Compositions for regenerating defective or absent myocardium

• US 9,289,532 B2
• Filed: 02/28/2014
• Issued: 03/22/2016
• Est. Priority Date: 07/15/2005
• Status: Active Grant

• Current Assignee: Cormatrix Cardiovascular, Inc.
• Original Assignee: Cormatrix Cardiovascular, Inc.
• Inventors: Matheny, Robert G
• Primary Examiner(s): Gamett, Daniel C
• Application Number:
  US14/192,992
• Publication Number:
  US 20150246160A1
• Time in Patent Office: 753 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/726 Glycosaminoglycans, i.e. mucopolysaccharides chondroitin sulfate, dermatan sulfate A61K31/737
• CPC Class Codes: A61K 35/22 Urine; Urinary tract, e.g. kidney or bladder; Intraglomerular mesangial cells; Renal mesenchymal cells; Adrenal gland
• CPC Class Codes: A61K 35/34 Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes vascular smooth muscle A61K35/44
• CPC Class Codes: A61K 35/37 Digestive system
• CPC Class Codes: A61K 35/38 Stomach; Intestine; Goblet cells; Oral mucosa; Saliva
• CPC Class Codes: A61K 35/407 Liver; Hepatocytes
• CPC Class Codes: A61K 35/50 Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
• CPC Class Codes: A61K 35/545 Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
• CPC Class Codes: A61K 38/1741 alpha-Glycoproteins
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61L 2300/412 Tissue-regenerating or healing or proliferative agents
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 2300/64 Animal cells
• CPC Class Codes: A61L 2400/06 : Flowable or injectable implant compositions
• CPC Class Codes: A61L 2430/20 : for reconstruction of the heart, e.g. heart valves
• CPC Class Codes: A61L 2430/30 : for muscle reconstruction
• CPC Class Codes: A61L 27/227 : Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61L 27/3629 : Intestinal tissue, e.g. small intestinal submucosa
• CPC Class Codes: A61L 27/3633 : Extracellular matrix [ECM]
• CPC Class Codes: A61L 27/367 : Muscle tissue, e.g. sphincter
• CPC Class Codes: A61L 27/3683 : subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• CPC Class Codes: A61L 27/3687 : characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
• CPC Class Codes: A61L 27/3804 : characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• CPC Class Codes: A61L 27/3834 : Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
• CPC Class Codes: A61L 27/3873 : Muscle tissue, e.g. sphincter
• CPC Class Codes: A61L 27/40 : Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
• CPC Class Codes: A61L 27/54 : Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/58 : Materials at least partially resorbable by the body

Abstract

Compositions of the invention for regenerating defective or absent myocardium comprise an emulsified or injectable extracellular matrix composition. The composition may also include an extracellular matrix scaffold component of any formulation, and further include added cells, proteins, or other components to optimize the regenerative process and restore cardiac function.

Claims

1. An injectable graft composition for myocardial tissue regeneration, said composition comprising acellular extracellular matrix (ECM) from a mammalian tissue source comprising intestine small submucosa, said ECM comprising endogenous proteoglycans, transforming growth factor-beta (TGF-β

), and vascular endothelial growth factor (VEGF), said ECM further comprising an exogenously added fibroblast growth factor-2 (FGF-2) and cytokine, said FGF-2 comprising greater than 0.1% by weight of said composition, said FGF-2 being linked to a molecule in said ECM, wherein said FGF-2 interacts with said proteoglycans to control and enhance matrix formation and remodeling, wherein, when said composition is administered to damaged cardiovascular tissue, said composition induces stem cell proliferation and differentiation of stem cells into cardiomyocytes.

2. An injectable composition for myocardial tissue regeneration, said composition comprising acellular extracellular matrix (ECM) from a mammalian tissue source comprising urinary bladder submucosa, said ECM comprising endogenous proteoglycans, transforming growth factor beta (TGF-β

), and vascular endothelial growth factor (VEGF), said ECM further comprising an exogenously added fibroblast growth factor-2 (FGF-2) and cytokine, said FGF-2 comprising greater than 0.1 wt. % of said composition, said FGF-2 being linked to said ECM, wherein said FGF-2 saturates available fibroblast cell receptors from the ECM to cells and interacts with said proteoglycans to control and enhance matrix formation and remodeling, wherein, when said composition is administered to damaged cardiovascular tissue, said composition induces stem cell proliferation and differentiation of stem cells into cardiomyocytes.

3. An injectable graft composition for myocardial tissue regeneration, said composition comprising acellular extracellular matrix (ECM) from a mammalian tissue source comprising stomach submucosa, said ECM comprising native proteoglycans, transforming growth factor-beta (TGF-β

), and vascular endothelial growth factor (VEGF), said ECM further comprising an exogenously added bioactive component comprising a fibroblast growth factor-2 (FGF-2), said FGF-2 comprising greater than 0.1% by weight of said composition, said FGF-2 being linked to a molecule in said ECM, wherein said FGF-2 interacts with said proteoglycans to control and enhance matrix formation and remodeling, wherein, when said composition is administered to damaged cardiovascular tissue, said composition induces stem cell proliferation and differentiation of stem cells into cardiomyocytes.

4. The composition of claim 3, wherein said composition further comprises an exogenously added cytokine.

5. An injectable graft composition for myocardial tissue regeneration, said composition comprising acellular extracellular matrix (ECM) from a mammalian tissue source comprising liver basement submucosa, said ECM comprising native proteoglycans, transforming growth factor-beta (TGF-β

), and vascular endothelial growth factor (VEGF), said ECM further comprising an exogenously added bioactive component comprising a fibroblast growth factor-2 (FGF-2), said FGF-2 comprising greater than 0.1% by weight of said composition, said FGF-2 being linked to a molecule in said ECM, wherein said FGF-2 interacts with said proteoglycans to control and enhance matrix formation and remodeling, wherein, when said composition is administered to damaged cardiovascular tissue, said composition induces stem cell proliferation and differentiation of stem cells into cardiomyocytes.

6. The composition of claim 5, wherein said composition further comprises an exogenously added cytokine.

7. An injectable graft composition for myocardial tissue regeneration, said composition comprising acellular extracellular matrix (ECM) from a mammalian tissue source comprising liver basement membrane, said ECM comprising native proteoglycans, transforming growth factor-beta (TGF-β

), and vascular endothelial growth factor (VEGF), said ECM further comprising an exogenously added bioactive component comprising a fibroblast growth factor-2 (FGF-2), said FGF-2 comprising greater than 0.1% by weight of said composition, said FGF-2 being linked to a molecule in said ECM, wherein said FGF-2 interacts with said proteoglycans to control and enhance matrix formation and remodeling, wherein, when said composition is administered to damaged cardiovascular tissue, said composition induces stem cell proliferation and differentiation of stem cells into cardiomyocytes.

8. The composition of claim 7, wherein said composition further comprises an exogenously added cytokine.

9. An injectable graft composition for myocardial tissue regeneration, said composition comprising acellular placental extracellular matrix (ECM), said ECM comprising native proteoglycans, transforming growth factor-beta (TGF-β

), and vascular endothelial growth factor (VEGF), said ECM further comprising an exogenously added bioactive component comprising a fibroblast growth factor-2 (FGF-2), said FGF-2 comprising greater than 0.1% by weight of said composition, said FGF-2 being linked to a molecule in said ECM, wherein said FGF-2 interacts with said proteoglycans to control and enhance matrix formation and remodeling, wherein, when said composition is administered to damaged cardiovascular tissue, said composition induces stem cell proliferation and differentiation of stem cells into cardiomyocytes.

10. The composition of claim 9;

wherein said composition farther comprises an exogenously added cytokine.

11. An injectable graft composition for myocardial tissue regeneration, said composition comprising acellular heart extracellular matrix (ECM), said ECM comprising native proteoglycans, transforming growth factor-beta (TGF-β

), and vascular endothelial growth factor (VEGF), said ECM further comprising an exogenously added bioactive component comprising a fibroblast growth factor-2 (FGF-2), said FGF-2 comprising greater than 0.1% by weight of said composition, said FGF-2 being linked to a molecule in said ECM, wherein said FGF-2 interacts with said proteoglycans to control and enhance matrix formation and remodeling, wherein, when said composition is administered to damaged cardiovascular tissue, said composition induces stem cell proliferation and differentiation of stem cells into cardiomyocytes.

12. The composition of claim 11, wherein said composition further comprises an exogenously added cytokine.