Injectable microspheres for tissue construction

• US 20030211083A1
• Filed: 12/12/2002
• Published: 11/13/2003
• Est. Priority Date: 03/15/2001
• Status: Active Grant

• Current Assignee: Biosphere Medical Inc. (Merit Medical Systems, Inc.)
• Original Assignee: Biosphere Medical Inc. (Merit Medical Systems, Inc.)
• Inventors: Vogel, Jean-Marie, Boschetti, Egisto
• Granted Patent: US 7,338,657 B2
• Time in Patent Office: Days
• US Class Current: 424/93.7
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• 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 35/36 Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells islets of Langerhans A61K35/39
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 2533/30 Synthetic polymers
• CPC Class Codes: C12N 5/0075 using microcarriers

Abstract

The present invention relates to injectable compositions comprising biocompatible, hydrophilic, non-toxic and substantially spherical microspheres associated with stem cells useful for tissue construction and generation. The invention also relates to methods of tissue construction and generation, for the treatment of various tissue damage and defects, using the injectable compositions.

Claims

1. An injectable composition suitable for tissue construction and generation in a mammal which comprises biocompatible, hydrophilic, non-toxic and substantially spherical microspheres associated with stem cells and a biocompatible carrier, wherein said composition is injectable through needles of about 18 to about 26 gauge and said microspheres are not capable of being displaced, or eliminated by the lymphatic system.

2. The composition of claim 1, wherein the stem cells are mesenchymal stem cells isolated from bone marrow, muscle tissues, dermis, or combinations thereof.

3. The composition of claim 1, wherein the microspheres have diameters ranging from about 10 μ

m to about 500 μ

m before injection.

4. The composition of claim 3, wherein the microspheres have diameters ranging from about 40 μ

m to about 300 μ

m before injection.

5. The composition of claim 4, wherein the microspheres have diameters ranging from about 100 μ

m to about 300 μ

m before injection.

6. The composition of claim 1, wherein the composition comprises the microspheres in an amount from about 10% to about 90% by weight and the biocompatible carrier in an amount from about 10% to about 90% by weight.

7. The composition of claim 6, wherein the composition comprises the microspheres in an amount from about 10% to about 50% by weight and the biocompatible carrier in an amount from about 50% to about 90% by weight.

8. The composition of claim 1, wherein the composition is a suspension of said microspheres in said biocompatible carrier.

9. The composition of claim 1, wherein the biocompatible carrier is an emulsion.

10. The composition of claim 1, wherein the biocompatible carrier is organic or non-aqueous solvent.

11. The composition of claim 1, wherein the biocompatible carrier is an aqueous based solution, a hydro-organic solution, or mixtures thereof.

12. The composition of claim 1, wherein the biocompatible carrier is a medium suitable for mesenchymal stem cell culturing.

13. The composition of claim 1, wherein the microspheres swell upon contact with physiological fluids.

14. The composition of claim 1, wherein diameters of the microspheres after injection are about 1 to 4 times of diameters of the microspheres immediately prior to injection.

15. The composition of claim 1, wherein the microspheres comprise one or more elastomers.

16. The composition of claim 15, wherein the elastomers are selected from the group consisting of acrylic polymers, vinyl alcohol polymers, acrylate polymers, polysaccharides, silicones, and mixtures thereof.

17. The composition of claim 1, wherein the microspheres are swellable and comprise polymers selected from the group consisting of sodium acrylate polymer, acrylamide polymer, acrylamide derivative polymer or copolymer, sodium acrylate and vinyl alcohol copolymer, vinyl acetate and acrylic acid ester copolymer, vinyl acetate and methyl maleate copolymer, isobutylene-maleic anhydride crosslinked copolymer, starch-acrylonitrile graft copolymer, crosslinked sodium polyacrylate polymer, and crosslinked polyethylene oxide.

18. The composition of claim 1, wherein the composition is biodegradable.

19. The composition of claim 1, further comprises therapeutic agent, radiopacifying agent, contrast medium, or mixtures thereof.

20. The composition of claim 19, wherein said agents or medium are bound to the microspheres.

21. The composition of claim 19, wherein the therapeutic agent is anti-inflammatory agent.

22. The composition of claim 1, wherein the microspheres are capable of being chemically modified to have therapeutic effects, vascularization effects, anti-vascularization effects, visualization properties, anti-inflammatory effects, anti-bacterial effects, antihistamine effects, or combinations thereof.

23. A method of tissue construction and generation in a mammal comprising administering to said mammal a therapeutically effective amount of a composition of biocompatible, hydrophilic, non-toxic and substantially spherical microspheres associated with stem cells in a biocompatible carrier, wherein the composition is injectable through a needle of about 18 to about 26 gauge and the microspheres are not capable of being displaced, or eliminated by the immune system.

24. The method of claim 23, wherein the stem cells are mesenchymal stem cells isolated from bone marrow, muscle tissues, dermis, or combinations thereof.

25. The method of claim 23, wherein the administration comprises injecting said composition into the mammal.

26. The method of claim 23, wherein the tissue construction and generation is for the treatment of tissue defects in the mammal'"'"'s heart, coronary vessels, blood vessels, spinal cord, bone, cartilage, tendon, ligament, breast, liver, gallbladder, bile duct, pancreas, intestinal tissues, urinary system, skin, hernia, vocal cord, dental tissues, or combinations thereof.

27. The method of claim 23, wherein the mammal is a human.

28. The method of claim 23, wherein the administration comprises injecting said composition extracorporeally into organs, components of organs, or tissues prior to their inclusion into said mammal'"'"'s body, organs, or components of organs.

29. The method of claim 23, wherein the composition is injected directly into the site in need of tissue repair.