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WO2021137236A1 - Procédé et dispositifs pour le traitement de métastases osseuses - Google Patents

Procédé et dispositifs pour le traitement de métastases osseuses Download PDF

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Publication number
WO2021137236A1
WO2021137236A1 PCT/IL2020/051364 IL2020051364W WO2021137236A1 WO 2021137236 A1 WO2021137236 A1 WO 2021137236A1 IL 2020051364 W IL2020051364 W IL 2020051364W WO 2021137236 A1 WO2021137236 A1 WO 2021137236A1
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Prior art keywords
bone
matrix
cancer
biomatrix
anticancer drug
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PCT/IL2020/051364
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English (en)
Inventor
Razi Vago
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BG Negev Technologies and Applications Ltd
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BG Negev Technologies and Applications Ltd
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Publication of WO2021137236A1 publication Critical patent/WO2021137236A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/614—Cnidaria, e.g. sea anemones, corals, coral animals or jellyfish
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006—Properties of materials and coating materials
    • A61F2002/30062—(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30108—Shapes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30667—Features concerning an interaction with the environment or a particular use of the prosthesis
    • A61F2002/30677—Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2002/3092—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth having an open-celled or open-pored structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2002/3093—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth for promoting ingrowth of bone tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2002/30932—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth for retarding or preventing ingrowth of bone tissue

Definitions

  • the present disclosure generally relates to the field of methods and devices for treatment of bone cancer, in particular to methods and devices for localized treatment of bone metastases.
  • Cancer is the major cause of mortality in developed countries. The vast majority of patients die as a result of metastasis at secondary sites rather than the primary tumor.
  • cancerous diseases such as breast cancer, prostate cancer, and kidney cancer are characterized by the fact that at early stages of the disease, cancerous cells migrate from the tissue of origin into bone tissue (Kang et al., 2005; Sterling et al., 2011 ; Croucher et al., 2016).
  • Bone is the third most common site for the spread of cancer, and invasion of such cancerous cells to bone gives rise to the deadly condition of bone metastasis.
  • the spine is the most common site of bone metastasis.
  • Other common sites include ribs, skull, pelvis (hip bone), femur (leg bone) and humerus (arm bone).
  • the cells After docking, the cells remain dormant often even for years after the primary tumor (Croucher et al., 2016). However, at some point and for unknown reason, the cells “reawake” being more aggressive, and a vicious cycle is activated during which the disease is accelerated by continuously increasing activation and proliferation of the cancerous cells alongside an increased activity of osteoblasts causing rapid bone degeneration.
  • bone metastatic cancers are rarely curable. Treatment options available for bone metastasis are for most part symptomatic and/or palliative treatments which are meant for pain control, treatment and prevention of fractures, improvement in functional disability, etc. and do not improve overall patient survival.
  • aspects of the disclosure relate to method and devices for treatment of bone cancer, in particular to methods and devices for localized treatment of bone metastases.
  • the herein disclosed method and devices enable effective and localized treatment of bone metastases by delivery and/or implantation of three-dimensional matrix within a bone marrow of a bone affected by the metastasis in proximity to or within the affected area, typically in proximity to the growth plate of the bone.
  • the three-dimensional matrix is advantageously drug eluting in that it is embedded with a drug and enables its sustained and/or controlled release/delivery.
  • the three-dimensional matrix is bone-growth promoting, i.e. it can serve as a scaffold for bone growth/regeneration, thereby slowing or even preventing the bone loss typically associated with bone metastases which severely impedes a patient's quality of life due to fractures and pain.
  • a method for treating, ameliorating or inhibiting progression of bone cancer and/or bone metastases in a patient in need thereof comprising: positioning/implanting a bio-fabricated three-dimensional biomatrix into a bone of a patient in an area thereof affected by the bone cancer; wherein the biomatrix is embedded with an anticancer drug; the anticancer drug configured to be gradually released from the biomatrix, thereby inhibiting growth and/or causing death of the cancer cells within the affected area; and wherein the biomatrix has an inherent ability to induce bone regeneration and/or to inhibit bone degeneration within the affected area.
  • the bone cancer is secondary bone cancer.
  • the positioning/implanting comprises inserting the biomatrix through a diaphysis of the bone.
  • the area is spongy bone.
  • the spongy or compact bone is in proximity to a growth-plate of the bone.
  • the inserting/implanting comprises introducing the biomatrix through a sleeve, the sleeve forming a channel from a periosteum of the bone to the affected area.
  • the area of insertion/implanting is determined based on a previously obtained scan of the bone.
  • the scan is a PET-CT scan.
  • the biomatrix comprises a skeletal material of marine origin, that can be of corals of various specious or artificially cloned corals or hydrocorals.
  • the skeletal material comprises calcite and/or aragonite.
  • the skeletal material is obtained from corals, sea urchins hydrocorals or any combination thereof.
  • the skeletal material is obtained from corals of the species Millepora dichotama.
  • the biomatrix further comprises mesenchymal stem cells (MSCs) and/or osteoblast cells.
  • MSCs mesenchymal stem cells
  • the biomatrix is a bone matrix.
  • the bone matrix is produced by osteoblast cells autologous to the patient.
  • the anticancer drug is selected from the group consisting of: Cabozantinib, Docetaxel (DTX), Bortezmib, Neratinib, Nintedanib, Denosumab, Herceptin or any combination thereof.
  • the biomatrix further comprises a medicament capable of preventing loss of bone density and/or capable of inducing bone growth/ bone regeneration.
  • the medicament is a bisphosphonate and/or a bone morphogenetic protein (BMP).
  • the biomatrix comprises an outer coating configured to provide controlled release of the anti-cancer drug.
  • the outer coating comprises hyaluronic acid (HA).
  • a method for preventing or inhibiting bone metastases in a patient suffering from a solid tumor comprising: inserting/implanting a bio-fabricated three-dimensional biomatrix into a bone of a patient in an area thereof susceptible to establishing bone metastases; wherein the biomatrix is embedded with an anticancer drug; the anticancer drug configured to be gradually released from the biomatrix, thereby inhibiting growth and/or causing death of cancerous cells in the susceptible area.
  • the cancerous cells are dormant cancer cells or active bone metastases.
  • the area is spongy bone.
  • the spongy bone is in proximity to a growth-plate of the bone.
  • the inserting/implanting comprises introducing the biomatrix through a sleeve, the sleeve forming a channel from a periosteum of the bone to the susceptible area.
  • the positioning/implanting comprises inserting the biomatrix through a diaphysis of the bone.
  • the bone is a long bone.
  • the bone is a femur bone (leg bone), a rib, pelvis bone (hip bone), a humerus bone (arm bone) or any combination thereof.
  • the biomatrix comprises a skeletal material of marine origin or artificially cloned corals or hydrocorals, the skeletal material comprising calcite and/or aragonite.
  • the skeletal material is obtained from corals, sea urchins hydrocorals or any combination thereof.
  • the skeletal material is obtained from corals of the species Millepora dichotama.
  • the biomatrix further comprises mesenchymal stem cells (MSCs) and/or osteoblast cells.
  • MSCs mesenchymal stem cells
  • the biomatrix is or includes a bone matrix.
  • the bone matrix is produced by osteoblast cells autologous to the patient.
  • the anticancer drug is selected from the group consisting of: Cabozantinib, Docetaxel (DTX), Bortezmib, Neratinib, Nintedanib, Denosumab, Herceptin or any combination thereof.
  • the biomatrix further comprises a medicament capable of preventing loss of bone density and/or capable of inducing bone growth/ bone regeneration.
  • the medicament is a bisphosphonate and/or a bone morphogenetic protein (BMP).
  • BMP bone morphogenetic protein
  • the biomatrix comprises an outer coating configured to provide controlled release of the anti-cancer drug.
  • the outer coating comprises hyaluronic acid (HA).
  • a device for treating bone cancer and/or bone metastases in a patient in need thereof comprising a bio-fabricated three- dimensional biomatrix configured to induce bone growth and/or bone regeneration, and an anticancer drug embedded in the bio-fabricated three-dimensional biomatrix; wherein the biomatrix comprises a bone matrix produced by osteoblast cells autologous to the patient.
  • the anticancer drug is selected from the group consisting of: Cabozantinib, Docetaxel (DTX), Bortezmib, Neratinib, Nintedanib, Denosumab, Herceptin or any combination thereof.
  • the biomatrix further comprises a medicament capable of preventing loss of bone density and/or capable of inducing bone growth/bone regeneration.
  • the medicament is a bisphosphonate and/or a bone morphogenetic protein (BMP).
  • BMP bone morphogenetic protein
  • the biomatrix comprises an outer coating configured to provide controlled release of the anti-cancer drug.
  • the outer coating comprises hyaluronic acid (HA).
  • a method for producing a bio-fabricated three-dimensional bone matrix configured to induce bone growth and/or bone regeneration, the biomatrix embedded with an anticancer drug, the method comprising: seeding mesenchymal stem cells (MSCs) on skeletal material of marine origin, thereby inducing their differentiation into a bone matrix producing osteoblast cells; and adding an anticancer drug to the osteoblast cells such that the bone matrix produced by the osteoblast cells is embedded with the anticancer drug.
  • MSCs mesenchymal stem cells
  • the skeletal material is obtained from corals, sea urchins hydrocorals or any combination thereof. According to some embodiments, the skeletal material is obtained from corals of the species Millepora dichotama.
  • the matrix has pores with a pore size of 100-250 ⁇ m.
  • the osteoblast cells are autologous to the patient.
  • the anticancer drug is selected from the group consisting of: Cabozantinib, Docetaxel (DTX), Bortezmib, Neratinib, Nintedanib, Denosumab, Herceptin or any combination thereof.
  • the matrix further comprises a medicament capable of preventing loss of bone density and/or capable of inducing bone growth/ bone regeneration.
  • the medicament is a bisphosphonate and/or a bone morphogenetic protein (BMP).
  • the method further comprises coating, the matrix embedded with the anticancer drug with an outer coating configured to provide controlled release of the anti-cancer drug.
  • the outer coating comprises hyaluronic acid (HA).
  • Certain embodiments of the present disclosure may include some, all, or none of the above advantages.
  • One or more technical advantages may be readily apparent to those skilled in the art from the figures, descriptions and claims included herein.
  • specific advantages have been enumerated above, various embodiments may include all, some or none of the enumerated advantages.
  • FIG. 1 schematically illustrates the hereindisclosed method for preventing, ameliorating and/or treating bone cancer in particular secondary bone cancer, according to some embodiments
  • FIG. 2 Shows scanning electron micrograph (SEM) showing mineralization and fabrication of bone under laboratory conditions.
  • Mesenchymal stem cells (MSC) were seeded on top of biomaterial, following which they differentiated and precipitated bone crystals (hydroxyapatite).
  • FIG. 3 shows DIL and DIO membrane staining co-culture of MSCs (red) and cancer cells (green) growing on top of biomaterials;
  • FIG. 4 shows florescent staining of human calcein (red), demonstrating bone matrix formation by mesenchymal stem cells (DAPI) grown on a marine scaffold;
  • an element means one element or more than one element.
  • patient and “subject” may be used interchangeably and refer to human or other mammals suffering from bone cancer or bone metastases.
  • bone cancer and “primary bone cancer” may be used interchangeably and refer to cancers that start in the cells that make up the bone.
  • primary bone cancers include Ewing's sarcoma and osteosarcoma.
  • bone metastases metal-metastatic bone cancer
  • secondary bone cancer refer to cancer that has spread to the bones from where it started. The most common primary cancers spreading to the bone include prostate cancer, breast cancer, lung cancer, kidney cancer and thyroid cancer.
  • the secondary cancer can develop in any of the bones of the body including, but not limited to the skull, ribs, sternum, humerus, spine, pelvis, radius, ulna, femur, fibula and tibia bones. Most common sites include the spine, pelvis, thoracic bones and humerus bones.
  • the matrix may be synthetic. According to some embodiments, the matrix may made of or include a polymeric material.
  • the matrix may be bone like.
  • bone like refers a material resembling bone.
  • the bone-like material may be synthetically produced and may include natural and/or non-natural components.
  • the bone-like material may be biocompatible and/or biodegradable.
  • the bone-like material may be or include Osteocamp® by Bioventus®.
  • the bone bone-like material includes various combinations of collagen, bioactive glass, and calcium phosphate.
  • the collagen may be soluble or non-soluble.
  • the collagen may be or include type I collagen, type ⁇ collagen, type III collagen, type VII collagen, another suitable type of collagen, or a combination thereof. Each possibility is a separate embodiment.
  • the bone-like material includes about 15% to about 20% by weight collagen, about 55% to about 70% by weight bioactive glass, and about 15% to about 30% by weight a calcium phosphate.
  • the bioactive glass and the calcium phosphate together are about 80% to about 85% by weight of the bone-like material.
  • the bone-like material includes a collagen matrix and a plurality of bioactive glass particulates dispersed throughout the collagen matrix.
  • the collagen matrix is about 20% to about 60% by weight of the bone-like material
  • the bioactive glass is about 40% to about 80% of the bone-like material.
  • a majority of the bioactive glass particulates are about S3 ⁇ m to about 425 ⁇ m in size.
  • the collagen can be human, equine, bovine, porcine, murine, synthetic, or from another suitable source.
  • the collagen is in fibrillar form.
  • the collagen is not mineralized.
  • the collagen is uncompressed. In this manner, because the collagen is uncompressed, the bone-like material can also be characterized as being uncompressed.
  • the collagen matrix is in a flowable form.
  • Suitable flowable forms include a slurry, foam, gel, or paste. Each possibility is a separate embodiment.
  • the collagen matrix is a hardened, brittle, or otherwise dry cracker- like material.
  • the collagen matrix can be formed by drying the flowable collagen. At least a portion of the bioactive glass and/or the calcium phosphate can disposed (e.g., sprinkled or otherwise coated) onto a surface of the dried collagen matrix.
  • the collagen matrix is in a sponge-like or dough-likes forms.
  • the dried collagen matrix can be wetted with a suitable solution to form a sponge-like collagen matrix.
  • suitable solutions include, but are not limited to, blood, marrow, another bodily fluid, a simulated body fluid, saline, phosphate buffered saline, gel, or another biocompatible fluid, or any combination of the foregoing. Each possibility is a separate embodiment.
  • the collagen matrix includes a surface configured to receive bioactive glass and/or calcium phosphate, for example, in granular or particulate form.
  • the collagen matrix of the bone-like material is porous. At least a portion of the pores can be configured to permit in-growth of bone. In this manner, the collagen matrix, and thus the bone-like material may be osteoconductive.
  • the matrix may be a biomatrix.
  • the biomatrix may be derived, extracted, purified or otherwise obtained from a natural source. Each possibility is a separate embodiment.
  • the biomatrix may be bio-fabricated.
  • bio-fabricated refers to the production of complex living and non-living biological products from raw materials such as living cells, molecules, extracellular matrices, and biomaterials.
  • matrix As used herein, the terms “matrix”, “biomatrix”, “three dimensional biomatrix” and 3D biomatrix” refer to scaffolds for hard tissue (e.g. bone tissue) engineering.
  • hard tissue e.g. bone tissue
  • the term “embedded” when referring to the association of the anticancer drug (and/or other medicament) with the matrix refers to a direct association between the drug and the matrix such as absorption of the drug by the matrix, intercalation of the drug in the matrix or incorporation of the drug within pores of the matrix.
  • the drug may, in addition to being embedded in the matrix (i.e. in addition to being directly associated with the matrix), be incorporated into coatings or other materials associated with the matrix (i.e. being indirectly associated with the matrix).
  • the terms “treating”, “ameliorating” and “inhibiting progression” may be used interchangeably and refer to administering of (or a recommendation to administer) the hereindisclosed device in response to diagnosis of cancer in the bones (whether primary or secondary).
  • the administration of the device may, for example, be provided/recommended, based on a scan, such as, but not limited to, a PET-CT scan indicating presence of cancerous cells in the bone.
  • the terms “preventing” and “inhibiting development of” may be used interchangeably and refer to an administering of (or a recommendation to administer) the hereindisclosed device in response to diagnosis of a primary cancer prone to cause bone metastases. That is the administering of the device is independent of an actual diagnosis of cancerous cells in the bones although such cells may already be present in the bones, for example in a dormant state.
  • the terms “growth plate” refers to the epiphyseal plate or physis, and is the area of growing tissue near the ends of the long bones of children and adolescents. In adults, who have stopped growing, the plate is replaced by an epiphyseal line. According to some embodiments, the terms “growth plate”, “epiphyseal plate” and “epiphyseal line” may be used interchangeably.
  • a method for treating, ameliorating or inhibiting progression of bone cancer and/or bone metastases in a patient in need thereof comprising: positioning/implanting a three-dimensional matrix into a bone of a patient in an area thereof affected by the bone cancer; wherein the matrix is embedded with an anticancer drug; the anticancer drug configured to be gradually released from the matrix, thereby inhibiting growth and/or causing death of the cancer cells within the affected area; and wherein the matrix has an inherent ability to induce bone regeneration and/or to inhibit bone degeneration within the affected area.
  • the matrix is a biomatrix.
  • the biomatrix is a bio-fabricated biomatrix.
  • the positioning/implanting of the matrix comprises inserting the matrix through a diaphysis of the bone to the dedicated area, the dedicated area being spongy bone.
  • the area of implantation is in part of the spongy bone being in proximity to (e.g. at a distance of less than 5 cm, less than 3 cm or less than 2cm or including the growth-plate of the bone.
  • the area of insertion/implanting may be determined based on an obtained scan (e.g. PET-CT scan) of the bone.
  • the method may further include a step of scanning the bone (e.g. PET-CT scanning) the bone to determine an optimal site of implantation.
  • the method may be prophylactic, i.e. directed to preventing the development of bone metastases in patients suffering from a cancer susceptible to develop bone metastases.
  • the bone into which the matrix is implanted may be determined based on a skilled “guess” e.g. based on statistics of cancer spread, the location of the primary tumor, the patient's medical history or any combination thereof. Each possibility is a separate embodiment.
  • the bone into which the matrix is implanted is a long bone.
  • the bone into which the matrix is implanted is a femur bone (leg bone), a rib, pelvis bone (hip bone), a humerus bone (arm bone) or any combination thereof.
  • leg bone a femur bone
  • hip bone pelvis bone
  • humerus bone arm bone
  • the decision whether a prophylactic implantation should be performed may depend on the type of cancer and its likelihood to develop bone metastases.
  • pulmonary, breast, cervical, prostate and gastric cancers which are the most common malignant tumors, often develop into bone metastases.
  • a preferred site of prophylactic implantation may be determined according to the type of primary cancer.
  • Tumor cells spread to the bones mainly by hematogenous metastasis; however, the mechanisms underlying bone metastasis in pulmonary and prostate cancers are different. Specifically, pulmonary cancer cells metastasize to bones mainly by pulmonary veins, whereas prostate cancer cells spread to bones mainly via the vertebral venous system. The different routes of metastasis can produce different distribution features of bone metastases.
  • patients with head and neck tumors had been found to have a higher incidence of cervical spine metastasis than other patients; patients with thorax tumors had been found to have a higher incidence of thoracic bone metastasis than other patients; and patients with pelvic tumors had been found to have a higher incidence of pelvis bone metastasis than other patients.
  • cervical spine or thoracic bones had been found to be more frequently involved in patients with primary tumors above the diaphragm than those below the diaphragm, whereas lumbar spine or pelvis bones have been found to be more frequently metastasized in patients with primary tumors below the diaphragm than those above the diaphragm.
  • a large percentage of patients with breast cancer and lung cancer develop thoraic metastases.
  • a preferred site of prophylactic implantation may be the vertebrae, pelvis bones, thoracic bones or bones of the extremities (e.g. femur bones or humerus bones) or the skull.
  • the inserting/implanting comprises introducing the matrix through a sleeve that forms a channel from a periosteum of the bone to the affected area.
  • Introducing the matrix through the periosteum is advantageous, since this area of the bone readily undergoes remodelling at the end of the procedure. This as in contrast to cartilage, the reconstruction of which is complicated.
  • introducing the matrix through the periosteum reduces the load bearing and friction that would be inevitable if introduced via joint-cartilage fixation.
  • the sleeve may be permanently or temporarily implanted.
  • the term “permanently” refers to the sleeve being implanted for the entire duration of the patient's treatment and/or until the patient is determined cured.
  • the term “temporarily” refers to the sleeve being implanted for at least 1 month, at least two months, at least 6 months or at least one year, but not necessarily for the entire duration of the patient's treatment.
  • the temporal implantation may refer to the time passing before natural and/or osteoclast induced degradation of the matrix takes place.
  • the method includes retrieving the matrix through the sleeve, for example to enable examination of cells adhered thereto.
  • the method includes replacing the matrix.
  • the replacing may include retrieving a previously inserted/implanted matrix.
  • the replacing comprises inserting/implanting an additional matrix into the area by delivering it through the sleeve.
  • Adding an additional matrix may, for example, be necessary if the previously implanted matrix is degraded (e.g. due to the activity of osteoclasts).
  • adding an additional matrix may, for example, be required and/or desired if the anti-cancer drug was released in its entirety (or to its maximum extent) from the previously added matrix, while continuation of the treatment is still necessary and/or desired.
  • it may still be desired to leave the previously implanted matrix within the area due to it serving as a scaffold around which new bone has been or is being generated.
  • the sleeve may be made from stainless-steel, titanium, okolon, corals or any other biocompatible material of choice. Each possibility is a separate embodiment.
  • the sleeve maybe in a shape of a screw enabling the sleeve to be screwed through the diaphysis of the bone.
  • the screw may be formed with or attachable to a pipe, such as but not limited to a flexible pipe configured to allow additional doses of cancer drug to be delivered to the biomatrix.
  • the proximal end of the sleeve may include a cap, cover, lid or other means for closing off the open end of the sleeve.
  • the method may include removing the cap prior to delivery/retrieval of the biomatix and/or closing the cap after delivery/retrieval of the matrix.
  • the matrix is sized and shaped to confine it at an optimal depth and angle within the spongy bone, which allows optimal release of the embedded anti-cancer drug as well as correct/optimal bone regeneration.
  • the biomatrix maybe have a shape of a screw enabling it to be screwed through the diaphysis of the bone.
  • the biomatrix may be formed with or attachable to a pipe/sleeve, such as but not limited to a flexible pipe, configured to allow additional doses of cancer drug to be delivered to the biomatrix
  • optimal positioning and confining of the matrix within an affected area comprises positioning the matrix at an optimal depth and angle by tight fitting, such that mechanical stress is sufficient to orient the matrix optimally.
  • the positioning is via a specific extension or protrusion of the matrix, which anchors the matrix at the desired site/location.
  • the term “angle” refers to a position of the matrix relative to its periosteum.
  • the matrix may be positioned parallel to the periosteum, in which case the angle would be 0 degrees.
  • the matrix may be positioned perpendicularly to the periosteum in which case the angle would be 90 degrees.
  • the angle may be equal to or less than 10 degrees.
  • the angle may be equal to or less than 35 degrees.
  • the angle may be equal to or less than 55 degrees.
  • the angle may be equal to or less than 75 degrees.
  • the angle may be equal to or less than 95 degrees.
  • the angle may be equal to or less than 115 degrees. According to some embodiments, the angle may be equal to or less than 125 degrees. According to some embodiments, the angle may be equal to or less than 145 degrees. According to some embodiments, the angle may be equal to or less than 165 degrees. According to some embodiments, the angle may be equal to or less than 180 degrees.
  • the method comprises inserting/implanting more than one matrix, e.g. 2, 3, 4, 5 or more matrices.
  • the optimal number of matrices to be implanted may be determined according to the desired concentration of the drug desired, the size/extent of metastasis and/or the degree of bone degeneration. Each possibility is a separate embodiment.
  • the site of implantation may be a 3 -dimensional (3-D) space at or proximal to affected area.
  • the positioning optimizes access to blood vessels and bone marrow, most proximal to the affected area.
  • the matrix may be shaped prior to use. According to some embodiments, the matrix may be shaped during use. According to some embodiments, the matrix may be shaped based on an obtained scan of the desired site of implantation, thus ensuring that the dimensions of the matrix fit as precisely as possible to the site of implantation.
  • the matrix approximates the form of a cylinder, cone, tac, pin, screw, rectangular bar, plate, disc, pyramid, granule, powder, coral sand, ball, bone, condyle, rib, vertebra or cube. Each possibility is a separate embodiment.
  • the matrix is in the form of a hollow cylinder.
  • the matrix is in the form of a non-hollow cylinder.
  • the matrix approximates a shape which accommodates a site of desired implantation.
  • the size of the matrix will be on a millimeter scale, for example, having at least one long axis of about 2-200 mm, or about 1-18 mm, or about 0.5mm-3 mm, or about 6-12 mm, about 10-15 mm, or about 12-40 mm, or about 30-100 mm, or about 50- 150 mm, or about 100-200 mm.
  • the size of the matrix may be about the same as or larger than a tissue void at the site of implantation. This tissue void may be due to a bone degermation caused by the cancerous cells or may be created artificially prior to implantation.
  • the matrix comprises pores.
  • the average pore size may bel ⁇ m-1 mm, or 30-180 ⁇ m, or 50-500 ⁇ m, or 150-220 ⁇ m, or 250-1000 ⁇ m. Each possibility is a separate embodiment.
  • the matrix comprises skeletal material of marine origin, the skeletal material comprising calcite and/or aragonite.
  • the skeletal material is obtained from corals, sea urchins, hydrocorals or any combination thereof. Each possibility is a separate embodiment.
  • skeletal material is obtained from coral of any one or more of the following species: Favites halicora; Goniastrea retiformis; Acanthastrea echinata; Acanthastrea hemprichi; Acanthastrea ishigakiensis; Acropora aspera; Acropora austera; Acropora sp. “brown digitate Acropora carduus; Acropora cerealis ; Acropora leyfieldensis; Acropora clathrata; Acropora cophodactyla; Acropora sp.
  • the skeletal material is obtained and/or isolated from corals of the species Porites, Acropora, Millepora or any combination thereof. Each possibility is a separate embodiment. According to some embodiments, the skeletal material is obtained and/or isolated from corals of the species Millepora dichotama. According to some embodiments, the skeletal material is obtained and/or isolated from a barnacle, mollusc, bone, ivory, dentin or any combination thereof. Each possibility is a separate embodiment.
  • skeletal material of marine origin such as corals, which is comprised of CaCO 3 in the crystalline form of calcite or aragonite, has the advantage of supporting fast cellular invasion, adherence, proliferation and differentiation of mesenchymal stem cells into cartilage tissue.
  • three-dimensional (3-D) coral scaffolds attract mesenchymal stem cells from bone marrow and promote blood vessel formation to a site of cartilage repair.
  • Such scaffolds can be used for regeneration of cartilage in a subject for repair of partial or full-thickness cartilage defects.
  • the matrix further comprises mesenchymal stem cells (MSCs) and/or osteoblast cells. This may advantageously further promote bone growth at the area of implantation of the matrix.
  • MSCs mesenchymal stem cells
  • the matrix comprising skeletal material of marine origin such as corals
  • the matrix comprising skeletal material of marine origin may be produced according to a process comprising washing naturally occurring skeletal material with water to desalinate it, then disinfecting and drying the desalinated skeletal material at temperatures of about 80° to about 150° C., preferably 90° to 120° C., and grinding the disinfected and dried skeletal material into small particles, which in one embodiment comprise particles of 1-10 ⁇ m.
  • coral is ground into particles of 1-5, 1-20, 1-50, 1- 100, 5-10, 10-15, 15-20, 10-50, 10-100, 20-100, 50-100, 80-150, 100-200, 100-350 or 150-500 ⁇ m. Each possibility is a separate embodiment.
  • the anti -cancer drug may be embedded within and/or incorporated into the marine skeletal matrix by immersing the marine skeletal matrix in a solution containing the anticancer drug thereby facilitating its absorption into the marine skeletal matrix.
  • the method further includes a preliminary step of immersing the marine skeletal matrix in a solution containing the anticancer drug under conditions allowing absorption of the drug within the matrix.
  • the method further comprises applying negative pressure to the matrix when immersed to promote maximal uptake of the solution and/or the anticancer drug within the matrix.
  • the method further comprises exposing the matrix to a cold plasma treatment, a corona treatment, or a combination thereof, thereby increasing the uptake of the matrix.
  • the solution comprises an autologous or allogeneic fluid with respect to a cell or tissue of a subject.
  • the solution comprises water, saline and/or cell growth media. Each possibility is a separate embodiment.
  • the matrix may (instead of or in addition to the skeletal material of marine origin) include or be made of bone matrix.
  • the bone matrix may be produced by osteoblast cells, preferably osteoblast cells autologous to the patient.
  • the method further includes the preliminary steps of obtaining mesenchymal stem cells (from the patient or from another compatible human source). Differentiating the mesenchymal stem cells into bone producing osteoblast cells, growing the osteoblast cells until a bone-matrix of suitable size is obtained and retrieving/preparing the bone matrix for implantation.
  • the growing of the osteoblast cells comprises growing them in growth media containing the anticancer drug (at a suitable and predetermined concentration), such that the anti-cancer drug becomes embedded within/incorporated into the bone matrix during its production/generation.
  • the anti-cancer drug may be embedded within and/or incorporated into the bone matrix by immersing the bone matrix in a solution containing the anticancer drug, thereby facilitating its absorption into the bone matrix.
  • the method further includes a preliminary step of immersing the bone matrix in a solution containing the anticancer drug under conditions allowing absorption of the drug within the bone matrix.
  • the anticancer drug may be selected from the group consisting of: Cabozantinib, Docetaxel (DTX), Bortezmib, Neratinib, Nintedanib, Denosumab, Hercepdn or any combination thereof. Each possibility is a separate embodiment.
  • the matrix further includes a medicament capable of preventing loss of bone density and/or capable of inducing bone growth/ bone regeneration.
  • the medicament is a bisphosphonate and/or a bone morphogenetic protein (BMP).
  • the matrix comprises a polymer coating.
  • the polymer coating may be configured to strengthens the matrix, control the release of the anti-cancer drug and/or enhance bone regeneration. Each possibility is a separate embodiment.
  • the polymer coating may be permeable.
  • the polymer coating comprises a special porous membrane.
  • the term “permeable” refers to having pores and openings.
  • the polymer coating has pores and openings which allow entry of nutrients, a therapeutic compound, a cell population, a chelator, or a combination thereof.
  • the polymer coating has pores and openings which allow exit/release of nutrients, a therapeutic compound, a cell population, a chelator, or a combination thereof and/or blood vessels formation. Each possibility is a separate embodiment.
  • the polymer coating may be discontinuous thereby providing areas allowing direct contact between the matrix and the environment.
  • the polymer coating may be a film, may take on the form of discontinuous particles and/or aggregates or a combination thereof.
  • the polymer coating comprises a natural polymer comprising, collagen, elastin, silk, hyaluronic acid, chytosan, and any combinations thereof. Each possibility is a separate embodiment.
  • the polymer coating comprises synthetically modified natural polymers, and may include cellulose derivatives such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocelluloses, and chitosan.
  • suitable cellulose derivatives include methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate and cellulose sulfate sodium salt.
  • cellulose derivatives such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocelluloses, and chitosan.
  • suitable cellulose derivatives include methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl
  • the polymer coating comprises a synthetic biodegradable polymer.
  • the synthetic biodegradable polymer comprises alpha- hydroxy acids including poly-lactic acid, polyglycolic acid, enantioners thereof, co-polymers thereof, polyorthoesters, and combinations thereof. Each possibility is a separate embodiment.
  • the polymer coating is a poly(cianoacrylate), poly(alkyl- cianoacrylate), poly(ketal), poly(caprolactone), poly(acetal), poly(a-hydroxy-ester), poly(a- hydroxy-ester), poly(hydroxyl-alkanoate), poly(propylene-fumarate), poly (imino-carbonate), poly(ester), poly(ethers), poly(carbonates), poly(amide), poly(siloxane), poly(silane), poly(sulfide), poly(imides), poly(urea), poly(amide-enamine), poly(organic acid), poly(electrolytes), poly(p-dioxanone), poly(olefin), poloxamer, inorganic or organometallic polymers, elastomer, or any of their derivatives, or a copolymer obtained by a combination thereof.
  • the polymer coating comprises poly(D,L-lactide-co- glycolide) (PLGA). According to some embodiments, the polymer coating comprises poly(D,L- lactide) (PLA). According to some embodiments, the polymer coating comprises poly(D,L- glycolide) (PGA). According to some embodiments, the polymer coating comprises a glycosaminoglycan. Each possibility is a separate embodiment.
  • the polymer coating comprises synthetic degradable polymers, which may include, but are not limited to polyhydroxy acids, such as poly(lactide)s, poly(glycolide)s and copolymers thereof; poly(ethylene terephthalate); poly(hydroxybutyric acid); poly(hydroxyvaleric acid); poly [lactide-co-(e-caprolactone)] ; poly [glycolide-co(e-caprolactone)] ; poly(carbonate)s, poly(pseudo amino acids); poly(amino acids); poly(hydroxyalkanoate)s; poly(anhydrides); poly(ortho ester)s; and blends and copolymers thereof.
  • polyhydroxy acids such as poly(lactide)s, poly(glycolide)s and copolymers thereof
  • poly(ethylene terephthalate) poly(hydroxybutyric acid); poly(hydroxyvaleric acid); poly [lactide-co-(e-caprolactone)] ; poly [glycoli
  • the polymer coating comprises proteins, such as, but not limited to: zein, modified zein, casein, gelatin, gluten, serum albumin, collagen, actin, a- fetoprotein, globulin, macroglobulin, cohesin, laminin, fibronectin, fibrinogen, osteocalcin, osteopontin, osteoprotegerin.
  • proteins such as, but not limited to: zein, modified zein, casein, gelatin, gluten, serum albumin, collagen, actin, a- fetoprotein, globulin, macroglobulin, cohesin, laminin, fibronectin, fibrinogen, osteocalcin, osteopontin, osteoprotegerin.
  • the polymer coating may comprise cyclic sugars, cyclodextrins, synthetic derivatives of cyclodextrins, glycolipids, glycosaminoglycans, oligosaccharide, polysaccharides such as alginate, carrageenan ( ⁇ , ⁇ , ⁇ , ⁇ ) chitosane, celluloses, condroitin sulfate, curdlan, dextrans, elsinan, furcellran, galactomannan, gellan, glycogen, arabic gum, hemicellulose, inulin, karaya gum, levan, pectin, pollulan, pullulane, prophyran, scleroglucan, starch, tragacanth gum, welan, xanthan, xylan, xyloglucan, hyaluronic acid, chitin, or a poly(3-hydroxyalkanoate)s, such as poly( ⁇ -hydroxybutyrate), poly(
  • the polymer coating comprises a bioerodible polymer such as poly(lactide-co-glycolide)s, poly(anhydride)s, and poly(orthoester)s, which have carboxylic groups exposed on the external surface as the smooth surface of the polymer erodes, which may also be used.
  • the polymer coating contains labile bonds, such as polyanhydrides and polyesters.
  • the polymer coating may comprise chemical derivatives thereof (substitutions, additions, and elimination of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), blends of, e.g. proteins or carbohydrates alone or in combination with synthetic polymers.
  • chemical derivatives thereof substitutions, additions, and elimination of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art
  • the polymer coating is biodegradable.
  • biodegradable or grammatical forms thereof, refers to a material of this invention, which is degraded in the biological environment of the subject in which it is found.
  • the biodegradable material undergoes degradation, during which, acidic products, or in another embodiment, basic products are released.
  • bio- degradation involves the degradation of a material into its component subunits, via, for example, digestion, by a biochemical process.
  • biodegradation may involve cleavage of bonds (whether covalent or otherwise), for example in a polymer backbone of this invention.
  • biodegradation may involve cleavage of a bond (whether covalent or otherwise) internal to a side-chain or one that connects a side chain to, for example, a polymer backbone.
  • a side-chain or one that connects a side chain to, for example, a polymer backbone.
  • the matrix is covalently associated with the polymer coating via the use of a cross-linking agent.
  • cross-linking agent refers to an agent which facilitates the formation of a covalent bond between two atoms.
  • FIG. 1 schematically illustrates the hereindisclosed method for preventing, ameliorating and/or treating bone cancer, in particular, secondary bone cancer, according to some embodiments.
  • the method includes forming an access channel leading from outside the bone to the affected area (the desired site of implantation).
  • Forming the channel may include drilling through the periosteum of the bone along the diaphysis, until reaching and/or entering an area of the spongy bone including or being proximal to the affected area/desired site of implantation.
  • the desired site of implantation may be determined based on a bone scan obtained from the patient or based on an assumption/prior knowledge e.g. in proximity to a growth plate of the bone.
  • the biomatrix implanted is preferably embedded or otherwise associated with an anticancer drug.
  • the anticancer drug may initially be delivered at a burst concentration, whereafter an additional drug is gradually released.
  • Such differential release may, for example, be achieved through differential coating of the biomatrix or through differential association with the biomatrix.
  • the anticancer drug may be gradually released from the biomatrix at an essentially constant release rate.
  • the release rate of the anticancer drug is a result of degradation of the biomatrix, either naturally and/or as a result of the activity of osteoclasts within the affected area.
  • the release of the anticancer drug causes inhibition in the growth and/or death of cells in the affected area.
  • the anticancer drug may selectively inhibit and/or cause death of the cancer cells by targeting cancer specific markers.
  • the method further includes retrieving the biomatrix, through the sleeve, for example, in order to analyse the cells adhered to the matrix.
  • the method further includes replacing the biomatrix with a new biomatrix, for example, once the release of the anticancer drug has been exhausted.
  • the method further includes adding/delivering an additional biomatrix, for example, due to the previously implanted biomatrix being degraded.
  • Colonies of M. dichotoma were collected from shallow seawater zones adjacent to the Interuniversity Institute of Marine Science (IUI) in Eilat, Israel, at depths of 6-8 meters. Porites lutea were prepared from cores drilled out from long-lived massive colonies. Each colony was cut into fragments and glued with epoxy resin into the tops of PVC tubes. After an adjustment period of 3 months, cloned fragments were transferred to a laboratory tank system. Skeletons were cut to size and bleached with a commercial hypochlorite solution. After this preliminary cleaning process, samples were rinsed with distilled water and dried in air.
  • IUI Interuniversity Institute of Marine Science
  • Pieces 0.5 mm thick and approximately 0.5 cm 2 in area were polished using an 8" grinder (SBT 900, BIOACTVE CRYSTALLINE MATERIAL PROMOTING OSSIFICATION OF MSCS, South Bay Technologies, San Clemente, CA).
  • Analytical H 2 O 2 solution (Gerdrogen 30% by weight; Riedel- de Haen, Germany) was used to remove organic residues from the scaffold. The samples were autoclaved (121°C, 40 min) and oven dried overnight at 80°C.
  • DMEM Dulbecco modified Eagle's medium
  • DMEM Dulbecco modified Eagle's medium
  • fetal calf serum fetal calf serum
  • L-Glutamin fetal calf serum
  • Pen-Strep-Nystatin solution All from Biological Industries, Beit Haeemek, Israel. No osteo-inducing supplements were added.
  • Cell cultures were incubated in a humidified atmosphere of 5% CO2 at 37°C. The medium was replaced every 2 days.
  • FIG. 2 shows a scanning electron micrograph (SEM) image of mineralization and fabrication of bone crystals (hydroxyapatite) on the marine skeletal matrix.
  • metastatic bone cancer cells added to the cell culture, readily adhered to the bone matrix (as indicated by arrows) in a manner resembling their adherence in vivo.
  • the cells were imaged using florescent microscopy which clearly showed fluorescent emission from within the cells, demonstrating uptake by the cells of calcium (seen in red) from the biomaterial (DAPI staining in blue confirmed the overlap of calcein and the cells (FIG. 4).

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Abstract

L'invention concerne une biomatrice tridimensionnelle incorporée avec un médicament anticancéreux et ayant une capacité inhérente d'induire une régénération osseuse et/ou d'inhiber la dégénérescence osseuse et ses utilisations pour le traitement, l'amélioration ou l'inhibition de la progression du cancer des os et/ou des métastases osseuses.
PCT/IL2020/051364 2020-01-02 2020-12-31 Procédé et dispositifs pour le traitement de métastases osseuses Ceased WO2021137236A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070198023A1 (en) * 1997-08-13 2007-08-23 Kyphon Inc. Systems and methods for injecting flowable materials into bones
US20090324683A1 (en) * 2008-03-25 2009-12-31 Evans Bruce G Controlled release tissue graft combination biomaterials
US20110200563A1 (en) * 2007-11-19 2011-08-18 Razi Vago Calcium-mediated effects of coral and methods of use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070198023A1 (en) * 1997-08-13 2007-08-23 Kyphon Inc. Systems and methods for injecting flowable materials into bones
US20110200563A1 (en) * 2007-11-19 2011-08-18 Razi Vago Calcium-mediated effects of coral and methods of use thereof
US20090324683A1 (en) * 2008-03-25 2009-12-31 Evans Bruce G Controlled release tissue graft combination biomaterials

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DIAZ-RODRIGUEZ PATRICIA, LÓPEZ-ÁLVAREZ MIRIAM, SERRA JULIA, GONZÁLEZ PÍO, LANDÍN MARIANA: "Current stage of marine ceramic grafts for 3D bone tissue regeneration", MARINE DRUGS, vol. 17, no. 471, 15 August 2019 (2019-08-15), pages 1 - 16, XP055838651 *
VALLET-REGÍ MARÍA, RUIZ-HERNÁNDEZ EDUARDO: "Bioceramics: from bone regeneration to cancer nanomedicine", ADVANCED MATERIALS, vol. 23, no. 44, 18 October 2011 (2011-10-18), pages 5177 - 5218, XP055838642 *

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