MEDICAL DEVICE COATING WITH A BIOCOMPATIBLE LAYER

• US 20170360994A1
• Filed: 12/09/2015
• Published: 12/21/2017
• Est. Priority Date: 12/09/2014
• Status: Active Grant

• Current Assignee: Tangible Science, Llc
• Original Assignee: Tangible Science, Llc
• Inventors: HAVENSTRITE, Karen, MCCRAY, Victor W., FELKINS, Brandon M., COOK, Paul
• Granted Patent: US 10,525,170 B2
• Time in Patent Office: Days
• CPC Class Codes: A61L 15/46 Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
• CPC Class Codes: A61L 15/60 Liquid-swellable gel-forming materials, e.g. super-absorbents
• CPC Class Codes: A61L 2300/104 Silver, e.g. silver sulfadiazine
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2400/12 Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
• CPC Class Codes: A61L 27/34 Macromolecular materials
• 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 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence

Abstract

Medical devices with a hydrogel layer covalently attached to a portion of the outer surface of the medical device are provided along with methods for applying the coating. The hydrogel layer can include a first polymer species comprising polyethylene glycol (PEG) and a second polymer species. Examples of the second polymer species include PEG and polyacrylamide (PAM). The first and second species can be at least partially cross-linked. Methods for forming the hydrogel coatings on the medical devices are provided including nucleophilic conjugate reactions, such as Click reactions.

Claims

1. A medical device comprising:

an outer surface; and

a hydrogel layer covalently attached to at least a portion of the outer surface, the hydrogel layer adapted to contact a body tissue or fluid, wherein the hydrogel layer comprises a biocompatible polymer population having a first hydrophilic polymer species comprising polyethylene glycol (PEG) and a second hydrophilic polymer species comprising polyacrylamide, the first hydrophilic polymer species being at least partially covalently cross-linked to the second hydrophilic polymer species, wherein the medical device is not a contact lens.

2. The device of claim 1, wherein the device is configured to be implantable within a mammalian body.

3. The device of claim 2, wherein the device is a stent configured to keep a cavity open.

4. The device of claim 3, wherein the stent is configured to keep a blood vessel, bile duct, intestine, nasal passage or cavity, sinus cavity, or intraocular channel open.

5. The device of claim 2, wherein the device is a sensor, camera, vital sign monitor, drug depot device, neurostimulator, ultrasound, silicone implant, saline implant, hernia mesh, penile implant, orthopedic rod or plate or pin or nails, pacemaker, cardiac valve, ear tube, aneurysm coil, or intraocular lens.

6. The device of claim 1, wherein the device is a test strip.

7. The device of claim 6, wherein the device is a drug, salivary, urine, blood or semen test strip.

8. The device of claim 1, wherein the device is a tool configured to be inserted within a mammalian body.

9. The device of claim 8, wherein the device is a catheter, trocar, endoscope, or laparoscope.

10. The device of claim 1, wherein the device is configured to be used externally on a mammalian body.

11. The device of claim 10, wherein the device is configured for use as a bandage, wound dressing, external sensor, hearing aid, or artificial skin.

12. The device of any of claims 1-11, wherein the outer surface of the device comprises one or more of:

glass, plastic, titanium, nitinol, polyethylene, polypropylene, polyvinyl chloride, polytetraflouroethylene, polydimethylsiloxane, polyethylene terephthalate, polyamides, polyether urethane, polyether urethane urea, polystyrene, polycarbonate, polysulfones, polymethyl methacrylate, poly 2-hydroxyethylmethacrylate, polyvinylalcohol, polyglycolic acid, polycaprolactone, polylactic acid, polyortho ester, cellulose acetate, collagen, or silk.

13. The device of any of claims 1-11, wherein the outer surface of the device consists essentially of a material selected from the group consisting of:

glass, plastic, titanium, nitinol, polyethylene, polypropylene, polyvinyl chloride, polytetraflouroethylene, polydimethylsiloxane, polyethylene terephthalate, polyamides, polyether urethane, polyether urethane urea, polystyrene, polycarbonate, polysulfones, polymethyl methacrylate, poly 2-hydroxyethylmethacrylate, polyvinylalcohol, polyglycolic acid, polycaprolactone, polylactic acid, polyortho ester, cellulose acetate, collagen, or silk.

14. The device of any of claims 1-13, wherein the first species comprises a reactive electrophilic group or a reactive nucleophilic group and the second species comprises a reactive electrophilic group or a reactive nucleophilic group complementary to the first species, the reactive electrophilic group and the reactive nucleophilic group adapted to react to thereby form cross-links between the first species to the second species.

15. The device of claim 14, wherein the reactive electrophilic group is selected from the group consisting of:

amino-reactive groups, sulfhydryl-reactive groups, carboxyl groups, hydroxyl groups, haloalkyl groups, dienophile groups, aldehyde or ketone groups, alkenes, epoxides, and phosphoramidites.

16. The device of claim 14, wherein the reactive nucleophilic group is selected from the group consisting of:

amines, amino-reactive groups, sulfhydryl, sulfhydryl-reactive groups, carboxyl groups, hydroxyl groups, haloalkyl groups, dienophile groups, aldehyde or ketone groups, alkenes, epoxides, and phosphoramidites.

17. The device of claim 14, wherein at least one of the reactive electrophilic group of the first species or the reactive electrophilic group of the second species is covalently linked to the outer surface of the device.

18. The device of any of the preceding claims, wherein the hydrogel layer substantially surrounds the outer surface of the device.

19. The device of any of the preceding claims, wherein the hydrogel layer or the hydrogel layer and device are substantially optically clear.

20. The device of any of the preceding claims, wherein the hydrogel layer is adapted to allow optical transmission through the hydrogel layer to the device.

21. The device of any of the preceding claims, wherein the hydrogel layer is adapted to attenuate x-ray transmission.

22. The device of any of the preceding claims, wherein the hydrogel layer is adapted to enable diffusion of biologic molecules, glucose, solutes, polymers, drugs.

23. The device of any of the preceding claims, wherein the hydrogel layer comprises a thickness between about 5 nm to about 30 nm.

24. The device of any of the preceding claims, wherein the hydrogel layer comprises a thickness below about 100 nm.

27. The device of any of the preceding claims, wherein the hydrogel layer comprises a maximum thickness of about 10 microns.

28. The device of any of the preceding claims, wherein a first portion of the hydrogel layer comprises a first thickness different from a second thickness of a second portion of the hydrogel layer.

29. The device of any of the preceding claims, wherein each of the first and second hydrophilic polymer species is a branched species having a branch count between two to twelve branch arms.

30. The device of any of the preceding claims, wherein the first hydrophilic polymer species comprises a reactive electron pair accepting group and the second hydrophilic polymer species comprises a reactive nucleophilic group, the reactive electron pair accepting group and the reactive nucleophilic group adapted to react to thereby form cross-links between the first hydrophilic polymer species to the second hydrophilic polymer species.

31. The device of any of the preceding claims, wherein the hydrogel layer has a lower coefficient of friction than an underlying device surface.

32. The device of any of the preceding claims, wherein the hydrogel layer has a relative protein resistance compared to an underlying device surface.

33. The device of any of the preceding claims, wherein the hydrogel layer comprises between about 80% to about 98% water by weight.

58. The device of any of claims 29-57, wherein the biocompatible polymer layer further comprises at least one active agent.

59. The device of claim 58, wherein the at least one active agent is selected from the group consisting of a protein, drug, nanoparticle, cell, or solute.

25. The device of any of the proceeding claims, wherein the hydrogel layer comprises a thickness less than about 50 nm.

26. The device of any of the proceeding claims, wherein the hydrogel layer comprises a thickness less than about 1 micron.

34. A medical device comprising:

an outer surface covered by an outer biocompatible polymer layer, wherein the biocompatible polymer layer comprises a first polyethylene glycol (PEG) macromer subpopulation having an electron pair accepting moiety and a second macromer subpopulation comprising polyacrylamide having a first nucleophilic reactive moiety, wherein the first and second macromer subpopulations are cross-linked.

35. The device of claim 34, wherein the device is configured to be implantable within a mammalian body.

36. The device of claim 34, wherein the device is a stent configured to keep a cavity open.

37. The device of claim 36, wherein the stent is configured to keep a blood vessel, bile duct, intestine, nasal passage or cavity, sinus cavity, or intraocular channel open.

38. The device of claim 35, wherein the device is a glucose sensor, endoscopic camera, vital sign monitor, drug depot device, neurostimulator, ultrasound, breast implant, hernia mesh, penile implant, orthopedic rod or plate or pin or nails, pacemaker, cardiac valve, ear tube, aneurysm coil, or intraocular lens.

39. The device of claim 34, wherein the device is a tool configured to be inserted within a mammalian body.

40. The device of claim 39, wherein the device is a catheter, trocar, endoscope, or laparoscope.

41. The device of claim 34, wherein the device is configured to be used externally on a mammalian body.

42. The device of claim 41, wherein the device is configured for use as a bandage, wound dressing, external sensor, hearing aid, or artificial skin.

43. The device of any of claims 34-42, wherein the medical device is not a contact lens.

44. The device of any of claims 34-43, wherein the outer surface of the device comprises or consists essentially of any of the following:

glass, plastic, titanium, nitinol, polyethylene, polypropylene, polyvinyl chloride, polytetraflouroethylene, polydimethylsiloxane, polyethylene terephthalate, polyamides, polyether urethane, polyether urethane urea, polystyrene, polycarbonate, polysulfones, polymethyl methacrylate, poly 2-hydroxyethylmethacrylate, polyvinylalcohol, polyglycolic acid, polycaprolactone, polylactic acid, polyortho ester, cellulose acetate, collagen, or silk.

45. The device of any of claims 34-43, wherein the outer surface of the device consists essentially of a material selected from the group consisting of:

glass, plastic, titanium, nitinol, polyethylene, polypropylene, polyvinyl chloride, polytetraflouroethylene, polydimethylsiloxane, polyethylene terephthalate, polyamides, polyether urethane, polyether urethane urea, polystyrene, polycarbonate, polysulfones, polymethyl methacrylate, poly 2-hydroxyethylmethacrylate, polyvinylalcohol, polyglycolic acid, polycaprolactone, polylactic acid, polyortho ester, cellulose acetate, collagen, or silk.

46. The device of any of claims 34-45, wherein the biocompatible polymer layer is attached to the device by a covalent linkage between the electron pair accepting moiety of the first hydrophilic polymer macromer and a second nucleophilic reactive moiety on a surface of the device.

47. The device of any of claims 34-46, wherein the first species comprises a reactive electrophilic group or a reactive nucleophilic group and the second species comprises a reactive electrophilic group or a reactive nucleophilic group complementary to the first species, the reactive electrophilic group and the reactive nucleophilic group adapted to react to thereby form cross-links between the first species to the second species.

48. The device of claim 47, wherein the reactive electrophilic group is selected from the group consisting of:

amino-reactive groups, sulfhydryl-reactive groups, carboxyl groups, hydroxyl groups, haloalkyl groups, dienophile groups, aldehyde or ketone groups, alkenes, epoxides, and phosphoramidites.

49. The device of claim 47, wherein the reactive nucleophilic group is selected from the group consisting of:

amines, amino-reactive groups, sulfhydryl, sulfhydryl-reactive groups, carboxyl groups, hydroxyl groups, haloalkyl groups, dienophile groups, aldehyde or ketone groups, alkenes, epoxides, and phosphoramidites.

50. The device of claim 47, wherein at least one of the reactive electrophilic group of the first species or the reactive electrophilic group of the second species is covalently linked to the outer surface of the device.

51. The device of any of claims 34-50, wherein the biocompatible polymer layer comprises between about 50% and about 98% water by weight.

52. The device of any of claims 34-51, wherein the biocompatible polymer layer comprises between about 85% and about 98% water by weight.

53. The device of any of claims 34-52, wherein the hydrogel layer comprises a thickness between about 5 nm to about 30 nm.

54. The device of any of claims 34-52, wherein the hydrogel layer comprises a thickness below about 100 nm.

55. The device of any of claims 34-52, wherein the hydrogel layer comprises a thickness less than about 50 nm.

56. The device of any of claims 34-52, wherein the hydrogel layer comprises a thickness less than about 1 micron.

57. The device of any of claims 34-52, wherein the hydrogel layer comprises a maximum thickness of about 10 microns

60. A method of making a medical device with a hydrophilic polymer layer comprising:

reacting an outer surface of the medical device with a first polymer species of a hydrophilic polymer solution, wherein the first polymer species comprises a moiety at a first portion that forms a covalent attachment to the outer surface of the device; and

reacting the first polymer species of the hydrophilic polymer solution with a second polymer species of the hydrophilic polymer solution, the second polymer species comprising a moiety that forms a covalent bond to a second portion of the first polymer species in a second covalent reaction thereby forming a hydrogel coating comprising the first polymer species and the second polymer species at least partially cross-linked.

61. The method of claim 60, wherein the device is configured to be implantable within a mammalian body.

62. The method of claim 61, wherein the device is a stent configured to keep a cavity open.

63. The method of claim 62, wherein the stent is configured to keep a blood vessel, bile duct, intestine, nasal passage or cavity, sinus cavity, or intraocular channel open.

64. The method of claim 63, wherein the hydrophilic polymer layer reduces thrombosis of the stent.

65. The method of claim 61, wherein the device is a glucose sensor, endoscopic camera, vital sign monitor, drug depot device, neurostimulator, ultrasound, breast implant, hernia mesh, penile implant, orthopedic rod or plate or pin or nails, pacemaker, cardiac valve, ear tube, aneurysm coil, or intraocular lens.

66. The method of claim 65, wherein the hydrophilic polymer layer reduces an immune system reaction against the implant.

67. The method of claim 60, wherein the device is a tool configured to be inserted within a mammalian body.

68. The method of claim 67, wherein the device is a catheter, trocar, endoscope, or laparoscope.

69. The method of claim 68, wherein the hydrophilic polymer layer increases blood flow through the catheter when the catheter is inserted into a mammalian body.

70. The method of claim 60, wherein the device is configured to be used externally on a mammalian body.

71. The method of claim 70, wherein the device is configured for use as a bandage, wound dressing, external sensor, hearing aid, or artificial skin.

72. The method of any of claims 60-71, wherein the medical device is not a contact lens.

73. The method of any of claims 60-72, wherein the outer surface of the device comprises or consists essentially of any of the following:

glass, plastic, titanium, nitinol, stainless steel, polyethylene, polypropylene, polyvinyl chloride, polytetraflouroethylene, polydimethylsiloxane, polyethylene terephthalate, polyamides, polyether urethane, polyether urethane urea, polystyrene, polycarbonate, polysulfones, polymethyl methacrylate, poly 2-hydroxyethylmethacrylate, polyvinylalcohol, polyglycolic acid, polycaprolactone, polylactic acid, polyortho ester, cellulose acetate, collagen, or silk.

74. The method of any of claims 60-73, wherein the outer surface of the device consists essentially of a material selected from the group consisting of:

glass, plastic, titanium, nitinol, stainless steel, polyethylene, polypropylene, polyvinyl chloride, polytetraflouroethylene, polydimethylsiloxane, polyethylene terephthalate, polyamides, polyether urethane, polyether urethane urea, polystyrene, polycarbonate, polysulfones, polymethyl methacrylate, poly 2-hydroxyethylmethacrylate, polyvinylalcohol, polyglycolic acid, polycaprolactone, polylactic acid, polyortho ester, cellulose acetate, collagen, or silk.

75. The method of any of claims 60-74, wherein the reacting steps are performed at a temperature between about 15 degrees Celsius and about 100 degrees Celsius.

76. The method of any of claims 60-75, wherein the reacting steps are performed at a temperature between about 20 degrees Celsius and about 40 degrees Celsius.

77. The method of any of claims 60-76, wherein the reacting steps are performed at a pH between about 7 and about 11.

78. The method of any of claims 60-77, wherein the hydrophilic polymer layer is substantially optically clear.

79. The method of any of claims 60-78, wherein the covalent attachment between the outer surface of the device and the first portion of the first polymer species is formed by a first nucleophilic conjugate reaction.

80. The method of any of claims 60-79, wherein the second covalent reaction is a second nucleophilic conjugate reaction.

81. The method of any of claims 60-80, wherein the partial cross-linking is between an electrophilic moiety of the first species and a nucleophilic moiety of the second species in a nucleophilic conjugate reaction.

82. The method of any of claims 60-81, wherein the hydrophilic polymer layer includes a first species selected from the group consisting of:

polyethylene glycol (PEG), phosphorylcholine, poly(vinyl alcohol), poly(vinylpyrrolidinone), poly(N-isopropylacrylamide) (PNIPAM), polyacrylamide (PAM), poly(-oxazoline), polyethylenimine (PEI), poly(acrylic acid), polymethacrylate, polyelectrolytes, hyaluronic acid, chitosan, chondroitin sulfate, alginate, hydroxypropylmethylcellulose, and dextran.

83. The method of any of claims 60-82, wherein the hydrophilic polymer layer includes a second species selected from the group consisting of:

polyethylene glycol (PEG), phosphorylcholine, poly(vinyl alcohol), poly(vinylpyrrolidinone), poly(N-isopropylacrylamide) (PNIPAM), polyacrylamide (PAM), poly(2-oxazoline), polyethylenimine (PEI), poly(acrylic acid), polymethacrylate, polyelectrolytes, hyaluronic acid, chitosan, chondroitin sulfate, alginate, hydroxypropylmethylcellulose, and dextran.

84. The method of any of claims 60-83, wherein the hydrophilic polymer layer includes a first species comprising polyethylene glycol (PEG).

85. The method of any of claims 60-84, wherein the hydrophilic polymer layer includes a second species comprising polyacrylamide.

86. The method of any of claims 60-85, wherein the first species comprises a reactive electrophilic group or a reactive nucleophilic group and the second species comprises a reactive electrophilic group or a reactive nucleophilic group complementary to the first species, the reactive electrophilic group and the reactive nucleophilic group adapted to react to thereby form cross-links between the first species to the second species.

87. The method of claim 86, wherein the reactive electrophilic group is selected from the group consisting of:

amino-reactive groups, sulfhydryl-reactive groups, carboxyl groups, hydroxyl groups, haloalkyl groups, dienophile groups, aldehyde or ketone groups, alkenes, epoxides, and phosphoramidites.

88. The method of claim 86, wherein the reactive nucleophilic group is selected from the group consisting of:

amines, amino-reactive groups, sulfhydryl, sulfhydryl-reactive groups, carboxyl groups, hydroxyl groups, haloalkyl groups, dienophile groups, aldehyde or ketone groups, alkenes, epoxides, and phosphoramidites.

89. The method of claim 88, wherein at least one of the reactive electrophilic group of the first species or the reactive electrophilic group of the second species is covalently linked to the outer surface of the device.

90. The method of any of claims 60-89, further comprising:

modifying the outer surface of the device to form the plurality of reactive nucleophilic sites or a plurality of electrophilic sites on the outer surface.

91. The method of claim 90, wherein the modifying step comprises exposing the outer surface of the medical device to a gas plasma treatment.

92. The method of any of claims 60-91, further comprising adding a bifunctional monomer or a polymer to a prepolymerization mixture used to form the hydrophilic polymer layer.

93. The method of claim 92, wherein the bifunctional monomer or polymer does not substantially change the optical properties of the medical device.

94. The method of claims 92-93, wherein the bifunctional monomer or polymer provides additional nucleophilic or electrophilic reactive sites on the surface of the device.

95. The method of any of claims 60-94, further comprising modifying an outer surface of the device.

96. The method of claim 95, wherein modifying the outer surface of the device includes one or more of:

pH adjustment, plasma activation, light activation, activation of the liquid monomer mix, wet activation, and adding a monomer that reacts with the outer surface of the device that still leaves reactive sites.

97. The method of any of claims 79-96, wherein both of the first and second nucleophilic conjugate reactions are Click reactions.

98. The method of claim 97, wherein the Click reaction is a conjugate addition reaction.

99. The method of claim 97, wherein both of the first and second nucleophilic conjugate addition reactions are 1,4-nucleophilic addition reactions.

100. The method of claim 99, wherein the first and second nucleophilic conjugate addition reactions are both Michael-type reactions.

101. The method of any of claims 60-100, wherein the reacting steps are performed at a pH between about 5 and about 11.

102. The method of any of claims 60-101, further comprising adding at least one active agent to the hydrophilic polymer layer.

103. The method of claim 102, wherein the at least one active agent is selected from the group consisting of a UV-absorbing agent, a visibility tinting agent, an antimicrobial agent, a bioactive agent, a leachable lubricant, a leachable tear-stabilizing agent, or any mixture thereof.

104. The method of claim 103, wherein the antimicrobial agent comprises silver nanoparticles.

105. The method of any of claims 60-104, wherein the hydrophilic polymer layer has a thickness of less than about 50 nm.