HK1259282B - Drug eluting stent and method of use of the same for enabling restoration of functional endothelial cell layers - Google Patents

Description

Drug-eluting stents and methods of using the same for restoring a functional endothelial cell layer

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 62/438,432, filed December 22, 2016, the entire contents of which are incorporated herein by reference.

Technical Field

The present disclosure relates to drug eluting stents, methods of making and using drug eluting stents, and methods for predicting long-term stent efficacy and patient safety after implantation of drug eluting stents. More specifically and without limitation, the present disclosure relates to the design of drug eluting stents comprising a stent framework (e.g., metal-based or made of biodegradable material) and one or more layers covering all or part of the surface of the stent, the layers being capable of hosting a drug and releasing the drug in a sustained manner, thereby minimizing or eliminating patient risks associated with implantation of the drug eluting stent. The stents disclosed herein are capable of restoring endothelial cell layer function after implantation.

Background Art

Over the years, the use of coatings for medical devices and drug delivery has become necessary, especially to enhance the capabilities of medical devices and implants.Drug eluting medical devices have become a major biomedical device used to treat cardiovascular diseases.

Heart disease and heart failure are two of the most common health conditions in the United States and worldwide. In coronary artery disease, the blood vessels in the heart become narrowed. When this happens, the oxygen supply to the heart muscle decreases. Initially, the main treatment for coronary artery disease was surgery such as CABG (Coronary Artery Bypass Graft), a common and effective procedure performed by cardiac surgeons. However, mortality and morbidity rates are quite high.

In the 1960s, some doctors developed less invasive treatments using medical devices. These devices are inserted through a small incision in the femoral artery. For example, balloon angioplasty (which uses a balloon catheter (which expands to open the artery) to dilate an artery that has narrowed, and is also called PTCA (Percutaneous Transluminal Coronary Angioplasty)) is used in patients with coronary artery disease. After balloon angioplasty, about 40 to 50% of coronary arteries typically develop restenosis (re-narrowing of the blood vessel after it has been opened, usually by balloon angioplasty) within 3 to 6 months due to thrombosis (the development of a blood clot in the blood vessel that can block the vessel and prevent blood flow) or abnormal tissue growth. Therefore, restenosis is one of the main limitations of PTCA's effectiveness.

The introduction of bare metal stents (BMS) in the late 1980s for maintaining dilation of coronary arteries partially alleviated this problem, as well as the problem of artery dissection following balloon inflation during PTCA procedures.

A stent is a mesh tube mounted on a balloon catheter (e.g., a long, thin, flexible tube that can be inserted into the body). In this example, the stent is passed through the heart. However, BMS is still initially associated with an overall restenosis rate of about 25% in patients six months after stent implantation. Often, the stent struts end up being embedded in growing arterial tissue. This tissue is typically composed of smooth muscle cells (SMCs), whose proliferation can be triggered by the original damage to the artery during stent placement.

As depicted in Figure 1, the entire inner surface of a blood vessel 100 is covered with "active," functional ECs 101, i.e., endothelial cells that spontaneously produce nitric oxide (NO), a small molecule that acts as a signal to stop the proliferation of underlying SMCs 103. Typically, this natural release of NO by ECs 101 occurs when the ECs 101 are in direct contact with one another, such as when a continuous, tightly packed membrane lines the inner surface of an artery.

When the stent (or balloon) is expanded within the vessel 150, the stent struts in contact with the vessel wall will partially disrupt the EC layer and damage the artery, for example, at contact points 105a and 105b. As a result, the natural release of NO is highly disrupted, at least locally, at contact points 105a and 105b. This damage can trigger the proliferation of SMCs, such as SMCs 107a and 107b, as a repair mechanism. Uncontrolled proliferation of SMCs can lead to reclosure of the vessel or "restenosis." If, as SMCs 107a and 107b proliferate, ECs 101 can also proliferate and eventually cover the stent struts and SMCs 107a and 107b again through a continuous membrane, NO release can then be restored and SMC proliferation can be stopped. As a result, the risk of restenosis can be reduced (if not eliminated) and the condition can be stabilized.

Since the 1990s, one of the greatest challenges in the field of interventional cardiology has been to first understand and then ensure this "race" for complete EC coverage and restoration of EC layer function. The endothelium is a single layer of cells that lines all blood and lymphatic vasculature. An important function of the endothelium is to regulate the movement of fluids, macromolecules, and leukocytes between the vasculature and the interstitial tissue. This function is mediated in part by the ability of endothelial cells to form strong cell-cell contacts using a number of transmembrane junction proteins, including VE-cadherin and p120-catenin. Colocalization of the two proteins is indicative of a well-functioning endothelial cell layer.

Historically, two strategies have been considered to restore arteries after stent implantation. One goal of most drug-eluting stent (DES) designs is to promote the proliferation of active endothelial cells (ECs) to accelerate their migration and ultimately cover the surface of the stent. If these new ECs are active, such as forming a continuous and tightly packed membrane, they typically spontaneously release nitric oxide (NO), thereby hindering the proliferation of stomata (SMCs).

Another goal of most DES designs is to inhibit the proliferation of smooth muscle cells (SMCs). Typically, this goal has been achieved by locally releasing anti-proliferative agents (usually anti-angiogenic drugs, similar to anti-cancer agents) from the stent surface.

Many DES on the market are based on polymer release matrices from which the drug is eluted. First- and second-generation stents are typically coated with biostable polymers. In such stents, the polymer remains permanently attached to the stent and is generally assumed to have minimal effects on both inflammatory responses and EC proliferation. However, in some cases, these stents fail to release 100% of the drug loaded into their coating. In particular, a significant portion of the drug is sometimes retained in the polymer coating for extended periods of time. Furthermore, most drugs used to date are not selective and tend to inhibit EC proliferation more than SMC proliferation.

This shortcoming can have sudden and potentially fatal consequences for the patient and, therefore, for the DES industry. Indeed, although restenosis in the first year may be reduced from approximately 20% with bare metal stents (BMS) to approximately 5% with drug-eluting stents (DES), the widespread introduction of DES has brought two new challenges: (1) the phenomenon of late thrombosis, i.e., reocclusion of the artery a year or more after stent implantation, and (2) the progressive growth of the neointimal layer, which again leads to restenosis. Thus, DES generally achieves a delay in the onset of restenosis in the years following DES implantation, but can cause other complications (e.g., thrombosis).

The implantation of bare metal stents is considered to be a source of thrombosis in addition to restenosis, but the thrombosis is usually treated by systemic dual antiplatelet therapy (DAPT) which combines two antithrombotic agents (e.g. aspirin and clopidogrel). For example, patients who have had stents implanted often use this DAPT for 1 to 2 months. With drug eluting stents, many examples of arterial reocclusion due to coagulation (thrombosis) have been reported after discontinuation of DAPT. Therefore, many cardiologists maintain DAPT for 3, 6, 9 and now 12 months or longer. In 2005-2006, multiple examples were reported where myocardial infarction with full stent thrombosis could occur just a few weeks after discontinuation of 18 months of DAPT.

Late-onset thrombosis is a sudden complication that can be fatal if the patient is not in medical follow-up, or even if the patient is in medical follow-up, the patient is far away from a cath lab or well-equipped medical center. In addition, DAPT may have a bottleneck that is difficult to manage, that is, some patients may decide to stop after a period of use, forget to refill their medication, forget to take their medication, or may need to undergo unforeseen clinical interventions, and therefore have to stop antithrombotic treatment.

The exact cause of delayed thrombosis remains incompletely understood. Pathologists speculate that delayed thrombosis reveals incomplete EC coverage of the stent, leaving the metal or polymer material in prolonged contact with blood, where platelet adhesion may occur, potentially leading to catastrophic thrombus precipitation. An alternative explanation proposes that incomplete EC coverage may be the result of incomplete drug release from the release layer, which inhibits EC proliferation as it attempts to migrate and cover the surface of the polymer+drug+SMC layer.

The thickness of the stent struts can further become a source of obstruction to EC proliferation. When ECs need to proliferate on a surface, their rate of proliferation is often negatively (and significantly) affected by the height of the obstruction, which they need to overcome to fully cover the surface. Therefore, not all stent designs and drug release profiles are equal. For example, when a DES is implanted in an artery, the damaged EC layer must overcome an obstruction whose height is roughly equal to the thickness of the stent struts + the thickness of the drug-releasing polymer layer + the thickness of the SMC layer that has begun to form. The first two thicknesses are related to the design of the DES, while the latter thickness is related to the efficacy of the drug, its loading in the release layer, and its release rate. Therefore, there remains a need to develop new stents and methods of manufacturing stents that can reduce patient risks associated with stent implantation (e.g., restenosis, thrombosis, MACE).

Summary of the Invention

The present disclosure relates to drug eluting stents, methods of making and using drug eluting stents, and a method of predicting stent efficacy and patient safety. In one embodiment, a drug eluting stent (1) combines four parts: a stent framework (2), a drug-containing layer (3), a drug (4), and a biocompatible base layer (5) supporting the drug-containing layer. In one embodiment, the stent is designed and the method of making the stent is designed to control the time to achieve sufficient re-endothelialization of the stent surface/vessel wall and improve endothelial function recovery by controlling the thickness of the drug-containing layer and the distribution of the thickness. In one embodiment, the thickness of the drug-containing layer in the luminal side is different from the thickness in the abluminal side. In one embodiment, the stent minimizes delayed thrombosis, that is, restenosis of the artery one year or more after stent implantation, and the progressive thickness of the neointimal layer that again leads to restenosis. In one embodiment, the stent and the method of making the stent are such that they reduce the number or frequency of major adverse cardiac events (MACE). In one embodiment, neointimal coverage or reendothelialization of the stent strut surface significantly improves strength efficacy and patient safety within 90 days.

The stent frame (2) can be made of a single piece (or multiple pieces) of metal or wire or tube. For example, the stent frame can include cobalt-chromium (e.g., MP35N or MP20N alloy), stainless steel (e.g., 316L), nitinol, tantalum, platinum, titanium, suitable biocompatible alloys, other suitable biocompatible materials and/or combinations thereof.

In some embodiments, the stent frame (2) can be biodegradable. For example, the stent frame (2) can be made of magnesium alloy, polylactic acid, polycarbonate polymer, salicylic acid polymer, and/or combinations thereof. In other words, any biocompatible but also biodegradable material can be manufactured in such a way that its radial force is strong enough to be implanted and support to stabilize injury and vessel retraction, but the thickness of the stent is less than 120 μm.

In other embodiments, the stent frame (2) may be made of one or more plastics, such as polyurethane, polytetrafluoroethylene, polyethylene, and the like.

The drug-containing layer (3) can be made of a polymer and can include one or more layers covering all or part of the stent surface. In addition, the drug-containing layer (3) can carry the drug (4) and release the drug (4) in a sustained manner.

In one embodiment, the drug-containing layer may have a non-uniform coating thickness. For example, the thickness of the drug-containing layer on the luminal side of the stent and the thickness of the drug-containing layer on the lateral side of the stent are smaller than the thickness of the drug-containing layer on the abluminal side of the stent.

In one embodiment, the drug-containing layer can release the drug within 30 days of implantation in a blood vessel, for example due to uneven coating thickness. For example, the release time can be verified using standard animal PK studies. Thus, when the drug-eluting stent (1) is implanted in a human blood vessel, the drug (4) can be released from the coating (3) within 30 days or less. In other embodiments, the drug is released at a different rate, such as 45 days or less, 60 days or less, 90 days or less, or 120 days or less.

In some embodiments, the drug may be contained only on the abluminal surface of the stent.

In embodiments where the drug-containing layer (3) is made of a biodegradable or bioabsorbable polymer, the polymer can be biodegraded or bioabsorbed within 45 to 60 days after stent implantation. In other embodiments, the polymer is biodegraded or bioabsorbed within a period of, for example, 45 days or less, 60 days or less, 90 days or less, or 120 days or less.

In some embodiments, the polymer on the luminal surface and/or the side surface of the stent can be different from the polymer on the abluminal surface. For example, the one or more polymers forming the drug-containing layer on the luminal surface of the stent and the drug-containing layer on the side surface of the stent degrade faster than the one or more polymers forming the drug-containing layer on the abluminal surface of the stent.

The biocompatible base layer (5) can be formed on the stent frame (2) and can have a surface that is more biocompatible than the stent frame (2). For example, the biocompatible base layer (5) can be made of polybutyl methacrylate, PTFE, PVDF-HFP, poly(styrene-b-isobutylene-b-styrene), parylene C, PVP, PEVA, SBS, PC, TiO2, or any material (or a combination thereof) with good biocompatibility.

Additional exemplary embodiments of the present disclosure are provided below and are numbered for reference purposes only:

1. A drug-eluting stent, comprising:

bracket frame;

drug-containing layer;

a drug embedded in the drug-containing layer; and

A biocompatible base layer is provided on the stent frame and supports the drug-containing layer.

wherein the drug-containing layer has a non-uniform coating thickness, and optionally, wherein the drug-containing layer is configured to completely dissolve 45 to 60 days after implantation of the drug-eluting stent.

2. The drug-eluting stent of embodiment 1, wherein the drug-containing layer is configured to release the drug within 30 days of implantation in a blood vessel.

3. The drug-eluting stent of embodiment 1, wherein the thickness of the drug-containing layer on the luminal surface of the stent and the thickness of the drug-containing layer on the side surface of the stent are smaller than the thickness of the drug-containing layer on the abluminal surface of the stent.

4. The drug-eluting stent of embodiment 3, wherein the ratio between the thickness of the drug-containing layer on the luminal surface and the thickness of the drug-containing layer on the abluminal surface is 2:3 to 1:7.

5. The drug-eluting stent according to embodiment 3 or 4, wherein the ratio between the thickness of the drug-containing layer on the lateral surface and the thickness of the drug-containing layer on the abluminal surface is 2:3 to 1:7.

6. The drug-eluting stent according to any one of embodiments 1 to 5, wherein the drug is embedded only in the drug-containing layer on the abluminal surface of the stent.

7. The drug eluting stent of any one of embodiments 1 to 6, wherein the stent framework is made from a single piece of metal, wire, or tube.

8. The drug eluting stent of embodiment 7, wherein the metal comprises at least one of stainless steel, nitinol, tantalum, cobalt-chromium MP35N or MP20N alloy, platinum, and titanium.

9. The drug eluting stent of any one of embodiments 1 to 6, wherein the stent framework is made of a biodegradable material.

10. The drug-eluting stent of any one of embodiments 1 to 9, wherein the drug comprises at least one of an antithrombotic agent, an anticoagulant agent, an antiplatelet agent, an antitumor agent, an antiproliferative agent, an antibiotic, an anti-inflammatory agent, a gene therapy agent, a recombinant DNA product, a recombinant RNA product, collagen, a collagen derivative, a protein analog, a carbohydrate, a carbohydrate derivative, an inhibitor of smooth muscle cell proliferation, a promoter of endothelial cell migration, proliferation and/or survival, and combinations thereof.

11. The drug eluting stent of embodiment 10, wherein the drug comprises sirolimus and/or a derivative or analogue.

12. The drug eluting stent of embodiment 1, wherein the drug-containing layer has a thickness of 5 to 12 μm.

13. The drug eluting stent of embodiment 1, wherein the drug-containing layer is selected from the group consisting of poly(hydroxyalkanoate) (PHA), poly(esteramide) (PEA), poly(hydroxyalkanoate-co-esteramide), polyacrylate, polymethacrylate, polycaprolactone, poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly(propylene oxide) (PPO), poly(propylene fumarate) (PPF), poly(D-lactide), poly(L-lactide), poly(D,L-lactide), poly(meso-lactide), poly(L-lactide-co-meso-lactide), poly(D-lactide-co-meso-lactide), poly (D,L-lactide-co-meso-lactide), poly(D,L-lactide-co-PEG), poly(D,L-lactide-co-trimethylene carbonate), poly(lactide-co-glycolide), poly(glycolic acid-co-trimethylene carbonate), poly(trimethylene carbonate), PHA-PEG, PBT-PEG (PolyActive(R)), PEG-PPO-PEG (Pluronic(R)) and PPF-co-PEG, polycaprolactone, polyglycerol sebacate, polycarbonate, biopolyester, polyethylene oxide, polybutylene terephalate, polydioxanone, hybrids, complexes, collagen matrix with growth regulators, proteoglycans, mucopolysaccharides, vacuum-formed intestinal submucosa, fiber, chitin, dextran, and mixtures thereof.

14. The drug eluting stent of embodiment 13, wherein the drug-containing layer is selected from tyrosine-derivatized polycarbonates.

15. The drug eluting stent according to embodiment 13, wherein the drug-containing layer is selected from poly (β-hydroxyalkanoate) and its derivatives.

16. The drug eluting stent of embodiment 13, wherein the drug-containing layer comprises polylactide-co-glycolide 50/50 (PLGA).

17. The drug eluting stent of embodiment 1, wherein the biocompatible base layer comprises at least one of poly(n-butyl methacrylate), PTFE, PVDF-HFP, poly(styrene-b-isobutylene-b-styrene), parylene C, PVP, PEVA, SBS, PC, or TiO2.

18. The drug-eluting stent of embodiment 1, wherein the biocompatible base layer comprises an electro-grafted polymer layer, the electro-grafted polymer layer and the drug-containing layer having an interdigitated surface.

19. The drug eluting stent of embodiment 18, wherein the electrografted polymer layer has a thickness of 10 nm to 1000 nm.

20. The drug eluting stent of embodiment 18, wherein the electrografted polymer layer comprises monomers selected from vinylics, epoxides, and cyclic monomers that undergo ring-opening polymerization and aryl diazonium salts.

21. The drug eluting stent of embodiment 24, wherein the monomer is further selected from butyl methacrylate, methyl methacrylate, hydroxyethyl methacrylate, epsilon caprolactone, and 4-aminophenyldiazonium tetrafluoroborate.

22. A drug-eluting stent comprising:

bracket frame;

biodegradable medicated layer;

a drug embedded in the drug-containing layer; and

A biocompatible base layer is provided on the stent frame and supports the drug-containing layer.

The drug-containing layer is configured to dissolve significantly 45 to 60 days after implantation of the drug-eluting stent.

23. The drug eluting stent of embodiment 22, wherein the drug-containing layer is formed from a plurality of polymers.

24. The drug eluting stent of embodiment 23, wherein the one or more polymers forming the drug-containing layer on the luminal surface of the stent and the drug-containing layer on the lateral surface of the stent degrade faster than the one or more polymers forming the drug-containing layer on the abluminal surface of the stent.

25. The drug eluting stent of embodiment 22, wherein the stent framework is made from a single piece of metal, wire, or tube.

26. The drug eluting stent of embodiment 25, wherein the metal comprises at least one of stainless steel, nitinol, tantalum, cobalt-chromium MP35N or MP20N alloy, platinum, and titanium.

27. The drug eluting stent of embodiment 23, wherein the stent framework is made of a biodegradable material.

28. The drug-eluting stent of embodiment 22, wherein the drug comprises at least one of an antithrombotic agent, an anticoagulant agent, an antiplatelet agent, an antitumor agent, an antiproliferative agent, an antibiotic, an anti-inflammatory agent, a gene therapy agent, a recombinant DNA product, a recombinant RNA product, collagen, a collagen derivative, a protein analog, a carbohydrate, a carbohydrate derivative, an inhibitor of smooth muscle cell proliferation, a promoter of endothelial cell migration, proliferation and/or survival, and combinations thereof.

29. The drug eluting stent of embodiment 22, wherein the drug comprises sirolimus and/or a derivative or analog.

30. The drug eluting stent of embodiment 22, wherein the drug-containing layer has a thickness of 5 to 12 μm.

31. The drug eluting stent of embodiment 22, wherein the drug-containing layer is selected from the group consisting of poly(hydroxyalkanoate) (PHA), poly(esteramide) (PEA), poly(hydroxyalkanoate-co-esteramide), polyacrylate, polymethacrylate, polycaprolactone, poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly(propylene oxide) (PPO), poly(propylene fumarate) (PPF), poly(D-lactide), poly(L-lactide), poly(D,L-lactide), poly(meso-lactide), poly(L-lactide-co-meso-lactide), poly(D-lactide-co-meso-lactide), poly(D,L-lactide-co-meso-lactide), poly(D,L-lactide-co-PEG) , poly(D,L-lactide-co-trimethylene carbonate), poly(lactide-co-glycolide), poly(glycolic acid-co-trimethylene carbonate), poly(trimethylene carbonate), PHA-PEG, PBT-PEG (PolyActive(R)), PEG-PPO-PEG (Pluronic(R)) and PPF-co-PEG, polycaprolactone, polyglycerol sebacate, polycarbonate, biopolyester, polyethylene oxide, polybutylene terephthalate, polydioxanone, hybrids, composites, collagen matrix with growth regulators, proteoglycans, mucopolysaccharides, vacuum-formed small intestinal submucosa, fiber, chitin, dextran and mixtures thereof.

32. The drug eluting stent of embodiment 31, wherein the drug-containing layer is selected from tyrosine-derivatized polycarbonates.

33. The drug eluting stent of embodiment 31, wherein the drug-containing layer is selected from poly (β-hydroxyalkanoate) and its derivatives.

34. The drug eluting stent of embodiment 31, wherein the drug-containing layer comprises polylactide-co-glycolide 50/50 (PLGA).

35. The drug eluting stent of embodiment 22, wherein the biocompatible base layer comprises at least one of poly(n-butyl methacrylate), PTFE, PVDF-HFP, poly(styrene-b-isobutylene-b-styrene), parylene C, PVP, PEVA, SBS, PC, or TiO2.

36. The drug eluting stent of embodiment 22, wherein the biocompatible base layer comprises an electrografted polymer layer, the electrografted polymer layer and the drug-containing layer having an interdigitated surface.

37. The drug eluting stent of embodiment 36, wherein the electrografted polymer layer has a thickness of 10 nm to 1000 nm.

38. The drug eluting stent of embodiment 36, wherein the electrografted polymer layer comprises monomers selected from vinyls, epoxides, and cyclic monomers that undergo ring-opening polymerization and aryl diazonium salts.

39. The drug eluting stent of embodiment 38, wherein the monomer is further selected from butyl methacrylate, methyl methacrylate, hydroxyethyl methacrylate, epsilon caprolactone, and 4-aminophenyldiazonium tetrafluoroborate.

40. A method of using a stent according to any one of embodiments 1 to 39, the method comprising implanting the stent into a subject to treat vascular stenosis, or to prevent restenosis, thrombosis, tumor growth, hemangioma, or blocked tear glands.

41. The method of embodiment 40, wherein the stent is implanted in a blood vessel.

42. The method of embodiment 41, wherein the blood vessel is a left main coronary artery, a circumflex artery, a left anterior descending coronary artery, an iliac vessel, a carotid artery, or a neurovascular vessel.

43. A treatment method comprising: a step of delivering a stent according to any one of embodiments 1 to 39 into a lumen; a step of radially expanding the stent within the lumen; and a step of eluting the drug from the drug coating on the surface of the stent, allowing the drug to act on the lumen and/or albumin surface.

44. A method of reducing, minimizing or eliminating patient risks associated with stent implantation by using any of the stents according to any of embodiments 1 to 39.

45. A method of manufacturing a drug eluting stent, the method comprising:

Providing a support frame; and

The stent framework is non-uniformly coated with at least one polymer mixed with at least one drug.

46. The method of embodiment 45, wherein the uneven coating comprises coating the luminal surface and/or the side surface of the stent with a coating thinner than the coating on the abluminal surface, preferably, wherein the thinner coating is a drug-containing layer and/or a biocompatible base layer below the drug-containing layer.

47. The method of embodiment 45, further comprising dissolving the at least one polymer and the at least one drug to form the at least one polymer mixed with the at least one drug.

48. The method of embodiment 45, wherein unevenly coating the stent framework comprises spray coating the stent framework with at least one polymer mixed with at least one drug.

49. The method of embodiment 46, wherein unevenly coating the stent frame comprises rotating the stent frame to generate centrifugal force during spray coating.

50. The method of embodiment 49, wherein the centrifugal force causes the thickness of the mixture on the abluminal surface of the stent frame to be greater than the thickness of the mixture on the luminal surface of the stent frame and on the side surfaces of the stent frame.

51. The method of embodiment 45, further comprising drying the coated stent framework in a vacuum oven.

52. The method of embodiment 51, wherein the coated stent framework is dried at 40°C to 50°C.

53. The method of embodiment 48, wherein the flow rate of the spray is 24 μL/s or less.

54. The method of embodiment 48, wherein the volume of the spray is 192 μL/s or less.

55. The method of embodiment 48, wherein the spray coating is performed at a pressure of 0.3 bar or less.

56. The method of embodiment 49, wherein the rotation speed of the stent is at least 2000 rpm.

57. The method of embodiment 48, wherein the distance between the nozzle for spray coating and the stent frame is 6.5 mm or less.

58. The method according to any one of embodiments 45 to 57, further comprising:

At least one polymer is electrografted onto the stent framework prior to spray coating the mounted framework.

59. The method of embodiment 58, further comprising:

The electrografted polymer is baked at room temperature or higher before spray coating the mounted frame.

60. The method of embodiment 59, wherein the baking is performed under atmospheric conditions.

61. The method of embodiment 59, wherein the baking is performed in nitrogen.

62. The method of embodiment 59, wherein the baking is performed in a vacuum.

63. A method for verifying the long-term efficacy and safety of a stent in humans by implanting a rabbit animal model, the method comprising:

At 90 to 120 days after implantation, the stents implanted in the rabbit model are imaged using at least one of scanning electron microscopy (SEM) or Evans Blue uptake to verify that the endothelial layer of the vessel covers at least 90% of the stent surface and that the Evans Blue uptake of the endothelium covering the stent is less than 30%.

64. A method for reducing and/or eliminating restenosis, thrombosis or MACE in a blood vessel associated with stent implantation, comprising the following steps:

a) inhibiting the proliferation of smooth muscle cells in the stent-implanted blood vessels within the first 30 days of stent implantation; and

b) Achieve sufficient re-endothelialization of the blood vessels within 3 months of stent implantation, thereby achieving endothelial function recovery within 12 months of stent implantation.

65. The method of embodiment 64, wherein the blood vessel is a blood vasculature vessel.

66. The method of embodiment 64, wherein the step of inhibiting smooth muscle proliferation is achieved by controlled release of a suitable drug from the implanted stent at an appropriate dosage and release profile.

67. The method of embodiment 66, wherein the drug is completely released 30 days after stent implantation.

68. The method of embodiment 64, wherein the implanted stent has a layer of a biocompatible and biodegradable carrier material to promote complete release of the drug within 30 days of implantation.

69. The method of embodiment 64, wherein the biocompatible and biodegradable carrier material is PLGA or PLA.

70. The method of embodiment 68, wherein the drug carrier layer completely disappears within 60 days of implantation.

71. The method of embodiment 67, wherein the surface of the implanted stent is smooth or lacks significant obstacles for endothelial cells to grow, reestablish appropriate cell-cell interactions, and cover the surface of the stent struts.

72. The method of embodiment 66, wherein the polymer is coated on the surface of the stent using electrografting or chemical grafting coating techniques.

73. The method of embodiment 66, wherein the scaffold has a thickness of about 80 um to 110 um.

74. The method of embodiment 73, wherein the scaffold has a thickness of about 100 to 110 μm.

75. The method of embodiment 68, wherein the suitable drug is selected from sirolimus, paclitaxel, everolimus, biolimus, novolimus, tacrolimus, pimecrolimus and zotarolimus.

76. The method of embodiment 66, wherein the suitable stent can be a metal stent or a biodegradable stent.

77. The method of embodiment 66, wherein the suitable scaffold is a polymeric scaffold that is partially or fully biodegradable.

78. A method for predicting long-term stent efficacy and patient safety after implantation of a drug-eluting stent, the method comprising evaluating the percentage of functional restoration of endothelial coverage of a stent and/or a blood vessel after stent implantation in an animal model, wherein substantially complete reendothelialization at approximately 90 days after stent implantation is predictive of long-term stent efficacy and patient safety after stent implantation. For example, the evaluation can include using an animal model to evaluate the percentage of coverage, the thickness and permeability of the endothelial layer, and the structure of the endothelial layer. The structure can include the type of tissue, such as tissue composition in terms of smooth muscle cells, stroma, and endothelial cells.

79. The method of embodiment 78, wherein long-term stent efficacy includes an absence of significant restenosis of the vessel in the area of stent implantation.

80. The method of embodiment 78, wherein patient safety comprises absence of vascular thrombosis within 1 year after stent implantation. In some embodiments, absence of thrombosis may occur 5 years after stent implantation.

81. The method of embodiment 78, wherein patient safety comprises a significant absence of MACE within 1 year after stent implantation. In some embodiments, MACE may be absent 5 years after stent implantation.

82. The stent or method of any one of embodiments 1 to 81, wherein the non-uniform thickness of the drug-containing layer is achieved by spray coating of the drug-containing layer.

83. A stent or method according to any one of embodiments 1 to 81, wherein the thinner portion of the drug-containing layer releases the drug faster than the thicker portion of the drug-containing layer, preferably within 10 to 20 days, and wherein the drug is substantially completely released from the drug-containing layer within 30 days of stent implantation.

84. Use of the stent according to any one of embodiments 1 to 39 in the manufacture of a medicament or device for treating or preventing vascular diseases, preferably vascular stenosis or preventing restenosis, thrombosis, tumor growth, hemangioma or blocked lacrimal gland.

85. The stent or method of any one of embodiments 1 to 83, wherein the stent framework comprises an 8-peak design.

86. The stent or method of any one of embodiments 1 to 83, wherein the stent framework comprises a 10-peak design.

87. The stent or method of any one of embodiments 1 to 83, wherein the stent framework comprises an 11-peak design.

88. The stent or method of any one of embodiments 1 to 83, wherein the stent framework comprises a plurality of stent poles having a wavy design.

89. The stent or method of any one of embodiments 1 to 83, wherein the stent framework comprises a plurality of single linking poles alternating between two linking poles and three linking poles in the axial direction between the stent struts.

90. The stent or method of any one of embodiments 1 to 83, wherein the stent framework comprises four connecting rods on a first axial end and four connecting rods on a second axial end.

91. The stent or method of any one of embodiments 1 to 83, wherein the width of the crown is greater than the width of the stem.

92. The stent of any one of embodiments 1-39 and 85-91, wherein the stent is a non-stainless steel stent.

93. The stent of embodiment 92, wherein the stent comprises a cobalt-chromium alloy.

94. The method of embodiment 46, wherein the coating is designed as a thinner layer to release at least one drug from the drug-containing layer faster than a thicker layer, preferably within 10-20 days, more preferably wherein substantially complete release is achieved within 30 days of stent implantation.

95. The method according to embodiment 94, wherein the drug-containing layer comprises one or more drugs that inhibit smooth muscle cell proliferation and/or promote endothelial cell migration, proliferation and/or survival after stent implantation, preferably sirolimus.

96. The method of embodiment 94, wherein the coating is designed to promote functional re-endothelialization of the stent within several months of stent implantation, thereby achieving endothelial function restoration within 12 months of stent implantation.

97. The method of embodiment 94, wherein the coating is designed to completely dissolve between 45 and 60 days after implantation.

98. The method of any one of embodiments 46 and 94-98, wherein the drug-containing layer comprises PLGA and, when present, the biocompatible base layer comprises PBMA.

99. A method according to embodiment 78, wherein the percentage of functional recovery of endothelial coverage of the stent and/or blood vessel in the patient is reasonably predicted from studies in an animal model, preferably a rabbit animal model.

100. The method according to embodiment 78 or 79, wherein the percentage of functional recovery of the endothelial coverage of the stent is evaluated by SEM, Evans blue staining, OCT, VE-cadherin/P120 confocal staining co-localization, or a combination thereof.

101. The method of embodiment 78, wherein the stent is implanted in a cardiac vessel.

102. The method of embodiment 78 or 79, wherein the stent is a stainless steel stent.

103. The method of embodiment 78 or 79, wherein the stent is a non-stainless steel stent.

104. The method of embodiment 78 or 79, wherein the stent comprises a cobalt-chromium alloy.

105. The method of any one of embodiments 78-89 and 99-104, wherein the stent is a drug eluting stent.

106. The method according to embodiment 105, wherein the drug eluting stent comprises one or more drugs that inhibit smooth muscle cell proliferation and/or promote endothelial cell migration, proliferation and/or survival after stent implantation, preferably sirolimus.

107. The method of embodiment 105, wherein the stent is selected from any one of the stents of any one of embodiments 1-39 and 84-93.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings depict only example embodiments of the disclosure and, therefore, are not intended to limit its scope. They are intended to increase particularity and detail.

FIG. 1A depicts a blood vessel 100 prior to stent implantation.

FIG. 1B depicts a blood vessel 150 after stent implantation.

Figure 2 depicts a Xience Xpedition stent imaged using SEM imaging 60 days after implantation. The SEM image shows partial strut coverage, with uncovered areas limited to the mid- and distal regions of the stent. Endothelial coverage on the stent struts is approximately 50%.

FIG3 depicts a drug-eluting stent according to some embodiments of the present disclosure 60 days after implantation using SEM imaging. The SEM image shows good stent coverage, with a few uncovered struts located in the middle of the stent. The endothelial coverage on the stent struts is approximately 80%.

FIG4A depicts the Xience Xpedition stent 60 days post-implantation using total imaging with Evans blue uptake, where the positive staining area was 41.8%.

Figure 4B depicts a confocal microscopic image of the Xience Xpedition scaffold of Figure 4A 60 days after implantation, which was mounted under a 10x objective and stained with double immunofluorescence for VE-cadherin (red channel) and p120 (endothelial p120-catenin) (green channel). Scale bar is 1 mm.

Figure 4C depicts a confocal microscopic image of a region of the Xience Xpedition scaffold of Figure 4B 60 days after implantation, using a 20x objective lens, showing poor expression of VE-cadherin at the endothelial border, typically indicative of poor barrier function. VE-cadherin is in the red channel (555 nm), P120 is in the green channel (488 nm), and DAPI is counterstained in the blue channel (405 nm). Scale bar 50 μm.

Figure 4D depicts a confocal microscopy image of another area of the Xience Xpedition stent of Figure 4B using a 20x objective lens, wherein the area has poor expression of VE-cadherin at the endothelial border, which generally indicates poor barrier function. VE-cadherin is in the red channel (555nm), P120 is in the green channel (488nm), and the blue channel (405nm) is DAPI counterstain. The scale bar is 50μm. As described in Figures 4A-4D, the endothelial coverage of the two markers was 21.2% on the struts; and 21.2% between the struts.

5A depicts a drug eluting stent according to some embodiments of the present disclosure 60 days after implantation using total imaging with Evans blue uptake, wherein the positive staining area was 35.7%.

Figure 5B depicts a confocal microscopic image of the drug-eluting stent of Figure 5A 60 days after implantation, which was mounted under a 10x objective and stained with double immunofluorescence for VE-cadherin (red channel) and P120 (green channel). Scale bar is 1 mm.

Figure 5C depicts a confocal microscopic image of a region of the drug-eluting stent of Figure 5B 60 days after implantation, using a 20x objective lens, showing a region with partial endothelial barrier function. VE-cadherin is shown in the red channel (555 nm), P120 in the green channel (488 nm), and DAPI counterstain is shown in the blue channel (405 nm). Scale bar, 50 μm.

Figure 5D depicts a confocal microscopic image of another region of the drug-eluting stent of Figure 5B 60 days after implantation using a 20x objective lens, wherein the region has poorly expressed VE-cadherin at the endothelial border, typically indicating poor barrier function. VE-cadherin is the red channel (555nm), P120 is the green channel (488nm), and the blue channel (405nm) is DAPI counterstaining. The scale bar is 50 μm. As described in Figures 5A-5D, the endothelial coverage of the two markers was 36.8% on the struts; and 38.8% between the struts.

Figure 6 depicts a Xience Xpedition stent imaged using SEM at 90 days post-implantation. The SEM image shows partial coverage of the stent, with the uncovered area primarily located in the middle. The endothelial coverage on the stent struts was approximately 70%.

FIG7 depicts a drug eluting stent according to some embodiments of the present disclosure 90 days after implantation using SEM imaging. The SEM image shows complete stent coverage. The endothelial coverage percentage on the stent struts is approximately 99%.

FIG8A depicts a Xience Xpedition stent 90 days post-implantation using a total image with Evans Blue uptake, where the positive staining area was 31.8%.

Figure 8B depicts a confocal microscopic image of the Xience Xpedition scaffold of Figure 8A 90 days after implantation, which was mounted under a 10x objective and stained with double immunofluorescence for VE-cadherin (red channel) and P120 (green channel). Scale bar is 1 mm.

FIG8C depicts a confocal microscopic image of an area of the Xience Xpedition scaffold of FIG8B 90 days after implantation using a 20x objective lens, wherein the area has evidence of adequate endothelial barrier function (i.e., colocalized p120/VE-cadherin). VE-cadherin is in the red channel (555 nm), p120 is in the green channel (488 nm), and the blue channel (405 nm) is counterstained with DAPI. Scale bar is 50 μm.

Figure 8D depicts a confocal microscopic image of another area of the Xience Xpedition stent of Figure 8B 90 days after implantation using a 20x objective lens, wherein the area has poorly expressed VE-cadherin at the endothelial border, typically indicating poor barrier function. VE-cadherin is the red channel (555nm), P120 is the green channel (488nm), and the blue channel (405nm) is DAPI counterstaining. The scale bar is 50μm. As described in Figures 8A-8D, the endothelial coverage of the two markers was 46.8% on the struts; and 46.1% between the struts.

9A depicts a drug eluting stent according to some embodiments of the present disclosure 90 days after implantation using total imaging with Evans blue uptake, with a positive staining area of 6.4%.

Figure 9B depicts a confocal microscopic image of the drug-eluting stent of Figure 9A 90 days after implantation, which was mounted under a 10x objective and stained with double immunofluorescence for VE-cadherin (red channel) and P120 (green channel). Scale bar is 1 mm.

FIG9C depicts a confocal microscopic image of an area of the drug-eluting stent of FIG9B 90 days after implantation using a 20x objective lens, wherein the area has evidence of adequate endothelial barrier function (i.e., colocalized p120/VE-cadherin). VE-cadherin is in the red channel (555 nm), p120 is in the green channel (488 nm), and the blue channel (405 nm) is counterstained with DAPI. Scale bar is 50 μm.

Figure 10 shows that the drug release timeframe for the XIENCE V stent and XIENCE PRIME is approximately 120 days. The drug release timeframe for the ENDEAVORRESOLUTE (ie, a stent according to some embodiments of the present disclosure) is approximately 180 days.

Figure 11 shows the relative positions of the layers of a stent according to some embodiments of the present disclosure. The luminal surface (6) faces the blood flow, and the abluminal surface (8) faces or contacts the vessel wall.

12A depicts a drug eluting stent according to some embodiments of the present disclosure 45 days after implantation using Evans Blue uptake imaging, wherein the positive staining area is 28.57%.

FIG. 12B depicts the drug eluting stent 45 days after implantation using Evans blue uptake, where the positive staining area was 55.0%.

FIG. 12C depicts the drug-eluting stent 45 days after implantation using Evans blue uptake imaging, where the positive staining area was 56.79%.

12D is a table summarizing the results of Evans Blue uptake data at day 45 for experiments conducted with scaffolds according to embodiments of the present disclosure (BuMA Supreme) and scaffolds not according to the present disclosure (Xience and Synergy).

Figure 13A depicts a drug-eluting stent according to some embodiments of the present disclosure 45 days after implantation, showing a confocal microscopy image of an area of the drug-eluting stent using a 20x objective lens, wherein the area has evidence of adequate endothelial barrier function (i.e., co-localized p120/VE-cadherin). VE-cadherin is in the red channel (555 nm), p120 is in the green channel (488 nm), and the blue channel (405 nm) is DAPI counterstain.

Figure 13A depicts a drug-eluting stent according to some embodiments of the present disclosure 45 days after implantation, showing a confocal microscopy image of an area of the drug-eluting stent using a 20x objective lens, wherein the area has evidence of adequate endothelial barrier function (i.e., co-localized p120/VE-cadherin). VE-cadherin is in the red channel (555 nm), p120 is in the green channel (488 nm), and the blue channel (405 nm) is DAPI counterstain.

Figure 13B depicts a drug eluting stent 45 days after implantation, showing a confocal microscopic image of an area of the drug eluting stent using a 20x objective lens, wherein the area has evidence of adequate endothelial barrier function (i.e., co-localized p120/VE-cadherin). VE-cadherin is the red channel (555 nm), p120 is the green channel (488 nm), and the blue channel (405 nm) is DAPI counterstain.

Figure 13C depicts a drug eluting stent 45 days after implantation, showing a confocal microscopic image of an area of the drug eluting stent using a 20x objective lens, wherein the area has evidence of adequate endothelial barrier function (i.e., co-localized p120/VE-cadherin). VE-cadherin is the red channel (555 nm), p120 is the green channel (488 nm), and the blue channel (405 nm) is DAPI counterstain.

13D is a table summarizing the results of VE-cadherin/P120 co-localization data at 45 days for experiments performed with scaffolds according to embodiments of the present disclosure (BuMA Supreme) and scaffolds not according to the present disclosure (Xience and Synergy).

14A depicts a drug eluting stent according to some embodiments of the present disclosure 90 days after implantation using Evans Blue uptake imaging, wherein the positive staining area was 23.21%.

FIG. 14B depicts the drug eluting stent 90 days after implantation using Evans blue uptake, where the positive staining area was 42.95%.

FIG. 14C depicts the drug eluting stent 90 days after implantation using Evans blue uptake imaging, where the positive staining area was 41.79%.

14D is a table summarizing the results of Evans Blue uptake data at 90 days for experiments conducted with scaffolds according to embodiments of the present disclosure (BuMA Supreme) and scaffolds not according to the present disclosure (Xience and Synergy).

Figure 15A depicts a drug eluting stent according to some embodiments of the present disclosure 90 days after implantation, showing a confocal microscopy image of an area of the drug eluting stent using a 20x objective lens, wherein the area has evidence of adequate endothelial barrier function (i.e., co-localized p120/VE-cadherin). VE-cadherin is in the red channel (555 nm), p120 is in the green channel (488 nm), and the blue channel (405 nm) is DAPI counterstain.

Figure 15A depicts a drug eluting stent according to some embodiments of the present disclosure 90 days after implantation, showing a confocal microscopy image of an area of the drug eluting stent using a 20x objective lens, wherein the area has evidence of adequate endothelial barrier function (i.e., co-localized p120/VE-cadherin). VE-cadherin is in the red channel (555 nm), p120 is in the green channel (488 nm), and the blue channel (405 nm) is DAPI counterstain.

Figure 15B depicts a drug eluting stent 90 days after implantation, showing a confocal microscopic image of an area of the drug eluting stent using a 20x objective lens, wherein the area has evidence of adequate endothelial barrier function (i.e., co-localized p120/VE-cadherin). VE-cadherin is the red channel (555 nm), p120 is the green channel (488 nm), and the blue channel (405 nm) is DAPI counterstain.

Figure 15C depicts a drug eluting stent 90 days after implantation, showing a confocal microscopic image of an area of the drug eluting stent using a 20x objective lens, wherein the area has evidence of adequate endothelial barrier function (i.e., co-localized p120/VE-cadherin). VE-cadherin is the red channel (555 nm), p120 is the green channel (488 nm), and the blue channel (405 nm) is DAPI counterstain.

15D is a table summarizing the results of VE-Cadherin/P120 co-localization data at 90 days for experiments performed with scaffolds according to embodiments of the present disclosure (BuMA Supreme) and scaffolds not according to the present disclosure (Xience and Synergy).

DETAILED DESCRIPTION

The present disclosure relates to drug eluting stents, methods of making and using drug eluting stents, and methods for predicting long-term stent efficacy and patient safety after implantation of a drug eluting stent. According to some embodiments of the present disclosure, a drug eluting stent (1) comprises four parts: a stent frame (2), a drug-containing layer (3), a drug (4), and a biocompatible base layer (5). In one embodiment, the stent can be made of stainless steel. In another embodiment, the stent can be made of a CoCr alloy. In one embodiment, the stent has a diameter of 80-120 μm. The drug-containing layer can be formed of PLGA and the biocompatible base layer can be formed of PBMA. The biocompatible base layer can be formed using an electrografting method.

Bracket frame:

Stents are typically made of a scaffold or skeleton, which includes a pattern or network of interconnected structural elements or struts, which are formed by a wire, tube or sheet of material rolled into a cylindrical shape. The skeleton gets its name because it remains open in shape and, if necessary, expands the wall of the passage in the patient. Typically, the stent can be compressed or curled onto a catheter so that it can be delivered to and deployed at the treatment site. Delivery includes inserting the stent into a small lumen using a catheter and transporting it to the treatment site. Deployment includes expanding the stent to a larger diameter when the stent is in the desired position.

The stent frame (2) can be made of a single piece (or multiple pieces) of metal or wire or tube, including 3D printing and laser cutting (e.g., starting from a wire). For example, the stent frame can be non-stainless steel or include stainless steel, nitinol, tantalum, cobalt-chromium (e.g., MP35N or MP20N alloy), platinum, titanium, suitable biocompatible alloys, other suitable biocompatible materials, and/or combinations thereof. In some embodiments, the stent is a non-stainless steel stent. In other embodiments, the stent frame can be made of a metal material or alloy, such as, but not limited to, cobalt-chromium alloy (ELGILOY), stainless steel (316L), high nitrogen stainless steel (e.g., BIODUR 108), cobalt-chromium alloy L-605, ELASTINITE (nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or a combination thereof. "MP35N" and "MP20N" are trade names for alloys of cobalt, nickel, chromium, and molybdenum, which can be obtained from Standard Press Steel Co. of Jenkintown, Pennsylvania. MP35N is composed of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. MP20N is composed of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.

In other embodiments, the stent frame (2) may be made of one or more plastics, such as polyurethane, polytetrafluoroethylene, polyethylene, etc. In such embodiments, the stent frame (2) may be manufactured, for example, using 3D printing.

The stent frame (2) can form a mesh. Thus, the stent frame (2) can expand upon implantation, either by external forces, such as from a balloon catheter, and/or by internal forces, such as expansion of the mesh caused by an increase in temperature within the blood vessel. After expansion, the stent frame (2) can hold the blood vessel open.

In some embodiments, the stent framework (2) can be biodegradable. To achieve healing of the diseased vessel, the presence of the stent is necessary only for a limited period of time because the artery undergoes physiological remodeling over time after deployment. The development of bioresorbable stents or frameworks can avoid permanent metal implants in the vessel, allowing for subsequent expansion of the lumen and remodeling of the vessel, and leaving only the healed native vascular tissue after the framework is completely resorbed. Stents made of bioresorbable, biodegradable, bioabsorbable and/or biocorrodible materials (such as bioresorbable polymers) can be designed so that they are fully absorbed only after or a period of time after their clinical need has ended. Therefore, a fully bioresorbable stent can reduce or eliminate the risk of potential long-term complications and delayed thrombosis, facilitate non-invasive diagnostic MRI/CT imaging, allow for restoration of normal vasomotion, and provide the possibility of plaque regression. For example, the stent framework (2) can be made of chitosan, magnesium alloy, polylactic acid, polycarbonate polymer, salicylic acid polymer and/or a combination thereof. Advantageously, the biodegradable stent framework (2) can allow the vessel to return to normalcy after the obstruction has been cleared and flow has been restored through the stent (1). As used herein, the term "biodegradable" is interchangeable with the terms "bioabsorbable" or "bioerodible" and generally refers to polymers or certain specific alloys (such as magnesium alloys) that are capable of being completely degraded and/or corroded when exposed to body fluids such as blood and can be gradually reabsorbed, absorbed and/or eliminated by the body. For example, the process of decomposition and absorption of the polymer in the stent can be caused by hydrolysis and metabolic processes.

"Biodegradable scaffold" is used herein to refer to a scaffold made of a biodegradable polymer. Other representative examples of polymers that can be used to make biodegradable scaffolds include, but are not limited to, poly(N-acetylglucosamine) (chitin), chitosan, poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polyorthoesters, polyanhydrides, poly(glycolic acid), poly(glycolide), poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide), poly(caprolactone), poly(trimethylene carbonate), polyesteramides, poly(glycolic acid-co-trimethylene carbonate), copoly(ether-esters) (e.g., PEO/PLA), polyphosphazenes, biomolecules (e.g., fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid), poly Urethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alpha olefin copolymers, acrylic polymers and copolymers other than polyacrylates, vinyl halide polymers and copolymers (e.g., polyvinyl chloride), polyvinyl ethers (e.g., polyvinyl methyl ether), polyvinylidene halides (e.g., polyvinylidene chloride), polyacrylonitrile, polyvinyl ketone, polyvinyl aromatic compounds (e.g., polystyrene), polyvinyl esters (e.g., polyvinyl acetate), acrylonitrile styrene copolymers, ABS resins, polyamides (e.g., nylon 66 and polycaprolactam), polycarbonates, polyoxymethylene, polyimides, polyethers, polyurethanes, rayon, rayon triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, and carboxymethyl cellulose. Another type of polymer based on poly(lactic acid) that can be used includes graft copolymers and block copolymers, such as AB block copolymers ("diblock copolymers") or ABA block copolymers ("triblock copolymers"), or mixtures thereof.

Other representative examples of polymers that may be suitable for making biodegradable stents include ethylene vinyl alcohol copolymer (commonly known by the generic name EVOI-I or the trade name EVAL), poly(butyl methacrylate), poly(vinylidene fluoride-co-hexafluoropropylene) (e.g., SOLEF 21508, available from Solvay Solexis PVDF, Thorofare, N.J.), polyvinylidene fluoride (also known as KYNAR, available from ATOFINA Chemicals, Philadelphia, Pa.), ethylene vinyl acetate copolymer, and polyethylene glycol. The properties and uses of these biodegradable polymers are known in the art, for example, as disclosed in U.S. Patent No. 8,017,144 and U.S. Application Publication No. 2011/0,098,803.

In some aspects, a biodegradable stent as described herein can be made of polylactic acid (PLA), polyglycolic acid (PGA), poly(D,L-lactide-co-glycolide), polycaprolactone, or copolymers thereof.

In some aspects, a biodegradable stent as described herein can be made from polyhydroxy acids, polyalkanoates, polyanhydrides, polyphosphazenes, polyetheresters, polyesteramides, polyesters, and polyorthoesters.

In some preferred aspects, the biodegradable scaffolds as described herein can be made of chitosan, collagen, elastin, gelatin, fibrin glue, or a combination thereof.

As used herein, "chitosan-based scaffolds" or "chitosan scaffolds" refer to scaffolds whose primary component is chitosan. For example, a chitosan-based scaffold as described herein can contain chitosan at least 50% by weight, or at least 60% by weight, or at least 70% by weight, or at least 80% by weight of the total scaffold. Even more particularly, a chitosan-based scaffold as described herein can have a chitosan content of about 70% to about 85% by weight of the total chitosan scaffold.

Chitosan-based scaffolds as described herein can also be coated with a polymer layer to modulate degradation time. For example, chitosan-based scaffolds as described herein can be dip-coated with an acetone solution of poly(D,L-lactide-co-glycolide).

Chitosan-based scaffolds can also be coated with a barium sulfate layer by immersing the scaffold in an aqueous suspension of barium sulfate. In some aspects, the weight of the barium sulfate coating can be about 15 to about 30 weight percent of the total weight of the scaffold. In addition, the chitosan scaffold can be perforated.

The stent designed according to the standards of the present disclosure can be a coronary stent, a vascular stent, or any other drug-containing implantable device for the vascular system, as well as any medical device that effectively reduces the restenosis and thrombosis rates in a sustainable manner to ensure long-term patient safety.

In one embodiment, a thinner stent is used. However, the stent struts should be of sufficient thickness to ensure the stability of the stent structure without the risk of cracking over time. As an example, the stent thickness for a 316L stainless steel stent is approximately 100-110 μm, and the stent thickness for a CoCr stent is approximately 80 μm.

Drug-containing layer:

The present disclosure provides a window of opportunity for vascular endothelial recovery after the stent is implanted into the heart vessel in terms of patient safety and stent efficacy. In one embodiment, it is necessary to fully complete the re-endothelialization of the stent and establish an appropriate endothelial structural foundation or endothelial cell arrangement during the window period disclosed herein, so that functional recovery of the stent endothelial coverage can be obtained, and restenosis and/or thrombosis can be significantly prevented or reduced. In one embodiment, sufficient re-endothelialization of the stent/vascular wall is obtained within the first 2-3 months, so that vascular endothelial function recovery can be achieved within 12 months. The adequacy of endothelial recovery can be determined by any means known in the art. In animal models, it can be measured by methods including Evans blue staining (the presence of staining is a negative marker for the desired endothelial cell layer function), VE-cadherin/p120 staining (the presence of good overlap in staining is a positive marker for the desired endothelial cell layer function), etc. In vivo, it can be measured, for example, by neointimal coverage and neointimal thickness (measured at different time points by OCT methods known in the art) on the surface of the stent struts. For example, a thickness below a first threshold may indicate that insufficient infrastructure has been formed, which would result in inadequate restoration of endothelial function, whereas a thickness above a second, higher threshold may indicate a smooth muscle cell to endothelial cell ratio that is too high, which is sometimes a good indicator of excessive smooth muscle cell proliferation.

In one embodiment, endothelial repair refers to re-establishing the correct connection between endothelial cells and restoring the biological function of the endothelium on the surface of the stent or along the vascular wall/neointimal layer. Endothelial refers to a functional endothelial layer. Vascular function recovery can be measured by any means known in the art. For example, it can be measured by the neointimal coverage and neointimal thickness of the stent strut surface (measured at different time points (such as SEM inspection of stent coating) by OCT (such as one to three months) or other methods known in the art). Other means of measuring endothelial function can also be used (Evans blue (for example, at the 30th, 60th and 90th days; endothelial layer staining should not be made), VE cadherin/P120 confocal microscopy staining overlap is desirable).

In one embodiment, the drug eluting stent is designed to achieve complete drug release within 30 days and substantial neointimal coverage at 3 months.

For the purposes of this disclosure, "complete drug release" of a stent (drug-containing layer) refers to about 95% to about 100% drug release, preferably about 95% to about 96%, about 96% to about 97%, about 97% to about 98%, about 98% to about 99% and about 99% to about 100% drug release. Drug release is evaluated in animal models (e.g., rabbit models) or in vitro models, which are understood by those of ordinary skill in the art to be predictive of drug release in subjects implanted with a stent of the present disclosure. In one embodiment, "complete release" refers to residual drug levels below detectable levels and/or below therapeutic levels.

For purposes of this disclosure, the drug-containing layer is said to have "completely dissolved" (also referred to as biodegraded) when about 95% to about 100% of the drug-containing layer has dissolved (also referred to as biodegraded) from the stent, preferably about 95% to about 96%, about 96% to about 97%, about 97% to about 98%, about 98% to about 99%, and about 99% to about 100% of the drug-containing layer has dissolved from the stent. The dissolution (also referred to as biodegradation) of the drug-containing layer of the stent is evaluated in an animal model (e.g., a rabbit model) or in vitro model, which one of ordinary skill in the art understands to be predictive of the dissolution (also referred to as biodegradation) of the drug-containing layer of the stent in a subject implanted with the stent of the present disclosure. In one embodiment, "completely dissolved" means that the level of residual material is below a detectable level.

The drug-containing layer (3) can be made of a polymer and can include one or more layers covering all or part of the stent surface. In addition, the drug-containing layer (3) is capable of carrying the drug (4) and releasing the drug (4) in a sustained manner. Examples of polymers used in the drug-containing layer (3) can include, but are not limited to, poly(hydroxyalkanoate) (PHA), poly(esteramide) (PEA), poly(hydroxyalkanoate-co-esteramide), polyacrylate, polymethacrylate, polycaprolactone, poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly(propylene oxide) (PPO), poly(propylene fumarate) (PPF), poly(D-lactide), poly(L-lactide), poly(D,L-lactide), poly(meso-lactide), poly(L-lactide-co-meso-lactide), poly(D-lactide-co-meso-lactide), poly(D,L-lactide-co-meso-lactide), [00145] Poly(D,L-lactide), poly(D,L-lactide-co-PEG), poly(D,L-lactide-co-trimethylene carbonate), poly(lactide-co-glycolide), poly(glycolic acid-co-trimethylene carbonate), poly(trimethylene carbonate), PHA-PEG, PBT-PEGPEG-PPO-PEG and PPF-co-PEG, polycaprolactone, polyglycerol sebacate, polycarbonate, biopolyesters, polyethylene oxide, polybutylene terephthalate, polydioxanone, hybrids, complexes, collagen matrices with growth regulators, proteoglycans, mucopolysaccharides, vacuum-formed intestinal submucosa, fiber, chitin, dextran and/or mixtures thereof.

The degradation rate of the drug-containing polymer layer is generally determined by its composition. One of ordinary skill in the art can select one or more polymers using standard PK animal testing to confirm that the polymer degrades 45 to 60 days after implantation. In addition, the manufacturer of the polymer or polymer matrix may provide the degradation properties of the drug-containing polymer, such as a degradation curve. One of ordinary skill in the art can derive the degradation rate of the drug-containing polymer based on the degradation properties and select the polymer based on the degradation rate.

In one embodiment, the drug-containing layer (3) can have a thickness of 1 to 200 μm, for example, a thickness of 5 to 12 μm. In one embodiment, the drug-containing layer has a thickness of 3.5-10 μm. In one embodiment, the thickness of the abluminal surface is 1.5-200 μm, and the thickness of the luminal surface is 1-66 μm.

In certain aspects, the drug-containing layer (3) may have an uneven coating thickness. For example, the coating thickness of the stent luminal surface (6) and the side surface (7) may be thinner than the distal luminal surface (8). In one embodiment, the coating thickness ratio of the luminal surface (6) to the distal luminal surface (8) may be 2:3 to 1:7. Similarly, the coating thickness ratio of the side surface (7) to the distal luminal surface (8) may be 2:3 to 1:7. Therefore, the drug release of the luminal surface (6) and the side surface (7) may be faster than that of the distal luminal surface (8). Compared with the distal luminal surface (8), the faster release of the drug on the luminal surface (6) and the side surface (7) can cause the endothelial layer on the luminal surface (6) and the side surface (7) to recover faster. In another embodiment, the coating thickness ratio of the luminal surface (6) to the distal luminal surface (8) may be 1:1. The ranges provided herein are understood to be abbreviations of all values within the range. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or sub-range such as 1, 1.5, 2.0, 2.8, 3.90, 4, 5, 6, 7, 8, 9, and 10.

In some embodiments, the drug-containing layer (3) can be coated only on the abluminal surface (8) of the stent. In such embodiments, no drug release from the luminal surface (6) and the side surface (7) can allow the endothelial layer on the luminal surface (6) and the side surface (7) to recover earlier. In other embodiments, drug release from the luminal surface (6) and the side surface (7) can be less than 15 days or 10-20 days, which can allow the endothelial layer on the luminal surface (6) and the side surface (7) to recover earlier.

Furthermore, in such an embodiment, the polymer on the luminal surface (6) and the lateral surface (7) can degrade faster than the polymer on the abluminal surface (8). For example, the polymer on the luminal surface (6) and the lateral surface (7) can comprise PLGA, and the polymer on the abluminal surface (8) can comprise PLA. Typically, PLGA degrades faster than PLA, and this information can be readily obtained from the polymer manufacturer.

In some embodiments, it is sometimes advantageous that a 30-day drug (4) release time frame and a 45 to 60-day drug-containing coating (3) biodegradable/dissolvable time frame can allow for functional recovery of the endothelial layer. Within the above-mentioned time frame, as measured in a rabbit animal model, recovery of a functional EC layer can be fully complete within 90 days. This can then lead to long-term safety of drug-eluting stents in humans. In one embodiment, the stent is unevenly coated with the drug-containing layer, resulting in a thinner drug coating on the lumen or luminal surface of the stent, which allows the drug to disappear from the stent within 10 to 20 days.

The drug-containing coating can soften, dissolve, or erode away from the stent to elute at least one bioactive agent. This elution mechanism can be referred to as surface erosion, in which the outer surface of the drug-polymer coating dissolves, degrades, or is absorbed by the body; or bulk erosion, in which the bulk of the drug-polymer coating biodegrades to release the bioactive agent. The eroded portion of the drug-polymer coating can be absorbed, metabolized, or otherwise excreted by the body.

The drug-containing coating can also include a polymer matrix. For example, the polymer matrix can include a caprolactone-based polymer or copolymer, or different cyclic polymers. The polymer matrix can include different synthetic and non-synthetic or naturally occurring macromolecules and derivatives thereof. Polymer is advantageously selected from one or more biodegradable polymers of different combinations, such as polymers, copolymers and block polymers. Some examples of such biodegradable (also referred to as bioresorbable or bioabsorbable) polymers include polyglycolide, polylactide, polycaprolactone, polyglycerol sebacate, polycarbonate (for example tyrosine-derived polycarbonate), biopolyesters (such as poly (β-hydroxyalkanoate) (PHA)) and derived compounds, polyethylene oxide, polybutylene terephthalate, polydioxanone, hybrids, complexes, collagen matrix with growth regulators, proteoglycans, mucopolysaccharides, vacuum-formed SIS (small intestinal submucosa), fiber, chitin and glucan. Any of these biodegradable polymers can be used alone, or used in combination with these or other biodegradable polymers in different components. The polymer matrix preferably comprises a biodegradable polymer such as polylactide (PLA), polyglycolic acid (PGA) polymer, poly(e-caprolactone) (PCL), polyacrylate, polymethacrylate or other copolymers. The drug can be dispersed throughout the polymer matrix. The drug or bioactive agent can diffuse out of the polymer matrix to elute the bioactive agent. The drug can diffuse out of the polymer matrix and enter the biomaterial surrounding the stent. The bioactive agent can be separated from the drug polymer and diffuse out of the polymer matrix into the surrounding biomaterial. In another embodiment, the drug coating composition can be prepared using the drug 42-epi-(tetrazolyl)-sirolimus (described in U.S. Patent No. 6,329,386 assigned to Abbott Laboratories, Abbott Park, 111.) and dispersed in a coating prepared from a phosphorylcholine coating of Biocompatibles International P.L.C. described in U.S. Patent No. 5,648,442.

The polymer matrix of the drug-containing layer can be selected to provide a desired drug/bioactive agent elution rate. The drug can be synthesized so that a specific bioactive agent can have two different elution rates. For example, a bioactive agent with two different elution rates will allow for rapid delivery of the pharmacologically active drug within 24 hours of surgery, and for example, a slower, more stable delivery of the drug over the next two to six months. An electrograft primer coating can be selected to firmly secure the polymer matrix to the stent frame, the polymer matrix containing the rapidly deployed bioactive agent and the slowly eluting drug.

In some embodiments, the drug (4) can be encapsulated in the drug-containing layer (3) using microbead, microparticle, or nanoencapsulation technology with albumin, liposomes, ferritin, or other biodegradable proteins and phospholipids prior to application to the primed stent.

Drugs or bioactive agents

For example, drugs (4) can include, for example, antithrombotic agents, anticoagulants, antiplatelet agents, antitumor agents, antiproliferative agents, antibiotics, anti-inflammatory agents, gene therapy agents, recombinant DNA products, recombinant RNA products, collagen, collagen derivatives, protein analogs, carbohydrates, carbohydrate derivatives, smooth muscle cell proliferation inhibitors, endothelial cell migration, proliferation and/or survival promoters, and combinations thereof. In one embodiment, the drug is an anti-angiogenic drug. In another embodiment, the drug is an angiogenic drug. In some embodiments, the drug/bioactive agent can control cell proliferation. Control of cell proliferation can include enhancing or inhibiting the growth of target cells or target cell types. In some embodiments, the cells are vascular smooth muscle cells, endothelial cells, or both. In some embodiments, the drug inhibits the proliferation of smooth muscle cells and/or promotes endothelial cell proliferation.

More broadly, drug (4) can be any therapeutic substance that provides therapeutic properties for preventing and treating a disease or condition. For example, an antitumor agent can prevent, kill or block the growth and spread of cancer cells near a stent. In another embodiment, an antiproliferative agent can prevent or stop cell growth. In another embodiment, an antisense agent can act at the genetic level to interrupt the process of producing a disease-causing protein. In a fourth embodiment, an antiplatelet agent can act on platelets to inhibit their function in blood clotting. In a fifth embodiment, an antithrombotic agent can actively delay the formation of a blood clot. According to a sixth embodiment, in anticoagulant therapy using compounds such as heparin and coumarins, an anticoagulant can delay or prevent blood clotting. In a seventh embodiment, an antibiotic can kill or inhibit the growth of microorganisms and can be used to fight disease and infection. In an eighth embodiment, an anti-inflammatory agent can be used to counteract or reduce inflammation near a stent. According to a ninth embodiment, a gene therapy agent can alter the expression of a human gene to treat, cure or ultimately prevent disease. In addition, organic drugs can be any small molecule therapeutic materials, and similarly, pharmaceutical compounds can be any compounds that provide therapeutic effects. Recombinant DNA products or recombinant RNA products can contain altered DNA or RNA genetic material. In another embodiment, bioactive agents with pharmaceutical value can also include collagen and other proteins, carbohydrates, and derivatives thereof. For example, bioactive agents can be selected to inhibit vascular restenosis (a disease corresponding to the narrowing or contraction of the diameter of a body cavity in which a stent is placed).

Alternatively or concurrently, the bioactive agent can be an agent for one or more conditions including, but not limited to, coronary artery restenosis, cardiovascular restenosis, angiographic restenosis, arteriosclerosis, hyperplasia, and other diseases and conditions. For example, a bioactive agent can be selected to inhibit or prevent vascular restenosis (a condition corresponding to a narrowing or contraction of the diameter of a body lumen in which a stent is placed). The bioactive agent can alternatively or concurrently control cell proliferation. Control of cell proliferation can include enhancing or inhibiting the growth of target cells or target cell types.

Examples of antiplatelet agents, anticoagulants, antifibrin agents, and antithrombin agents include heparin sodium, low molecular weight heparin, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogs, dextran, D-phe-pro-arg-chloromethyl ketone (a synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibodies, recombinant hirudin, thrombin inhibitors such as Angiomax ^™ (bivalirudin, Biogen, Inc., Cambridge, Mass.), calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (ω3-fatty acids), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol-lowering drug sold under the trade name Lovastatin from Merck & Co., Inc., Whitehouse Pharmaceuticals). Station, NJ), monoclonal antibodies (such as those specific for platelet-derived growth factor (PDGF) receptors), sodium nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioproteinase inhibitors, triazolopyrimidine (a PDGF antagonist), nitric oxide, nitric oxide donors, superoxide dismutase, superoxide dismutase mimetics, 4-amino-2,2,6,6-tetramethylpiperidin-1-oxyl (4-amino-TEMPO), estradiol, dietary supplements (such as various vitamins), and combinations thereof.

In some embodiments, the bioactive agent may include podophyllotoxin, etoposide, camptothecin, camptothecin analogs, mitoxantrone, sirolimus (rapamycin), everolimus, zotarolimus, biotin A9, myolimus, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, novolimus, zotarolimus (ABT-578), 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxypropyl)rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazolylrapamycin, 40-epi-(N1-tetrazolyl)-rapamycin, and derivatives or analogs thereof. Podophyllotoxin is generally a kind of organic highly toxic drug, and it has antitumor properties and can inhibit DNA synthesis. Etoposide is generally a kind of antitumor drug, and it can be derived from the semi-synthetic form of podophyllotoxin, and is used to treat monocytic leukemia, lymphoma, small cell lung cancer and testicular cancer. Camptothecin is generally a kind of anticancer drug, and it can be used as a topoisomerase inhibitor. Camptothecin analogs (such as aminocamptothecin) related to the camptothecin structure can also be used as anticancer drugs. Mitoxantrone is a kind of anticancer drug, and it is generally used to treat leukemia, lymphoma and breast cancer. Sirolimus is a kind of drug, and it usually interferes with the growth cycle of normal cells, and can be used to reduce restenosis. Bioactive agent can comprise analogs and derivatives of these agents alternatively or simultaneously. Due to the anticonvulsant properties and therapeutic effect of antioxidants, described antioxidants can be used in combination with the above embodiments or used alone.

The anti-inflammatory agent can be a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, or a combination thereof. In some embodiments, the anti-inflammatory agent includes but is not limited to alclofenac, alclometasone, alclometasone dipropionate, progesterone acetate, alpha-amylase, ancifar, ancifit, amfenac sodium, ampridose hydrochloride, anakinra, aniroic acid, anizafen, azapropazone, balsalazide disodium, bendazone, benxaprofen, benzydamine hydrochloride, bromelain, bropimol, budesonide, carprofen, ciprofen, cinpentazone, cliprofen, clobetasone propionate, clobetasone butyrate, clopirac, closporin, triflumethasone acetate, cortodoxort, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflunisal sodium, Diflunisal, difluprednate, diflustatone, dimethyl sulfoxide, hydroxybenzoate, enmedrysone, enmolomab, enolicon sodium, epiriazole, etodolac, etofenamate, felbinac, fenamox, fenbufen, fenclorac, fenclorac, fendosal, fenpipalone, fentiazate, flurazadone, fluzacort, flufenamic acid, flumidazole, flunisolide acetate, flunisolide, flunisolide meglumine, fluocortol butyl acetate, fluorometholone acetate, fluquinazone, flurbiprofen, flutofen, fluticasone propionate, furoprofen, furobufen, halcitronellal, halobetasol propionate, halopredasol acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen pyridinemethanol, iloprofen Dapoxetine, indomethacin, indomethacin sodium, indobuprofen, indoxol, indoletetrazole, isoflurane acetate, oxazepine acetate, isoxathiazolin, ketoprofen, lofemidazole hydrochloride, lornoxicam, ethidol, meclofenamic acid sodium, meclofenamic acid, meclofenamic acid dibutyl, mefenamic acid, mesalamine, mesalamine, mecilazine, methylprednisolone sulfonate, momiflumate, nabumetone, naproxen, naproxen sodium, naproxen, nimazone, olsalazine sodium, octoprin, oxaprocin, oxaprozin, hydroxyphenylbutazone, renitolin hydrochloride, sodium pentothiosulfate, phenylbutazone sodium glycerol, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam ethanolamine, pirprofen, prenazarote, prifezone , produracil, proquinezone, proxazole, proxazole citrate, dimethoprim, clomazal, salsalate, sanguinimidium chloride, sclazone, simetaxin, sudoxicam, sulindac, suprofen, tamethacin, talniflumate, talosalate, tipoferron, tenidap, tenidap sodium, tenoxicam, tenoxicam, benzylisoquinone, tetrahydromethindamide, tiopinic acid, mercaptohydrocortisone valerate, tolmetin, tolmetin sodium, triclosan, triflubamate, zidomecin, zomepirate sodium, aspirin (acetylsalicylic acid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus, pimecrolimus, their prodrugs, their co-drugs (co-drugs) and combinations thereof.

For the removal of blood clots and thrombi, examples of therapeutic agents may include (i) tissue plasminogen activator, tPA, BB-10153, rTPA, urokinease, streptokinase, alteplase and desmoteplase, (ii) antiplatelet agents such as aspirin, clopidogrel and ticclopidine, and (iii) GIIb/IIIa inhibitors such as abciximab, tirofiban and eptifibatide.

The dosage or concentration of the drug required to produce a favorable therapeutic effect should be less than the level at which the drug produces toxic effects and greater than the level at which non-therapeutic results are obtained. This applies to antiproliferative agents, prohealing agents or any other active agents contained in any of the various embodiments of the present invention. The therapeutically effective dose can also be determined by suitable clinical studies (for example, but not limited to Phase II or Phase III studies). The effective dose can also be determined by applying a suitable pharmacokinetic-pharmacodynamic model in humans or other animals. Those of ordinary skill in the art understand the standard pharmacological testing procedures for determining dosage. In some embodiments, the stent has a drug content of about 5 μg to about 500 μg. In some embodiments, the stent has a drug content of about 100 μg to about 160 μg. In one embodiment, the content of the drug in the drug-containing layer is 0.5-50% by weight. In other embodiments, the drug-containing layer comprises 0.5-10 ug/mm2 of drug (for example 1.4 ug/mm2).

When the drug eluting stent (1) is implanted in a human blood vessel, the drug (4) can be released from the drug-containing coating (3) within 30 days. Alternatively, for example, the drug can be released within 45 days, 60 days, or 120 days. The drug release rate can be measured by standard PK animal studies, in which fluid samples and tissues and stents are extracted from the animals at selected time points and the drug concentration is measured to best design the properties of the stent. As is well known to those of ordinary skill in the art, these animal studies can reasonably predict what will occur in humans. In addition, in embodiments in which the drug-containing coating (3) is made of a biodegradable or bioabsorbable polymer, the polymer can be biodegraded or bioabsorbed within 45 to 60 days. For example, 50:50 PLGA (as described in Example 1 below) can exhibit an in vivo degradation time of approximately 60 days.

Biocompatible base layer (5)

A biocompatible base layer (5) can be formed on the stent frame (2) and below the drug-containing layer (3), which can have a surface that is more biocompatible than the stent frame (2). For example, the biocompatible surface of the biocompatible base layer (5) enables the endothelial layer on the luminal surface (6) and the side surface (7) of the stent to recover function earlier than the bare metal surface of the frame, which can lead to faster migration and replication rates of ECs than the bare metal surface.

The biocompatible base layer (5) can be made of poly(n-butyl methacrylate), PTFE, PVDF-HFP, poly(styrene-b-isobutylene-b-styrene), parylene C, PVP, PEVA, SBS, PC, TiO2, or any material (or combination thereof) with good biocompatibility. In one embodiment, the base layer comprises PBMA or consists essentially of PBMA.

Other Materials

All embodiments may also include additional components such as, but not limited to, lubricants, fillers, plasticizers, surfactants, diluents, release agents, agents that act as carriers or binders for active agents, anti-sticking agents, defoaming agents, viscosity modifiers, potential residual levels of solvents, and potentially any other agents that aid in or are desirable in the processing of the material and/or that are useful or desirable as a component of, or if included in, the final product.

How to use the bracket:

In one embodiment, a stent is a medical device used to improve narrow or blocked areas of a body's cavities, such as blood vessels, bile ducts (usually plastic stents), trachea, esophagus, airway, urethra, etc. Stents are inserted into these and other hollow organs to ensure that adequate clearance is maintained within them.

One use of medical stents is to expand body cavities (such as blood vessels) that have contracted in diameter due to, for example, the effects of damage (known as atherosclerosis) or the occurrence of cancerous tumors. Atherosclerosis refers to lesions within the arteries, which include a buildup of plaque that can obstruct blood flow through the blood vessels. Over time, the size and thickness of the plaque can increase and can ultimately lead to clinically significant arterial stenosis, or even complete occlusion. When expanding a body cavity that has contracted in diameter, medical stents provide a tubular support structure within the body cavity. Stents can also be used for intravascular repair of aneurysms, abnormal enlargement of a portion of the body cavity, or balloon-like expansion (which may be related to weakness in the body cavity wall).

Stents are not only used for mechanical interventions, but are also used as carriers for delivering biological therapies. Biotherapies use drug-eluting stents to locally administer therapeutic substances. The therapeutic substance can also mitigate biological reactions that are unfavorable to the presence of the stent. Drug-eluting stents (i.e., drug-containing stents) can be manufactured by the methods disclosed herein to include a polymer carrier that contains an active or bioactive agent or drug.

In one embodiment, the stent is used in a method for treating a disease or condition of a subject. Examples of diseases or conditions in which stents can be used include other diseases of the vascular system (heart disease, thrombosis), tumors, hemangiomas, tear gland obstruction, and lumen. The stent can be used for percutaneous coronary intervention (PCI) and peripheral applications, such as the superficial femoral artery (SFA). In some embodiments, by utilizing cell proliferation inhibitors (such as cytostatics (e.g., paclitaxel)) or immunosuppressants as drugs, the stent can be used to treat vascular stenosis or prevent restenosis. In some embodiments, the ureteral stent of the present disclosure is introduced into the kidney and/or bladder of a subject.

As used herein, the term "subject" refers to humans and non-human animals, including veterinary subjects. The term "non-human animals" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, mice, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles. In a preferred embodiment, the subject is a human and can be referred to as a patient.

As used herein, the terms "treat," "treating," or "treatment" preferably refer to the act of obtaining a beneficial or desired clinical result, including, but not limited to, alleviating or ameliorating one or more signs or symptoms of a disease or condition, reducing the extent of the disease, stabilizing the state of the disease (i.e., not worsening), improving or alleviating the disease state, reducing the rate or time of progression, and alleviating (whether partial or complete), whether detectable or undetectable. "Treatment" can also refer to prolonging survival compared to expected survival in the absence of treatment. Treatment need not be curative.

Methods of introducing a stent into a subject

In one embodiment, the stent is introduced into the subject via a catheter or by implantation. In other embodiments, the stent is introduced via a balloon catheter.

The terms "inserting a stent," "delivering a stent," "placing a stent," "applying a stent," and similar expressions as described herein all refer to the introduction and transportation of a stent through a body cavity to an area in need of treatment by means of a device such as a guidewire, a balloon catheter, or other delivery system for a self-expanding stent. Typically, this is accomplished by placing the stent on one end of a guidewire, inserting the end of the guidewire through the subject's body cavity, advancing the guidewire in the body cavity to the treatment site, and removing the guidewire from the lumen. Insertion may also be aided by other accessories such as a delivery sheath, a push rod, a catheter, a thruster, a guide catheter, an endoscope, a cystoscope, or a fluoroscope. Other methods of delivering a stent are well known in the art.

Manufacturing method

Take the metal bracket frame as an example:

1) Stent manufacturing

The stent frame can be laser cut from the metal tube. After laser cutting, the stent frame will undergo an electro-polishing process to make the stent frame edges smooth.

2) Grassroots manufacturing

The stent frame is placed in a container filled with butyl methacrylate (monomer). During the electrografting process, some initiators will initiate the polymerization of butyl methacrylate, and the base layer (polybutyl methacrylate) will be bonded (covalently bonded) to the stent frame to provide a surface with better biocompatibility.

3) Manufacturing of drug-containing layer

A spray solution was prepared by mixing 50/50 PLGA (biodegradable polymer) and sirolimus (drug) in a certain weight ratio and dissolved in chloroform. The stent frame with the base layer was fixed on a rotator and spray-coated with the spray solution.

Example of manufacturing the stent frame (2):

In some embodiments, the stent framework can include a prefabricated magnesium alloy mesh. Six to nine months after implantation, the alloy can be completely biodegraded. Additionally or alternatively, the stent framework can maintain mechanical radial strength for at least three months. Similarly, the stent framework can include prefabricated poly-L-lactic acid (PLLA) or other biocompatible fully biodegradable polymers. Such polymers can maintain mechanical radial strength for at least three months.

In some embodiments, the stent frame can be cut from the metal tube, for example using a laser. An electropolishing process can smooth the stent frame after cutting.

Example of making a biocompatible base layer (5):

electrochemical reaction

In one embodiment, n-butyl methacrylate monomer can be dissolved in N,N-dimethylformamide (DMF) solvent. In certain aspects, sodium chloride can be added as an electrolyte to increase the conductivity of the solution. The solution can be swirled and mixed for 120 minutes. In one embodiment, the concentration of methacrylate can be 20%, the concentration of sodium chloride can be 5.0×10⁻² M, and the concentration of DMR can be 80%.

The reactor containing the bottom coating solution can use an electrochemical reaction to coat the stent frame with the solution. For example, the reactor can use a voltage of 20 V to coat the frame at a pressure of 2 bar for about 120 minutes. The reactor can contain a nitrogen environment.

The biocompatible substrate can then be baked in a vacuum (e.g., at 10 mbar or less). In one embodiment, baking can be performed at about 40° C. for 180 minutes. The biocompatible substrate formed in this way can have a thickness of about 200 nm.

Example of preparing drug-containing layer (3):

In one embodiment, the drug-containing layer is applied to the stent via a spray coating process. In other embodiments, the process of applying the drug-containing layer to the stent (directly or on the surface of a biocompatible substrate) includes, for example, dipping, vapor deposition, and/or brushing.

Example 1. Spray coating process

A. Process

In some embodiments, a drug-containing layer (3) can be formed using a spray coating process for disposing a polymer coating on a stent frame (or on a polymer-coated stent, such as a stent coated with an electrograft coating described below). In one embodiment, a 20 mm long electrografted stent is spray coated with a biodegradable polyester (polylactide-co-glycolide 50/50, PLGA) containing sirolimus. The copolymer (0.25% w/v) is dissolved in chloroform. Sirolimus is then dissolved in the chloroform/polymer mixture to obtain a final ratio of sirolimus/polymer of (1/5). In another embodiment, the mixture can include 50/50 PLGA (e.g., 5 g) and rapamycin (e.g., 0.5 g) dissolved in chloroform (e.g., 600 mL). The mixture is then applied to the stent mounted on a rotating mandrel by spraying using a fine nozzle using the following parameters:

Alternatively, those of ordinary skill in the art can adjust these parameters to meet the conditions of the present disclosure, to produce the drug layer (thinner on the luminal surface) of uneven distribution on the stent surface. In some embodiments, it is possible to use those in U.S. Patent Application No. 13/850,679 (published as 2014/0296967A1), U.S. Patent Application No. 11/808,926 (published as 2007/0288088A1) and U.S. Provisional Patent Application No. 60/812,990 to regulate parameters, which are all incorporated herein by reference in their entirety.

The conditions of the drug spray can be adjusted so that the drug-containing coating (3) can be applied to the luminal surface (6), side surface (7) and distal luminal surface (8) of the stent. See Figure 10. Due to the high-speed rotation spray and centrifugal action, the drug-containing coating (3) can have a higher (and adjustable) thickness on the distal luminal surface (facing the blood vessel wall) (8) compared to the luminal surface (facing the blood) (6) and side surface (7). One embodiment of the present disclosure is a stent with such an uneven coating. In one embodiment, it was found that the relatively high speed rotation and low pressurization process when coating the stent with a drug-containing solution produced this result. It was then dried in a vacuum oven at 40°C. Using the above parameters, the coating weight on the stent of this embodiment was 800+/-80μg, and it had a thickness of about 5-7μm. The drug loading in the stent of this embodiment was 164+/-16μg.

B. In vivo studies in rabbits

The stents prepared by this method were used in vivo. A first stent was prepared according to the example method having the following stent frame structure: In this example, the stent frame comprises stainless steel with a 10-peak design. This design can result in improved radial strength and increased uniformity of the stent after expansion compared to designs with fewer peaks. The stent (cobalt chromium) has the following additional features: a conformal coating of a drug-containing layer of a biodegradable polymer (PLGA, 3.5-10um) with 1.4ug/mm2 of sirolimus; 80um strut thickness; and an electrografted durable/biocompatible base layer made of PBMA with a thickness of 100nm-200nm (supporting the drug-containing layer).

Multiple stents with these properties were implanted in rabbits. All surgeries were performed using aseptic technique. Rabbits were placed in the supine position with the hind legs abducted and externally rotated at the hip with the knees extended. To maintain physiological homeostasis during surgery, animals were maintained with 0.9% sodium chloride, USP, at a rate of 10-20 ml/kg/hr intravenously and placed on a warm water blanket. Heart rate, blood pressure, temperature, respiratory rate, _oxygen saturation, carbon _dioxide level, and isoflurane concentration were monitored and recorded every 15 minutes. The left and right iliac arteries were injured by balloon endothelial denudation. Using fluoroscopic guidance, a 3.0 mm × 8 mm standard angioplasty balloon catheter was placed over a guidewire over the distal iliac artery and inflated to 8 ATM with 50:50 contrast agent/saline. The catheter was then withdrawn proximally in its inflated state to approximately the level of the iliac bifurcation. The balloon was deflated and repositioned distally, and the 10 ATM endothelial denudation was repeated on the same segment of the vessel that was initially denuded. After balloon stripping, a coronary stent (BuMA Supreme by BuMA BMS, Xience [Xience Xpedition]) (3.0 mm x 15.0 mm) was immediately implanted into the stripped segment of the iliofemoral artery according to predetermined allocation. Using fluoroscopic guidance, the pre-installed stent/catheter was delivered to the distal iliac artery over a guidewire. The stent was deployed with a target balloon to artery ratio of ~1.3 to 1.0 at the recommended nominal inflation pressure (10 ATM) delivered within 30 seconds. Repeat angiography was performed to evaluate stent placement and patency. Following post-implantation angiography, all catheters/sheaths were withdrawn, the surgical wound was closed, and the animal was recovered. For example, as shown in FIG3 , when a stent according to the present disclosure (Buma Supreme) was implanted in a rabbit for 60 days, the stent exhibited better endothelial coverage (80%) compared to the Xience Xpedition (50%) described in FIG2 , as evaluated by scanning electron microscopy (SEM).

Furthermore, as shown in Figures 5A-5D, 60 days after implantation in rabbits, the stent according to the present disclosure exhibited better functional endothelial coverage (38%) compared to the Xience Xpedition stent described in Figures 4A-4D (21%).

As further shown in FIG. 7 , 90 days after implantation in rabbits, the stent according to the present disclosure exhibited superior endothelial coverage (99%) compared to the Xience Xpedition stent depicted in FIG. 6 (70%).

Finally, as shown in Figures 9A-9C, 90 days after implantation in rabbits, the stent according to the present disclosure exhibited better functional endothelial coverage (100%) compared to the Xience Xpedition stent described in Figures 8A-8D (46%).

A second set of experiments was prepared according to the example method using the following scaffold frame structure:

The stent (BuMA Supreme) was coated with a conformal coating of a biodegradable polymer (PLGA) using the same spray coating process described above. The struts were 80 μm thick and the stent was made of cobalt-chromium alloy. The eG layer was made of PBMA (100-200 nm) and a PLGA drug-containing layer (3.5 to 10 μm) with 1.4 μg/mm² of sirolimus.

Similar to the previous experiment, the scaffold was implanted in a rabbit, and their endothelialization (such as the 45th and 90th day) was studied using Evans Blue and VE-cadherin/P120 co-location. For the Evans Blue of 45 days, the results are exemplified in Figures 12 A to 12 D; For the VE-cadherin/P120 co-location of 45 days, the results are exemplified in Figures 13 A to 13 D; For the Evans Blue of 90 days, the results are exemplified in Figures 14 A to 14 D; With the VE-cadherin/P120 co-location of 90 days, the results are exemplified in Figures 5 A to 15 D. As shown in these figures, according to the scaffold (BuMA Supreme scaffold) disclosed herein, there is a VE-cadherin/P120 endothelial cell co-location (that is, endothelialization is better and more functional) greater than that of the scaffold tested according to other drug eluting scaffolds disclosed herein. Furthermore, the permissibility of the endothelial cell layer covering the stent of the present disclosure (BuMA Supreme stent) as assessed by Evans blue staining was lower than that of other drug eluting stents tested not according to the present disclosure, indicating that the endothelium was more functional in the BuMA Supreme stent.

It is also envisioned that the stent frame may include a wavy design having an alternating pattern of two-three-two-three connecting rods arranged spirally in the axial direction. This design can improve the flexibility of the stent and can result in better adaptation to the blood vessel after the stent is expanded. In some embodiments, the two ends of the stent may have two connecting rods or three connecting rods in a two-three-two-three pattern. In other embodiments, the two ends of the stent may have four connecting rods, which can increase the axial strength of the stent. The dimensions of this embodiment design may include, for example, a pole width of 90 μm and a crown width of 100 μm. When having a crown width greater than the pole width, the stent may have greater radial strength and a reduced crossing profile with the blood vessel after the stent is expanded. In addition, the dimensions of this embodiment design may include a wall thickness of 80 μm or 90 μm.

C. Human Clinical Trials

Human clinical trials were conducted using stents made of stainless steel (316L) (BUMA stents). The stents were designed to have an OD of 1.6 and 6 peaks (first design) or an OD of 1.8 and 9 peaks (second design). The first design had a stem width of 110 μm, while the second design had a stem width of 90 μm. The first design had a wall thickness of 100 μm, while the second design had a wall thickness of 110 μm. These stents were coated by the spray coating method described above.

A clinical trial titled "Prospective Randomized Controlled 3 to 12 Month OCT Study Evaluating Endothelial Healing Between the Novel Sirolimus-Eluting Stent BUMA and the Everolimus-Eluting Stent XIENCE V" was conducted. The BUMA stent was designed to have a 30-day drug release time frame and a 60-day coating/drug-containing layer biodegradable time frame, and was manufactured according to Example 1 above. On the other hand, the Xience V stent was designed to have a 120-day drug release time frame, and the coating was biostable. Twenty patients were enrolled in the study. The BUMA stent and the XIENCE V stent were overlapped and implanted into the same lesion in the same vessel of the same patient. The study showed that at 3-month and 12-month OCT follow-up, the struts of both stents were well covered. However, at 12 months, the struts of the BUMA stent had significant coverage compared to the struts of the XIENCE V stent (99.2% for BUMA vs. 98.2% for XIENCE V, P<0.001). In addition, the struts of the BUMA stent had thicker neointimal hyperplasia thickness and larger neointimal area than the struts of the XIENCE V stent (0.15±0.10 mm for BUMA vs. 0.12±0.56 mm for XIENCE V, P<0.001). As explained above, a thickness below a first threshold (e.g., 0.1 mm) can indicate an insufficient number of endothelial cells, while a thickness above a higher second threshold (e.g., 0.50 mm) can indicate a ratio of smooth muscle cells to endothelial cells that is too high. In addition, the BUMA stent had more uniform strut coverage compared to the XIENCE V stent. Studies have shown that the BUMA stent has better long-term safety compared to the XIENCE V stent.

Another clinical trial entitled "Biodegradable polymer-based sirolimus-eluting stent with different elution and absorption kinetics" was conducted. The BUMA stent was designed to have a 30-day drug release time frame and a 60-day coating biodegradation (disappearance/dissolution/dissipation of the drug-containing layer) time frame, and it was manufactured according to Example 1 above. The EXCEL stent was designed to have a 180-day drug release time frame, and a 180 to 270-day coating biodegradation time frame. 2,348 patients were enrolled in the study. The BUMA stent showed a lower incidence of stent thrombosis compared to the EXCEL stent. In particular, the 1-year stent thrombosis rate of the BUMA stent was lower than that of the EXCEL stent, and this difference was demonstrated within the first month after implantation.

Another clinical trial called the "PIONEER-II study" compared the 1-month optical coherence tomography (OCT) results between the BUMA stent and the Xience V stent. The BUMA stent was designed to have a 30-day drug release time frame and a 60-day biodegradable time frame for the drug-containing layer, and it was manufactured according to Example 1 above. The Xience V stent was designed to have a 120-day drug release time frame, and the coating was biostable. Fifteen patients were enrolled in the study. The study showed that the BUMA stent showed better coverage of strut neointimal coverage by OCT at 1 month follow-up compared to the Xience V stent (83.8% for BUMA vs. 73.0% for Xience V, P<0.001).

Example 2. Dispense coating process

A. Process

In some embodiments, the drug-containing layer (3) can be formed using a spread coating process to place a polymer coating on the stent framework (or on a polymer-coated stent, such as a stent coated with an electrograft coating described below). In one embodiment, after drying, a 20 mm stent is spread coated with a biodegradable polyester (polylactide, p-PLA) containing sirolimus. The copolymer (5% w/v) is dissolved in chloroform. Then, sirolimus is dissolved in the chloroform/polymer mixture to obtain a final ratio of 1/5 sirolimus/polymer of 1:5. A micro-dispenser is operated with the stent struts and connections and the mixture is spread onto the abluminal surface (8) of the stent using the micro-dispenser using the following parameters:

The coating was applied only to the abluminal surface (8) of the stent. Drying was performed in a vacuum oven at 40°C. In this example, the coating weight on the stent was 500 ± 50 μg, and the coating thickness was approximately 9-12 μm. In addition, in this example, the drug loading was 125 ± 12 μg.

Electrografted coating (eG coating)

In some embodiments, the biocompatible base layer (5) may further comprise/be made of an electrograft coating. More details about the electrograft coating process of the stent can be obtained in the art, including, for example, U.S. Patent Application No. 13/850,679 (published as 2014/0296967A1), U.S. Patent Application No. 11/808,926 (published as 2007/0288088A1) and U.S. Provisional Patent Application No. 60/812,990, all of which are incorporated herein by reference.

The electrografted layer can serve as an adhesion primer for the drug-containing layer (3) (e.g., during manufacturing, curling and/or stenting). The electrografted primer coating can be uniform. The layer can have a thickness of 10 nm to 1.0 micron, for example, 10 nm to 0.5 micron or 100 nm to 300 nm. Such a thickness can ensure that the coating does not crack. The electrografted layer is generally able to prevent cracking and delamination of the biodegradable polymer layer, and the electrografted layer generally exhibits equal (if not better) recolonization compared to the stainless steel BMS. In addition, due to the mutual intersection between the two polymer layers, the use of an electrografted layer having a thickness of at least about tens of nanometers or hundreds of nanometers can ensure good enhancement of the adhesion of the drug-containing layer (3). Therefore, the selection of the properties of the electrografted polymer can be based on the properties of the release matrix polymer, which itself can be selected based on the desired load and kinetics of drug release. In some embodiments, the electrografted polymer and the release matrix polymer can be at least partially miscible to form a good interface. This is the case, for example, when the two polymers have similar solubilities or Hildebrand parameters, or when the solvent for one of the polymers is at least a good swellant for the other polymer.

Typically, the electrografted polymer can be selected from polymers known to be biocompatible. For example, the polymer can be selected from those obtained via a proliferative chain reaction, such as vinyls, epoxides, cyclic monomers that undergo ring-opening polymerization, and the like. Thus, polybutyl methacrylate (p-BuMA), polymethyl methacrylate (PMMA), or poly-ε-caprolactone (p-ECL) can be used. Alternatively or simultaneously, polyhydroxyethyl methacrylate (p-HEMA) can also be used.

The electrografted layer (e.g., p-BuMA layer) can further have a passivating behavior and can prevent the release of heavy metal ions from the stent framework (e.g., into the bloodstream or into the arterial wall). The heavy metal ions may contribute to the initial inflammation caused by the introduction of the metal stent into the blood, which can cause partial oxidation of any metal until the Nernst equilibrium is reached. In particular, the thickness of the arterial wall of the electrografted layer and the biodegradable (drug-free) branch is generally less than that of the bare metal stent branch, demonstrating fewer granulomas, i.e., less inflammation.

In one embodiment, the electrografted layer may be biodegradable and thus may disappear from the surface of the stent after the drug-containing layer has also disappeared.

The electrografted layer can have a non-thrombotic (or anti-thrombotic) effect and a pro-healing effect (e.g., promoting the proliferation and adhesion of active ECs). If ECs begin to proliferate on top of the drug-containing layer (e.g., before they completely disappear), the hydrolysis of the biodegradable polymer can still continue below, and eventually the ECs can contact the electrografted layer. If the electrografted layer itself is biodegradable, then this pro-healing effect can be similar to the pro-healing effect of the stent frame. The pro-healing effect of a biostable electrografted layer may be better, as the electrografted layer ensures proper recolonization of ECs over a longer period of time.

In some embodiments, the electrografted layer may additionally be made of an antifouling material.

Polymers that can be used as electrografted coatings include, but are not limited to, vinyl polymers such as acrylonitrile polymers, methacrylonitrile polymers, methyl methacrylate polymers, ethyl methacrylate polymers, propyl methacrylate polymers, butyl methacrylate polymers, hydroxyethyl methacrylate polymers, hydroxypropyl methacrylate polymers, cyanoacrylate polymers, acrylic polymers, methacrylic acid polymers, polymers of styrene and its derivatives, N-vinyl pyrrolidone polymers, vinyl halide polymers and polyacrylamides, isoprene polymers, ethylene polymers, propylene polymers, ethylene oxide polymers, polymers containing molecules with cleavable rings (such as lactones, particularly ε-caprolactone), lactide polymers, glycolic acid polymers, ethylene glycol polymers, as well as polyamides, polyurethanes, poly(orthoesters), polyaspartic acid esters, and the like.

In some embodiments, the electrografted coating can be a vinyl polymer or copolymer, such as polybutyl methacrylate (poly-BUMA), polyhydroxyethyl methacrylate (poly-HEMA), poly-2-methacryloyloxyethyl phosphorylcholine/butyl methacrylate (poly-MPC/BUMA), polymethacryloyloxyethyl phosphorylcholine/dodecyl methacrylate/trimethylsilylpropyl methacrylate (poly-MPC/DMA/TMSPMA), etc. In certain aspects, the electrografted coating can be a biodegradable polymer, such as polycaprolactone, polylactide (PLA), or polyethylene glycol lactide (PLGA).

Adhesion between the electrografted coating and the biodegradable layer (drug-containing layer or topcoat layer)

The drug-containing layer can be adhered to the electrografted layer by the following processes: forming a chemical bond with the electrografted polymer; inserting a chemical precursor of the drug-containing layer into the electrografted polymer to cause its formation within the electrografted polymer film; forcing the pre-formed biodegradable polymers in the electrografted layer to interpenetrate by intercrossing, etc. Intercrossing generally refers to the fact that the polymer chains of the biodegradable polymer can "creep" or "reptate" within the electrografted layer and can form at least one "loop" within the electrografted layer. For polymers, a "loop" can refer to the typical size of the chain when randomly configured, and it can be evaluated using the radius of gyration of the polymer. Typically, the radius of gyration of the polymer is less than 100 nm, which suggests that in order to improve adhesion, the electrografted layer can be thicker than this threshold to be able to support at least one loop of the polymer of the drug-containing layer.

In embodiments using interdigitated layers, the electrografted layer can be thicker than about 100 nm, can have the same wettability (e.g., hydrophobicity/hydrophilicity) as the polymer of the drug-containing layer, can have a glass transition temperature less than the glass transition temperature of the polymer of the drug-containing layer, and/or can be at least partially swelled by a solvent for the polymer of the drug-containing layer or by a solvent for a dispersion containing the polymer of the drug-containing layer.

In some embodiments, interdigitation can be induced by spreading a solution containing a drug-containing layer (and optionally a drug) on a stent frame coated with an electrografting layer. For example, the drug-containing layer can comprise PLGA, optionally dissolved in dichloroethane, dichloromethane, chloroform, or the like, along with a hydrophobic drug (e.g., sirolimus, paclitaxel, ABT-578, etc.). In such an embodiment, the electrografting layer can comprise p-BuMA.

In some embodiments, this spreading can be carried out by dipping or by spraying. In the embodiment using spraying, the nozzle of the solution above the spray can face the stent frame, and the stent frame can be rotated to present all outer surfaces to the spray. In some aspects, the solution to be sprayed can have a low viscosity (for example, <1cP, the viscosity of pure chloroform is about 0.58cP), the nozzle can be very close to the rotating stent, and the pressure of the inert carrier gas (for example, nitrogen, argon, compressed air, etc.) in the nozzle can be less than 1 bar. These conditions can cause the liquid to be atomized into small droplets of liquid, and the droplets can travel in the spray chamber atmosphere to impact the surface of the electrografted layer of the stent. In the embodiment where the electrografted polymer layer and the spray solution have the same wettability, the droplets can show a very low contact angle, so the droplet collection on the surface can be film-forming. Such a spray system can manufacture a stent with a very small mesh structure between the struts.

The relative motion of the nozzle relative to the support can make it possible to deposit a uniform and/or relatively thin (e.g., <1 μm) layer in a single spray. Rotation and/or ventilation can cause the solvent to evaporate, leaving a polymer layer (optionally including a drug) on the surface. Then, the second layer can be sprayed on the first layer, and so on to achieve the desired thickness. In an embodiment where multiple sprays are used to achieve the desired thickness, a "low pressure" spray system can be implemented in batches, where multiple supports rotate in parallel with a nozzle that sprays on each and all supports in turn, thereby causing other supports to evaporate when another support is sprayed.

In addition to these embodiments, the manufacturing process may include any of the manufacturing methods disclosed in US20070288088A1, which is incorporated herein by reference.

The described embodiments are to be considered in all respects only as illustrative and not restrictive. Therefore, the scope of the present disclosure is indicated by the appended claims rather than by the preceding description. All changes within the meaning and scope of the equivalents of the claims are included within their scope.

Claims (40)

1. A drug-eluting stent, comprising: Support frame; Drug-containing layer; The drug embedded in the drug-containing layer; and The biocompatible base layer is disposed on the scaffold frame and supports the drug-containing layer. The drug-eluting layer has a non-uniform coating thickness, and the polymers forming the drug-eluting layer on the stent cavity surface and the stent side surface degrade faster than the polymers forming the drug-eluting layer on the stent distal cavity surface. The drug-eluting layer is configured to completely dissolve 45 to 60 days after implantation of the drug-eluting stent. 2. The drug-eluting stent of claim 1, wherein the drug-containing layer is configured to release the drug within 30 days of implantation into the blood vessel. 3. The drug-eluting stent according to claim 1, wherein the polymer of the stent cavity surface and the side surfaces comprises PLGA, and the polymer of the stent distal cavity surface comprises PLA. 4. The drug-eluting stent according to claim 1, wherein the stent frame is made of a single piece of metal, wire, or tube. 5. The drug-eluting stent of claim 4, wherein the metal comprises at least one of stainless steel, nickel-titanium, tantalum, cobalt-chromium MP35N or MP20N alloy, platinum and titanium. 6. The drug-eluting stent of claim 1, wherein the stent frame is made of a biodegradable material. 7. The drug-eluting stent according to claim 1, wherein the drug comprises at least one of an antithrombotic agent, an anticoagulant, an antiplatelet agent, an antitumor agent, an antiproliferative agent, an antibiotic, an anti-inflammatory agent, a gene therapy agent, collagen, collagen derivatives, carbohydrates, carbohydrate derivatives, and promoters of endothelial cell migration and/or proliferation and/or survival, and combinations thereof. 8. The drug-eluting scaffold according to claim 7, wherein the antiproliferative agent is a smooth muscle cell proliferation inhibitor, the gene therapy agent is a recombinant DNA product or a recombinant RNA product, and the collagen or collagen derivative includes protein analogs. 9. The drug-eluting stent of claim 7, wherein the drug comprises sirolimus and/or its derivatives. 10. The drug-eluting stent of claim 7, wherein the drug comprises a sirolimus analogue. 11. The drug-eluting stent of claim 1, wherein the drug-containing layer has a thickness of 5 to 12 μm. 12. The drug-eluting stent according to claim 1, wherein the drug-containing layer is selected from poly(hydroxyalkanoate) (PHA), poly(esteramide) (PEA), poly(hydroxyalkanoate-co-esteramide), polyacrylate, polymethacrylate, polycaprolactone, poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly(propylene oxide) (PPO), poly(propylene fumarate) (PPF), poly(D-lactide), poly(L-lactide), poly(D,L-lactide), poly(meta-lactide), poly(L-lactide-co-meta-lactide), poly(D-lactide-co-meta-lactide), poly(D,L-lactide-co-meta-lactide). Poly(D,L-lactide-co-PEG), poly(D,L-lactide-co-trimethylene carbonate), poly(lactide-co-glycolic acid), poly(glycolic acid-co-trimethylene carbonate), poly(trimethylene carbonate), PHA-PEG, PBT-PEG (PolyActive®), PEG-PPO-PEG (Pluronic®) and PPF-co-PEG, polycaprolactone, polyglycerol sebacate, polycarbonate, biopolyester, polyethylene oxide, polybutylene terephthalate, polydioxanone, collagen matrix with growth regulators, proteoglycans, mucopolysaccharides, vacuum-formed submucosa of the small intestine, fibers, chitin, dextran and mixtures thereof. 13. The drug-eluting stent of claim 12, wherein the drug-containing layer is selected from tyrosine-derived polycarbonate. 14. The drug-eluting stent of claim 12, wherein the drug-containing layer is selected from poly(β-hydroxyalkanoates) and their derivatives. 15. The drug-eluting stent of claim 12, wherein the drug-containing layer comprises polylactide-co-glycolic acid 50/50. 16. The drug-eluting stent of claim 1, wherein the biocompatible base layer comprises at least one of poly(n-butyl methacrylate), PTFE, PVDF-HFP, poly(styrene-b-isobutylene-b-styrene), phenelzine C, PVP, PEVA, SBS, PC, or TiO2. 17. The drug-eluting scaffold of claim 1, wherein the biocompatible base layer comprises an electrically grafted polymer layer having intersecting surfaces with the drug-containing layer. 18. The drug-eluting stent of claim 17, wherein the electrically grafted polymer layer has a thickness of 10 nm to 1000 nm. 19. The drug-eluting scaffold of claim 17, wherein the electrografted polymer layer comprises a monomer and an aryl diazonium salt, the monomer being selected from ethylene derivatives, epoxides, and cyclic monomers undergoing ring-opening polymerization. 20. The drug-eluting stent of claim 19, wherein the monomer is further selected from butyl methacrylate, methyl methacrylate, hydroxyethyl methacrylate, ε-caprolactone, and 4-aminophenyldiazotetrafluoroborate. 21. A method for manufacturing the drug-eluting stent of claim 1, the method comprising: Provide support frames; and The scaffold frame is non-uniformly coated with at least one polymer mixed with at least one drug. Uneven coating includes coating the cavity surface and/or sides of the support with a coating that is thinner than the coating on the distal cavity surface. 22. The method of claim 21, wherein the thinner coating is a drug-containing layer and/or a biocompatible base layer beneath the drug-containing layer. 23. The method of claim 21, further comprising dissolving at least one polymer and at least one drug to form at least one polymer mixed with at least one drug. 24. The method of claim 21, wherein unevenly coating the stent frame comprises spraying the stent frame with at least one polymer mixed with at least one drug. 25. The method of claim 21, wherein unevenly coating the support frame comprises rotating the support frame during spray coating to generate centrifugal force. 26. The method of claim 25, wherein the centrifugal force causes the thickness of the mixture on the distal cavity surface of the support frame to be greater than the thickness of the mixture on the cavity surface of the support frame and the side surface of the support frame. 27. The method of claim 21, further comprising drying the coated support frame in a vacuum oven. 28. The method of claim 27, wherein the coated support frame is dried at 40°C to 50°C. 29. The method of claim 24, wherein the spray flow rate is 24 μL/s or less. 30. The method of claim 24, wherein the spray volume is 192 μL/s or less. 31. The method of claim 24, wherein the spray coating is performed at a pressure of 0.3 bar or lower. 32. The method of claim 25, wherein the rotational speed of the support is at least 2000 rpm. 33. The method of claim 24, wherein the distance between the nozzle for spray coating and the support frame is 6.5 mm or less. 34. The method of claim 21, further comprising: Prior to the spray-coated frame, at least one polymer is electrically grafted onto the support frame. 35. The method of claim 34, further comprising: Before spray coating the installed frame, bake the electrically grafted polymer at room temperature or higher. 36. The method of claim 35, wherein the baking is performed under atmospheric conditions. 37. The method of claim 35, wherein the baking is carried out in nitrogen. 38. The method of claim 35, wherein the baking is performed in a vacuum. 39. Use of the stent according to any one of claims 1 to 20 in the manufacture of a medicament or device for treating or preventing vascular disease or preventing restenosis, thrombosis, tumor growth, hemangioma or obstruction of the lacrimal gland. 40. The use according to claim 39, wherein the vascular disease is vascular stenosis.