CA2725296A1

CA2725296A1 - Stent fabrication via tubular casting processes

Info

Publication number: CA2725296A1
Application number: CA2725296A
Authority: CA
Inventors: Kamal Ramzipoor; Alfred N. K. Chia; Liwei Wang; Chang Yeul Lee
Original assignee: Amaranth Medical Pte
Current assignee: Amaranth Medical Pte
Priority date: 2008-06-20
Filing date: 2009-06-19
Publication date: 2009-12-23
Anticipated expiration: 2029-06-19
Also published as: WO2009155560A1; AU2009259862A1; EP2303185B1; US20140236285A1; US10646359B2; US20140039600A1; US20090319028A1; AU2009259862B2; EP2792335A1; CA2725296C; US10893960B2; EP2303185A4; US20140035192A1; US20120232643A1; CN102065794A; JP2011525137A; CN102065794B; US20170157806A1; US8206635B2; EP2303185A1

Abstract

Tubular casting processes, such as dip-coating, may be used to form substrates from polymeric solutions which may be used to fabricate implantable devices such as stents. The polymeric substrates may have multiple layers which retain the inherent properties of their starting materials and which are sufficiently ductile to prevent brittle fracture. Parameters such as the number of times the mandrel is immersed, the duration of time of each immersion within the solution, as well as the delay time between each immersion or the drying or curing time between dips and withdrawal rates of the mandrel from the solution may each be controlled to result in the desired mechanical characteristics. Additional post-processing may also be utilized to further increase strength of the substrate or to alter its shape.

Claims

1. A method of delivering a polymeric stent within a vessel, comprising:
immersing a mandrel into at least a first polymeric solution such that at least a first layer of a biocompatible polymer substrate is formed upon the mandrel and has a first diameter defined by the mandrel:
heat treating the substrate at or near a glass transition temperature of the substrate to set the first diameter;
forming an expandable stent scaffold from the substrate; and reducing the first diameter of the stent to a second delivery diameter which is less than the first diameter,

2. The method of claim 1 further comprising:
positioning the stent having the second diameter at a target location within the vessel;
expanding the stent to a third diameter that is larger than the second diameter at the target location, and allowing the stern to self-expand into further contact with the vessel at the target location.

3. The method of claim 2 wherein expanding the stent comprises expanding the stent to the third diameter with an inflation balloon.

4. The method of claim 3 further comprising removing the inflation balloon from the stent.

5. The method of claim 2 wherein allowing the stent to self-expand comprises allowing the stent to self-expand into secure contact against an inner surface of the vessel.

6, The method of claim 1 further comprising:
positioning the stent having the second diameter at a target location within the vessel;
expanding the stent to a third diameter that is larger than the second diameter at the target location until the stent is in contact with a vessel wall.

7. The method of claim 1 wherein prior to heat treating the substrate, further comprising:
controlling a number of immersions of the mandrel into the first polymeric solution;
controlling a duration of time of each immersion of the mandrel; and, controlling a delay time between each immersion of the mandrel.

8. A method of forming a polymeric substrate, comprising:
immersing a mandrel into at least a first polymeric solution such that at least a first layer of a biocompatible polymer substrate is formed upon the mandrel and has a first diameter defined by the mandrel;
forming an expandable stent scaffold having the first diameter;
reducing the first diameter of the stent to a second smaller diameter, and wherein the stent experiences physiological condition-induced material strain less than 6%
in axial, radial, and bending modes,

9. The method of claim 8 wherein prior to reducing the first diameter, further comprising:
controlling a number of immersions of the mandrel into the first polymeric solution;
controlling a duration of time of each immersion of the mandrel; and controlling a delay time between each immersion of the mandrel.

10. The method of claim 9 further comprising controlling a withdrawal rate of the mandrel from the first polymeric solution after each immersion.

11. The method of claim 8 wherein the first polymeric solution comprises a polymer having a molecular weight ranging, from 239,000 g/mol to 2,120,000 g/mol.

12. The method of claim 8 wherein a molecular weight of the first layer is configured to accelerate a degradation rate of the first layer.

13. The method of claim 8 wherein the first polymeric solution is selected from the group consisting of polyethylene, polycarbonates, polyamides, polyestheramides, polyetheretherketone, polyketals, polyurethane, polyolefin, polyethylene terephthalate, polylactide, poly-L-polyacetals, lactide, poly-glycolide, poly(lactide-co-glycolide), polycaprolactone, caprolactones, polydioxanones, polyanhydrides, polyorthocarbonates, polyphosphazenes, chitin, chitosan, poly(amino acids), polyorthoesters, oligomers, honaopolymers, methyl cerylate, methyl methacrylate, acryli acid, methacrylic acid, acrylamide, hydroxyethy acrylate, hydroxyethyl methacrylate, glyceryl scrylate, glyceryl methacrylate, methacrylamide, ethacrylamide, styrene, vinyl chloride, binaly pyrrolidone, polyvinyl alcohol, polycoprolactam, polylauryl lactam;
polyjexamethylene adipamide, polyexamethylene dodecanediamide, trimethylene carbonate, poly(.beta.-hydroxybutyrate), poly(g-ethyl glutamate), poly(DTH
iminocarbonate), poly(bisphenol A
iminocarborrate), polycyanoacrylate, polyphosphazene, methyl cerylate, methyl methacrylate, acryli acid, methacrylic acid, acrylamide, hydroxyethy acrylate, hydroxyethyl methacrylate, glyceryl scrylate, glyceryl methacrylate, methacrylamide, ethacrylamide, and copolymers, terpolymers and combinations and mixtures thereof.

14. The method of claim 8 wherein immersing a mandrel comprises further immersing the mandrel into a second polymeric solution such that a second layer of polymer is formed upon the first layer.

15. The method of claim 14 wherein a molecular weight of the first layer is configured to accelerate a degradation rate of the second layer.

16. The method of claim 14 wherein the second polymeric solution comprises a drug or agent selected from the group consisting of antipoliferative, antineoplastic, antigenic, anti-inflammatory, antirestenotic, antilipid, antimitotics, metalloproteinase inhabitors, and anti-sclerosing agents.

17. The method of claim 14 wherein the second polymeric solution comprises a radio-opaque material.

18. The method of claim 14 wherein the second polymeric solution comprises a BaSO4 solution.

19. The method of claim 9 wherein controlling a number of immersions comprises immersing the mandrel between 2 and 20 times.

20. The method of claim 9 wherein controlling a duration of time comprises immersing the mandrel between 15 seconds and 240 minutes.

21. The method of claim 9 wherein controlling a delay time comprises delaying immersion of the mandrel between 15 seconds and 60 minutes.

22. The method of claim 8 wherein immersing a mandrel comprises inserting the mandrel into the first polymeric solution at a rate of 5 mm/ min to 1000 mm/min.

23. The method of claim 8 further comprising applying a force within a lumen defined through the polymeric substrate such that the substrate expands from a first diameter to a second larger diameter.

24. The method of claim 23 further comprising applying heat to the polymeric substrate while applying the force.

25. The method of claim 8 further comprising rotating the mandrel while applying heat.

26. The method of claim 8 further comprising controlling an angle of the mandrel relative to the polymeric solution.

27. The method of claim 8 wherein the substrate has a length of 1 cm to 40 cm.

28. The method of claim 8 further comprising controlling a relative humidity of less than 30%.

29. The method of claim 8 further comprising controlling a temperature of the polymeric solution to be below a boiling point of a solvent contained within the polymeric solution.

30. The method of claim 8 further comprising mold-transferring one or more patterns from an outer surface of the mandrel to an inner surface of the substrate.

31. The method of claim S further comprising controlling a crystallinity percentage of the substrate within a range of 10% to 50%.

32. The method of claim 8 wherein the substrate formed upon the mandrel is isotropic.

33. The method of claim 8 further comprising drying the substrate at a glass transition temperature of the polymeric solution.

34. The method of claim 8 further comprising:
subjecting the substrate to a first elevated temperature above a glass transition temperature of the substrate while reducing the first diameter; and cooling the substrate to a second temperature lower than the glass transition temperature such that the substrate transitions to a glass state and imparts a shape memory effect.

35. The method of claim 34 wherein reducing comprises reducing the first diameter ranging from 3 mm to 10 mm to the second diameter ranging from 1,5 mm to 5 mm.

36. The method of claim 34 wherein cooling comprises reducing the substrate temperature to the second temperature below the glass transition temperature.

37. The method of claim 8 wherein the substrate formed upon the mandrel exhibits a 20%
radial deformation when placed under a 0.1 N to 5 N per cm load.

38. The method of claim 8 wherein the substrate formed upon the mandrel exhibits a percent elongation of between 97% to 123% at failure when placed under the 73 to 77 MPa load.

39. The method of claim 8 wherein the substrate formed upon the mandrel exhibits a percent reduction in diameter of between 5% to 80% without fracture formation when placed under a compressive load.

40. The method of claim 8 further comprising expanding a diameter of the stent via an expandable balloon by 5% to 80% without fracture formation.

41. The method of claim 8 wherein the stent is adapted to exhibit a percent reduction in axial length of between 10% to 50% without fracture formation when placed under an axial load.

42. A stent, comprising:
one or more circumferentially expandable support members each defining an undulating configuration;
one or more coupling members connecting adjacent support members and aligned in parallel with respect to a longitudinal axis defined by the stent, wherein the support members and coupling members are formed by the method of claim 7.

43. The stent of claim 42 wherein at least two coupling members in appositional relation to one another connect adjacent support members.

44. The stent of claim 42 wherein the coupling members between adjacent support members are alternating in pattern.

45. A method of delivering a polymeric stent within a vessel, comprising:
immersing a mandrel into at least a first polymeric solution such that at least a first layer of a biocompatible polymer substrate is formed upon the mandrel and has a first diameter defined by the mandrel;

heat treating the substrate at or near a glass transition temperature of the substrate to set the first diameter;
forming an expandable stent scaffold from the substrate;
reducing the first diameter of the stent to a second delivery diameter which is less than the first diameter;
positioning the stent having the second diameter at a target location within the vessel:
expanding the stent to a third diameter that is larger than the second diameter at the target location; and allowing the stent to self-expand into further contact with the vessel at the target location.

46. The method of claim 45 wherein prior to heat treating the substrate, further comprising:
controlling a number of immersions of the mandrel into the first polymeric solution;
controlling a duration of time of each immersion of the mandrel: and, controlling a delay time between each immersion of the mandrel.

47. The method of claim 45 wherein expanding the stent comprises expanding the stent to the third diameter with an inflation balloon.

48. The method of claim 47 further comprising removing the inflation balloon from the stent.

49. The method of claim 45 wherein allowing the stent to self-expand comprises allowing the stent to self-expand into secure contact against an inner surface of the vessel.

50. A method of forming a polymeric substrate, comprising:
immersing a mandrel into at least a first polymeric solution such that at least a first layer of a biocompatible polymer substrate is formed upon the mandrel and has a first diameter defined by the mandrel;
curing the substrate;
forming an expandable stent scaffold having the first diameter from the substrate: and reducing the first diameter of the stent to a second smaller diameter, wherein the stent retains one or more mechanical properties of the polymer resin such that the stent exhibits ductility upon application of a load.

51. The method of claim 50 wherein prior to forming an expandable stent scaffold, further comprising:

controlling a number of immersions of the mandrel into the first polymeric solution;
controlling a duration of time of each immersion of the mandrel; and controlling a delay time between each immersion of the mandrel.

52. The method of claim 51 further comprising controlling a withdrawal rate of the mandrel from the first polymeric solution after each immersion.

53. The method of claim 50 wherein the first polymeric solution comprises a polymer having a relatively high molecular weight.

54. The method of claim 50 wherein the first polymeric solution is selected from the group consisting of polyethylene, polycarbonates, polyamides, polyesteramides, polyetheretherketone, polyacetals, polyketals, polyurethane, polyolefin, polyethylene terephthalate, polylactide, poly-L-lactide, poly-glycolide, poly(lactide-co-glycolide), polycaprolactone, caprolactones, polydioxanones, polyanhydrides, polyorthocarbonates, polyphosphazenes, chitin, chitosan, poly(amino acids), polyorthoesters, oligomers, homopolymers, methyl cerylate, methyl methacrylate, acryli acid, methacrylic acid, acrylamide, hydroxyethy acrylate, hydroxyethyl methacrylate, glyceryl scrylate, glyceryl methacrylate, methacrylamide, ethacrylamide, styrene, vinyl chloride, binaly pyrrolidone, polyvinyl alcohol, polycoprolactarn, polylauryl lactam, polyjexamethylene adipamide, polyexamethylene dodecaoediamide, trimethylene carbonate, poly(.beta.-hydroxybutyrate), poly(g-ethyl glutamate), poly(DTH
iminocarbonate), poly(bisphenol A
iminocarbonate), polycyanoacrylate, polyphosphazene, methyl cerylate, methyl niethacrylate, acryli acid, methacrylic acid, acrylamide, hydroxyethy acrylate, hydroxyethyl methacrylate, glyceryl scrylate, glyceryl methacrylate, methacrylamide, ethacrylamide, and copolymers, terpolymers and combinations and mixtures thereof.

55. The method of claim 50 wherein immersing a mandrel comprises further immersing the mandrel into a second polymeric solution such that a second layer of polymer is formed upon the first layer.

56. The method of claim 55 wherein the second polymeric solution comprises a drug or agent selected from the group consisting of antipoliferative, antineoplastic, antigenic, anti-inflammatory, antirestenotic, antilipid, antimitotics, metalloproteinase inhabitors, and anti-selerosing agents.

57. The method of claim 55 wherein the second polymeric solution comprises a radio-opaque material.

58. The method of claim 57 wherein the mandrel is immersed at one or both ends of the substrate into the radio-opaque material.

59. The method of claim 55 wherein the second polymeric solution comprises a BaSO4 solution.

60. The method of claim 51 wherein controlling a number of immersions comprises immersing the mandrel between 2 and 20 times.

61. The method of claim 51 wherein controlling a duration of time comprises immersing the mandrel between 15 seconds and 240 minutes,

62. The method of claim 51 wherein controlling a delay time comprises delaying immersion of the mandrel between 15 seconds and 60 minutes.

63. The method of claim 50 wherein immersing a mandrel comprises inserting the mandrel into the first polymeric solution at a rate of 5 mm min to 1000 mm/min.

64. The method of claim 50 further comprising applying a force within a lumen defined through the polymeric substrate such that the substrate expands from a first diameter to a second larger diameter.

65. The method of claim 64 wherein applying a force comprises introducing a pressurized gas within the lumen.

66. The method of claim 64 further comprising constraining expansion of the polymeric substrate via a molding tube.

67. The method of claim 66 further comprising expanding at least a portion of the polymeric substrate into a shape defined by the molding tube.

68. The method of claim 64 further comprising applying heat to the polymeric substrate while applying the force.

69. The method of claim 50 further comprising rotating the mandrel while applying heat.

70. The method of claim 50 further comprising controlling an angle of the mandrel relative to the polymeric solution.

71. The method of claim 70 wherein controlling an angle comprises alternating an angle of the mandrel up to 180°.

72. The method of claim 50 wherein the substrate has a length of 1 cm to 40 cm.

73. The method of claim 50 further comprising controlling a relative humidity of less than 30%.

74. The method of claim 50 further comprising controlling a temperature of the polymeric solution to be below a boiling point of a solvent contained within the polymeric solution.

75. The method of claim 50 further comprising mold-transferring one or more patterns from an outer surface of the mandrel to an inner surface of the substrate.

76. The method of claim 50 further comprising controlling a crystallinity percentage of the substrate.

77. The method of claim 50 wherein the substrate formed upon the mandrel is isotropic.

78. The method of claim 50 curing the substrate comprises drying the substrate at a glass transition temperature of the polymeric solution.

79. The method of claim 50 wherein prior to forming an expandable stent scaffold, further comprising:
subjecting the substrate to a first elevated temperature above a glass transition temperature of the substrate while reducing the first diameter; and cooling the substrate to a second temperature lower than the glass transition temperature such that the substrate transitions to a glass state and imparts a shape memory effect.

80. The method of claim 79 wherein reducing comprises reducing the first diameter ranging from 3 mm to 9 mm to the second diameter ranging from 1.5 mm to 5 mm.

81. The method of claim 79 wherein cooling comprises reducing the substrate temperature to the second temperature below the glass transition temperature.

82. The method of claim 50 wherein the expandable stent scaffold exhibits a 20% radial deformation when placed under a 0,1 N to 20 N load.

83. The method of claim 50 wherein the expandable stent scaffold exhibits a percent reduction in diameter of between 5% to 70% without fracture formation when placed under a compressive load.

84. The method of claim 50 wherein forming an expandable stent scaffold comprises machining the stent from the substrate.

85. The method of claim 84 further comprising expanding a diameter of the stent via an expandable balloon by 5% to 70% without fracture formation.

86. The method of claim 84 wherein the stent is adapted to curve up to 180° about a 1 cm curvature radius without fracture formation.

87. The method of claim 84 wherein the stent is adapted to exhibit a percent reduction in axial length of between 10% to 30% without fracture formation when placed under an axial load.

88. A method of fabricating a stent from a polymeric substrate, comprising:
immersing a mandrel into at least a first polymeric solution such that at least a first layer of a biocompatible polymer substrate is formed upon the mandrel and has a first diameter defined by the mandrel;
processing the polymeric substrate to form an expandable stent scaffold configured for delivery and deployment within a vessel; and reducing the first diameter of the stent scaffold to a second smaller diameter, wherein the stent scaffold retains one or more mechanical properties of the polymer resin such that the stent scaffold exhibits ductility upon application of a load.

89. The method of claim 88 wherein prior to forming an expandable stent scaffold, further comprising:
controlling a number of immersions of the mandrel into the first polymeric solution;
controlling a duration of time of each immersion of the mandrel;
controlling a delay time between each immersion of the mandrel;

90. The method of claim 89 further comprising controlling a withdrawal rate of the mandrel from the first polymeric solution after each immersion.

91. The method of claim 88 wherein the first polymeric solution comprises a polymer having a relatively high molecular weight.

92. The method of claim 88 wherein immersing a mandrel comprises further immersing the mandrel into a second polymeric solution such that a second layer of polymer is formed upon the first layer.

93. The method of claim 92 wherein the second polymeric solution comprises a drug or agent selected from the group consisting of antipoliferative, antineoplastic, antigenic, anti-inflammatory, antirestenotic, antilipid, antimitotics, metalloproteinase inhibitors, and anti-sclerosing agents.

94. The method of claim 92 wherein the second polymeric solution comprises a radio-opaque material.

95. The method of claim 94 wherein the mandrel is immersed at one or both ends of the substrate into the radio-opaque material.

96. The method of claim 92 wherein the second polymeric solution comprises a BaSO4 solution.

97. The method of claim 89 wherein controlling a number of immersions comprises immersing the mandrel between 2 and 20 times.

98. The method of claim 89 wherein controlling a duration of time comprises immersing the mandrel between 15 seconds and 240 minutes.

99. The method of claim 89 wherein controlling a delay time comprises delaying immersion of the mandrel between 15 seconds and 60 minutes.

100. The method of claim 88 wherein immersing a mandrel comprises inserting the mandrel into the first polymeric solution at a rate of 5 mm-min to 1000 mm/min.

101. The method of claim 88 further comprising applying a force within a lumen defined through the polymeric substrate such that the substrate expands from a first diameter to a second larger diameter,

102. The method of claim 101 wherein applying a force comprises introducing a pressurized gas within the lumen.

103. The method of claim 101 further comprising constraining expansion of the polymeric substrate via a molding tube.

104. The method of claim 103 further comprising expanding at least a portion of the polymeric substrate into a shape defined by the molding tube.

105. The method of claim 101 further comprising applying heat to the polymeric substrate while applying the force.

106. The method of claim 88 further comprising rotating the mandrel while applying heat.

107. The method of claim 88 further comprising controlling an angle of the mandrel relative to the polymeric solution.

108. The method of claim 107 wherein controlling an angle comprises alternating an angle of the mandrel up to 180°.

109. The method of claim 88 wherein the substrate has a length of 1 cm to 40 cm.

110. The method of claim 88 further comprising controlling a relative humidity of less than 30%.

111. The method of claim 88 further comprising controlling a temperature of the polymeric solution to be below a boiling point of a solvent contained within the polymeric solution.

112. The method of claim 88 further comprising mold-transferring one or more patterns from an outer surface of the mandrel to an inner surface of the substrate.

113. The method of claim 88 further comprising controlling a crystallinity percentage of the substrate.

114. The method of claim 88 further comprising drying the substrate at a glass transition temperature of the polymeric solution.

115. The method of claim 88 further comprising:
subjecting the substrate to a first elevated temperature above a glass transition temperature of the substrate while reducing the first diameter; and cooling the substrate to a second temperature lower than the glass transition temperature such that the substrate transitions to a glass state and imparts a shape memory effect.

116. The method of claim 115 wherein reducing comprises reducing the first diameter ranging from 3 mm to 9 mm to the second diameter ranging from 1.5 mm to 5 mm.

117. The method of claim 1 i 5 wherein cooling comprises reducing the substrate temperature to the second temperature of 20° C below the glass transition temperature.

118. The method of claim 115 wherein the substrate formed upon the mandrel exhibits a ductility percent reduction of 5% to 50%.

119. The method of claim 115 wherein the substrate formed upon the mandrel exhibits a percent elongation of between 10% to 300% at failure when placed under a 100 N
to 300 N load.

120. The method of claim 115 wherein processing the polymeric substrate comprises laser machining or mechanical machining.

121. The method of claim 115 wherein the stent exhibits a percent reduction in diameter of between 5% to 70% without fracture formation when placed under a compressive load.

122. The method of claim 115 further comprising expanding a diameter of the stent via an expandable balloon by 5% to 70% without fracture formation.

123. The method of claim 115 wherein the stent is adapted to curve up to 180° about a 1 cm curvature radius without fracture formation.

124. The method of claim 115 wherein the stent is adapted to exhibit a percent reduction in axial length of between 10% to 30% without fracture formation when placed under an axial load.

125. A stent processed from a polymeric substrate, comprising:
an implantable stent scaffold having a first expanded diameter and a second delivery diameter which is less than the first diameter, the stent scaffold retaining one or more mechanical properties of the polymer substrate.

126. The stent of claim 125 wherein the stent scaffold exhibits a percent reduction for ductility of 5% to 50% and a percent elongation of 10% to 300% without failure.

127. The stent of claim 125 wherein the stent scaffold has a first expanded diameter of 3 mm to 9 mm and a second delivery diameter of 1.5 mm to 5 mm.

128. The stent of claim 125 wherein the stent is adapted to exhibit a 20%
radial deformation when placed under a 0.1 N to 20 N load.

129. The stent of claim 125 wherein the stent is adapted to exhibit a percent elongation of between 10% to 300% at failure when placed under a 100 N to 300 N load.

130. The stent of claim 125 wherein the stent is adapted to exhibit a percent reduction in diameter of between 5% to 70% without fracture formation when placed under a compressive load.

131. The stent of claim 125 wherein the stent is adapted to be further expanded in diameter of between 5% to 70% without fracture formation.

132. The stent of claim 125 wherein the stent is adapted to curve up to 180° about a 1 cm curvature radius without fracture formation.

133. The stent of claim 125 wherein the stent is adapted to exhibit a percent reduction in axial length of between 10% to 30% without fracture formation when placed under an axial load.