer 210 may be an inner or an outer layer.

[0056] Referring to FIGS. 3A-3C, various illustrations of meshes having differing pore sizes are present. FIG. 3A shows an example mesh comprising pores of a relatively large size, e.g., from 1-5 mm. FIG. 3B shows an example mesh comprising pores of an intermediate size, e.g., from 50 m-1 mm. FIG. 3C shows an example mesh considered not to be porous.

[0057] Pores may be of any suitable size, e.g., from about 50 m up to 5 mm or any size in between. For example, the diameter of the pore may be 50 m, 55 m, 60 m, 65 m, 70 m, 75 m, 85 m, 90 m, 95 m, 100 m, 200 m, 300 m, 400 m, 500 m, 600 m, 700 m, 800 m, 900 m, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, and so forth, or any value in between.

[0058] In some embodiments, the pore size may help modulate the rate of bioabsorption or biodegradation of the surgical mesh and release of chemotherapeutic agents. For example, increasing the pore size may increase the available surface area of the mesh to promote or increase release of chemotherapeutic agents or radioactive elements. Decreasing the pore size may decrease the available surface area of the mesh to promote slower release of chemotherapeutic agents or radioactive elements.

[0059] In still other embodiments, pores may help reduce unwanted side effects from implanted meshes, e.g., the occurrence of foreign body reactions (e.g., granuloma formation), as well as reducing associated infections. In some embodiments, the size of the pores may be about 75 m (e.g., to allow infiltration by various red and white blood cells and rapid neovascularization).

[0060] In general, the surgical mesh may be of any suitable shape or size, e.g., square, rectangular, oval, circular, diamond, etc. The shape and size of the surgical mesh may be determined by the target location of the mesh, e.g., prostate, liver, intestines, etc. The multilayered mesh may be cut to any suitable geometry, governed by the particular location, type of cancer, dimensions of patient, etc. to provide a suitable, customized fit. Once implanted, the meshes may be surgically glued or sutured in place. The shape of the mesh and the positioning of the therapeutic within the mesh depends upon the application. Accordingly, the mesh can be specifically configured and customized to deliver therapeutics to a specific target region.

[0061] FIGS. 4A-4D show various illustrations of a biodegradable pellet. In some embodiments, the pellet may be embedded within a mesh. In other embodiments, the pellet may be administered directly (not within a mesh). Pellets may be distributed throughout each layer of a multilayered mesh, or in other embodiments, may be distributed throughout a subset of layers of a multilayered mesh.

[0062] Pellets may range in size from 100 m up to 5 mm, or any size in between. The pellets may be uniformly shaped or irregularly shaped. In some embodiments, radioactive pellets may range in size from about 0.002 m to about 200 m, from 10 m to 100 m, and from about 20-50 m.

[0063] The pellet can take on a variety of shapes. In other embodiments, the pellet may take the shape of a sphere. In still other embodiments, the pellet may take the shape of a grain of rice, or cylinder. Here, it is understood that many different type of geometries are suitable and all are within the scope of the embodiments described herein. For the following figures, it is understood that the pellet comprises one or more biodegradable polymers mixed with one or more chemotherapeutic agents and one or more radioactive elements.

[0064] FIG. 4A shows an illustration of an example pellet, according to the embodiments set forth herein. In this example, the inner layer 410 comprises a radioactive element. An optional outer layer 420, may act as a coating, e.g., to help control the rate of biodegradation of the pellet.

[0065] In some embodiments, pellets may be formed using radioactive powders. Radioactive powders include but are not limited to I.sup.125, Pd.sup.103, Rn.sup.86, Rn.sup.222, Y.sup.90, P.sup.32 or Au.sup.198. In some embodiments, a single type of radioactive power is mixed with a polymer to form a pellet, while in other embodiments; multiple types of radioactive powders are mixed with a polymer to form a pellet. The radiation pellet produces a field that is uniform or substantially uniform in all directions.

[0066] For applications in which a higher radiation penetration is optimal, particles that emit gamma radiation may be selected, e.g., Rn.sup.222 or Au.sup.198. For applications, in which a lower radiation penetration is optimal, particles that emit beta particles may be selected.

[0067] Pellets may be placed in the tumor bed or within the tissue to be treated (interstitial therapy), or within a region from which the tumor has been removed (intracavitary therapy).

[0068] FIG. 4B shows an illustration of an example pellet, according to the embodiments set forth herein. In this example, the inner layer 430 comprises a chemotherapeutic agent. An optional outer layer 440, may act as a coating, e.g., to help control the rate of biodegradation of the pellet. Outer layer 440 may be the same or different from layer 420.

[0069] FIG. 4C shows an illustration of an example pellet, according to the embodiments set forth herein. In this example, the inner layer 410 comprises a radioactive element. An optional middle layer 425, may act as a coating, e.g., to separate the chemotherapeutic layer 430 from the radioactive layer 410. Layer 430 comprises a chemotherapeutic agent. An optional outer layer 445, may act as a coating, e.g., to help control the rate of biodegradation of the pellet. Outer layer 440 may the same or different from layer 420 or 440. In this example, the pellet may be fully biodegradable.

[0070] FIG. 4D shows an illustration of an example pellet, according to the embodiments set forth herein. In this example, the inner layer 450 comprises a blend of chemotherapeutic agent(s) and radioactive element(s). An optional outer layer 455, may act as a coating, e.g., to help control the rate of dissolution of the pellet. Outer layer 455 may be the same or different from layer 445, 420, or 440.

[0071] Turning now to FIGS. 5A-5B, example illustrations of a multilayered mesh 500 are presented with pellets dispersed throughout. In FIG. 5A, three layers of mesh are formed, for example, two outer layers 510 and an inner layer 520. The layers undergo bonding or compression, e.g., using high compression technology, to form a multilayered mesh 500, as shown in FIG. 5B. In this example, the outer layers 510 contain a chemotherapeutic agent in the form of a pellet, wherein the pellets are dispersed throughout the outer layer, while the inner layer contains a radioactive element in the form of a pellet dispersed throughout the inner layer 520.

[0072] Turning now to FIGS. 6A-6C, example illustrations of a multilayered mesh 600 are presented with pellets dispersed throughout. The meshes are bioabsorbed as a function of time. Three layers of mesh are formed, for example, two outer layers and an inner layer, and undergo bonding or compression, e.g., using high compression technology, to form multilayered mesh 600, as shown in FIG. 6A. In this example, each layer contains a chemotherapeutic agent in the form of a pellet (see, FIG. 4B) and a radioactive element in the form of a pellet (see, FIG. 4A) dispersed throughout each layer.

[0073] As shown in FIG. 6B, three layers of mesh are formed, for example, two outer layers and an inner layer, and undergo bonding or compression, e.g., using high compression technology, to form a multilayered mesh 620. In this example, each layer has embedded pellets, the pellets each containing a chemotherapeutic agent and a radioactive element (See, FIG. 4C) dispersed throughout each layer.

[0074] As shown in FIG. 6C, three layers of mesh are formed, for example, two outer layers and an inner layer, that undergo bonding or compression, e.g., using high compression technology, to form a multilayered mesh 630, as shown in FIG. 6C. In this example, each layer contains a chemotherapeutic agent and a radioactive element in the same pellet (See, FIG. 4D) dispersed throughout each layer.

[0075] The amount of radioactive element required to provide therapeutic levels of radiation varies depending upon: (1) the particular radioisotope or combination of radioisotopes, (2) preparation of the isotope, and (3) the particular therapeutic application. In some embodiments, 0.1-5 millicuries, or 1-2 millicuries, per centimeter is a suitable target for radiation delivery. It is presumed that the mechanical integrity of the biodegradable polymer will not be impaired by the dosage of radioactivity delivered. In some embodiments, the particles are layered uniformly over the inner layers of mesh.

[0076] In some embodiments, the pellets containing the radioactive element may be spaced 0.1 cm, 0.2 cm, 0.3 cm, 0.4 cm, 0.5 cm apart, 1 cm apart, 2 cm apart, 3 cm apart, 4 cm apart, 5 cm apart, or more, or any unit in between.

[0077] In some embodiments, particles released into the body from biodegradation/bioabsorption of the mesh or pellet, include biocompatible particles such as palladium particles that are not known to be toxic when implanted interstitially, or yttrium oxide particles also are not associated with toxic effects.

[0078] Suitable biodegradable polymers include but are not limited to: polymers derived from natural sources such as collagen, polysaccharides, microbial polyesters, etc; synthetic degradable polymers such as aliphatic polyesters including polyglycolic acid, polylactic acid, polycaprolactone and polydioxanone; polyortho esters; polyanhydrides; degradable polycarbonates; mono and poly amino acids in which conventional peptide bonds have been modified or replaced with other linkages; etc. and mixed with radioactive elements and/or chemotherapeutic agents. Dissolvable materials are known in the art, and all such materials are contemplated for use herein (e.g., Pulapura et al., J. of Biomaterials Applications, (1992) v:6, p 216-250).

[0079] In some embodiments, the pellet or mesh comprises one or more additional ingredients e.g., to stabilize or preserve the activity of the chemotherapeutic, to modulate the dissolution or dispersal rate of the chemotherapeutic, to maintain sterility of the chemotherapeutic, etc. These ingredients include but are not limited to: antioxidants, bacteriostats, buffers, carbohydrates, chelating agents such as EDTA or glutathione, coloring, diluents, emulsifiers, excipients, flavoring and/or aromatic substances, lubricants, pH buffering agents, physiologically acceptable carriers, polypeptides (e.g., glycine), preservatives, proteins, salts for influencing osmotic pressure, solubilizers, stabilizers, surfactants, wetting agents, etc. Buffers include but are not limited to saline, neutral buffered saline, phosphate buffered saline, etc. Carbohydrates include but are not limited to dextrans, glucose, mannose, mannitol, sucrose, etc. Stabilizing excipients include but are not limited to sugars, carbohydrates, lipids and various polymers.

[0080] In certain embodiments, the tumor or cancer arises from a hyperproliferative disorder or condition. In some cases, the cancer is a solid tumor. Examples of solid tumors include malignancies, e.g., adenocarcinomas, carcinomas, and sarcomas of the various organ systems, such as those affecting the bladder, brain, breast, cervix, colorectal, digestive/gastrointestinal system, gallbladder, head and neck, intestines, kidney, liver, lymphoid, lung, muscle ovarian, pancreas, pharynx, prostate, rectum, renal system, skin, soft tissue, thyroid, uterus, urothelial, and vagina. The cancer may be at an early, intermediate, late stage, metastatic cancer, etc.

[0081] Exemplary chemotherapeutic or cytotoxic agents that can be administered in pellet form, dispersed through the mesh, or in a dual pellet including both the chemotherapeutic agent and the radioactive element, include but are not limited to: alkylating agents; antitumor antibiotics, anthracyclines, anti-metabolites, mitotic inhibitors, plant alkaloids, topoisomerase inhibitors, or other miscellaneous antineoplastic agents.

[0082] Alkylating agents include but are not limited to: mustard gas derivatives (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan, and ifosfamide), ethylenimines (e.g., thiotepa and hexamethylmelamine); alkylsulfonates (e.g., busulfan), hydrazines and triazines (e.g., altretamine, procarbazine, dacarbazine and temozolomide); nitrosureas (e.g., carmustine, lomustine, and streptozocin); and metal salts (e.g., carboplatin, cisplatin, cis-dichlorodiamine platinum (II) cisplatin, and oxaliplatin) as well as melphalan, cyclothosphamide, dibromomannitol, streptozotocin, mitomycin C.

[0083] Anti-metabolites include but are not limited to: folic acid antagonists (e.g., methotrexate), pyrimidine antagonists (e.g., 5-fluorouracil, 5-fluorouracil decarbazine, foxuridine, cytarabine, capecitabine, and gemcitabine), purine antagonists (e.g., 6-mercaptopurine and 6-thioguanine), adenosine deaminase inhibitor (e.g., cladribine, fludarabine, nelarabine and pentostatin) as well as 6-mercaptopurine and 6-thioguanine.

[0084] Antitumor antibiotics, include but are not limited to: anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, mitoxantrone, and idarubicin), chromomycins (e.g., dactinomycin and plicamycin), mitomycin or bleomycin.

[0085] Mitotic inhibitors include but are not limited to: vincristine, vinblastine, taxol and maytansinoids.

[0086] Plant alkaloids, include but are not limited to: vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine); taxanes (e.g., paclitaxel and docetaxel); podophyllotoxins (e.g., etoposide and tenisopide), camptothecan analogs (e.g., irinotecan and topotecan).

[0087] Topoisomerase inhibitors include but are not limited to: topoisomerase I inhibitors (e.g., irinotecan or topotecan); or topoisomerase II inhibitors (e.g., amsacrine, etoposide, etoposide phosphate, teniposide).

[0088] Miscellaneous antineoplastics include but are not limited to: ribonucleotide reductase inhibitors (e.g., hydroxyurea); adrenocortical steroid inhibitors (e.g., mitotane); enzymes (e.g., asparaginase or pegaspargase), antimicrotubule agents (e.g., estramustine), retinoids (e.g., such as bexarotene, isotretinoin, tretinoin (ATRA)).

[0089] Additional chemotherapeutic agents include compounds that are capable of interfering with signal transduction pathways, agents that promote apoptosis, or proteosome inhibitors.

[0090] Radioactive include -, -, or -emitters, or - and -emitters. Such radioactive isotopes include, but are not limited to: actinium (.sup.225Ac), astatine (.sup.211At), bismuth (.sup.213Bi), carbon (.sup.14C), chromium (.sup.51Cr), chlorine (.sup.36Cl), cobalt (.sup.57Co or .sup.58Co), gallium (.sup.67Ga), lutetium (.sup.177Lu), indium (.sup.111In), iodine (.sup.131I or .sup.125I), iron (.sup.59Fe), yttrium (.sup.90Y), phosphorus (.sup.32P), praseodymium (.sup.143Pr), rhenium (.sup.186Re), rhodium (.sup.188Rh), selenium (.sup.75Se), sulfur (.sup.35S), technetium (.sup.99Tc), tritium (.sup.3H), etc.

[0091] The pellets or meshes can be prepared with a pharmaceutically acceptable carrier, which can be, for example, any suitable pharmaceutical excipient. The carrier includes any and all binders, fillers, solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, drug stabilizers, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329; Remington: The Science and Practice of Pharmacy, 21st Ed. Pharmaceutical Press 2011 and subsequent versions thereof). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. Other disclosure herein relating to the pellets or meshes can also be followed.

[0092] In some embodiments, the biodegradable pellets comprise a polymer that is dissolvable, or insoluble but dispersible under physiological conditions, or a combination of both. Polymers may include (e.g., polymers such as PLGA, carboxymethylcellulose (CMC), hyaluronic acid etc.). The pellets may further comprise micro- or nano-particles comprising absorbed, conjugated, dispersed, or encapsulated therapeutics, wherein the micro- or nano-particles are designed to deliver the therapeutic to the subject. Many materials suitable for forming the polymer are known within the art, and all such materials are contemplated for use herein.

[0093] In terms of arrangement of the multilayered mesh, in some embodiments, chemotherapy elements may be placed in the inner layer to facilitate leaching out of the therapeutic agent once the radiation dose has been delivered resulting in sequential anti neoplastic therapy. Radioactive elements may be placed in the outer layers, as these elements can penetrate through layers.

[0094] When designing a mesh, properties of meshes, e.g., the type of filament, the tensile strength, and the porosity, should all be considered. These properties determine the weight of the mesh and its biocompatibility. Meshes should be designed to have a sufficient tensile strength to be able to perform their function, e.g., in terms of providing support and isolating spaces or compartments, e.g., the pelvis, delivering therapeutic agents, etc. In preferred embodiments, light-weight meshes are selected due to their increased flexibility and reduction in complications. Larger pores correlate with increased rates of incorporation and decreased risk of encapsulation. For meshes placed in the peritoneal cavity, consideration should also be given to the risk of adhesion formation. Many different configurations are possible, and all such configurations fall within the scope of present invention embodiments.

[0095] The subject or recipient may be mammalian, and in particular, a human. In other embodiments, the subject or recipient may include domestic or livestock animals, e.g., cats, cows, dogs, goats, guinea pigs, horses, pigs, rabbits, rodents, or sheep.

[0096] The subject or recipient may be a human individual, suffering from cancer. The subject or recipient may be a child or an adult. The subject or recipient may be a healthy individual, at risk of developing cancer, e.g., a human undergoing a mastectomy for prevention of breast cancer might also benefit from the multilayer meshes described herein.

[0097] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the scope of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms comprises and comprising should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification claims refers to at least one of something selected from the group consisting of A, B. C . . . and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.

[0098] The Examples provided herein are meant to assist one of ordinary skill in the art in carrying out the invention and are not intended in any way to limit the scope of the invention.

EXAMPLES

Example 1. Fabrication of Meshes

[0099] The meshes disclosed herein may be formed or derived from human, porcine or other biosynthetic materials. In some embodiments, meshes are obtained from dermal tissue, bladder tissue, intestinal tissue, or any other suitable tissue or organ comprising extracellular matrix or connective tissue. In some embodiments, a multi-layer mesh formed of human or porcine tissue or organs are formed from individual layers, with each layer having a chemotherapeutic agent or a radioactive element or a combination of both therein, and wherein the individual layers undergo bonding or high compression to join together and form a mesh suitable for implantation.

[0100] In still other embodiments, 3-D printing may be used to print a mesh of biological or biosynthetic materials with embedded chemotherapeutics and other biologic factors. The mesh may be printed in multiple layers, with a given layer having the same composition or having a different composition (e.g., with respect to chemotherapeutic agents, radioactive agents, or a combination of chemotherapeutic and radioactive elements).

[0101] As a non-limiting example, in some embodiments, a human or porcine dermis, intestine, bladder, or any suitable source obtained from a mammal, may undergo a decellularization process to remove cells, leaving behind a mesh formed primarily of extracellular matrix, e.g., a scaffold of collagen and elastin and optionally with growth factors. See, e.g., U.S. Pat. No. 6,893,666. In some embodiments, the mesh will also have pores. Chemotherapeutic agents may be incorporated into the layers of mesh using any suitable technique, including coating the chemotherapeutic agent on the surface of the mesh layer, soaking the mesh in a solution comprising one or more chemotherapeutic agents, or forming pellets comprising chemotherapeutic agents that are embedded in the mesh.

[0102] Similarly, for layers involving radioactive elements, the radioactive agent may be applied as a coating on the surface of the mesh layer, by soaking the mesh in a solution comprising one or more radioactive elements, or by forming biodegradable pellets comprising radioactive agents that are embedded in the mesh. For layers that involve combinations of chemotherapeutic and radioactive elements, such combinations may be applied in a similar manner.

[0103] Techniques for forming biological meshes from mammalian tissues are known in the art, see, e.g., FitzGerald et al., Biologic versus Synthetic Mesh Reinforcement: What are the Pros and Cons? Clin Colon Rectal Surg (2014) 27:140-148.

[0104] In another non-limiting example, layers of the mesh may be synthesized or grown, in vitro. Fibroblasts or other extracellular matrix secreting cells may be cultured to produce an extracellular matrix, according to available techniques, see, e.g., Scherzer et al., Fibroblast-Derived Extracellular Matrices: An Alternative Cell Culture System That Increases Metastatic Cellular Properties PLOS (2015) 10(9):e0138065.

[0105] In another non-limiting example, each layer of the mesh may be generated by 3D printing with a biological material. Techniques for printing biological materials are known in the art, e.g., see, Murphy et al., 3D bio-printing of tissues and organs Nature Biotechnology (2013) 32:773-785. 3D printing allows meshes to be printed in an additive manner such that layers with differing compositions can be printed on top of each other, e.g., an inner layer may be printed with a chemotherapeutic agent, an outer layer may be printed with a radioactive agent, and so forth. A given layer having chemotherapeutic and/or radioactive elements may be additively printed on another layer having chemotherapeutic and/or radioactive elements.

[0106] Of course, a layer may be printed with a 3D process, the layer may be embedded with chemotherapeutic and/or radioactive pellets, coated with chemotherapeutic and/or radioactive elements, etc., and a subsequent layer of the mesh may then be printed on the modified layer. Many such modifications are understood to be within the scope of the embodiments disclosed herein.

Example 2. Fabrication of Pellets

[0107] According to the embodiments disclosed herein, radioactive or chemotherapeutic agents may be incorporated into dissolvable pellets, which are then embedded into the mesh. Techniques for forming pellets may be based on e.g., U.S. Pat. No. 6,248,057. Briefly, bioabsorbable materials, such as polymers, may be mixed with the chemotherapeutic agent or radioactive element, and formed into a pellet.

Example 3. Surgical Implantation of Meshes or Pellets

[0108] As described herein, the multilayer biological meshes are suitable for surgical implantation. A patient who has been diagnosed with cancer may undergo surgery to remove part or all of the cancer. As part of the procedure, the surgeon resects part or all of the tumor and places the mesh at the site where the tumor was removed in the tumor bed. In still other embodiments, for sites where the tumor is unresectable or is too close to vascular structures for a safe excision, the surgeon may embed the mesh therein in order to shrink or otherwise impede the growth of the tumor.

[0109] In some embodiments, the surgical meshes are designed to degrade slowly, over a period of weeks, months, or years. In other embodiments, the meshes are designed to degrade rapidly, within a matter of hours or days. By designing the mesh to have varying degradation rates, delivery of one or more therapeutics can be customized to a particular patient and type of tumor/cancer.

[0110] The thickness of the mesh may be based on the time frame in which the therapy is needed. The size of the mesh can be customized to fit core (body) sizes. During surgical placement, meshes can be cut down to size, e.g., to fit into a particular location, or multiple meshes may be placed together for larger target sites. To prevent migration after surgical placement, the mesh may be sutured or glued into place.

[0111] The implantable meshes, as described herein, have a number of advantages over existing meshes. For example, the multilayer biological meshes can deliver both radioactive elements and chemotherapeutic agents to a desired site, e.g., a tumor bed, within a solid tumor, etc. In some embodiments, the mesh may be bioabsorbed over a relatively long timeframe, so that the mesh remains in a fixed or relatively fixed position, allowing the continuous delivery of chemotherapeutic and radioactive elements to a particular site. Thus, these meshes are bioabsorbable, and as the absorption process continues, so does the degradation of the mesh, along with continuous release of chemotherapeutic agents and radioactive elements. Thus, unlike delivery using pellets, which can translocate to a different position or even a completely different position in the body, the meshes herein are fixed until they are absorbed.

[0112] In some embodiments, the layers of the mesh may be configured to have different bioabsorption rates. For example, an outer layer could be designed, e.g., based on the type of polymer, based on the thickness and the porosity of the layer, etc., to bioabsorb rapidlythus, rapidly delivering a high dose of one or more therapeutics to the target site. The inner layers can be designed to have different properties, having a bioabsorption rate of a slower timeframe, thus delivering a steady dose of the therapeutic agent on a long time frame to kill any residual tumor cells. These approaches are anticipated to lead to lower levels of cancer recurrence and resistance, as residual cells (not killed by an initial treatment) will be targeted and killed over a longer timeframe.

[0113] These examples are purely intended to be exemplary and are not intended to be limiting, as numerous different embodiments are understood to fall within the scope of present invention embodiments.