Photo-crosslinking preparation and medical device

Abstract

The invention discloses a photo-crosslinking preparation and a medical device, and relates to the technical field of blood vessel treatment. The photo-crosslinking preparation comprises a photosensitizer, an active oxygen scavenger and a photosensitive enhancer, the mass ratio of the photosensitizer to the active oxygen scavenger is (1: 0.01)-(1: 100), and the mass ratio of the photosensitive enhancer to the photosensitizer is (1: 0.01)-(1: 120). According to the photo-crosslinking preparation disclosed by the invention, collagen and elastin in a blood vessel wall can be induced to be rapidly combined and form a stent in situ by exciting the photosensitizer, so that healing and repairing of blood vessels are realized; according to the present invention, with the active oxygen scavenging agent, the active oxygen can be eliminated so as to reduce vascular cell damage, reduce aneurysm formation risk, reduce thrombosis formation risk and inflammatory response, and effectively maintain the smooth blood vessel, and in addition, the photosensitizer can be prevented from being affected by the active oxygen scavenging agent so as to avoid the problem that the blood vessel cross-linking effect is reduced through the photosensitizer;

Description

Technical Field

[0001] This invention relates to the field of vascular treatment technology, and more particularly to a photocrosslinking agent and a medical device. Background Technology

[0002] Atherosclerosis (AS) is a major cause of coronary heart disease, cerebral infarction, and peripheral artery disease. Percutaneous angioplasty and percutaneous endovascular stenting are revolutionary technologies for treating intravascular stenosis, greatly improving treatment outcomes for patients with atherosclerosis. However, drug-eluting stents still face risks such as in-stent restenosis and late-stage stent thrombosis. Furthermore, due to their rigid metallic structure and susceptibility to fracture, drug-eluting stents are not ideal for treating tortuous intracranial vessels and lower extremity vessels.

[0003] To address the drawbacks of drug-eluting stents, "interventional without implantation" drug-eluting balloons have emerged. Drug-eluting balloons are based on balloon angioplasty, with an anti-proliferative drug coated on the balloon surface. This drug is then delivered to the target lesion site via a balloon catheter. After balloon inflates, the anti-proliferative drug is transferred to the blood vessel wall, thereby persistently inhibiting the proliferation of vascular smooth muscle, reducing vascular stenosis, and achieving a therapeutic effect.

[0004] However, current drug-eluting balloons still face the following problems: (1) The drug coating has poor adhesion, resulting in a large amount of drug loss during delivery. A large amount of drug is lost before reaching the lesion site. For tortuous lesions and diffuse long lesions, it is difficult to deliver an effective amount of drug, resulting in poor treatment effect; (2) The drug coating generates a large number of microparticles during delivery and expansion. The size of the detached microparticles is as high as 300μm or more, which can easily cause vascular embolism and "slow blood flow" and "no-reflow" phenomena. It can easily cause intracranial arterial embolism stroke in thinner blood vessels and increase the amputation rate of lower limb arteries, which seriously affects the treatment effect; (3) The drug-eluting balloon is relatively hard. After the drug-eluting balloon enters the blood vessel, the frictional resistance of the drug coating on the surface of the balloon is large. For tortuous blood vessels, it is difficult for the drug-eluting balloon to be delivered to the lesion site, resulting in treatment failure.

[0005] Currently, a new technology has emerged—natural vascular stents, which are balloon dilatation catheters containing photosensitive compounds or drugs. Unlike traditional drug-eluting balloons, the balloon portion of this type of balloon dilatation catheter can scatter visible light, stimulating the photosensitive compounds to rapidly bind collagen and elastin in the blood vessel wall, forming a stent in situ and achieving vascular healing and repair.

[0006] Related technologies disclose a method of delivering exogenous proteins and cross-linking agents to the blood vessel wall via a balloon catheter, forming a "protein microscaffold" through in-situ cross-linking. This "protein microscaffold" can support the blood vessel wall, maintaining vascular gain, preserving vascular dilation size, and reducing the possibility of restenosis. However, the inventors discovered that during the treatment of atherosclerotic diseases using natural vascular stents, thrombi can easily form, obstructing blood vessels and causing ischemia; furthermore, it can easily lead to aneurysms, and once an aneurysm ruptures, it can be extremely life-threatening. Summary of the Invention

[0007] This invention discloses a photocrosslinking agent and a medical device to solve the technical problem of easy formation of thrombi and aneurysms during the treatment of atherosclerotic diseases using natural vascular stents in related technologies.

[0008] To solve the above problems, the present invention adopts the following technical solution: The first aspect of the present invention discloses a photocrosslinking agent.

[0009] The photocrosslinking formulation of the present invention includes a photosensitizer, a reactive oxygen species scavenger, and a photosensitizer enhancer, wherein the mass ratio of the photosensitizer to the reactive oxygen species scavenger is 1:0.01 to 1:100, and the mass ratio of the photosensitizer enhancer to the photosensitizer is 1:0.01 to 1:120.

[0010] According to an optional embodiment, the photosensitizer is an electron donor photosensitizer or an electron acceptor photosensitizer, wherein the electron donor photosensitizer includes one or more of arginine, diphenyliodonium hexafluorophosphate, dimethylaminoethyl methacrylate, fatty tertiary amines, and triethanolamine; and the electron acceptor photosensitizer includes one or more of vitamin B12, cobalt pentaammonia chloride, sodium persulfate, potassium persulfate, and ammonium persulfate.

[0011] According to one alternative embodiment, the photosensitizer includes one or more of the following: naphthalimide compounds, naphthalimide hydrophilic derivatives, camphorquinone, camphorquinone hydrophilic derivatives, riboflavin, riboflavin sodium phosphate, rose red, curcumin, eosin Y, and transition metal complexes.

[0012] According to an optional embodiment, the transition metal complex includes one or more of palladium complexes, iron complexes, ruthenium complexes, iridium complexes, nickel complexes, manganese complexes, platinum complexes, and osmium complexes.

[0013] According to an optional embodiment, the reactive oxygen species scavenger includes one or more of the following: N-acetylcysteine, cysteine, anthocyanins, proanthocyanidins, vitamin C, histidine, superoxide dismutase, glutathione, glutathione peroxidase, catalase, β-carotene, tea polyphenols, and flavonoids.

[0014] According to an optional embodiment, the photocrosslinking preparation further includes an active drug, which is one or more of an anti-proliferative drug, a vascular endothelial growth promoter, an antithrombotic drug, and an anti-inflammatory drug.

[0015] A second aspect of the present invention provides a medical device.

[0016] The medical device of the present invention includes a catheter, wherein a guide channel and a delivery channel are provided within the catheter, the guide channel is used to insert a guidewire, and the delivery channel is used to introduce fluid. The distal end of the catheter is an expansion portion, which is capable of expanding or contracting radially along the catheter. The medical device further includes a photocrosslinking agent coating, which is prepared by a photocrosslinking agent as described in any of the technical solutions of the present invention, and the photocrosslinking agent coating is at least partially provided on the outer wall of the expansion portion. The medical device further includes an optical fiber assembly, which is inserted into the catheter, and the distal end of the optical fiber assembly is a light-emitting portion, which at least partially extends to the area on the expansion portion where the photocrosslinking agent coating is provided.

[0017] A third aspect of the invention provides another medical device.

[0018] The medical device of the present invention includes a catheter, wherein a guide channel and a delivery channel are provided within the catheter. The guide channel is used to insert a guidewire, and the delivery channel is used to introduce fluid. The distal end of the catheter is an expansion portion, which is capable of expanding or contracting radially along the catheter. The expansion portion is provided with a plurality of micropores, which communicate with the delivery channel. The medical device further includes a photocrosslinking agent, which is the photocrosslinking agent described in any of the technical solutions of the present invention. The photocrosslinking agent is delivered to the micropores via the delivery channel and ejected from the micropores. The medical device further includes an optical fiber assembly, which is inserted into the catheter. The distal end of the optical fiber assembly is a light-emitting portion, which at least partially extends to the area on the expansion portion where the micropores are provided.

[0019] According to an optional embodiment, when the expansion portion is provided with a plurality of micropores, the sum of the minimum flow cross-sectional areas of the micropores is less than the minimum flow cross-sectional area of ​​the conveying channel.

[0020] According to one optional embodiment, the micropores have a pore size of 1~50 μm and a pore density of 0.5~200 pores / cm³. 2 .

[0021] The technical solution adopted in this invention can achieve the following beneficial effects: In a first aspect, the photocrosslinking formulation of the present invention includes a photosensitizer and a reactive oxygen species scavenger. By activating the photosensitizer, collagen and elastin in the blood vessel wall can be induced to bind rapidly and form a scaffold in situ, thereby achieving vascular healing and repair. By using the reactive oxygen species scavenger, reactive oxygen species can be eliminated, thereby reducing vascular cell damage and the risk of aneurysm formation. In addition, the reactive oxygen species scavenger can also reduce platelet aggregation and adhesion, reduce blood coagulation, and enhance fibrinolysis. Thus, in the process of using natural vascular stents to treat atherosclerotic diseases, the risk of thrombosis and inflammatory response can be effectively reduced, and vascular patency can be effectively maintained.

[0022] The photocrosslinking formulation of this invention solves the technical problem of easy formation of thrombi and aneurysms in the process of treating atherosclerotic diseases using natural vascular stents in related technologies.

[0023] Secondly, the photocrosslinking formulation of the present invention further includes a photosensitizer, which can promote electron transfer of the excited-state photosensitizer, thereby improving the crosslinking effect between the photosensitizer and proteins in blood vessels, so as to enhance the supporting effect of the formed scaffold and the therapeutic effect on blood vessels, and avoid the problem that the photosensitizer is affected by reactive oxygen species scavengers, which leads to a decrease in its vascular crosslinking effect. Attached Figure Description

[0024] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0025] Figure 1 This is a schematic diagram of the medical device according to an embodiment of this application; Figure 2 This is a schematic diagram of a medical device according to another embodiment of this application; Figure 3 This is a schematic diagram of the structure of the micropores in the embodiments of this application.

[0026] In the figure: 10, conduit; 11, guide channel; 12, delivery channel; 13, expansion section; 131, micropore; 132, retention groove; 20, photocrosslinking agent coating; 30, optical fiber assembly; 31, light-emitting part; 32, light-emitting device; 33, optical fiber body. Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0028] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0029] In the various embodiments of this application, "near end" and "far end" refer to the distance of each component from the user in the usage environment. The end closer to the user is designated as the "near end", and the end farther from the user is designated as the "far end".

[0030] In the treatment of atherosclerotic diseases using natural vascular stents, the photocrosslinking mechanism of these stents is similar to that of photodynamic therapy for tumors, involving type I and type II reactions. Besides forming triplet photosensitizers, this process also generates a large amount of reactive oxygen species (ROS), including singlet oxygen, superoxide anion radicals, hydroxyl radicals, and hydrogen peroxide—all cytotoxic species. In addition to promoting vascular crosslinking, excessive ROS damage cellular proteins, lipids, and DNA, leading to the death of numerous vascular and endothelial cells. Simultaneously, it causes lipid peroxidation of unsaturated fatty acids on the vascular endothelial cell membrane, altering cell membrane permeability and increasing calcium... 2+ Increased influx and increased lipid peroxides can disrupt the balance between prostacyclin (PGI2) and thromboxane B2 (TXB2), promote platelet aggregation and adhesion, activate the coagulation process, form thrombi, and further obstruct blood vessels, leading to ischemia. In addition, the death of a large number of vascular cells can easily lead to aneurysms, and once an aneurysm ruptures, it can be extremely life-threatening.

[0031] Therefore, the present invention provides a photocrosslinking agent and a medical device that can quickly and effectively complete vascular crosslinking, form a stent in situ, achieve vascular healing and repair, and at the same time reduce vascular cell damage, reduce the risk of aneurysm formation, reduce the risk of thrombosis, and effectively maintain vascular patency.

[0032] The following is in conjunction with the appendix Figures 1-3 The photocrosslinking agents and medical devices provided in this application will be described in detail through specific embodiments and application scenarios.

[0033] The photocrosslinking formulation of this embodiment includes a photosensitizer. The photosensitizer absorbs light energy of a specific wavelength and causes its electrons to undergo transitions, thereby making the photosensitizer chemically reactive. The photocrosslinking formulation of this embodiment, by activating the photosensitizer, can induce collagen and elastin in the blood vessel wall to rapidly bind and form a scaffold in situ, achieving vascular healing and repair.

[0034] For example, the photosensitizer in this embodiment is one or more selected from the following: naphthalimide compounds, naphthalimide hydrophilic derivatives, camphorquinone, camphorquinone hydrophilic derivatives, riboflavin, riboflavin sodium phosphate, rose red, curcumin, eosin Y, and transition metal complexes. For example, the transition metal complexes include one or more selected from the following: palladium complexes, iron complexes, ruthenium complexes, iridium complexes, nickel complexes, manganese complexes, platinum complexes, and osmium complexes. The photosensitizer in this embodiment absorbs wavelengths of 450 nm.

[0035] The photocrosslinking formulation of this embodiment further includes a reactive oxygen species (ROS) scavenger. Preferably, the mass ratio of the photosensitizer to the ROS scavenger is 1:0.01 to 1:100. The ROS scavenger is a reagent capable of reacting with and scavenging free radicals, and can protect cells from oxidative damage.

[0036] For example, reactive oxygen species scavengers include one or more of the following: N-acetylcysteine, cysteine, anthocyanins, proanthocyanidins, vitamin C, histidine, superoxide dismutase, glutathione, glutathione peroxidase, catalase, β-carotene, tea polyphenols, and flavonoids.

[0037] The photocrosslinking formulation of this embodiment, through the use of reactive oxygen species scavengers, can eliminate reactive oxygen species, thereby reducing vascular cell damage and the risk of aneurysm formation. Furthermore, the reactive oxygen species scavengers can also reduce platelet aggregation and adhesion, decrease blood clotting ability, and enhance fibrinolysis. Therefore, during the treatment of atherosclerotic diseases using natural vascular stents, it can effectively reduce the risk of thrombosis and inflammatory response, and effectively maintain vascular patency. In other words, the photocrosslinking formulation of this embodiment solves the technical problem of easy thrombosis and aneurysm formation during the treatment of atherosclerotic diseases using natural vascular stents in related technologies.

[0038] The photocrosslinking formulation of this embodiment further includes a photosensitizer. Preferably, the mass ratio of the photosensitizer to the photosensitizer is 1:0.01 to 1:120. The photosensitizer is a substance capable of enhancing the effect of the photosensitizer.

[0039] For example, the photosensitizer is an electron-donating photosensitizer. The electron-donating photosensitizer can donate electrons to the excited-state photosensitizer to form photosensitizer free radicals, thereby enhancing the protein cross-linking effect. For example, the electron-donating photosensitizer includes one or more of arginine, diphenyliodonium hexafluorophosphate, dimethylaminoethyl methacrylate, aliphatic tertiary amines, and triethanolamine.

[0040] For example, the photosensitizer is an electron acceptor photosensitizer. An electron acceptor photosensitizer can accept electrons from an excited-state photosensitizer to form a photosensitizer free radical or cause a transition metal complex photosensitizer to reach a higher valence state, thereby enhancing the protein cross-linking effect. For example, electron acceptor photosensitizers include one or more of vitamin B12, cobalt pentaammine chloride, sodium persulfate, potassium persulfate, and ammonium persulfate.

[0041] The inventors discovered in their research that while reactive oxygen species (ROS) scavengers can eliminate free radicals generated during light irradiation, they can reduce the vascular cross-linking effect. The photocross-linking formulation of this embodiment also includes a photosensitizer. This photosensitizer promotes electron transfer in the excited-state photosensitizer, thereby enhancing the cross-linking effect between the photosensitizer and proteins in blood vessels. This strengthens the support effect of the formed scaffold and the therapeutic effect on blood vessels, avoiding the problem of reduced vascular cross-linking effect caused by ROS scavengers.

[0042] In some embodiments, the photocrosslinking formulation further includes an active pharmaceutical ingredient, which is one or more of an anti-proliferative drug, a vascular endothelial growth promoter, an antithrombotic drug, and an anti-inflammatory drug. The photocrosslinking formulation of this embodiment also includes an active pharmaceutical ingredient, which can further enhance the therapeutic effect of the photocrosslinking formulation.

[0043] For example, the active pharmaceutical ingredient is rapamycin or a derivative thereof, ABT-578, zotaolimus, everolimus, biolimus A9, deforolimus (also known as rapamycin-42 (dimethyl phospholipase)), temsirolimus, tacrolimus, pimcrolimus, nitric oxide synthase, C3 exoenzyme, RhoA inhibitor, tubulusin, A3 agonist, CB2 agonist, 17-AAG, Hsp90 antagonist, tyrosine phosphorylation inhibitor, cathepsin S inhibitor, paclitaxel or a derivative thereof. The following are listed: paclitaxel, docetaxel, corticosteroids, glucocorticoids, dexamethasone, ceramides, dimethylsphingosine, ether-linked diglycerides, ether-linked phosphatidic acids, sphinganines, estrogens, takil, takil analogs, actinomycin D, prostaglandins, vitamin A, probucol, batimastat, statins, tramidil, mitomycin C and cytochalasin B, antiangiogenic agents, and antibodies. This embodiment also provides a medical device.

[0044] The medical device of this embodiment includes a catheter 10. The catheter 10 has a guide channel 11 and a delivery channel 12. The guide channel 11 is used to insert a guidewire, which guides the catheter 10 into the lesion area of ​​a patient's artery, vein, lacrimal duct, airway, nasal cavity, esophagus, bile duct, urethra, or other vascular or non-vascular cavities. The delivery channel 12 is used to introduce fluid, which can be gas or liquid, and is used to deliver the fluid to the dilation section 13. The distal end of the catheter 10 is the dilation section 13, which can expand or contract radially along the catheter 10, such as... Figure 1 As shown. Specifically, the expansion section 13 expands or contracts based on the volume of the conveyed fluid. Figure 1 A schematic diagram of the dilator 13 during dilation is shown. When the dilator 13 dilates, the outer wall of the dilator 13 is in contact with the inner wall of the blood vessel or the inner wall of the cavity, or has a predetermined distance between them.

[0045] The medical device of this embodiment further includes a photocrosslinking agent coating 20, which is prepared from a photocrosslinking agent according to any of the technical solutions in this embodiment. Preferably, the photocrosslinking agent coating 20 is at least partially provided on the outer wall of the expansion portion 13. Exemplarily, the photocrosslinking agent coating 20 can be a structure continuously disposed on the outer wall of the expansion portion 13, or it can be a structure spaced apart on the outer wall of the expansion portion 13. The thickness of the photocrosslinking agent coating 20 can be determined based on actual needs and is not limited here.

[0046] The medical device of this embodiment further includes an optical fiber assembly 30. The optical fiber assembly 30 is inserted into the catheter 10, and its distal end is a light-emitting portion 31. The light-emitting portion 31 extends at least partially into the area on the expansion portion 13 where a photocrosslinking agent coating 20 is provided, thereby ensuring that the light-emitting area of ​​the optical fiber assembly 30 at least partially covers the photocrosslinking agent coating 20. Exemplarily, the optical fiber assembly 30 is a columnar diffused optical fiber, a ring-shaped diffused optical fiber, or a spherical diffused optical fiber, preferably a columnar diffused optical fiber.

[0047] In some embodiments, the optical fiber assembly 30 includes a light-emitting part 31, a light-emitting device 32, and an optical fiber body 33. The light-emitting part 31 is located at the distal end of the optical fiber body 33, and the light-emitting device 32 is located at the proximal end of the optical fiber body 33. The light-emitting part 31 has its fiber cladding removed, leaving only the fiber core, to uniformly distribute the laser onto the blood vessel wall. After removing the fiber cladding, the fiber core of the light-emitting part 31 is treated with frosted glass or loaded with a light-scattering agent to enhance the laser dispersion in all directions. The optical fiber body 33 is a glass optical fiber or a plastic optical fiber; the core diameter of the optical fiber core in the optical fiber body 33 is 0.1~1.0 mm. By controlling the length of the fiber cladding removal, lesions of different lengths can be matched.

[0048] The medical device of this embodiment, through the action of the photocrosslinking agent coating 20, can not only form a stent in situ to achieve vascular healing and repair, but also reduce vascular cell damage, reduce the risk of aneurysm formation, reduce the risk of thrombosis, effectively maintain vascular patency, and ensure the vascular crosslinking effect.

[0049] This embodiment also provides another medical device.

[0050] This section only describes the differences compared to the aforementioned medical devices; the same parts will not be repeated here.

[0051] In this embodiment of the medical device, the expansion portion 13 is provided with a plurality of micropores 131, which are connected to the delivery channel 12, such as... Figure 2 As shown. In this embodiment, the delivery channel 12 is used not only for transporting fluids but also for transporting photocrosslinking agents. Through the delivery channel 12, the photocrosslinking agent can be transported from the proximal end of the conduit 10 to the micropore 131 located at its distal end, and pressure is used to eject the photocrosslinking agent from the micropore 131. For example, the pressure is 1 to 18 atmospheres. The light-emitting portion 31 extends at least partially into the area on the expansion portion 13 where the micropore 131 is provided, so that the light-emitting area of ​​the optical fiber assembly 30 at least partially covers the photocrosslinking agent.

[0052] For example, the photocrosslinking agent may be in powder or granular form and pre-stored at the proximal end of catheter 10; or the photocrosslinking agent may be in film form and coated at the proximal end of catheter 10. Injecting a solvent into the proximal end of catheter 10 can dissolve or disperse the photocrosslinking agent to facilitate delivery of the photocrosslinking agent through delivery channel 12. The solvent may be, for example, one or more of physiological saline, purified water, and contrast agents.

[0053] After the photocrosslinking agent is sprayed out from the micropore 131, it can pass through the inner layer of the blood vessel wall and enter the middle layer and even the outer layer of the blood vessel wall. Under laser excitation, the photosensitizer in the photocrosslinking agent promotes the binding of elastin in the blood vessel with collagen in the middle and outer layers to form a scaffold, thereby improving the stability and safety of the scaffold structure and enhancing the therapeutic effect.

[0054] Vascular plaques are filled with foamy macrophages containing large amounts of fat. These macrophages trigger inflammatory responses by secreting pro-inflammatory cytokines and chemokines. The inflammatory response at the plaque site is abnormally severe, and if the plaque cannot be effectively treated or stabilized, it can easily rupture or detach, causing vascular embolism and ischemic damage. The inventors discovered in their research that, due to plaque resistance, in related medical devices, fluid can only reach the outer surface of the plaque and cannot penetrate the interior, thus failing to completely encapsulate the plaque for treatment or stabilization. Even when the required flow rate is achieved, it poses a challenge to pressurizing the catheter, increasing the difficulty and risk of operation.

[0055] In some embodiments, when the expansion portion 13 is provided with a plurality of micropores 131, the sum of the minimum flow cross-sectional areas of the micropores 131 is less than the minimum flow cross-sectional area of ​​the conveying channel 12. The pore size of the micropores 131 is 1~50μm.

[0056] Under the preset jetting speed requirement of fluid ejected from micropores 131, since the sum of the minimum flow cross-sectional areas of all micropores 131 on the expansion section 13 is less than the minimum flow cross-sectional area of ​​the delivery channel 12, the flow velocity of the fluid flowing out of the micropores 131 when the fluid flows from the delivery channel 12 to the micropores 131 will increase significantly. Therefore, the fluid can more effectively penetrate into the intima, media, and adventitia of the blood vessel wall, allowing the photocrosslinking agent to be evenly distributed throughout the entire blood vessel wall. This enables the entire blood vessel wall to undergo protein crosslinking to form an in-situ scaffold and facilitate drug treatment, significantly enhancing the support effect and the therapeutic effect of the blood vessel. In addition, due to the significantly increased flow velocity of the fluid flowing out of the micropores 131, it can overcome plaque resistance and penetrate into the interior of the plaque, allowing the fluid to completely cover the plaque. This allows for better treatment of macrophages at the plaque and stabilizes the plaque, thereby significantly reducing the risk of plaque rupture or detachment caused by the dilation of the catheter 10.

[0057] As can be seen, the medical device of this embodiment, compared with the medical device with drug coating, can improve the transfer efficiency of photocrosslinked preparations, enhance the support effect of the stent and the therapeutic effect of blood vessels; at the same time, there is no drug delivery loss and drug particle generation, which can reduce distal vascular embolism and systemic toxicity.

[0058] In some embodiments, the density of micropores 131 is set to 0.5 pores / cm². 2 ~200 holes / cm 2 The therapeutic drug is sprayed onto the inner wall of the body cavity through the micropores 131, allowing the drug to be evenly transferred to the lesion site, avoiding excessive drug concentration at the lesion site, which could cause toxicity or insufficient treatment due to geographical absence of the lesion.

[0059] In some embodiments, the pore size of the micropore 131 first decreases and then increases along the fluid flow direction, such as... Figure 3 As shown, the aperture of the micropore 131 first decreases and then increases, which can increase the flow velocity and coverage area of ​​the fluid after passing through the micropore 131. This allows the fluid to pass through the inner layer of the blood vessel wall and enter the middle and outer layers of the blood vessel wall at a preset jet flow rate. At the same time, the jetted fluid can act on a larger area of ​​the blood vessel wall, enhancing the therapeutic effect. In addition, along the fluid flow direction, the aperture of the micropore 131 can also be set to gradually decrease, thereby increasing the flow velocity of the fluid jetted from the micropore 131.

[0060] In some embodiments, a retention groove 132 is provided on the inner wall of the output port of the micropore 131. The retention groove 132 is used to collect fluid, such as... Figure 3 As shown. During use, the expansion section 13 is inflated to abut against the inner wall of the blood vessel. At this time, the blood vessel wall is tightly attached to the outer wall of the expansion section 13, and may even be in a slightly expanded state. Meanwhile, the blood vessel wall corresponding to the retention groove 132 is close to the inner wall of the retention groove 132 due to its own elasticity. When fluid is ejected from the micropore 131, the ejected fluid will force the blood vessel wall to expand, so that a retention cavity is formed between the retention groove 132 and the blood vessel wall. For the ejected fluid, some of the fluid will pass through the inner layer of the blood vessel wall and enter the middle and outer layers, while the other part of the fluid that does not pass through the inner layer of the blood vessel wall is collected in the retention cavity. The fluid can continuously interact with the blood vessel wall in the retention cavity, preventing the fluid from flowing out from the expansion gap between the expansion section 13 and the blood vessel wall, thereby improving the drug utilization rate of the photocrosslinking agent and thus improving the therapeutic effect.

[0061] Examples 1 to 6 below use photocrosslinking agents as coating structures to illustrate the effects of photocrosslinking agents with different ratios.

[0062] Example 1 (1) Prepare the photocrosslinking agent coating solution: Weigh 20 mg of riboflavin and 40 mg of N-acetylcysteine ​​and dissolve them in a mixed solvent of ethanol and water (volume ratio of ethanol to water is 8:2). Disperse and dissolve by ultrasonication and filter with a 0.45 μm filter to obtain the coating solution.

[0063] (2) Take catheter 10 and use ultrasonic spraying to uniformly spray the above coating solution onto the outer wall of the expansion section. After spraying, the components of the photocrosslinking agent meet the following requirements: riboflavin concentration is 5 μg / mm. 2 The N-acetylcysteine ​​concentration was 10 μg / mm. 2 .

[0064] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The core diameter of the fiber is 400 μm and the emission wavelength is 450 nm.

[0065] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0066] Example 2 (1) Preparation of photocrosslinking agent coating solution: Weigh 20 mg of 4-amino-1,8-naphthimide and 0.2 mg of cysteine ​​and dissolve them in a mixed solvent of ethanol and water (volume ratio of ethanol to water is 8:2). Disperse and dissolve by ultrasonication and filter with a 0.45 μm filter to obtain coating solution.

[0067] (2) Take catheter 10 and use ultrasonic spraying to uniformly spray the above coating solution onto the outer wall of the expansion section. After spraying, the components of the photocrosslinking agent meet the following requirements: the concentration of 4-amino-1,8-naphthalimide is 5 μg / mm. 2 The cysteine ​​concentration was 0.05 μg / mm. 2 .

[0068] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The core diameter of the fiber is 400 μm and the emission wavelength is 450 nm.

[0069] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0070] Example 3 (1) Preparation of photocrosslinking agent coating solution: Weigh 20 mg of 4-amino-1,8-naphthimide and 2000 mg of histidine and dissolve them in a mixed solvent of ethanol and water (volume ratio of ethanol to water is 8:2). Disperse and dissolve by ultrasonication and filter with a 0.45 μm filter to obtain coating solution.

[0071] (2) Take catheter 10 and use ultrasonic spraying to uniformly spray the above coating solution onto the outer wall of the expansion section. After spraying, the components of the photocrosslinking agent meet the following requirements: the concentration of 4-amino-1,8-naphthalimide is 5 μg / mm.2 Histidine concentration was 500 μg / mm 2 .

[0072] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The core diameter of the fiber is 400 μm and the emission wavelength is 450 nm.

[0073] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0074] Example 4 (1) Prepare the photocrosslinking agent coating solution: Weigh 20 mg of riboflavin, 2000 mg of sodium persulfate and 40 mg of N-acetylcysteine ​​and dissolve them in a mixed solvent of ethanol and water (volume ratio of ethanol to water is 8:2). Disperse and dissolve by ultrasonication and filter with a 0.45 μm filter to obtain the coating solution.

[0075] (2) Take catheter 10 and use ultrasonic spraying to evenly spray the above coating solution onto the outer wall of the expansion section. After spraying, the components of the photocrosslinking agent meet the following requirements: riboflavin 5 μg / mm 2 The sodium persulfate concentration is 500 μg / mm. 2 The concentration of N-acetylcysteine ​​was 10 μg / mm. 2 .

[0076] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The core diameter of the fiber is 400 μm and the emission wavelength is 450 nm.

[0077] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0078] Example 5 (1) Preparation of photocrosslinking agent coating solution: Weigh 20 mg of 4-amino-1,8-naphthimide, 0.167 mg of diphenyliodonium hexafluorophosphate, and 0.2 mg of cysteine ​​and dissolve them in a mixed solvent of ethanol and water (volume ratio of ethanol to water is 8:2). Disperse and dissolve by ultrasonication and filter with a 0.45 μm filter to obtain coating solution.

[0079] (2) Take catheter 10 and use ultrasonic spraying to uniformly spray the above coating solution onto the outer wall of the expansion section. After spraying, the components of the photocrosslinking agent meet the following requirements: the concentration of 4-amino-1,8-naphthalimide is 5 μg / mm. 2 The concentration of diphenyliodonium hexafluorophosphate was 0.042 μg / mm. 2 The cysteine ​​concentration was 0.05 μg / mm. 2 .

[0080] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The core diameter of the fiber is 400 μm and the emission wavelength is 450 nm.

[0081] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0082] Example 6 (1) Preparation of photocrosslinking agent coating solution: Weigh 20mg of 4-amino-1,8-naphthimide, 2000mg of histidine and 100mg of arginine and dissolve them in a mixed solvent of ethanol and water (volume ratio of ethanol to water is 8:2). Disperse and dissolve by ultrasonication and filter with a 0.45μm filter to obtain coating solution.

[0083] (2) Take catheter 10 and use ultrasonic spraying to uniformly spray the above coating solution onto the outer wall of the expansion section. After spraying, the components of the photocrosslinking agent meet the following requirements: 4-amino-1,8-naphthylimide concentration 5 μg / mm 2 Histidine was 500 μg / mm 2 Arginine content was 25 μg / mm 2 .

[0084] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The core diameter of the fiber is 400 μm and the emission wavelength is 450 nm.

[0085] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0086] Comparative Example 1 (1) Preparation of photocrosslinking agent coating solution: Weigh 20 mg of 4-amino-1,8-naphthimide and dissolve it in a mixed solvent of ethanol and water (volume ratio of ethanol to water is 8:2). Disperse and dissolve by ultrasonication and filter with a 0.45 μm filter to obtain coating solution.

[0087] (2) Take catheter 10 and use ultrasonic spraying to evenly spray the above-mentioned coating solution onto the outer wall of the expansion section. After spraying, the concentration of 4-amino-1,8-naphthalimide is 5 μg / mm. 2 .

[0088] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The core diameter of the fiber is 400 μm and the emission wavelength is 450 nm.

[0089] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0090] Comparative Example 2 (1) Prepare the photocrosslinking agent coating solution: Weigh 20 mg of riboflavin and dissolve it in a mixed solvent of ethanol and water (volume ratio of ethanol to water is 8:2), disperse and dissolve it by ultrasonication, and filter it with a 0.45 μm filter to obtain the coating solution.

[0091] (2) Take catheter 10 and use ultrasonic spraying to evenly spray the above-mentioned coating solution onto the outer wall of the expansion section. After spraying, the riboflavin concentration is 5 μg / mm. 2 .

[0092] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The core diameter of the fiber is 400 μm and the emission wavelength is 450 nm.

[0093] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0094] Cytotoxicity tests were conducted using the medical devices obtained in Examples 1-6 and Comparative Examples 1 and 2. The specific test methods are as follows: The cytotoxicity of each group of medical devices under light irradiation was tested using the MTT assay. The experimental method is as follows: Human embryonic venous endothelial cells in the logarithmic growth phase were collected and added to 1 mL of culture medium to prepare a cell suspension. The cells were digested with an appropriate amount of 0.25% trypsin, and 4000 cells were seeded into 100 μL per well in a 96-well plate. The plates were then incubated overnight at 37°C in a 5% CO2 incubator.

[0095] Take the medical devices prepared in each group, cut off the expansion part 13, and extract the expansion part 13 in 5 mL of PBS for 24 h to obtain the test solution. Add 100 μL of the test solution to each well of the plate, repeating 3 times. Add 100 μL of 1% DMEM medium to each well of the blank control group. After incubation for 5 min, use a 450 nm laser at 200 mW / cm² to... 2 Irradiate with power for 1 minute, then incubate in an incubator for 2 hours. Afterward, remove the PBS, replace with fresh culture medium, and continue incubation for 24 hours.

[0096] Before the end of the culture, the supernatant in each well was discarded, and 10 μL of freshly prepared serum-free MTT culture medium (concentration 5 mg / mL) was added to each well. The mixture was incubated at 37℃ with 5% CO2 for 4 h. The supernatant was then aspirated, and 150 μL of DMSO was added to each well. The mixture was shaken for 5 min to fully dissolve the formazan precipitate in the cells. The optical density (OD) was measured using a microplate reader at a reference wavelength of 450 nm and a detection wavelength of 570 nm. Cell viability was calculated using the following formula: Cell viability % = (Average OD value of the tested group / Average OD value of the blank control group) × 100%. The results are shown in Table 1.

[0097] Table 1. Cell viability test results of Examples 1-6 and Comparative Examples 1 and 2 Example Cell viability after 24 hours Example 1 92% Example 2 91% Example 3 94% Example 4 93% Example 5 92% Example 6 95% Comparative Example 1 3.4% Comparative Example 2 4.0% As shown in Table 1, in Examples 1-6, the addition of reactive oxygen species (ROS) scavengers rapidly eliminated the ROS generated during light irradiation, preventing cell damage. Cell viability remained above 90% after 24 hours. In Comparative Examples 1 and 2, however, the absence of ROS scavengers resulted in the photosensitizer generating large amounts of ROS during light irradiation. These ROS caused cell damage, leading to low cell viability and indicating significant cell death, demonstrating serious side effects.

[0098] The medical devices obtained in Examples 1-6 and Comparative Examples 1 and 2 were used to perform vascular lumen maintenance tests. The specific test methods are as follows: Isolated porcine blood vessels were collected, and their diameter was measured. The expansion portion 13 of the medical device prepared in each embodiment and comparative example was inserted into the blood vessel, expanding it to 130% of its initial diameter. The laser was then turned on, and the balloon was withdrawn after irradiation for 1 minute. The blood vessel diameter before and after expansion was measured. The results are shown in Table 2.

[0099] Table 2. Detection results of vasodilation before and after Examples 1-6 and Comparative Examples 1 and 2. Example Pre-dilation vessel diameter (mm) Diameter of the dilated blood vessel (mm) Example 1 3.0 3.3 Example 2 3.0 3.4 Example 3 3.0 3.2 Example 4 3.0 3.9 Example 5 3.0 3.8 Example 6 3.0 3.8 Comparative Example 1 3.0 3.7 Comparative Example 2 3.0 3.7 As shown in Table 2, the analysis of Examples 1-3 and Comparative Examples 1 and 2 reveals that although reactive oxygen species (ROS) scavengers were added in Examples 1-3, and experiments have demonstrated their ability to scavenge free radicals and reduce cytotoxicity, the ROS scavengers added in Examples 1 and 3 significantly reduced the vascular cross-linking effect, resulting in poor maintenance of the vessel lumen diameter and the vessels becoming elastic and unable to provide support. In contrast, Examples 4-6, by adding photosensitizers, effectively cross-linked vascular proteins while maintaining low cytotoxicity, thus maintaining luminal patency and keeping the vessel diameter essentially at its maximum value (3.9 mm) or at a plateau.

[0100] It should be noted that, in this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes that element. Furthermore, it should be noted that the scope of the methods and apparatuses in the embodiments of this application is not limited to performing functions in the order shown or discussed, but may also include performing functions substantially simultaneously or in the reverse order, depending on the functions involved. For example, the described methods may be performed in a different order than described, and various steps may be added, omitted, or combined. Additionally, features described with reference to certain examples may be combined in other examples.

[0101] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A photocrosslinking agent, characterized in that, It includes a photosensitizer, a reactive oxygen species scavenger, and a photosensitizer enhancer, wherein the mass ratio of the photosensitizer to the reactive oxygen species scavenger is 1:0.01 to 1:100, and the mass ratio of the photosensitizer enhancer to the photosensitizer is 1:0.01 to 1:

120.

2. The photocrosslinking formulation according to claim 1, characterized in that, The photosensitizer is an electron donor photosensitizer or an electron acceptor photosensitizer, wherein... The electron donor photosensitizer includes one or more of arginine, diphenyliodonium hexafluorophosphate, dimethylaminoethyl methacrylate, aliphatic tertiary amine, and triethanolamine; The electron acceptor photosensitizer includes one or more of vitamin B12, cobalt pentamine chloride, sodium persulfate, potassium persulfate, and ammonium persulfate.

3. The photocrosslinking formulation according to claim 1, characterized in that, The photosensitizer includes one or more of the following: naphthalimide compounds, naphthalimide hydrophilic derivatives, camphorquinone, camphorquinone hydrophilic derivatives, riboflavin, riboflavin sodium phosphate, rose red, curcumin, eosin Y, and transition metal complexes.

4. The photocrosslinking formulation according to claim 3, characterized in that, The transition metal complexes include one or more of palladium complexes, iron complexes, ruthenium complexes, iridium complexes, nickel complexes, manganese complexes, platinum complexes, and osmium complexes.

5. The photocrosslinking formulation according to claim 1, characterized in that, The reactive oxygen species scavenger includes one or more of the following: N-acetylcysteine, cysteine, anthocyanins, proanthocyanidins, vitamin C, histidine, superoxide dismutase, glutathione, glutathione peroxidase, catalase, β-carotene, tea polyphenols, and flavonoids.

6. The photocrosslinking formulation according to any one of claims 1 to 5, characterized in that, It also includes active drugs, which are one or more of the following: anti-proliferative drugs, vascular endothelial-promoting drugs, antithrombotic drugs, and anti-inflammatory drugs.

7. A medical device, characterized in that, Includes a catheter (10), which has a guide channel (11) and a delivery channel (12). The guide channel (11) is used to insert a guide wire, and the delivery channel (12) is used to introduce fluid. The distal end of the catheter (10) is an expansion section (13), which can expand or contract radially along the catheter (10). The medical device further includes a photocrosslinking agent coating (20), which is prepared from the photocrosslinking agent according to any one of claims 1 to 6, and the photocrosslinking agent coating (20) is provided on at least part of the outer wall of the expansion portion (13). The medical device also includes an optical fiber assembly (30) inserted into the catheter (10), the distal end of the optical fiber assembly (30) being a light-emitting part (31), the light-emitting part (31) extending at least partially to the area on the expansion part (13) where the photocrosslinking agent coating (20) is provided.

8. A medical device, characterized in that, The device includes a catheter (10), which has a guide channel (11) and a delivery channel (12). The guide channel (11) is used to insert a guide wire, and the delivery channel (12) is used to introduce fluid. The distal end of the catheter (10) is an expansion section (13), which can expand or contract radially along the catheter (10). The expansion section (13) is provided with a plurality of micropores (131), which are connected to the delivery channel (12). The medical device further includes a photocrosslinking agent, which is the photocrosslinking agent according to any one of claims 1 to 6. The photocrosslinking agent is delivered to the micropore (131) through the delivery channel (12) and ejected from the micropore (131). The medical device also includes an optical fiber assembly (30), which is inserted into the catheter (10). The distal end of the optical fiber assembly (30) is a light-emitting part (31), which extends at least partially to the area on the expansion part (13) where the micropore (131) is provided.

9. The medical device according to claim 8, characterized in that, When the expansion part (13) is provided with a plurality of micro-holes (131), the sum of the minimum flow cross-sectional areas of the micro-holes (131) is less than the minimum flow cross-sectional area of ​​the conveying channel (12).

10. The medical device according to claim 9, characterized in that, The micropores (131) have a pore size of 1~50μm and a pore density of 0.5~200 pores / cm³. 2 .

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