Immobilized bioactive hydrogel matrices as surface coatings
View Patent ↗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.
1. A coated substrate, comprising:
a substrate having a surface, wherein the substrate is a medical device; and
a bioactive hydrogel matrix layer overlying the surface of the substrate and immobilized thereon, the hydrogel matrix layer comprising a polyglycan, a tissue-derived or synthetic polypeptide, and at least one enhancing agent selected from the group consisting of polar amino acids, divalent cation chelators, and combinations thereof.
2. The coated substrate of claim 1 , wherein the medical device is selected from the group consisting of active medical devices and passive medical devices.
3. The coated substrate of claim 1 , 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, 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 scaffolding materials.
4. 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.
5. The coated substrate of claim 1 , wherein at least one of the polyglycan and polypeptide components is covalently cross-linked to the surface of the substrate.
6. The coated substrate of claim 1 , wherein the polyglycan is a polysaccharide or a sulfated polysaccharide.
7. The coated substrate of claim 6 , wherein the polyglycan is a polysaccharide comprising more than about 10 monosaccharide residues joined to each other by glycosidic linkages.
8. The coated substrate of claim 6 , wherein the polysaccharide is selected from the group consisting of glycosaminoglycans and glucosaminoglycans.
9. The coated substrate of claim 6 , 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.
10. The coated substrate of claim 6 , wherein the sulfated polysaccharide is selected from the group consisting of heparan sulfate, chondroitin sulfate, dextran sulfate, dermatan sulfate, and keratan sulfate.
11. The coated substrate of claim 1 , wherein the polyglycan has a molecular weight range of about 2,000 to about 8,000,000 Da.
12. The coated substrate of claim 1 , wherein the polyglycan has a molecular weight range of about 20,000 to about 1,000,000 Da.
13. The coated substrate of claim 1 , wherein the polypeptide is a tissue-derived polypeptide selected from the group consisting of collagens, gelatins, keratin, decorin, aggrecan, and glycoproteins.
14. The coated substrate of claim 1 , 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.
15. The coated substrate of claim 1 , wherein the polypeptide is selected from the group consisting of laminin, nidogen, fibulin, and fibrillin.
16. The coated substrate of claim 1 , wherein the polypeptide has a molecular weight range of about 3,000 to about 3,000,000 Da.
17. The coated substrate of claim 1 , wherein the polypeptide has a molecular weight range of about 30,000 to about 300,000 Da.
18. The coated substrate of claim 1 , wherein the polyglycan is dextran or oxidized dextran and the polypeptide is gelatin.
19. The coated substrate of claim 18 , wherein the dextran or oxidized dextran is present at a concentration of about 0.01 to about 10 mM.
20. The coated substrate of claim 18 , wherein the gelatin is present at a concentration of about 0.01 to about 40 mM.
21. The coated substrate of claim 1 , wherein the hydrogel matrix further comprises intact collagen.
22. The coated substrate of claim 1 , wherein the at least one enhancing agent comprises at least one polar amino acid selected from the group consisting of tyrosine, cysteine, seine, threonine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, lysine, histidine, and mixtures thereof.
23. The coated substrate of claim 22 , wherein the polar amino acids are present at a concentration of about 3 to about 150 mM.
24. The coated substrate of claim 22 , wherein the polar amino acids are selected from the group consisting of L-glutamic acid, L-lysine, L-arginine, L-cysteine, and mixtures thereof.
25. The coated substrate of claim 24 , wherein the L-glutamic acid is present at a concentration of about 2 to about 60 mM.
26. The coated substrate of claim 24 , wherein the L-lysine is present at a concentration of about 0.5 to about 30 mM.
27. The coated substrate of claim 24 , wherein the L-arginine is present at a concentration of about 1 to about 40 mM.
28. The coated substrate of claim 24 , wherein the L-cysteine is present at a concentration of about 5 to about 500 μM.
29. The coated substrate of claim 1 , wherein the at least one enhancing agent comprises a divalent cation chelator.
30. The coated substrate of claim 29 , wherein the divalent cation chelator is ethylenediaminetetraacetic acid or a salt thereof.
31. The coated substrate of claim 30 , wherein the ethylenediaminetetraacetic acid is present at a concentration of about 0.01 to about 10 mM.
32. The coated substrate of claim 1 , wherein the polyglycan and polypeptide are covalently cross-linked to each other.
33. The coated substrate of claim 1 , wherein the matrix layer has a thickness of about 10 −4 cm to about 10 cm.
34. A coated substrate, comprising:
a substrate having a surface, wherein the substrate is a medical device; and
a bioactive hydrogel matrix layer overlying the surface of the substrate and immobilized thereon, the hydrogel matrix layer comprising a polyglycan and a polypeptide, wherein at least one of the polyglycan and polypeptide is covalently cross-linked to the surface of the substrate.
35. The coated substrate of claim 34 , 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, 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 scaffolding materials.
36. The coated substrate of claim 34 , wherein the polyglycan is a polysaccharide or a sulfated polysaccharide.
37. The coated substrate of claim 34 , wherein the polypeptide is a tissue-derived polypeptide selected from the group consisting of collagens, gelatins, keratin, decorin, aggrecan, and glycoproteins.
38. The coated substrate of claim 34 , wherein the polyglycan is dextran or oxidized dextran and the polypeptide is gelatin.
39. The coated substrate of claim 34 , wherein the hydrogel matrix further comprises at least one enhancing agent selected from the group consisting of polar amino acids, divalent cation chelators, and combinations thereof.
40. The coated substrate of claim 39 , wherein the hydrogel matrix further comprises intact collagen.
41. The coated substrate of claim 39 , wherein the at least one enhancing agent comprises at least one polar amino acid selected from the group consisting of tyrosine, cysteine, seine, threonine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, lysine, histidine, and mixtures thereof.
42. The coated substrate of claim 39 , wherein the at least one enhancing agent comprises a divalent cation chelator.
43. The coated substrate of claim 42 , wherein the divalent cation chelator is ethylenediaminetetraacetic acid or a salt thereof.
44. A coated substrate, comprising:
a substrate having a surface, wherein the substrate is a medical device; and
a bioactive hydrogel matrix layer comprising dextran or oxidized dextran and gelatin overlying the surface of the substrate and immobilized thereon.
45. The coated substrate of claim 44 , 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, 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 scaffolding materials.
46. The coated substrate of claim 44 , wherein the hydrogel matrix further comprises at least one enhancing agent selected from the group consisting of polar amino acids, divalent cation chelators, and combinations thereof.
47. The coated substrate of claim 46 , wherein the hydrogel matrix further comprises intact collagen.
48. The coated substrate of claim 46 , 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.
49. The coated substrate of claim 46 , wherein the at least one enhancing agent comprises a divalent cation chelator.
50. The coated substrate of claim 49 , wherein the divalent cation chelator is ethylenediaminetetraacetic acid or a salt thereof.
51. The coated substrate of claim 34 , wherein the polyglycan and polypeptide are covalently crosslinked to each other.