ANTITROMBOGENIC MEDICAL DEVICES AND METHODS

专利摘要:
antithrombogenic medical devices and methods. the present invention relates to methods for applying layers to medical devices, and related devices are provided. such devices may include stents. for example, the device may include a sidewall and a plurality of pores on the sidewall, which are sized to inhibit blood flow through the sidewall to an aneurysm to a degree sufficient to lead to thrombosis and aneurysm healing when the tubular limb is positioned in a blood vessel and adjacent to the aneurysm. the device may have an outer antithrombogenic layer distributed over at least a portion of the device.
公开号:BR112016010991B1
申请号:R112016010991-0
申请日:2014-11-11
公开日:2020-12-15
发明作者:Junwei Li；Min-Shyan Sheu；Xiaodong Ma；John Wainwright；Lincoln Eramo
申请人:Covidien Lp；
IPC主号:

专利说明:

BACKGROUND
[0001] Vasculature walls, particularly arterial walls, can develop areas of weakness and / or dilation called aneurysms. The rupture of certain aneurysms, for example, abdominal and cerebral aortic aneurysms or cerebral aneurysms in the neurovasculature, can cause hemorrhage and death. Aneurysms are usually treated by excluding the weakened part of the vessel from the arterial circulation. For the treatment of a cerebral aneurysm, such exclusion can be performed by: (i) surgical clipping, where a metal clip is fixed around the base of the aneurysm; (ii) plug the aneurysm with small flexible spirals (microspirals); (iii) use of embolic materials to "fill" the aneurysm; (iv) use of balloons or detachable spirals for the occlusion of the original vessel that supplies the aneurysm; and / or (v) intravascular stent placement including bypass flow therapy.
[0002] Stents include generally tubular prostheses, which expand radially, or otherwise, inside a vessel or in the lumen to provide therapy or support against vessel obstruction. Stents from various constructs can be used, including balloon expandable metal stents, self-expanding metal braided stents, metal mesh stents, rolled stents, laminated stents, and the like. Stent-grafts endoprostheses are also used, which include a tubular graft material supported by a metallic stent.
[0003] The coatings were applied to medical devices to provide lubricating and / or anti-adhesive properties and serve as a deposit for the release of the bioactive agent. As medical devices, especially those with uneven and / or rough surfaces, can be conducive to the formation of thrombi, coatings can be applied to these medical devices to reduce the formation of thrombi. The adhesion of these coatings to the substrate used to form the device can prove difficult, with delamination occurring in some cases. SUMMARY
[0004] In accordance with certain embodiments of the present invention, a medical device (for example, a stent) is provided with an outer layer (s) on top of that providing the device with reduced thrombogenicity. In embodiments, a medical device of the present invention includes an expandable tubular body that has a plurality of braided filaments configured to be implanted in a blood vessel, the braided filaments including a metal, such as platinum, cobalt, chromium, nickel, alloys thereof , and their combinations; wherein the filaments have an outer surface, including a phosphorylcholine; and where phosphorylcholine is less than 100 nanometers thick.
[0005] Systems using the medical devices of this invention are also provided. In embodiments, a system of the present invention includes a system for the treatment of an aneurysm. Such a system includes a core set configured for insertion into a blood vessel, the core set having a distal segment; an expandable tubular body carried by the joint distal segment of the core, the tubular body having a plurality of braided filaments configured to be implanted in a blood vessel, the braided filaments, including a metal, such as platinum, cobalt, chromium, nickel, alloys themselves, and their combinations; wherein the filaments have an outer surface, including a phosphorylcholine; and where phosphorylcholine is less than 100 nanometers thick.
[0006] Methods for treating medical conditions with the devices of the present invention are also provided. In the modalities, a method of the present description includes a method of treating an aneurysm formed in a wall of a main blood vessel. Such a method includes implanting the tubular body of a medical device of the present description into the main blood vessel so that a side wall of the medical device extends through a neck of the aneurysm, thereby causing thrombosis within the aneurysm.
[0007] In other embodiments, a method of treating an aneurysm formed in a wall of a patient's main blood vessel includes implantation of a metal flow separation stent having an outer surface of phosphorylcholine less than 100 nanometers thick in the main blood vessel through the neck of the aneurysm, in order to treat the aneurysm; and or (a) prescription to the patient on a reduced anti-platelet medication protocol, compared to a protocol that would be prescribed to the patient if an otherwise similar stent that does not have the outer surface of phosphorylcholine were implanted in the patient, or (b) declining to prescribe any anti-platelet medication to the patient.
[0008] In still other embodiments, a method of treating an aneurysm formed in a wall of a patient's main blood vessel includes installing a flow separation stent in the main blood vessel through the neck of the aneurysm, in order to treat the aneurysm, minus a portion of the stent that has an outer surface of phosphorylcholine less than 100 nanometers thick so that the stent has a peak concentration of thrombin that is less than 0.8 times the peak concentration thrombin from an otherwise similar stent that lacks the outer surface of phosphorylcholine; and or (a) the prescription for the patient a reduced anti-platelet medication protocol, compared to a protocol that would be prescribed to the patient, if the otherwise similar stent that does not have the outer surface of the phosphorylcholine were implanted in the patient , or (b) declining to prescribe any anti-platelet medication to the patient.
[0009] The object technology is illustrated, for example, according to several aspects described below. Several examples of aspects of the object technology are described as numbered clauses (1, 2, 3, etc.) for convenience. These are provided as examples and are not limited to the object technology. Note that any of the dependent clauses can be combined in any combination, and placed in a respective independent clause, for example, clause 1 or clause 5. The other clauses can be presented in a similar way. Clause 1. A medical device, comprising: an expandable tubular body comprising a plurality of braided filaments configured to be implanted in a blood vessel, the braided filaments comprising a metal selected from the group consisting of platinum, cobalt, chromium , nickel, alloys thereof, and combinations thereof; wherein the filaments have an outer surface comprising a phosphorylcholine; and where phosphorylcholine is less than 100 nanometers thick. Clause 2. The medical device in clause 1, where phosphorylcholine is selected from the group consisting of 2-methacryloyloxyethyl phosphorylcholine, 2-acryloyloxyethyl phosphorylcholine, and phosphorylcholines based on monomers such as 2- (meth) acryloyloxyethyl-2 '- (trimethylammonium) ethyl phosphate, 3- (meth) acryloyloxypropyl-2 '- (trimethylammonium) ethyl phosphate, 4- (meth) acryloyloxybutyl-2'- (trimethylammonium) ethyl phosphate, 5- (meth) acryloyloxypentyl-2' - (trimethylammonium) ethyl phosphate , 6- (meth) acryloxyhexyloxyhexyl-2 '- (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-2' - (triethylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-2'- (tripropylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-2 '- (tributylammonium) ethyl phosphate, 2- (meth) acryloyloxypropyl-2' - (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxybutyl-2 '- (trimethylammonium) ethyl phosphate , 2- (meth) acryloyloxypentyl-2'- (trimethylammonium) ethyl phosphate, 2- (meth) acryloxyhexyloxy-hexyl-2'- (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-3 '- (trimethylammonium) propyl phosphate, 3- (meth) acryloyloxypropyl-3 '- (trimethylammonium) propyl phosphate, 4- (meth) acryloyloxybutyl-3' - (trimethylammonium) propyl phosphate, 5- (met) acryloyloxypentyl-3 '- (trimethylammonium) propyl phosphate, 6- (met) acryloxyhexyloxyhexyl-3 '- (trimethylammonium) propyl phosphate, 2- (meth) acryloyloxyethyl-4'- (trimethylammonium) butyl phosphate, 3- (meth) acryloyloxypropyl-4' - (trimethylammonium) butyl phosphate, 4- (meth) acryloyloxybutyl-4 '- (trimethylammonium) butyl phosphate, 5- (meth) acryloyloxypentyl-4' - (trimethylammonium) butyl phosphate, 6- (met) acryloxyhexyloxy-hexyl-4 '- (trimethylammonium) butylphosphate , and their combinations. Clause 3. The medical device in Clause 1, in which the phosphorylcholine comprises a copolymer having a reactive chemical group. Clause 4. The medical device in Clause 3, in which the reactive chemical group is selected from the group consisting of amine, hydroxyl, epoxy, silane, aldehyde, carboxylate and thiol. Clause 5. The medical device in Clause 1, which further comprises a layer of silane between the metal and the phosphorylcholine. Clause 6. The medical device in Clause 5, in which the silane is selected from the group consisting of 3-glycidoxypro-piltrimethoxysilane, 2- (3,4-epoxycyclohexyl) ethyl-triethoxysilane, 2- (3,4 - epoxycyclohexyl) ethyl-trimethoxysilane, (3-glycidoxypropyl) trimethoxysilane, (3-glycidoxypropyl) triethoxysilane, 5,6-epoxy-hexyltriethoxysilane, (3-glycidoxypropyl) methyldiethoxysilane, (3-glycidoxypropyl), 3-glyoxypropyl) glycidoxypropyl) dimethylethoxysilane, 3-isocyanatopropyltriethoxysilane, (isocyanatomethyl) methyldimethoxysilane, 3-isocyanatopropyltrimethoxysilane, tris (3-trimethoxysilylpropyl) isocyanurate, (3-triethoxyethylpropyl) -ethoxyethylcarbamate, butylcarbonate; Clause 7. The medical device in Clause 1, wherein the tubular body comprises (a) platinum or platinum alloy filaments, combined with (b) the cobalt-chromium alloy filaments. Clause 8. The medical device of Clause 7, in which the filaments of platinum or platinum alloy have a layer of phosphorylcholine, and in which the filaments of cobalt-chromium alloy which have an intermediate layer between the silane filaments of cobalt alloy -chromium and phosphorylcholine. Clause 9. The medical device in Clause 7, in which phosphorylcholine, or a polymer or copolymer thereof, is chemically bonded directly to the platinum or platinum alloy filaments. Clause 10. The medical device of Clause 7, in which phosphorylcholine, or a polymer or copolymer thereof, is covalently bonded to that of platinum or platinum alloy filaments. Clause 11 The medical device in Clause 7, in which phosphorylcholine, or a polymer or copolymer thereof, is chemically bonded to a silane along the cobalt-chromium alloy filaments. Clause 12. The medical device of Clause 11, wherein the phosphorylcholine, or the polymer or copolymer thereof, is covalently bonded to a silane along the cobalt-chromium alloy filaments. Clause 13. The medical device in Clause 1, wherein the tubular body comprises filaments of platinum or platinum alloy. Clause 14. The medical device of Clause 13.0 in which phosphorylcholine, or a polymer or copolymer thereof, is covalently bonded to that of platinum or platinum alloy filaments. Clause 15. The medical device in Clause 13, in which the phosphorylcholine, or a polymer or copolymer thereof, is chemically bonded to the platinum or platinum alloy filaments. Clause 16. The medical device of Clause 1, in which the tubular body has a side wall formed by the braided filaments, the side wall which has a plurality of pores contained therein, the plurality of pores is sized to inhibit the flow of blood through the side wall for an aneurysm to a degree sufficient to lead to thrombosis and healing of the aneurysm when the tubular body is positioned in a blood vessel and adjacent to the aneurysm. Clause 17. The medical device of Clause 1, in which the tubular body has a side wall formed by the braided filaments, the side wall which has a plurality of pores inside, a plurality of pores with an average pore size that is less than or equal to 500 microns. Clause 18. The medical device in Clause 1, in which the tubular body is fixed in heat, so that the filaments are in at least their strained configuration in the tubular body. Clause 19. The medical device in Clause 1, where the outer surface is the outermost surface of the filaments. Clause 20. The medical device in Clause 1, wherein the medical device comprises a stent. Clause 21. The medical device in Clause 1, in which the phosphorylcholine has a thickness of about 1 to about 100 nanometers. Clause 22. The medical device in Clause 1, in which the tubular body is self-expanding. Clause 23. The medical device in Clause 1, in which the device is smaller than an identical thrombogenic device whose braided filaments are entirely empty metal. Clause 24. The medical device of Clause 1, in which the device has a time elapsed before the formation of the thrombin spike which is at least 1.5 times the time elapsed before the formation of the thrombin spike for an identical device whose strands braid - they are entirely empty metal. Clause 25. The medical device of Clause 1, in which the device has a peak concentration of thrombin that is less than 0.8 times the peak concentration of thrombin by an identical device whose braided filaments are entirely empty metal. Clause 26. A system for treating an aneurysm, the system comprising: a set of nuclei configured for insertion into a blood vessel, the set of nuclei having a distal segment; an expandable tubular body carried by the distal joint core segment, the tubular body comprising a plurality of braided filaments configured to be implanted in a blood vessel, the braided filaments comprising a metal selected from the group consisting of platinum, cobalt , chromium, nickel, alloys thereof, and their combinations; wherein the filaments have an outer surface comprising a phosphorylcholine; and where phosphorylcholine is less than 100 nanometers thick. Clause 27. The clause 26 system, in which phosphorylcholine is selected from the group consisting of 2-methacryloyloxyethyl phosphorylcholine, 2-acryloyloxyethyl phosphorylcholine, and phosphorylcholines based on monomers such as 2- (meth) acryloyloxyethyl-2 '- (trimethylammonium) ethyl phosphate, 3- (meth) acryloyloxypropyl-2 '- (trimethylammonium) ethyl phosphate, 4- (meth) acryloyloxybutyl-2'- (trimethylammonium) ethyl phosphate, 5- (meth) acryloyloxypentyl-2' - (trimethylammonium) ethyl phosphate, 6- (met) acryloxy-hexyloxy-hexyl-2 '- (trimethylammonium) ethyl phosphate, 2- (met) acryloyloxyethyl-2' - (triethylammonium) ethyl phosphate, 2- (met) acryloyloxyethyl-2'- (tripropylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-2 '- (tributylammonium) ethyl phosphate, 2- (meth) acryloyloxypropyl-2' - (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxybutyl-2 '- (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxypentyl-2'- (trimethylammonium) ethyl phosphate, 2- (meth) acryloxy-hexyloxy-hexyl-2'- (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-3 '- (trimethylammonium) propyl phosphate, 3- (met) ac ryloyloxypropyl-3 '- (trimethylammonium) propyl phosphate, 4- (meth) acryloyloxybutyl-3' - (trimethylammonium) propyl phosphate, 5- (meth) acryloyloxypentyl-3 '- (trimethylammonium) propyl phosphate, 6- (meth) acryloxy- hexyloxy-hexyl-3 '- (trimethylammonium) propyl phosphate, 2- (meth) acryloyloxyethyl-4'- (trimethylammonium) butyl phosphate, 3- (meth) acryloyloxypropyl-4' - (trimethylammonium) butyl phosphate, 4- (met) acryloyloxybutyl-4 '- (trimethylammonium) butyl phosphate, 5- (meth) acryloyloxypentyl-4' - (trimethylammonium) butyl phosphate, 6- (meth) acryloxyhexyloxy-hexyl-4 '- (trimethylammonium) butylphosphate, and combinations thereof. Clause 28. The system of Clauses 26, which further comprises a layer of silane between the metal and the phosphorylcholine. Clause 29. The Clause 28 system, in which the silane is selected from the group consisting of 3-glycidoxypropyltrimethoxysilane, 2- (3,4-epoxycyclohexyl) ethyl-triethoxysilane, 2- (3,4-epoxycyclo- hexyl) ethyl-trimethoxysilane, (3-glycidoxypropyl) trimethoxysilane, (3-glycidoxypropyl) triethoxysilane, 5,6-epoxy-hexyltriethoxysilane, (3-glycidoxypropyl) methyldiethoxysilane, (3-glycidoxypropyl) methyl-methoxy-siloxypropyl) , 3-isocyanatopropyltriethoxysilane, (isocyanatomethyl) methyldimethoxysilane, 3-isocyanatopropyltrimethoxysilane, tris (3-trimethoxysilpropyl) isocyanurate, (3-triethoxysilylpropyl) -t-butylcarbamate, triethoxyethylsilane, triethoxyethylsilane Clause 30. The Clause 26 system, wherein the tubular body comprises (a) platinum or platinum alloy filaments, combined with (b) the cobalt-chromium alloy filaments. Clause 31. The system of Clause 30, in which the filaments of platinum or platinum alloy have a layer of phosphorylcholine, and in which the filaments of cobalt-chromium alloy which have an intermediate layer between the silane filaments of cobalt- chromium and phosphorylcholine. Clause 32. The clause 30 system, in which phosphorylcholine is chemically bonded directly to the platinum or platinum alloy filaments. Clause 33. The clause 30 system, in which the phosphorylcholine is covalently linked to the platinum or platinum alloy filaments. Clause 34. The clause 30 system, in which phosphorylcholine is chemically linked to a silane along the cobalt-chromium alloy filaments. Clause 35. The clause 34 system, in which the phosphorylcholine is covalently linked to a silane along the cobalt-chromium alloy filaments. Clause 36. The system of Clause 26, in which the tubular body comprises filaments of platinum or platinum alloy. Clause 37. The clause 36 system, in which phosphorylcholine is covalently linked to platinum or platinum alloy filaments. Clause 38. The clause 36 system, in which the phosphorylcholine is chemically bonded to the platinum or platinum alloy filaments. Clause 39. The system of Clause 26, in which the tubular body has a side wall formed by the braided filaments, the side wall which has a plurality of pores contained therein, the plurality of pores is sized to inhibit the flow of blood through the wall lateral to an aneurysm to a degree sufficient to lead to thrombosis and healing of the aneurysm when the tubular body is positioned in a blood vessel and adjacent to the aneurysm. Clause 40. The system of Clause 26, in which the tubular body has a side wall formed by the braided filaments, the side wall which has a plurality of pores inside, a plurality of pores with an average pore size that is smaller or equal to 500 microns. Clause 41. The system of Clause 26, in which the tubular body is fixed in heat, so that the filaments are in at least their strained configuration in the tubular body. Clause 42. The Clause 26 system, where the outer surface is a more outer surface of the filaments. Clause 43. The clause 26 system, in which the tubular body comprises a stent. Clause 44. The Clause 26 system, in which the phosphorylcholine has a thickness of about 1 to about 100 nanometers. Clause 45. The system of Clause 26, in which the tubular body is self-expanding. Clause 46. The Clause 26 system, in which the tubular body is smaller than an identical thrombogenic body whose braided filaments are entirely empty metal. Clause 47. The system of Clause 26, in which the tubular body has an elapsed time before the formation of the thrombin peak which is at least 1.5 times the time elapsed before the formation of the thrombin peak for an identical tubular body whose filaments braids are entirely empty metal. Clause 48. The system of Clause 26, in which the tubular body has a peak concentration of thrombin that is less than 0.8 times the peak concentration of thrombin by an identical tubular body whose braided filaments are entirely empty metal. Clause 49. The clause 26 system, which further comprises a micro catheter configured to receive the core assembly and a tubular element in the lumen of the micro catheter in a sliding way. Clause 50. A method of treating an aneurysm formed in a wall of a main blood vessel, comprising the method: the implantation of the tubular body of any preceding clause in the main blood vessel so that a side wall of the medical device extends through an aneurysm neck, thus causing thrombosis within the aneurysm. Clause 51. A method of treating an aneurysm formed in a wall of a patient's main blood vessel, comprising the method: implantation of a metal flow separation stent having an outer surface of phosphorylcholine less than 100 nanometers thick in main blood vessel through the neck of the aneurysm, in order to treat the aneurysm; and both (a) prescribing to the patient on a reduced anti-platelet medication protocol, compared to a protocol that would be prescribed to the patient if an otherwise similar stent that does not have the outer surface of phosphorylcholine were implanted in the patient, or (b) declining to prescribe any anti-platelet medication to the patient. Clause 52. The method of clause 51, in which the stent comprises the tubular body of any previous number. Clause 53. The clause 51 method, in which the patient is one who has been diagnosed as being at risk of intracranial hemorrhage. Clause 54. The clause 51 method, in which the patient is one who has been diagnosed as being at risk of cerebral hemorrhage from an aneurysm. Clause 55. The clause 51 method, in which the main blood vessel is an intracranial artery. Clause 56. The clause 51 method, which further comprises accessing a region close to the aneurysm treatment by inserting a micro catheter into the main vessel, and delivering the stent through the micro catheter to the treatment region. Clause 57. The clause 51 method, in which the stent exhibits an elapsed time before the formation of the thrombin peak, which is at least 1.5 times the elapsed time of a similar stent that does not have the outer surface of phosphorylcholine. Clause 58. The clause 51 method, wherein the stent has a peak concentration of thrombin that is less than 0.8 times the peak concentration of thrombin for a similar stent that lacks the outer surface of phosphorylcholine. Clause 59. A method of treating an aneurysm formed in a wall of a patient's main blood vessel, comprising the method: the implantation of a flow separation stent in the main blood vessel through the neck of the aneurysm, in order to treat the aneurysm, minus a portion of the stent that has an outer surface of phosphorylcholine less than 100 nm in thickness so that the stent has a peak concentration of thrombin that is less than 0.8 times the concentration of thrombin peak of an otherwise similar stent that lacks the outer surface of phosphorylcholine; and both (a) prescribing to the patient on a reduced anti-platelet medication protocol, compared to a protocol that would be prescribed to the patient if an otherwise similar stent that does not have the outer surface of phosphorylcholine were implanted in the patient, or (b) declining to prescribe any anti-platelet medication to the patient. Clause 60. The clause 59 method, in which the stent comprises the tubular body of any previous number. Clause 61. The clause 59 method, in which the patient is one who has been diagnosed as being at risk of intracranial hemorrhage. Clause 62. The clause 59 method, in which the patient is one who has been diagnosed as being at risk of cerebral hemorrhage from an aneurysm. Clause 63. The clause 59 method, in which the main blood vessel is an intracranial artery. Clause 64. The method of clause 59, which also includes access to a region close to the aneurysm treatment by inserting a micro catheter into the main vessel, and delivering the stent through the micro catheter to the treatment region.
[0010] Additional features and advantages of the object technology will be defined in the description below, and in part will be apparent from the description or can be learned by practicing the present object technology. The advantages of object technology will be realized and achieved by the structure particularly pointed out in the written report and its modalities as well as in the attached drawings.
[0011] It is to be understood that both the previous general description and the following detailed description are exemplary and explanatory and are intended to provide an additional explanation of the object technology. BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The attached drawings, which are included to provide a better understanding of the object technology and are incorporated and constitute a part of this specification, illustrate aspects of the description and, together with the description, serve to explain the principles of the object technology.
[0013] Figure 1 is a side view of a stent including the same outer layer, according to some modalities.
[0014] Figure 2A is an enlarged view of the stent shown in Figure 1, according to some modalities.
[0015] Figures 2B-2C are detail views of a pore of the stent in Figure 1, under different conditions. DETAILED DESCRIPTION
[0016] In the following detailed description, several specific details are established in order to provide a complete understanding of the subject technology. However, it is understood that object technology can be practiced without these specific details. In other cases, well-known structures and techniques have not been shown in detail so as not to obscure the object technology. In addition, although the present invention may refer to modalities in which the device is an endovascular prosthesis, aspects of the modalities described herein can be used with any implantable device, such as coils, filters, polymeric supports, ventricular assist devices, self-expanding and expandable stent balloon, and other devices.
[0017] The present description provides devices having coatings, surface treatments and / or layers therein, as well as modalities for the application of coatings / surface treatments / layers for medical devices. The substrates used to form medical devices in accordance with the present invention can be formed from any suitable substance, including inert materials, such as metals, glass, ceramics, combinations thereof, and the like.
[0018] In the embodiments, the substrates of the present invention may be formed of inert materials, such as glass, ceramics and / or metals. Suitable metals include gold, silver, copper, steel, aluminum, titanium, cobalt, chromium, platinum, nickel, alloys thereof, combinations thereof, and the like. Suitable alloys include nickel-titanium (eg, nitinol), cobalt-nickel, cobalt-chromium alloy, and platinum-tungsten. A suitable cobalt based alloy is 35N LT ™ available from Fort Wayne Metals from Fort Wayne, Indiana, USA.
[0019] According to some modalities described here, a medical device (for example, stent) is provided, which reduced thrombogenicity. In addition, in some embodiments, such a device may be braided and / or have a flow diversion section.
[0020] The medical devices of the present invention can include one or more layers of polymer therein. In the embodiments, the present invention provides for the use of silanes to form an optional intermediate layer that binds to the substrate. In the embodiments, the polymer layers, layers of bioactive agents, their combinations, and the like, can then be applied and bonded directly to the substrate and / or any intermediate silane layer.
[0021] Silanes that can be used in forming the optional silane layer can have at least one functional group including, but not limited to acrylate, methacrylate, aldehyde, amino, epoxy, ester, combinations thereof, and the like. In the embodiments, additional silanes that can be used in forming the silane layer include, but are not limited to, 3-glycidoxypropyl trimethoxysilane (GPTS), 2- (3,4-epoxycyclohexyl) ethyl-triethoxysilane, 2- ( 3,4-epoxycyclohexyl) ethyl-trimethoxysilane, (3-glycidoxypropyl) trimethoxysilane, (3-glycidoxypropyl) triethoxysilane, 5,6-epoxy-hexyltriethoxysilane, (3-glycidoxypropyl) methyldiethoxysilane, (3-glycidoxypropyl), 3-glydoxypropyl), -glycidoxypropyl) dimethylethoxysilane, 3-isocyanatopropyltriethoxysilane, (isocyanatomethyl) methyldimethoxysilane, 3-isocyanatopropyltrimethoxysilane, tris (3-trimethoxysilpropyl) tylsylethylpropyl, butyl, tris (3-iso-methoxy-ethylamethyl) -ethan.
[0022] In the modalities, the silanes used to form the silane layer can be in solution, which is then applied to the substrate. Suitable solvents for forming the solution include, for example, ethanol, toluene, water, deionized water, methanol, isopropyl alcohol, n-butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, propylene acetate monomethyl ether (ethyl PM), toluene, chloroform, dichloromethane, combinations thereof, and the like. The solvents can be present in amounts from about 0.1% to about 99.9% by weight of the solution, in embodiments from about 50% to about 99.8% by weight of the solution. In some embodiments, the solution may include ethanol and water in a proportion of about 95% / 5%. The silane can be in solution at a concentration of about 0.1% to about 99.9%, in the form of about 0.2% to about 50%.
[0023] In the modality, an appropriate solution for applying a layer of silane may include GPTS in 95% / 5% ethanol / water.
[0024] To apply the polymer layer and / or the optional silane layer to the substrate, it may be desirable to first clean the substrate surface. For example, the surface of the substrate can first be sonicated and cleaned with a suitable solvent, such as acetone, isopropyl alcohol, ethanol, methanol, combinations thereof, and the like. The sonication can occur for a period of time between about 1 minute to about 20 minutes, in the modalities of about 5 minutes to about 15 minutes. However, in the modalities, sonication can occur for longer periods, up to 1 hour, up to 2 hours, or more than 2 hours. The solvents used in sonication / cleaning can be applied in the form of mixtures, or individual solvents can be applied sequentially, one or more times. Sonication can occur at room temperature, for example at about 21 ° C, or at temperatures from about 18 ° C to about 55 ° C, in the modalities from about 40 ° C to about 50 ° C, in the modalities about 45 ° C.
[0025] After cleaning, the substrates can be subjected to a treatment to improve the formation of hydroxyl groups (sometimes referred to in this document as hydroxylation). The substrate surface can be hydroxylated by subjecting it to a treatment with sodium hydroxide, nitric acid, sulfuric acid, hydrochloric acid, ammonium hydroxide, hydrogen peroxide, tert-butyl hydroperoxide, potassium dichromate, perchloric acid, plasma oxygen, water plasma, corona discharge, ozone, UV, combinations thereof, and the like. The material used for the hydroxylation can be at a concentration of about 10% to about 100%, in the modalities of about 15% to about 25%, in the modalities of about 20%. Hydroxylation can occur over a period of time from about 0.5 hours to about 2.5 hours, or more than 2.5 hours, in the modalities from about 1 hour to about 2 hours, in the modalities about 1.5 hours at room temperature. Hydroxylation can also occur with agitation of about 100 to about 160 revolutions per minute (rpm), in the modalities of about 120 to about 140 rpm, in the modalities of about 130 rpm.
[0026] After hydroxylation, the substrate can be rinsed with a suitable material, such as deionized water, ethanol, methanol, combinations thereof, and the like.
[0027] The hydroxylated substrate can then be treated with the polymer and / or silanes described above. For example, in the modalities, the substrate can be immersed in a solution including silane, for a period of time from about 0.5 hours to about 3.5 hours, in the modalities from about 1 hour to about 3 hours , in the modalities about 2 hours, at room temperature.
[0028] The silane solution having the substrate can also be subjected to agitation at a rate of about 100 to about 160 revolutions per minute (rpm), in the modalities of about 120 to about 140 rpm, in the modalities of about 130 rpm.
[0029] After immersion in the silane material, the substrate can then be dipped in, or sprayed with a suitable material, such as ethanol, toluene, deionized water, methanol, isopropyl alcohol, n-butanol, dimethylformamide (DMF), sulfoxide of dimethyl (DMSO), ethyl acetate, PM acetate, toluene, chloroform, dichloromethane, their combinations, and the like, from a time of about 5 times, in the modalities of about 3 times. The substrate with respective silanes can then be heated to a temperature of about 30 ° C to about 150 ° C, in the modes of about 70 ° C to about 90 ° C, in the modes of about 80 ° C. The warm-up can occur for a period from about 5 minutes to about 25 minutes, or more than 25 minutes, in the modalities of about 10 minutes to about 20 minutes, in the modalities of about 15 minutes.
[0030] Where applied to a substrate, the silane layer can have a thickness of less than 50 nanometers, or less than 20 nanometers or less than 10 nanometers, in the modalities of about 1 nanometer to about 10 nanometers.
[0031] Once the optional silane layer has been formed, the medical device can be treated with additional components to form an outer layer on top of the silane layer. For example, bioactive agents can bind to release functional groups from the silane layer. Similarly, polymeric and / or monomeric materials can bond to free functional groups on the optional silane substrate and / or layer, with or without biactive agents.
[0032] Suitable polymeric and / or monomeric materials that can be used to form an outer layer in the medical device of the present description, bonding to any substrate, the optional silane layer described above, or both, include any material suitable for use in the medical device. Such materials can provide desirable properties for the medical device, including reduced thrombogenicity, lubricity, drug delivery, protein or DNA delivery, prevention of restenosis, protein and cell adhesion, lubricity, RNA and / or gene delivery, anti - microbial, non-fouling, promoting endothelialization, combinations thereof, and the like.
[0033] In the embodiments, appropriate polymer and / or monomeric materials that can bond to the optional silane substrate and / or layer, and are used to form an outer layer in the medical device of the present description, include phosphorylcholines. Suitable phosphorylcholines include 2-methacryloyloxyethyl phosphorylcholine (MPC), 2-acryloyloxyethyl phosphorylcholine and the like, and combinations thereof. Other phosphorylchines may be used, including phosphorylchines based on monomers including, but not limited to, 2- (meth) acryloyloxyethyl-2 '- (trimethylammonium) ethyl phosphate, 3- (meth) acryloyloxypropyl-2' - (trimethylammonium) ethyl phosphate, 4- (meth) acryloyloxybutyl-2 '- (trimethylammonium) ethyl phosphate, 5- (meth) acryloyloxypentyl-2'- (trimethylammonium) ethyl phosphate, 6- (meth) acryloxyhexyloxy-hexyl-2'- ( trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-2 '- (triethylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-2' - (tripropylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-2 '- (tributylammonium) ethyl phosphate, 2- (meth) acryloyloxypropyl-2 '- (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxybutyl-2' - (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxypentyl-2 '- (trimethylammonium) ethyl phosphate , 2- (meth) acryloxyhexyloxyhexyl-2 '- (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-3'- 3- (meth) acryloyloxypropyl-3'- 4- (meth) acryloyloxybutyl-3' - 5- (meth) acryloyloxypentyl-3'- 6- (meth) acryloxy-hexyloxy-hexyl-3'- (trimethylammonium) propyl phosphate, 2- (meth) acryloyloxyethyl-4 '- (trimethylammonium) butyl phosphate, 3- (meth) acryloyloxypropyl-4' - (trimethylammonium) butyl phosphate, 4- (meth) acryloyloxybutyl-4 '- (trimethylammonium) butyl phosphate , 5- (meth) acryloyloxypentyl-4 '- (trimethylammonium) butyl phosphate, 6- (meth) acryloxy-hexyloxy-hexyl-4'- (trimethylammonium) butyl phosphate, and combinations thereof. As used herein, "(meth) acryl" includes both methacryl and / or acryl groups. Such phosphorylchines include those commercially available as LIPIDURE® phosphate (including, for example LIPIDURE®-NH01, a reactive MPC) from NOF Corporation of Tokyo, Japan. Phosphorylcholines may include reactive phosphorylcholines, for example in the form of a phosphorylcholine copolymer and a reactive chemical group. The reactive group can be, for example, amine, hydroxyl, epoxy, silane, aldehyde, thiol or carboxylate.
[0034] In the modalities, the phosphorylchines used to form the polymer layer can be in solution, which is then applied to the substrate and / or optional silane layer. Suitable solvents to form the solution having the polymer, such as the phosphorylcholins above, include, for example, ethanol, water, deionized water, methanol, isopropyl alcohol, n-butanol, dimethylformamide (DMF), dimethyl sulfoxide ( DMSO), ethyl acetate, PM acetate, toluene, chloroform, dichloromethane, combinations thereof, and the like. The polymers can be present in amounts from about 0.5% to about 95% by weight of the solution, in embodiments from about 1% to about 50% by weight of the solution. In some embodiments, the solution may include MPC at a concentration of about 5%.
[0035] The polymer can be applied to the optional silane substrate and / or layer using various methods, including dipping, spraying, brushing, combinations thereof, and the like. For example, in the embodiments, a substrate, optionally having a silane layer, can be immersed in a solution including the polymer for a period of time from about 30 seconds to about 90 seconds, in the embodiments from about 45 seconds to about 75 seconds and, in about 45 seconds, at room temperature. Additional information on the methods of applying polymers can be found in US Patent Application No. 13 / 844,577, filed on March 15, 2013, entitled COATED MEDICAL DEVICES AND METODS OF MAKING AND USING SAME, the entire which is incorporated by reference and forms part of this specification.
[0036] After immersion in the polymer solution, the substrate, now having a polymer layer, either directly attached to the substrate, the optional silane layer, or both, can be heated to a temperature of about 60 ° C to about 100 ° C, in the range of about 70 ° C to about 90 ° C, in the range of about 80 ° C. The warm-up can occur for a period from about 15 minutes to about 45 minutes, or more than 45 minutes, in the modalities of about 20 minutes to about 35 minutes, in the modalities of about 30 minutes.
[0037] After heating, the device can be washed again. For example, the device can be sonicated and cleaned with water, ethanol, methanol, isopropyl alcohol, n-butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, PM acetate, toluene, chloroform, dichloromethane, toluene, combinations thereof, and the like. The sonication can occur for a period of time between about 1 minute to about 10 minutes, or more than 10 minutes, in the modalities of about 2 minutes to about 8 minutes, in the modalities of about 5 minutes. Sonication can occur at room temperature.
[0038] After this wash, the device can be rinsed with a suitable material, such as water, methanol, isopropyl alcohol, n-butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, PM acetate, toluene , chloroform, dichloromethane, combinations thereof, and the like. The device can then be heated to a temperature of about 60 ° C to about 100 ° C, in the range of about 70 ° C to about 90 ° C, in the range of about 80 ° C. The warm-up can occur for a period from about 5 minutes to about 25 minutes, or more than 25 minutes, in the modalities of about 10 minutes to about 20 minutes, in the modalities of about 15 minutes.
[0039] After completing this heating step, the device is now ready to be packaged in any material suitable for use in medical device packaging.
[0040] The polymer layer of the resulting medical device may be less than about 2000 nanometers in thickness, less than about 1000 nanometers, in less than about 500 nanometers, in less than about 250 nanometers, in modalities less than about 100 nanometers, in modalities less than about 50 nanometers, in modalities less than about 25 nanometers, in modalities less than about 10 nanometers, in modalities of about 1 nanometer to about 100 nanometers, in the modalities from about 1 nanometer to about 50 nanometers, in the modalities from about 1 nanometer to about 25 nanometers, in the modalities from about 1 nanometer to about 10 nanometers . In the embodiments, the polymer layer is the outermost layer, and / or the outer surface of the medical device and / or any components that form the device, for example, filaments forming a stent.
[0041] As noted above, bioactive agents can be added to a medical device of the present invention, either as part of the device and / or as part of the layer (s) applied in accordance with the present description. A "bioactive agent", as used herein, includes any substance or mixture of substances that provides a therapeutic or prophylactic effect; a compound that affects or participates in tissue growth, cell growth and / or cell differentiation; a compound that may be able to invoke one or prevent biological action, such as an immune response; or a compound that can perform any other function in one or more biological processes. A variety of bioactive agents can be incorporated into the medical device. In addition, any agent that can improve tissue repair, limits the risk of restenosis, and modulates the mechanical or physical properties of the medical device, such as a stent, can be added during the preparation of the medical device. In the embodiments, the bioactive agent can be added to the polymer used to form the outer layer of the medical device.
[0042] Examples of classes of bioactive agents that can be used according to the present invention include antimicrobials, analgesics, anesthetics, antihistamines, anti-inflammatories, cardiovascular drugs, diagnostic agents, sympathomimetics, cholinomimetics, antimuscarinics, antispasmodics, hormones, growth factors, muscle relaxants, adrenergic neuron blockers, antineoplastic agents, immunogenic agents, immunosuppressive agents, steroids, lipids, polysaccharides, lipopolysaccharides, and enzymes. It should also be understood that combinations of bioactive agents can be used.
[0043] Other bioactive agents that may be in the present invention include anti-restenosis agents, including paclitaxel, paclitaxel derivatives, rapamycin, everolimus, sirolimus, QP-2 taxane, acetinomycin D, vincristine, methotrexate, angiopeptin, mitomycin, BCP 678, antisense C-myc, rapamycin derivatives, tacrolimus, everolimus, ABT-578, biolimus A9, tranilast, dexamethasone, methylprednisolone, interferon, leflunomide, cyclosporine, halofuginone, proteinase C inhibitors, metalotein inhibitors, batimastat, propyl hydroxylase inhibitors, VEGF, 17-β-estradiol, BCP 671, HMG CoA reductase inhibitors, their combinations, and the like.
[0044] Still other bioactive agents include sympathetic-mimetic agents; vitamins; anticholinergic agents (for example, oxybutynin); cardiovascular agents, such as coronary vasodilators and nitroglycerin; alkaloids; painkillers; non-narcotics such as salicylates, aspirin, acetaminophen, d-propoxyphene and the like; anti-cancer agents; anti-inflammatory agents such as hormonal agents, hydrocortisone, prednisolone, prednisone, non-hormonal agents, allo-purinol, indomethacin, phenylbutazone and the like; prostaglandins and cytotoxic drugs; antibacterials; antibiotics; anti-fungals; anti-viral; anticoagulants; and immunological agents.
[0045] Other examples of suitable bioactive agents that may be included in the present invention include: viruses and cells; peptides, polypeptides and proteins, as well as analogs, muteins, and their active fragments; immunoglobulins; antibodies; cytokines (for example, lymphokines, monocines, chemokines); blood clotting factors; hematopoietic factors; interleukins (IL-2, IL-3, IL-4, IL-6); interferons (IFN-β, (α-IFN and Y — IFN)); erythropoietin; nucleases; tumor necrosis factor; colony-stimulating factors (eg, GCSF, GM-CSF, MCSF); insulin; tumor suppressor and anti-tumor agents; blood proteins; gonadotropins (for example, FSH, LH, CG, etc.); hormones and hormonal analogues (for example, growth hormone); vaccines (for example, tumor, bacterial and viral antigens); somatostatin; antigens; blood clotting factors; growth factors (for example, nerve growth factor, insulin-like growth factor); protein inhibitors; protein antagonists; protein agonists; nucleic acids, such as antisense molecules, DNA and RNA; oligonucleotides; and ribozymes.
[0046] Suitable medical devices that can be prepared in accordance with the present invention include, but are not limited to, stents, filters, stent linings, grafts, catheters, stents / grafts, staples and other means of fixation, staples, sutures, pins, screws, prosthetic devices, drug delivery devices, anastomosis rings, surgical blades, contact lenses, intraocular lenses, surgical meshes, knotless wound closure, sealants, adhesives, intraocular lenses, anti-adhesion devices, anchors, tunnels, bone fillings, synthetic tendons, synthetic ligaments, fabric scaffolding, stapling devices, buttresses, lapbands, orthopedic hardware, pacers, pacemakers and other implants and implantable devices.
[0047] In the modalities, most of the accessible substrate surfaces can be covered with the polymer layer and the optional silane layer. In yet other embodiments, the entire substrate is covered. The layers can cover between about 1% to about 100% of the substrate surface, in the modalities of a stent, in the modalities of about 20% to about 90% of the substrate area.
[0048] As noted above, in the embodiments, the medical device according to the present invention is a stent. Any en-dovascular prosthesis can be treated in accordance with the methods of the present invention. The stent may be a braided stent or other form of stent, such as a laser cut stent, roll-up stent, expandable balloon stent, self-expanding stent, knitted stent, and the like.
[0049] In the modalities, a vascular braiding device, such as a stent is braided with filaments, which are formed from metal alloys and / or other high temperature materials. The resulting braid is then heat treated or "heat-set" at an elevated temperature, in order to reduce the internal stresses in the filaments and / or increase or confer a self-expanding capacity of the stent. Filaments that make up the tubular body of a stent that has been defined as heat are at their least stressed or in a reduced stressed state when the stent is in the configuration it was in during heat adjustment. Such a less stressed or reduced effort state may include an expanded or fully expanded state.
[0050] The stent can optionally be configured to act as a "flow bypass" device for the treatment of aneurysms, such as those found in blood vessels, including arteries in the brain or skull, or elsewhere in the body, as peripheral arteries. The stent may, in modalities, include those sold as PIPELINE ™ Embolization Devices by Covidien, Mansfield, Massachusetts. Such devices include those described in U.S. Patent No. 8,267,986, issued September 18, 2012 entitled VASCULAR STENTING FOR ANEURYSMS, the entire description of which is incorporated herein by reference.
[0051] For example, according to the present invention, a device with a flow bypass section may have pores with a "bypass flow pore size." A "pore size bypass flow" can refer to pores with an average pore size (in at least one section of a device) that is small enough to interfere with or inhibit fluid exchange through the pores of that section. For example, a device (eg, stent) may have an active section or a flow bypass section with a pore size flow deviation when the pores in the section are sized to inhibit blood flow through the side wall to an aneurysm to a degree sufficient to lead to thrombosis and aneurysm healing when the stent / prosthesis is positioned in a blood vessel and adjacent to or around the aneurysm neck.
[0052] For example, a bypass flow pore size can be achieved when the pores in the flow bypass or active section (or in the stent as a whole) have an average pore size of less than about 500 microns, when the device (eg, stent) is in the expanded state. (When the "expanded state" is used here to specify parameters of twisted stents such as pore sizes, the expanded state is one in which the stent self-panda stops, without any external expanding forces applied, and without any external longitudinal that stretches or applied compression forces. For simplicity of measurement, in this expanded state it can be that which the endoprosthesis can self-expand into a linear glass cylindrical tube with an inner diameter that is smaller than the maximum diameter for the which the stent will self-expand in the absence of any restraint or external forces.) In some embodiments, the average pore size may be less than about 320 microns. Some embodiments described herein and allow to provide a device and manufacturing methods in which the device has a flow deflection or lateral flow deflection section which has reduced thrombogenicity, or where the device as a whole has flow deviation and thrombogenicity properties reduced.
[0053] Consequently, some modalities provide a device, such as a braided stent, that may have a flow bypass section or other portion of the device that provides embolic properties, in order to interfere with blood flow in (or to) the body space (for example, an aneurysm) into (or through) the device is implanted. The porosity and / or pore size of one or more sections of the device can be selected to interfere with blood flow to a degree sufficient for thrombosis of the aneurysm or other body space.
[0054] For example, some modalities provide a device (for example, stent) that can be configured to interfere with blood flow to generally reduce blood exchange between the original recipient and an aneurysm, which can induce aneurysm thrombosis. A device (or a component of the device, such as a side wall of a stent or a section of such a side wall) that thus interferes with blood flow can be said to have a "bypass flow".
[0055] In addition, in some modalities, a device (for example, stent) can be provided with a porosity in the range of 5% to 95% and can be used in the expanded braid. In some embodiments, a porosity in the range of 30% -90% can be used. In addition, a porosity in the range of 50% -85% can be used. Porosity can be calculated as the percentage of the total area of the outer surface of the stent that is opened, where the total area of the outer surface is the sum of the open surface area (occupied by the pores) and the solid surface area (occupied by the filament).
[0056] In addition, in some embodiments, a device (e.g., stent) can be provided with a pore size of about 20 to about 300 microns (inscribed diameter). In some embodiments, a pore size of about 25 to about 250 microns (inscribed diameter) can be employed. In some embodiments, a pore size of about 50 to about 200 microns (inscribed diameter) can be employed.
[0057] The methods of treatment and methods of fabricating the modalities of the devices (e.g., stents) described herein are also provided.
[0058] Some types of processes described here include the assembly or maintenance of a braided device (for example, stent) in a longitudinally stretched configuration during the process of applying the polymer layer and any optional silane layer. Such a device can have an expanded configuration in which the pores thereof are generally elongated peripherally, which results in a decrease in pore size or a relatively "closed" configuration. In contrast, the pore size is increased or in a relatively "open" configuration when the device is in the longitudinally stretched configuration. In the longitudinally stretched configuration, many, if not all, of the pores of the device can be opened up to an enlarged pore size, or to a general maximum pore size.
[0059] For example, in some embodiments, the configuration drawn longitudinally can open the pores by orienting the individual filaments of the device to create a pattern of open pore quadrilaterals, such as squares, rectangles, rhombuses, parallelograms, trapezoids, etc., which can allow the pore size to be generally maximized. In addition, the quadrilaterals can be formed by filaments that intersect at angles of about 0 ° to about 15 ° from a right angle. In some embodiments, the angles can be from about 0 ° to about 10 ° from a right angle. In some embodiments, the angles can be from about 0 ° to about 5 ° from a right angle. In addition, in some embodiments, the filaments can form quadrilaterals at right angles, such as squares and rectangles, which allows the pore size to be maximized. However, not all pore shapes circumscribed by the filaments can be a right-angled quadrilateral, and some variation between pores in the same or different sections of a device is possible.
[0060] In modalities, the device (e.g., stent) can take the form of a vascular occlusion device, a revascularization device, and / or an embolization device. In some embodiments, the device may be expandable from a stent made of two or more filaments. Filaments can be formed from known flexible materials, including platinum, cobalt, chromium, nickel, alloys thereof, and combinations thereof. In some embodiments, the filaments may be wire which is generally circular, round or ovoid in cross-section. In addition, the filaments can be configured in such a way that the device is self-expanding. In some embodiments, the device can be manufactured from a first group of platinum filaments bonded with tungsten (for example, about 8% tungsten), and a second group of filaments made of cobalt-chromium alloys or alloy of cobalt-nickel (for example, 35N LT ™). In other embodiments, one or more of the filaments may be formed from a biocompatible metal material, or a biocompatible polymer.
[0061] The threads or filaments can be braided in a tubular structure like a screen. In at least one embodiment, during entanglement or coiling of the device (eg, stent), the filaments can be braided using a 1-over-2-under-2 pattern. In other modalities, however, other methods of interlacing can be followed, without departing from the scope of the description. The device may have a porosity configured to reduce the hemodynamic flow in and / or induce thrombosis within, for example, an aneurysm, but simultaneously allow perfusion to a recipient whose adjacent ostium branch is traversed by a part of the device. As will be appreciated, the porosity of the device can be adjusted by "packing" the device during implantation, as is known in the art. The ends of the device can be cut to length and therefore remain free for radial expansion and contraction. The device can have a high degree of flexibility, due to the materials used, the density of the filaments and the fact that the ends of the threads or filaments are not attached to each other.
[0062] In addition to the methods described above, in embodiments, the filament combinations of the present invention may have different polymer layers applied. For example, in embodiments, a medical device of the present invention may include braided filaments of platinum or platinum alloy with or in combination with filaments of cobalt-nickel or cobalt-chromium alloy. Platinum or platinum alloy filaments may have a phosphorylcholine layer (for example, without intervening layers between the filament and phosphorylcholine), while cobalt-nickel or cobalt-chromium alloy filaments may have a intermediate silane layer between the alloy filaments and an outer layer of phosphorylcholine. In such cases, phosphorylcholine can bind directly to the filaments of platinum or platinum alloy by covalent bonding, chemical bonding, their combinations, and the like. Likewise, phosphorylcholine can be chemically bonded to a layer of silane on the cobalt-nickel or cobalt-chromium alloy filaments, or phosphorylcholine can be covalently bonded to a layer of silane on alloy filaments. cobalt-nickel or cobalt-chromium.
[0063] Other combinations are also contemplated. For example, a platinum or platinum alloy filament catalyst may also have an intermediate silane layer in addition to an outer layer of phosphorylcholine, while a cobalt-nickel alloy or cobalt-chromium alloy filament may have an outer layer of phosphorylcholine but no intermediate silane layer.
[0064] Figure 1 illustrates a self-expanding, tubular device, such as a stent 100, which includes a layer of polymer 110 arranged over at least a portion of it. An optional silane layer (not shown) can be between the filaments used to form the stent 100 and the polymer layer 110. The tubular stent 100 includes an elongated hollow body, which can be formed from a plurality of braided filaments, as discussed here. Some embodiments disclosed herein may include a layer of polymer along the entire length of the stent or only along a portion of it. Stent 100 may include a bypass portion 112. The bypass portion 112 may include a plurality of pores that have a bypass flow pore size; instead of or in addition to this property, the flow bypass portion 112 may have a flow bypass porosity. The flow bypass portion 112 may include a portion of the stent 100, or the entire stent. The bypass flow pore size can be a pore size within a relevant part of the stent, for example, within the flow bypass portion 112 or a portion thereof, or a "calculated" pore size, which is calculated from measured or nominal base stent parameters such as interlace angle, number of filaments, filament size, filament diameter, stent diameter, longitudinal weft threads per inch, radial weft threads per inch, etc. Such a computed pore size can be considered to be a type of average pore size. The size of the bypass flow pores can be of a size that interferes with or inhibits blood flow through the side wall of the stent 100, for example, between the original recipient and a sufficient aneurysm to induce or cause aneurysm thrombosis. The layer can be arranged partially or completely along the flow diversion portion 112, or along another part of the stent 100.
[0065] In some embodiments, the pores of the flow bypass portion 112 may have an average pore size of less than 500 microns (inscribed diameter), or from about 20 to about 300 microns (inscribed diameter) . In addition, the average pore size can be from about 25 to about 250 microns (inscribed diameter). In addition, the average pore size can be about 50 to about 200 microns (inscribed diameter).
[0066] The average pore size of the flow diversion portion 112 can be the average size of the pores measured with or without layer materials disposed in them. Thus, the average pore size of the flow bypass portion of a stent can be within the flow bypass ranges. In addition, the average pore size of the flow bypass portion of a stent can be within the flow bypass ranges. In addition, the flow bypass portion 112 may have pores with sizes above or below the average pore size range.
[0067] Figure 2A illustrates an enlarged view of a section of the flow bypass portion 112 of the stent 100. In this embodiment, the flow bypass portion 112 includes a plurality of filaments 120, which are braided together to form the body tubular stent 100. Figure 2A illustrates the self-expanding stent 100 in an expanded or relaxed state. In this expanded or relaxed state, filaments 120 intersect to form the pores of stent 100.
[0068] Figure 2B illustrates a single pore 140 of the flow bypass section 112, when in the relaxed state. Pore 140 is formed by a plurality of filaments 142, 144, 146, and 148. As shown, filaments 142, 144 intersect each other to form an obtuse angle of 150. In some embodiments, the obtuse angle 150 can be about 110 ° to about 170 °. In addition, the obtuse angle 150 can be from about 120 ° to about 165 °. In addition, the obtuse angle 150 can be about 130 ° to about 160 °, and in some embodiments, the obtuse angle 150 can be about 150 °.
[0069] Therefore, the size or configuration of pore 140 is "closed" or relatively small in its expanded or relaxed state shown in Figure 2B, when compared to the relatively "open" size of pore 140 when stent 100 is in a longitudinally stretched configuration, as shown in Figure 2C. Figure 2C illustrates that filaments 142, 144, 146, and 148 intersect at angles 160 that approach a right angle, for example, within about 0 ° C to about 15 ° from a right angle . In some embodiments, angles 160 can be from about 0 ° to about 10 ° from a right angle. In some embodiments, angles 160 can be from about 0 ° to about 5 ° from a right angle.
[0070] As noted above, filaments 142, 144, 146 and 148 can be made of different materials with different layers in them. For example, at least one of the filaments 142, 144, 146 and 148 can be formed from a cobalt-nickel alloy or cobalt-chromium alloy that has both a silane layer and an outer polymeric layer applied to it (not shown) , while at least one of the other filaments may be formed from a platinum or platinum alloy filament that has a polymer layer, but without any intermediate silane layer (not shown).
[0071] In addition, in order to maximize the pore size, in some embodiments, the filaments can form quadrilaterals at right angles, such as squares and / or rectangles. However, not all pore shapes circumscribed by the filaments can be a right-angled quadrilateral, and some variation between pores in the same or different sections of a stent is possible.
[0072] A device can be prepared according to some modalities by intertwining a plurality of filaments to form a braided stent, filter or other braided device. The device can then be cleaned and heat treated, if necessary, to impart desired features to the device. Thereafter, the device may have layers applied to it using aspects of the methods disclosed herein.
[0073] Some embodiments of the devices and methods described herein may therefore provide a device, such as a stent or a stranded stent, having an outer layer that has little or no thrombogenicity, which also has a deviation pore size flow rate and / or a flow offset porosity that is / are apparent throughout the stent, or in a flow offset portion or section of the stent.
[0074] The antithrombogenic polymer layer of the present description reduces the thrombogenicity of the stent, device, section, etc., having the polymer layer, in comparison with a stent, device, similar section, etc., without the polymer layer. The reduction in thrombogenicity can be significant. Layered stents in accordance with the present invention were tested to increase antithrombogenicity by means of a platelet, in which the formation of thrombin is measured by detecting the fluorescence of a fluorescent additive, in a test solution containing a sample of the stent. The time elapsed before the formation of the thrombin peak was observed. Stents with polymer layers in accordance with the present description resulted in a significant delay in the formation of peak thrombin, compared to a similar stent, which had no polymer layer. In particular, the time that elapsed before the formation of the thrombin peak was found to be about 4 times greater than the similar stent that lacks the polymer layer. Therefore, the thrombin peak time before formation with the device, stent, section, etc. having the polymer layer can be greater than 1.5 times, or more than 2 times, or more than 3 times, or about 4 times larger than a similar device, stent, section, etc., without the polymer layer.
[0075] Stents with polymer layers in accordance with the present description resulted in a significantly longer latency phase (the time that elapsed before the formation of thrombin) compared to a similar stent, which does not have the polymer. In particular, the latency phase was about 4 times greater than the similar stent that lacks the polymer layer. Therefore, the thrombin peak time before formation with the device, stent, section, etc. having the polymer layer can be greater than 1.5 times, or more than 2 times, or more than 3 times, or about 4 times larger than a similar device, stent, section, etc., without the polymer layer.
[0076] Stents with polymer layers in accordance with the present description resulted in a significant delay in the formation of peak thrombin, compared to a similar stent, which lacks the polymer layer. In particular, the peak concentration of thrombin found was about 0.3 times greater than the similar stent that lacks the polymer layer. Therefore, the peak concentration of thrombin with the device, stent, section, etc. having the polymer layer can be less than 0.8 times, or less than 0.6 times, or less than 0.5 times , or about 0.3 times larger than a similar device, stent, section, etc., without the polymer layer.
[0077] The thickness of the layers can be less than 100 nanometers, less than 50 nanometers, less than 25 nanometers, or less than 10 nanometers, or from 1 nanometer to 10, 25, 50 or 100 nanometers. In embodiments, the thickness of the polymer layers is from about 2 to about 3 nanometers. In various embodiments of the stent, device, etc., the foregoing properties may be present alone or in any combination, or may not be present.
[0078] The processes and devices of the present invention have several advantages. The methods of the present invention, in some cases, forming a silane on a medical device, followed by the formation of the same polymer layer, can improve the adhesion of the polymer layer to the substrate surface, thereby increasing the coverage on the substrate . Medical devices that have polymer layers in accordance with the present invention, therefore, both have a greater coverage area, as well as an ability to retain the outer layers and prevent delamination thereof. In addition, the use of materials such as phosphorylchines such as the polymer layer provides medical devices with very low thrombogenicity.
[0079] The following examples are presented to illustrate the modalities of the present description. These Examples are intended to be illustrative only and are not intended to limit the scope of this description. In addition, parts and percentages are by weight, unless otherwise indicated. As used herein, "room temperature" refers to a temperature of about 20 ° C to about 30 ° C. EXAMPLE 1
[0080] tubular braided stents were treated as follows. Each of the stents was configured as follows: 48 braided filaments, of which 12 were made of platinum alloy with 8% tungsten, with a filament diameter of 0.0012 inches, 12 were cobalt-chrome (35N LT ™), with 0.0012 inch filament diameter, and 24 were 35NLT, with. filament diameter of 0.0014 inches; general external diameter 5.2 mm and longitudinal weft threads per inch of 275, the two dimensions prevailing when in an expanded condition, without restrictions and without being stretched.
[0081] The stents were supplied in a clean "bare metal" condition, and prepared as follows. Each stent was hydroxylated (-OH), through acid (for example. HNO3, Or a mixture of H2SO4 / H2O2), Hydroxide (for example, NaOH, or a mixture of NH3OH / H2O2) Or plasma treatment (for example, H2O, O3). The hydroxylated metal was washed with ethanol and deionized water (DI), and placed in a container with a solution of 3-glycidoxypropyltrimethoxysilane (GPTS) for silanization. The GPTS was in a solution using 95% / 5% by volume of the ethanol / water mixture as a solvent at a GPTS concentration of 2% by weight. The stent in the solution was shaken at 130 revolutions per minute (rpm) for a period of about 90 minutes. The immersion and stirring process was carried out at room temperature. After that, the metal was washed with ethanol and water, and cured at 80 ° C for 15 minutes. (The temperature can be changed to 110 ° C or 120 ° C and the curing time can vary between 15 minutes and 90 minutes).
[0082] The silanized stent was then dipped in a solution of reactive MPC containing amino groups (LIPIDURE®-NH01, with a concentration of 5%) for 1 minute and cured at 80 ° C for at least 30 minutes. After curing, the metal surface was washed with sonicating water for 5 minutes to remove the covalently unbound polymer. The washed metal surface was dried at a temperature of about 80 ° C for 15 minutes. After completing the process and cutting to length, stents can be described as tubular braided stents, open at each end with a lumen that extends from one end to the other, and with an outer layer of MPC over all stent filaments. The MPC was bonded directly to the platinum alloy filaments, and bonded to a silane layer on the cobalt-chromium alloy filaments.
[0083] The stents with layers applied to them in accordance with this Example 1 were tested for decreased thrombogenicity by means of a platelet chart, using the following assay. A test solution was prepared as a mixture of (a) lyophilized platelets (catalog No. 101258, Biodata Corporation, Horsham, PA; reconstituted with TRIS buffered saline at a premixed concentration of 200,000 platelets per microliter), (b ), lyophilized from normal control plasma (PlasmaCon N, catalog No. 30-201, R2 Diagnostics, South Bend, IN; reconstituted with water), (c) fluorogenic substrate (Z-Gly-Gly-Arg-AMC-HCl , catalog no. I-1140, Bachem Americas Inc., Torrance, CA; 40 mM premix concentration in dimethyl sulfoxide), and (d) calcium chloride (catalog no. 2235062.5KG, Sigma Aldrich, St Louis, MO; premix concentration in 1 M in water). These were combined in the test solution in proportions (by volume) from 1 part fluorogenic substrate to 2 parts calcium chloride to 6 parts platelets to 100 parts plasma. The final concentration of the fluorogenic substrate was about 400μM and the final concentration of calcium chloride was about 20 mM.
[0084] A calibration mixture was prepared by adding a reference thrombin calibrating solution (catalog No. TS20.00, Stago Diagnostics Inc., Parsippany, NJ) and the fluorogenic substrate for the control plasma, in proportions ( in volume) from 1 part of substrate to 11 parts of calibrating solution for 98 parts of control plasma, reaching a final fluorogenic substrate concentration of about 400 μM.
[0085] Samples of stents prepared according to this Example 1 ("test stents") and identical but bare metal stents ("stents") were prepared by cutting sections of each stent to a length of 9 mm. The 9 mm sections of test stents and bare stents were placed individually in separate wells of a black, opaque 96-well polystyrene microplate (Fisher Scientific, Waltham, MA). The test solution (330 microliters) was added to each well containing a test stent or stent sample, as well as several wells each containing a 4 mm glass sphere (Fisher Scientific, catalog No. 11-312B) for serve as a positive control, and several empty wells to serve as a "blank" or negative control. The calibration mixture (330 microliters) was added to several empty wells (separate from the negative control wells) to provide a calibration reference. Fluorescence was measured in a Fluoroskan ASCENTTM microplate reader (Fisher Scientific, catalog no. 5210470) with an excitation wavelength of 360 nm, emission wavelength of 460 nm, reading interval of 20 to 30 seconds, and the total experimental time of 150 minutes.
[0086] Test stents resulted in a significant delay in the formation of peak thrombin compared to bare stents. In particular, the time elapsed before the formation of the thrombin peak was four times the time observed with bare stents (109.3 minutes for test stents compared to 29.4 minutes for bare stents). Test stents also resulted in a longer delay phase, that is, the time that elapsed before thrombin formation started; the delay phase observed for test stents was about four times, while for conventional stents (99.3 minutes for test stents compared to 26.2 minutes for nuss stents). Test stents also resulted in a lower peak thrombin concentration than bare stents; the peak thrombin concentration observed for test stents was about 0.3 times greater than that of conventional stents (150.3 nM for test stents, compared to 473.6 nM for bare stents).
[0087] The test stents also turned out to be only slightly more thrombogenic than those of empty (blank) polystyrene wells. In particular, the time elapsed before the formation of the thrombin peak of the test stents was found to be about 97% than the measurement for the empty wells (109.3 minutes for the test stents, compared to 112.3 minutes for empty wells). The delay phase observed for the test stents was about 97% than one of the empty wells (99.3 minutes for the test stents, compared to 102.9 minutes for the empty wells). Test stents also resulted in a peak concentration of thrombin that was only about 6% higher than that of empty wells (150.3 nm for test stents compared to 141.9 nM for empty wells ).
[0088] The thickness of the silane layer applied to the cobalt-chromium filaments was measured to be about 1 to about 10 nanometers, and the thickness of the MPC layer applied to the platinum-tungsten filaments, and the filaments of cobalt-chromium on the silane layer, was measured to be about 2 to about 3 nanometers. Treatment Methods
[0089] As mentioned elsewhere in this document, the present invention also includes methods of treating a vascular disease, such as an aneurysm or intracranial aneurysm, with any of the stent modalities described herein. The low thrombogenicity stents of the present invention can, in some embodiments, be implanted around the neck of the aneurysm and the flow-diverting properties used to reduce blood flow between the aneurysm and the mother vessel, causing blood thrombosis inside the aneurysm causing the aneurysm to improve.
[0090] Significantly, the low thrombogenicity stents described here can facilitate the treatment of a large population of patients for whom flow diversion therapy has not previously been possible. Such patients are those who have already suffered from a hemorrhagic aneurysm or who have been diagnosed as being at risk of bleeding from an aneurysm in the intracranial arterial system. These patients cannot currently be treated with commercially available flow diversion stents because these stents are bare metal, braided stents whose implantation requires the patient to take anti-platelet medication (typically aspirin and PLAVIX ™ (clopidogrel)) for a long time period of time after implantation. The purpose of the anti-platelet drug is to counteract the tendency of the metal stent to cause thrombosis (blood clots) to form in the patient's vascular system. However, for a patient who suffers from, or is at risk for, intracranial hemorrhage, taking anti-platelet medication can cause, or put the patient at greater risk of, such bleeding. Low-thrombogenicity flow bypass stents, such as some stents described here, can make flow bypass therapy possible for patients who cannot tolerate anti-platelet medication because reduced thrombogenicity can reduce or eliminate the need for solvents of blood.
[0091] In order to implant any of the stents described here, the stent can be mounted in a delivery system. Suitable delivery systems are described in US Patent Applications Serial No. 14 / 040,477, filed September 27, 2013, entitled DELIVERY OF MEDICAL DEVICES; U.S. Patent Application Publication No. 2013/0226276, filed August 29, 2013, entitled METODS AND APPARATUS FOR LUMINAL STENTING; and US Patent No. 8,273,101, filed September 25, 2012, entitled SYSTEM AND METOD FOR DELIVERING AND DEPLOYING AN OCCLUDING DEVICE WITHIN A VESSEL. Full descriptions of both of these documents are hereby incorporated by reference and a part of this specification is provided. In particular, the teachings of these documents relating to stent delivery systems and methods can be employed to deliver any of the stents described herein, in the same way, to the same physical location (s), and using the same components that are revealed in these embedded documents.
[0092] Generally, the delivery system may include an elongated core assembly, which has a distal segment that supports or contains the stent, and both components can be slidably received in a lumen of a micro catheter or other elongated envelope for delivery in any region where the distal opening of the micro catheter can advance. The core set is used to advance the stent through the microcatheter and out of the distal end of the microcatheter so that the stent can self-expand into place in the blood vessel, through an aneurysm or other treatment site.
[0093] A treatment procedure can begin with obtaining percutaneous access to the patient's arterial system, typically through a main blood vessel in a leg or an arm. A guide wire can be placed through the percutaneous and advanced access point to the treatment site, which can be in an intracranial artery. The microcatheter is then advanced over the guidewire to the treatment site and positioned so that an open distal end of the catheter is adjacent to the treatment site. The guide wire can then be removed from the microcatheter and the assembly of the core, together with the stent mounted or supported on it, thus, it can be advanced through the microcatheter and out of the distal end thereof. The stent can then self-expand in juxtaposition with the inner wall of the blood vessel. In the case of an aneurysm to be treated, the stent is placed around the neck of the aneurysm so that a side wall of the stent (for example, a section of the braided tube) separates the interior of the aneurysm from the lumen of the artery original. Once the stent has been placed, the core assembly and microcatheter are removed from the patient. The lateral wall of the stent can now perform a function of deflecting the flow in the aneurysm, causing blood thrombosis in the aneurysm and leading to the healing of the aneurysm.
[0094] Because of the low-thrombogenic properties of the stents described here, certain additional aspects of treatment methods are possible. For example, the patient may have previously suffered from, or who has been diagnosed as at risk of bleeding from, an anatomical arterial aneurysm, such as the intracranial arterial system. The patient may have been diagnosed as being at risk for intracranial hemorrhage, cerebral hemorrhage from an aneurysm, etc. The patient may be prescribed a reduced regimen of anti-platelet medication, compared to the regimen or protocol that would be required for a patient who received an otherwise similar stent, which had no outer layer of phosphorylcholine or surface. The regimen can be "reduced" in the sense that the patient takes a lower dose, less medication, less potent medication, follows a lower dosing frequency, and / or takes medication for a shorter period of time after implantation stent, or otherwise. Alternatively, the patient may receive a blood medication prescription.
[0095] The devices and methods discussed here are not limited to the application of layers on stents, but can include any number of other implantable devices. Treatment sites may include blood vessels and areas or regions of the body, such as organ bodies.
[0096] Although this document contains many details, these should not be interpreted as limitations on the scope of the subject technology, but rather as illustrations of different examples and aspects of the technology in question. It should be appreciated that the scope of application of the technology in question includes other modalities that will not be discussed in detail above. Various other modifications, alterations and variations can be made in the arrangement, operation and details of the method and apparatus of the technology in question disclosed here, without departing from the scope of the present disclosure. Unless otherwise stated, reference to an element in the singular is not intended to mean "one and only one" unless explicitly stated, but it is intended to mean "one or more". Furthermore, it is not necessary for a device or method to solve all problems that are solvable by different modalities of the present description, in order to be encompassed within the scope of the disclosure.

权利要求:
Claims (18)
[0001]
1. Medical device, characterized by the fact that it comprises: an expandable tubular body comprising a plurality of braided filaments configured to be implanted in a blood vessel, in which the filaments have an outer surface comprising a phosphorylcholine, the plurality of braided filaments comprises: platinum or platinum alloy filaments, where platinum or platinum alloy filaments have phosphorylcholine chemically bonded directly to platinum or platinum alloy filaments, and cobalt-chromium alloy filaments, where filaments of cobalt-chromium alloys have an intermediate layer of silane between the cobalt-chromium alloy filaments and phosphorylcholine; and where phosphorylcholine is less than 100 nanometers thick.
[0002]
2. Medical device according to claim 1, characterized by the fact that phosphorylcholine is selected from the group consisting of 2-methacryloyloxyethyl phosphorylcholine, 2-acryloyloxyethyl phosphorylcholine, and phosphorylchines based on monomers including 2- (meth) acryloyloxyethyl-2 '- (trimethylammonium) ethyl phosphate, 3- (meth) acryloyloxypropyl-2' - (trimethylammonium) ethyl phosphate, 4- (meth) acryloyloxybutyl-2 '- (trimethylammonium) ethyl phosphate, 5- (meth) acryloyloxypentyl-2'- (trimethylammonium) ethyl phosphate, 6- (meth) acryloyloxy-hexyl-2 '- (trimethylammonium) ethyl phosphate, 2- (met) acryloyloxyethyl-2' - (triethylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-2'- (tripropylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-2 '- (tributylammonium) ethyl phosphate, 2- (meth) acryloyloxypropyl-2'- (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxybutyl-2' - (trimethylammonium ) ethyl phosphate, 2- (meth) acryloyloxypentyl-2 '- (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxyhexyl-2' - (trimethylammonium) ethyl phosphate, 2- (meth) acryloyloxyethyl-3'- (trimethylammonium ) pr opyl phosphate, 3- (meth) acryloyloxypropyl-3'- (trimethylammonium) propyl phosphate, 4- (meth) acryloyloxybutyl-3'- (trimethylammonium) propyl phosphate, 5- (meth) acryloyloxypentyl-3'- (trimethylammonium) propyl phosphate , 6- (meth) acryloyloxy-hexyl-3'- (trimethylammonium) propyl phosphate, 2- (meth) acryloyloxyethyl-4 '- (trimethylammonium) butyl phosphate, 3- (meth) acryloyloxypropyl-4' - (trimethylammonium) butyl phosphate , 4- (meth) acryloyloxybutyl-4 '- (trimethylammonium) butyl phosphate, 5- (meth) acryloyloxypentyl-4' - (trimethylammonium) butyl phosphate, 6- (met) acryloyloxy-hexyl-4'- (trimethylammonium) butylphosphate, and combinations thereof.
[0003]
Medical device according to claim 1, characterized by the fact that phosphorylcholine comprises a copolymer having a reactive chemical group.
[0004]
4. Medical device according to claim 3, characterized by the fact that the reactive chemical group is selected from the group consisting of amine, hydroxyl, epoxy, silane, aldehyde, carboxylate and thiol.
[0005]
5. Medical device according to claim 1, characterized by the fact that silane is selected from the group consisting of 3-glycidoxypropyltrimethoxysilane, 2- (3,4-epoxycyclohexyl) ethyltriethoxysilane, 2- (3 , 4-epoxycyclohexyl) ethyl-trimethoxysilane, (3-glycidoxypropyl) trimethoxysilane, (3-glycidoxypropyl) triethoxysilane, 5,6-epoxy-hexyltriethoxysilane, (3-glycidoxypropyl) methyldiethoxysilane, (3-glyoxypropyl), 3-methylidoxypropyl) glycidoxypropyl) dimethylethoxysilane, 3-isocyanatopropyltriethoxysilane, (isocyanatomethyl) methyldimethoxysilane, 3-isocyanatopropyltrimethoxysilane, tris (3-trimethoxylsilpropyl) isocyanurate, (3- triethoxysilpropyl) -thiylethylcarbamate, 3-triethylethylcarbamate.
[0006]
Medical device according to claim 1, characterized by the fact that phosphorylcholine, or a polymer or cup-polymer thereof, is covalently attached to the filaments of platinum or platinum alloy.
[0007]
Medical device according to claim 1, characterized by the fact that phosphorylcholine, or a polymer or cup-polymer thereof, is chemically bonded to a silane along the cobalt-chromium alloy filaments.
[0008]
8. Medical device according to claim 7, characterized by the fact that phosphorylcholine, or the polymer or cup-polymer thereof, is covalently bonded to a silane along the cobalt-chromium alloy filaments.
[0009]
9. Medical device according to claim 1, characterized by the fact that the tubular body has a side wall formed by the braided filaments, the side wall which has a plurality of pores contained therein, the plurality of pores is sized to inhibit the flow of blood through the side wall to an aneurysm to a degree sufficient to cause thrombosis and the aneurysm to heal when the tubular body is positioned in a blood vessel and adjacent to the aneurysm.
[0010]
10. Medical device according to claim 1, characterized by the fact that the tubular body has a side wall formed by the braided filaments, the side wall, which has a plurality of pores inside, a plurality of pores with an average size of pore that is less than or equal to 500 microns.
[0011]
11. Medical device according to claim 1, characterized by the fact that the tubular body is fixed by heat, so that the filaments are in at least their least tensioned configuration in the tubular body.
[0012]
Medical device according to claim 1, characterized in that the outer surface is a more outer surface of the filaments.
[0013]
13. Medical device according to claim 1, characterized by the fact that the medical device comprises a stent.
[0014]
Medical device according to claim 1, characterized by the fact that the phosphorylcholine has a thickness of about 1 to about 100 nanometers.
[0015]
15. Medical device according to claim 1, characterized by the fact that the tubular body is self-expanding.
[0016]
16. Medical device according to claim 1, characterized in that the device is less thrombogenic than an identical device whose braided filaments are entirely bare metal.
[0017]
17. Medical device according to claim 1, characterized in that the device has a time elapsed before the formation of peak thrombin, which is at least 1.5 times the time elapsed before the formation of the peak thrombin for a identical device whose braided filaments are entirely bare metal.
[0018]
18. Medical device according to claim 1, characterized by the fact that the device has a peak thrombin concentration, which is less than 0.8 times the peak thrombin concentration by an identical device whose braided filaments are metal entirely naked.

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法律状态:
2019-08-06| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-06-09| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application according art. 36 industrial patent law|

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2020-10-27| B09A| Decision: intention to grant|

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2020-12-15| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 11/11/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US14/087,459|US9668890B2|2013-11-22|2013-11-22|Anti-thrombogenic medical devices and methods|

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US14/087,459|2013-11-22|

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PCT/US2014/064930|WO2015077081A1|2013-11-22|2014-11-11|Anti-thrombogenic medical devices and methods|

---