Immobilized bioactive hydrogel matrices as surface coatings

• US 20030232198A1
• Filed: 02/21/2003
• Published: 12/18/2003
• Est. Priority Date: 02/21/2002
• Status: Active Grant

• Current Assignee: Pioneer Surgical Technology Incorporated (Surgalign Holdings, Inc.)
• Original Assignee: Encelle, Inc. (Surgalign Holdings, Inc.)
• Inventors: Hill, Ronald Stewart, Klann, Richard Chris, Lamberti, Francis V.
• Granted Patent: US 7,303,814 B2
• Time in Patent Office: Days
• US Class Current: 428/423.1
• CPC Class Codes: A61F 2/0063 Implantable repair or support meshes, e.g. hernia meshes
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61L 2300/112 Phosphorus-containing compounds, e.g. phosphates, phosphonates
• CPC Class Codes: A61L 2300/412 Tissue-regenerating or healing or proliferative agents
• CPC Class Codes: A61L 2420/04 Coatings containing a composite material such as inorganic/organic, i.e. material comprising different phases
• CPC Class Codes: A61L 2420/06 Coatings containing a mixture of two or more compounds
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/025 Other specific inorganic materials not covered by A61L27/04 - A61L27/12
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/22 Polypeptides or derivatives thereof , e.g. degradation products
• CPC Class Codes: A61L 27/222 Gelatin
• CPC Class Codes: A61L 27/24 Collagen
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/3608 Bone, e.g. demineralised bone matrix [DBM], bone powder
• CPC Class Codes: A61L 27/446 with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
• CPC Class Codes: A61L 27/46 with phosphorus-containing inorganic fillers
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/10 : Macromolecular materials
• CPC Class Codes: A61P 19/00 : Drugs for skeletal disorders
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: B29C 39/003 : characterised by the choice of material
• CPC Class Codes: B29L 2031/7532 : Artificial members, protheses
• CPC Class Codes: C08L 5/02 : Dextran; Derivatives thereof
• CPC Class Codes: C08L 89/00 : Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00
• CPC Class Codes: Y10T 428/29 : Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
• CPC Class Codes: Y10T 428/2947 : Synthetic resin or polymer in plural coatings, each of different type
• CPC Class Codes: Y10T 428/31551 : Of polyamidoester [polyurethane, polyisocyanate, polycarbamate, etc.]
• CPC Class Codes: Y10T 428/31786 : Of polyester [e.g., alkyd, etc.]

Abstract

The present invention is directed to a stabilized bioactive hydrogel matrix coating for substrates, such as medical devices. The invention provides a coated substrate comprising a substrate having a surface, and a bioactive hydrogel matrix layer overlying the surface of the medical device, the hydrogel matrix comprising a first high molecular weight component and a second high molecular weight component, the first and second high molecular weight components each being selected from the group consisting of polyglycans and polypeptides, wherein at least one of the first and second high molecular weight components is immobilized (e.g., by covalent cross-linking) to the surface of the substrate.

Claims

1. A coated substrate, comprising:

a substrate having a surface; and

a bioactive hydrogel matrix layer overlying the surface of the substrate and immobilized thereon, the hydrogel matrix layer comprising a first high molecular weight component and a second high molecular weight component, the first and second high molecular weight components each being selected from the group consisting of polyglycans and polypeptides.

2. The coated substrate of claim 1, wherein the substrate is a medical device.

3. The coated substrate of claim 2, wherein the medical device is selected from the group consisting of active medical devices and passive medical devices.

4. The coated substrate of claim 2, wherein the medical device is selected from the group consisting of ex vivo bioreactors for liver, kidney or other organ support systems, catheters, artificial arteries, artificial organs, tissue fragment-containing devices, cell-containing devices, ligament replacements, bone replacements, glucose sensors, coronary pacemakers, lap-bands, monitors, artificial larynxes, prostheses, brain stimulators, bladder pacemakers, shunts, stents, tubes, defibrillators, cardioverters, heart valves, joint replacements, fixation devices, ocular implants, cochlear implants, breast implants, neurostimulators, bone growth stimulators, vascular grafts, muscle stimulators, left ventricular assist devices, pressure sensors, vagus nerve stimulators, drug delivery systems, sutures, staples, and cell scaffolding materials.

5. The coated substrate of claim 1, wherein the surface of the substrate is constructed of a material selected from the group consisting of acrylates, polyglycolic-polylactic acid copolymers, polyhydroxybutyrates, polyesters, expanded polytetrafluoroethylene (ePTFE), bioactive glass, ceramics, coralline materials, processed tissue, polycarbonate, polyurethane/polycarbonate copolymers, metals, and mixtures, composites or subassemblies thereof.

6. The coated substrate of claim 1, wherein at least one of the first and second high molecular weight components is covalently cross-linked to the exposed surface of the medical device.

7. The coated substrate of claim 1, wherein the first high molecular weight component is a polyglycan and the second high molecular weight component is a polypeptide.

8. The coated substrate of claim 7, wherein the polyglycan is a polysaccharide or a sulfated polysaccharide.

9. The coated substrate of claim 8, wherein the polyglycan is a polysaccharide comprising more than about 10 monosaccharide residues joined to each other by glycosidic linkages.

10. The coated substrate of claim 8, wherein the polysaccharide is selected from the group consisting of glycosaminoglycans and glucosaminoglycans.

11. The coated substrate of claim 8, wherein the polysaccharide is selected from the group consisting of dextran, heparan, heparin, hyaluronic acid, alginate, agarose, carageenan, amylopectin, amylose, glycogen, starch, cellulose, and chitin.

12. The coated substrate of claim 8, wherein the sulfated polysaccharide is selected from the group consisting of heparan sulfate, chondroitin sulfate, dextran sulfate, dermatan sulfate, and keratan sulfate.

13. The coated substrate of claim 7, wherein the polyglycan has a molecular weight range of about 2,000 to about 8,000,000 Da.

14. The coated substrate of claim 7, wherein the polyglycan has a molecular weight range of about 20,000 to about 1,000,000 Da.

15. The coated substrate of claim 7, wherein the polypeptide is a tissue-derived or synthetic polypeptide.

16. The coated substrate of claim 15, wherein the polypeptide is a tissue-derived polypeptide selected from the group consisting of collagens, gelatins, keratin, decorin, aggrecan, and glycoproteins.

17. The coated substrate of claim 15, wherein the polypeptide is derived from tissue selected from the group consisting of submucosal tissues, arteries, vocal chords, pleura, trachea, bronchi, pulmonary alveolar septa, ligaments, auricular cartilage, abdominal fascia, liver, kidney, neurilemma, arachnoid, dura mater, and pia mater.

18. The coated substrate of claim 15, wherein the polypeptide is selected from the group consisting of laminin, nidogen, fibulin, and fibrillin.

19. The coated substrate of claim 7, wherein the polypeptide has a molecular weight range of about 3,000 to about 3,000,000 Da.

20. The coated substrate of claim 7, wherein the polypeptide has a molecular weight range of about 30,000 to about 300,000 Da.

21. The coated substrate of claim 7, wherein the polyglycan is dextran and the polypeptide is gelatin.

22. The coated substrate of claim 21, wherein the dextran is present at a concentration of about 0.01 to about 10 mM.

23. The coated substrate of claim 21, wherein the gelatin is present at a concentration of about 0.01 to about 40 mM.

24. The coated substrate of claim 1, wherein the hydrogel matrix further comprises at least one enhancing agent, wherein the enhancing agent is selected from the group consisting of polar amino acids, amino acid analogues, amino acid derivatives, intact collagen, and divalent cation chelators.

25. The coated substrate of claim 24, wherein the at least one enhancing agent comprises at least one polar amino acid selected from the group consisting of tyrosine, cysteine, serine, threonine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, lysine, histidine, and mixtures thereof.

26. The coated substrate of claim 25, wherein the polar amino acids are present at a concentration of about 3 to about 150 mM.

27. The coated substrate of claim 25, wherein the polar amino acids are selected from the group consisting of L-glutamic acid, L-lysine, L-arginine, L-cysteine, and mixtures thereof.

28. The coated substrate of claim 27, wherein the L-glutamic acid is present at a concentration of about 2 to about 60 mM.

29. The coated substrate of claim 27, wherein the L-lysine is present at a concentration of about 0.5 to about 30 mM.

30. The coated substrate of claim 27, wherein the L-arginine is present at a concentration of about 1 to about 40 mM

31. The coated substrate of claim 27, wherein the L-cysteine is present at a concentration of about 5 to about 500 μ

M.

32. The coated substrate of claim 24, wherein the at least one enhancing agent comprises a divalent cation chelator.

33. The coated substrate of claim 32, wherein the divalent cation chelator is ethylenediaminetetraacetic acid or a salt thereof.

34. The coated substrate of claim 33, wherein the ethylenediaminetetraacetic acid is present at a concentration of about 0.01 to about 10 mM.

35. The coated substrate of claim 1, wherein the first high molecular weight component and the second high molecular weight component are covalently cross-linked to each other.

36. The coated substrate of claim 1, wherein the matrix layer has a thickness of about 10⁻

4 cm to about 10 cm.

37. A method of preparing a coated substrate, comprising the steps of:

providing a first high molecular weight component selected from the group consisting of polyglycans and polypeptides;

providing a substrate having a surface;

immobilizing the first high molecular weight component on the surface of the substrate;

contacting the first high molecular weight component with a second high molecular weight component selected from the group consisting of polyglycans and polypeptides, said contacting step occurring either before, during or after said immobilizing step, thereby forming an immobilized bioactive hydrogel coating on the surface of the substrate.

38. The method of claim 37, further comprising, prior to said immobilizing step, chemically modifying the first high molecular weight component to form reactive sites thereon capable of participating in covalent bonding.

39. The method of claim 38, wherein said modifying step comprises oxidizing the first high molecular weight component.

40. The method of claim 39, wherein said modifying step comprises treating the first high molecular weight component with a salt of periodic acid.

41. The method of claim 37, further comprising modifying the surface of the substrate to form reactive sites thereon capable of participating in covalent bonding prior to said immobilizing step.

42. The method of claim 41, wherein modifying the surface of the substrate comprises forming a plurality of reactive amine groups on the surface.

43. The method of claim 37, wherein the substrate is a medical device.

44. The method of claim 43, wherein the medical device is selected from the group consisting of active medical devices and passive medical devices.

45. The method of claim 43, wherein the medical device is selected from the group consisting of ex vivo bioreactors for liver, kidney or other organ support systems, catheters, artificial arteries, artificial organs, tissue fragment-containing devices, cell-containing devices, ligament replacements, bone replacements, glucose sensors, coronary pacemakers, lap-bands, monitors, artificial larynxes, prostheses, brain stimulators, bladder pacemakers, shunts, stents, tubes, defibrillators, cardioverters, heart valves, joint replacements, fixation devices, ocular implants, cochlear implants, breast implants, neurostimulators, bone growth stimulators, vascular grafts, muscle stimulators, left ventricular assist devices, pressure sensors, vagus nerve stimulators, drug delivery systems, sutures, staples, and cell scaffolding materials.

46. The method of claim 37, wherein the surface of the substrate is constructed of a material selected from the group consisting of acrylates, polyglycolic-polylactic acid copolymers, polyhydroxybutyrates, polyesters, expanded polytetrafluoroethylene (ePTFE), bioactive glass, ceramics, coralline materials, processed tissue, polycarbonate, polyurethane/polycarbonate copolymers, metals, and mixtures, composites or subassemblies thereof.

47. The method of claim 37, wherein the first high molecular weight component is a polyglycan and the second high molecular weight component is a polypeptide.

48. The method of claim 47, wherein the polyglycan is a polysaccharide or a sulfated polysaccharide.

49. The method of claim 48, wherein the polysaccharide is selected from the group consisting of dextran, heparan, heparin, hyaluronic acid, alginate, agarose, carageenan, amylopectin, amylose, glycogen, starch, cellulose, and chitin.

50. The method of claim 48, wherein the sulfated polysaccharide is selected from the group consisting of heparan sulfate, chondroitin sulfate, dextran sulfate, dermatan sulfate, and keratan sulfate.

51. The method of claim 47, wherein the polyglycan has a molecular weight range of about 2,000 to about 8,000,000 Da.

52. The method of claim 47, wherein the polypeptide is a tissue-derived or synthetic polypeptide.

53. The method of claim 47, wherein the polypeptide is a tissue derived polypeptide selected from the group consisting of collagens, gelatins, keratin, decorin, aggrecan, and glycoproteins.

54. The method of claim 47, wherein the polypeptide is derived from tissue selected from the group consisting of submucosal tissues, arteries, vocal chords, pleura, trachea, bronchi, pulmonary alveolar septa, ligaments, auricular cartilage, abdominal fascia, liver, kidney, neurilemma, arachnoid, dura mater, and pia mater.

55. The method of claim 47, wherein the polypeptide has a molecular weight range of about 3,000 to about 3,000,000 Da.

56. The method of claim 47, wherein the polyglycan is dextran and the polypeptide is gelatin.

57. The method of claim 37, further comprising contacting the first high molecular weight component with at least one enhancing agent, said contacting step occurring either before, during or after said immobilizing step, the enhancing agent being selected from the group consisting of polar amino acids, amino acid analogues, amino acid derivatives, intact collagen, and divalent cation chelators.

58. The method of claim 57, wherein the at least one enhancing agent comprises at least one polar amino acid selected from the group consisting of tyrosine, cysteine, serine, threonine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, lysine, histidine, and mixtures thereof.

59. The method of claim 37, wherein the first high molecular weight component comprises a plurality of pendant reactive groups.

60. The method of claim 37, wherein the first high molecular weight component comprises a reactive group located at a terminus thereof.

61. The method of claim 37, wherein said immobilizing step comprises reacting carboxyl groups of the first high molecular weight component with amine groups on the surface of the substrate.

62. The method of claim 37, wherein said immobilizing step comprises covalently cross-linking the first high molecular weight component to the surface of the substrate.