Blood vessel cross-linking agent and medical device

Abstract

The invention discloses a blood vessel cross-linking agent and a medical device, and relates to the technical field of blood vessel treatment. The blood vessel cross-linking agent comprises a photosensitizer and an anti-inflammatory composition, and the mass ratio of the photosensitizer to the anti-inflammatory composition is (1: 0.02)-(1: 100); wherein the anti-inflammatory composition comprises an anti-inflammatory drug and a temperature-sensitive hydrogel, and the mass ratio of the anti-inflammatory drug to the temperature-sensitive hydrogel is (1: 1)-(1: 100). According to the blood vessel cross-linking agent 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; the anti-inflammatory composition disclosed by the invention comprises the anti-inflammatory drug and the temperature-sensitive hydrogel, also has the effects of durably resisting inflammation and eliminating side effects of active oxygen, and also can reduce the risk of degradation of the anti-inflammatory drug under illumination and ensure the activity and concentration of the anti-inflammatory drug.

Description

Technical Field

[0001] This invention relates to the field of vascular treatment technology, and more particularly to a vascular crosslinking 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 to form a "protein microscaffold" through in-situ cross-linking. This "protein microscaffold" can support the blood vessel wall to maintain vascular gain, preserve vascular dilation size, and reduce the possibility of restenosis. However, the inventors have found that using natural vascular stents to treat atherosclerotic diseases can easily lead to severe vascular inflammation and vulnerable plaque formation, resulting in serious side effects. Summary of the Invention

[0007] This invention discloses a vascular crosslinking agent and a medical device to solve the technical problem in related technologies where the use of natural vascular stents to treat atherosclerotic diseases easily leads to severe vascular inflammatory reactions and the formation of vulnerable plaques, resulting in serious side effects.

[0008] To solve the above problems, the present invention adopts the following technical solution: The first aspect of the present invention provides a vascular cross-linking agent.

[0009] The vascular crosslinking agent of the present invention comprises a photosensitizer and an anti-inflammatory composition, wherein the mass ratio of the photosensitizer to the anti-inflammatory composition is 1:0.02 to 1:100; wherein the anti-inflammatory composition comprises an anti-inflammatory drug and a thermosensitive hydrogel, wherein the mass ratio of the anti-inflammatory drug to the thermosensitive hydrogel is 1:1 to 1:100.

[0010] According to one optional embodiment, the lower critical dissolution temperature of the thermosensitive hydrogel is 32°C to 43°C.

[0011] According to one optional embodiment, the lower critical dissolution temperature of the thermosensitive hydrogel is 37°C to 42°C.

[0012] According to an optional embodiment, the thermosensitive hydrogel is one or more of poly(N-isopropylacrylamide), chitosan / β-glycerophosphate disodium complex gel, poloxamer, poly(DL-lactic acid)-poly(ethylene glycol)-poly(DL-lactic acid), and poly(DL-lactic acid)-poly(ethylene glycol).

[0013] According to one optional embodiment, the photosensitizer is one or more selected from naphthalimide compounds, naphthalimide hydrophilic derivatives, camphorquinone, camphorquinone hydrophilic derivatives, riboflavin, riboflavin sodium phosphate, rose red, curcumin, eosin Y, and transition metal complexes.

[0014] According to one alternative embodiment, the anti-inflammatory drug is at least one of dexamethasone, ulinastatin, rapamycin, aspirin, resveratrol, and celecoxib.

[0015] According to an optional embodiment, the anti-inflammatory composition further includes a carrier, said carrier being one or more of the following: lecithin, hyaluronic acid, chitosan, polyvinylpyrrolidone, polyvinyl alcohol, shellac, gum arabic, poloxamer, phosphatidylethanolamine, phosphatidylserine, polypeptide dendrimer, albumin, silk fibroin, sericin, silk peptide, and casein.

[0016] A second aspect of the present invention provides a medical device.

[0017] 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 vascular crosslinking agent coating, which is prepared using a vascular crosslinking agent as described in any of the technical solutions of the present invention, and the vascular crosslinking 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 vascular crosslinking agent coating is provided.

[0018] A third aspect of the invention provides another medical device.

[0019] 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 vascular crosslinking agent, which is the vascular crosslinking agent described in any of the technical solutions of the present invention. The vascular crosslinking 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.

[0020] 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.

[0021] The technical solution adopted in this invention can achieve the following beneficial effects: The vascular cross-linking agent of the present invention comprises a photosensitizer and an anti-inflammatory composition. 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. Secondly, the anti-inflammatory composition of the vascular cross-linking agent of the present invention comprises an anti-inflammatory drug and a thermosensitive hydrogel. Through the action of the anti-inflammatory drug, vascular inflammation can be alleviated, and the side effects of reactive oxygen species can be eliminated. Furthermore, when the photosensitizer is activated by light, the temperature of the target blood vessel can be increased due to the photothermal effect, thus promoting the thermosensitive hydrogel to form a solid or semi-solid gel in situ from a liquid state. The solid or semi-solid gel can adhere and fix the anti-inflammatory drug to the blood vessel and plaque site and release it slowly. The anti-inflammatory composition has the effects of long-lasting anti-inflammatory action and elimination of reactive oxygen species side effects. The gel can also form a local anti-inflammatory drug enrichment area, which is beneficial for the absorption and effect of the anti-inflammatory drug. In addition, the in-situ formed solid or semi-solid gel can encapsulate the anti-inflammatory drug, which can not only further reduce the release rate of the anti-inflammatory drug, but also reduce the risk of degradation of the anti-inflammatory drug under light, thus ensuring the activity and concentration of the anti-inflammatory drug and ensuring its anti-inflammatory effect. Attached Figure Description

[0022] 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.

[0023] Figure 1 This is a schematic diagram of a 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.

[0024] In the figure: 10, catheter; 11, guide channel; 12, delivery channel; 13, expansion section; 131, micropore; 132, retention groove; 20, vascular cross-linking agent coating; 30, optical fiber assembly; 31, light-emitting part; 32, light-emitting device; 33, optical fiber body. Detailed Implementation

[0025] 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.

[0026] 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.

[0027] 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".

[0028] In the process of treating atherosclerotic diseases using natural vascular stents, the inventors discovered that the photocrosslinking mechanism of natural vascular stents is similar to photodynamic therapy, involving type I and type II reactions. Besides forming triplet photosensitizers, it also generates a large amount of reactive oxygen species (ROS), including singlet oxygen, superoxide anion radicals, and hydroxyl radicals, all of which are cytotoxic. In addition to promoting vascular crosslinking, excessive ROS can damage cellular proteins, lipids, and DNA, leading to cell damage. These damaged cells are eliminated by the body, subsequently triggering the production of endogenous damage-related molecular patterns and the release of cytokines. Increased cytokine release can recruit and activate more inflammatory cells, leading to a systemic, long-term inflammatory response and causing vascular plaque instability, resulting in serious side effects.

[0029] Therefore, this invention provides a vascular cross-linking agent and a medical device that can quickly and effectively complete vascular cross-linking, form a scaffold in situ, and achieve vascular healing and repair. Simultaneously, during light irradiation, the photothermal effect raises the temperature of the target blood vessel, thus promoting the in-situ formation of a solid or semi-solid gel from a liquid state. The solid or semi-solid gel can adhere and fix anti-inflammatory drugs to the blood vessel and plaque site and release them slowly, giving the anti-inflammatory composition a long-lasting anti-inflammatory effect and the ability to eliminate reactive oxygen species side effects. Furthermore, the in-situ formed solid or semi-solid gel can encapsulate the anti-inflammatory drug, further reducing the release rate and the risk of degradation under light irradiation, thereby ensuring the activity and concentration of the anti-inflammatory drug and its anti-inflammatory effect.

[0030] The following is in conjunction with the appendix Figures 1-3 The vascular crosslinking agent and medical device provided in this application will be described in detail through specific embodiments and application scenarios.

[0031] The vascular cross-linking agent of this embodiment includes a photosensitizer. The photosensitizer can absorb light energy of a specific wavelength and cause its electrons to undergo transitions, thereby making the photosensitizer chemically reactive. The vascular cross-linking agent of this embodiment, by stimulating 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.

[0032] 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.

[0033] The vascular cross-linking agent of this embodiment further includes an anti-inflammatory composition. Preferably, the mass ratio of the photosensitizer to the anti-inflammatory composition is 1:0.02 to 1:100. The anti-inflammatory composition includes an anti-inflammatory drug. The anti-inflammatory composition of this embodiment includes an anti-inflammatory drug with anti-inflammatory effects, which can alleviate vascular inflammation and eliminate the side effects of reactive oxygen species through the action of the anti-inflammatory drug.

[0034] For example, the anti-inflammatory drug is at least one of dexamethasone, ulinastatin, rapamycin, aspirin, resveratrol, and celecoxib.

[0035] The anti-inflammatory composition of this embodiment also includes a thermosensitive hydrogel. Preferably, the mass ratio of the anti-inflammatory drug to the thermosensitive hydrogel is 1:1 to 1:100. The thermosensitive hydrogel has the property that its phase change behavior is sensitive to temperature; temperature changes can trigger a sol-gel or gel-sol transition.

[0036] In this embodiment, the vascular cross-linking agent and the anti-inflammatory composition also include a thermosensitive hydrogel. When the photosensitizer is excited by light, the temperature of the target blood vessel can be increased due to the photothermal effect, which can promote the thermosensitive hydrogel to form a solid or semi-solid gel in situ from a liquid state. The solid or semi-solid gel can adhere and fix the anti-inflammatory drug to the blood vessel and plaque site and release it slowly, so that the anti-inflammatory composition has a long-lasting anti-inflammatory effect and can eliminate the side effects of reactive oxygen species. The gel can also form a local anti-inflammatory drug enrichment area, which is conducive to the absorption and effect of the anti-inflammatory drug. In addition, the solid or semi-solid gel formed in situ can encapsulate the anti-inflammatory drug, which can not only further reduce the release rate of the anti-inflammatory drug, but also reduce the risk of degradation of the anti-inflammatory drug under light, thus ensuring the activity and concentration of the anti-inflammatory drug and ensuring the anti-inflammatory effect of the anti-inflammatory drug.

[0037] Preferably, the low critical dissolution temperature of the thermosensitive hydrogel is 32℃~43℃. This temperature range is within the range that normal human tissue can tolerate, and within this temperature range, normal tissue will not be damaged.

[0038] More preferably, the lower critical dissolution temperature of the thermosensitive hydrogel is 37°C to 42°C. For example, the thermosensitive hydrogel is one or more of poly(N-isopropylacrylamide), chitosan / β-glycerophosphate disodium composite gel, poloxamer, poly(DL-lactic acid)-poly(ethylene glycol)-poly(DL-lactic acid), and poly(DL-lactic acid)-poly(ethylene glycol). Having a lower critical dissolution temperature above 37°C ensures that the thermosensitive hydrogel only forms a solid or semi-solid gel in situ from a liquid state when heated by the photothermal effect under light irradiation. This avoids in-situ gel formation during delivery or gel formation upon entering the bloodstream, thereby significantly improving safety and gelation efficiency.

[0039] For example, the anti-inflammatory composition of this embodiment may be in the form of lyophilized, non-lyophilized, microencapsulated, nanoencapsulated (e.g., micelles, liposomes, nanocrystals, dendritic molecular carriers, polymer nanoparticles, etc.), protein-bound, or freeze-dried forms. It is not limited thereto; the anti-inflammatory composition of this embodiment may also be in the form of tablets, gels, capsules, powders, pastes, creams, ointments, or solutions.

[0040] In some embodiments, the anti-inflammatory composition further includes a carrier. Exemplary carriers are one or more selected from lecithin, hyaluronic acid, chitosan, polyvinylpyrrolidone, polyvinyl alcohol, shellac, gum arabic, poloxamer, phosphatidylethanolamine, phosphatidylserine, polypeptide dendrimers, albumin, silk fibroin, sericin, silk peptides, and casein. The anti-inflammatory composition of this embodiment further includes a carrier, which, by loading the anti-inflammatory drug and the thermosensitive hydrogel onto the carrier, can enhance the sustained-release effect of the anti-inflammatory drug.

[0041] This embodiment also provides a medical device.

[0042] 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 1A 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.

[0043] The medical device of this embodiment further includes a vascular crosslinking agent coating 20, which is prepared using a vascular crosslinking agent according to any of the technical solutions in this embodiment. Preferably, the vascular crosslinking agent coating 20 is at least partially provided on the outer wall of the expansion portion 13. Exemplarily, the vascular crosslinking 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 vascular crosslinking agent coating 20 can be determined based on actual needs and is not limited here.

[0044] The medical device of this embodiment further includes an optical fiber assembly 30. The optical fiber assembly 30 is inserted into the catheter 10. The distal end of the optical fiber assembly 30 is a light-emitting portion 31, which at least partially extends to the area on the expansion portion 13 where a vascular crosslinking agent coating 20 is provided, thereby ensuring that the light-emitting area of ​​the optical fiber assembly 30 at least partially covers the vascular crosslinking 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.

[0045] 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.

[0046] The medical device of this embodiment, through the action of the vascular crosslinking agent coating 20, can not only form a stent in situ to achieve vascular healing and repair, but also has the effects of long-lasting anti-inflammatory and clearing reactive oxygen side effects. At the same time, it can also reduce the risk of degradation of anti-inflammatory drugs under light exposure, and ensure the activity and concentration of anti-inflammatory drugs.

[0047] This embodiment also provides another medical device.

[0048] This section only describes the differences compared to the aforementioned medical devices; the same parts will not be repeated here.

[0049] 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 2As shown. In this embodiment, the delivery channel 12 is used not only for delivering fluid but also for delivering a vascular crosslinking agent. Through the delivery channel 12, the vascular crosslinking agent can be delivered from the proximal end of the catheter 10 to a micropore 131 located at its distal end, and pressure is used to eject the vascular crosslinking 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, thereby ensuring that the light-emitting area of ​​the optical fiber assembly 30 at least partially covers the vascular crosslinking agent.

[0050] For example, the vascular crosslinking agent may be in powder or granular form and pre-stored at the proximal end of catheter 10; or the vascular crosslinking 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 vascular crosslinking agent to facilitate delivery of the vascular crosslinking agent through delivery channel 12. The solvent may be, for example, one or more of physiological saline, purified water, and contrast agents.

[0051] After the vascular cross-linking 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 vascular cross-linking 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 treatment effect.

[0052] 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.

[0053] 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 2 μm to 100 μm. Preferably, the pore size of the micropores 131 is 5 μm to 50 μm. More preferably, the pore size of the micropores 131 is 5 μm to 20 μm.

[0054] 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 vascular cross-linking agent to be evenly distributed throughout the entire blood vessel wall. This enables the entire blood vessel wall to undergo protein cross-linking 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.

[0055] As can be seen, the medical device of this embodiment, compared with the medical device with drug coating, can improve the transfer efficiency of vascular cross-linking agent, enhance the support effect of 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.

[0056] In some embodiments, the density of micropores 131 is set to 0.5 pores / cm². 2 ~500 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.

[0057] 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.

[0058] 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 3As shown. During use, the expansion section 13 is inflated until it abuts 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 vascular cross-linking agent and thus improving the treatment effect.

[0059] Examples 1 to 3 below use vascular crosslinking agents as coating structures to illustrate the anti-inflammatory effects of vascular crosslinking agents with different ratios.

[0060] Example 1 (1) Preparation of vascular crosslinking agent coating solution: Weigh 20mg of 4-amino-1,8-naphthimide, 10mg of dexamethasone and 100mg of poly-N-isopropylacrylamide 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.

[0061] (2) Take catheter 10 and use ultrasonic spraying to evenly spray the above-mentioned coating solution onto the outer wall of the dilation portion. After spraying, the components of the vascular crosslinking agent meet the following requirements: 4-amino-1,8-naphthylimide concentration 5 μg / mm 2 Dexamethasone concentration was 2.5 μg / mm. 2 The poly(N-isopropylacrylamide) content is 25 μg / mm. 2 .

[0062] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The fiber core diameter is 400 μm and the emission wavelength is 450 nm.

[0063] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0064] Example 2 (1) Preparation of vascular cross-linking agent coating solution: Weigh 20mg of 4-amino-1,8-naphthimide, 0.2mg of dexamethasone and 0.2mg of poloxamer 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.

[0065] (2) Take catheter 10 and use ultrasonic spraying to evenly spray the above-mentioned coating solution onto the outer wall of the dilation portion. After spraying, the components of the vascular crosslinking agent meet the following requirements: 4-amino-1,8-naphthylimide concentration 5 μg / mm 2 The concentration of dexamethasone was 0.05 μg / mm. 2 The poloxamer concentration was 0.05 μg / mm. 2 .

[0066] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The fiber core diameter is 400 μm and the emission wavelength is 450 nm.

[0067] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0068] Example 3 (1) Preparation of vascular crosslinking agent coating solution: Weigh 10 mg of 4-amino-1,8-naphthimide, 10 mg of rapamycin and 990 mg of poloxamer 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.

[0069] (2) Take catheter 10 and use ultrasonic spraying to evenly spray the above-mentioned coating solution onto the outer wall of the dilation portion. After spraying, the components of the vascular crosslinking agent meet the following requirements: 4-amino-1,8-naphthylimide concentration 5 μg / mm 2 Rapamycin was 250 μg / mm 2 poloxamer was 250 μg / mm 2 .

[0070] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The fiber core diameter is 400 μm and the emission wavelength is 450 nm.

[0071] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0072] Comparative Example (1) Preparation of vascular crosslinking agent coating solution: Weigh 20 mg of 4-amino-1,8-naphthimide and 10 mg of dexamethasone 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.

[0073] (2) Take catheter 10 and use ultrasonic spraying to evenly spray the above-mentioned coating solution onto the outer wall of the dilation portion. After spraying, the components of the vascular crosslinking agent meet the following requirements: 4-amino-1,8-naphthylimide concentration 5 μg / mm 2 The corresponding dexamethasone concentration was 2.5 μg / mm. 2 .

[0074] (3) Insert a cylindrical diffused fiber assembly 30 into the conduit 10. The fiber core diameter is 400 μm and the emission wavelength is 450 nm.

[0075] After the above components are packaged and sterilized with ethylene oxide, a medical device is obtained.

[0076] The medical devices obtained in Examples 1-3 and the comparative examples were used to test the level of vascular inflammation. The specific testing method is as follows: Healthy rabbits were selected as experimental models to determine the level of vascular inflammation after treatment in Examples 1-3 and the comparative example. After identifying the target blood vessel, catheter 10 from Examples 1-3 and the comparative example was delivered to the target location, causing the dilation portion 13 to expand to 1.3 times the initial diameter of the blood vessel. The laser was turned on and irradiated for 1 minute before catheter 10 was withdrawn. Venous blood was collected from rabbits 1 hour before surgery, 1 day after surgery, 7 days after surgery, and 28 days after surgery. Serum was collected by centrifugation and the concentration of the cytokine interleukin-6 (IL-6) was detected by immunofluorescence assay. The results are shown in Table 1.

[0077] Table 1. Results of IL-6 concentration detection after treatment with the medical devices in Examples 1-3 and the comparative examples.

[0078] Interleukin-6 (IL-6) is a cellular inflammation marker that reflects the degree of inflammation at the vascular site after treatment. Examples 1-3 exhibit a sustained anti-inflammatory effect due to the ability to form a gel in situ. As shown in Table 1 above, in Examples 1-3, the IL-6 concentration only slightly increased one day post-operation compared to pre-operation; in Examples 1-3, the IL-6 concentration seven days post-operation was comparable to the pre-operation concentration, indicating a low level of inflammation, which helps maintain sustained patency of the lumen and results in an extremely low restenosis rate.

[0079] In contrast, the control group, which did not include gel, had poor anti-inflammatory drug transfer and retention. From 1 to 28 days post-surgery, the IL-6 concentration was significantly increased compared to pre-surgery levels, indicating that the blood vessels at the treatment site had a long-term inflammatory response, which easily stimulated the migration and proliferation of vascular smooth muscle, leading to severe restenosis.

[0080] The restenosis rate was tested using the medical devices obtained in Examples 1-3 and the comparative examples. The specific testing method is as follows: Healthy white pigs were selected as experimental models to determine the restenosis rate after treatment in Examples 1-3 and the comparative examples. After identifying the target blood vessel, catheter 10 from Examples 1-3 and the comparative example was delivered to the target location, expanding the dilator 13 to 1.3 times the initial diameter of the blood vessel. The laser was turned on, and after irradiation for 1 minute, catheter 10 was withdrawn. The pigs were euthanized 28 days post-surgery, and the treated segment of the blood vessel was harvested. After fixation, dehydration, infiltration, embedding, tissue sectioning, and HE staining, the sections were scanned for analysis. The area within the internal elastic membrane was considered the vascular intima. The area of ​​the internal elastic membrane and the lumen area of ​​the vascular sections were measured. The vascular area stenosis rate was defined as: Stenosis rate % = (1 - Lumen area) / Internal elastic membrane area × 100%. The vascular area stenosis rate for each group was calculated. The results are shown in Table 2.

[0081] Table 2. Results of IL-6 concentration detection after treatment with the medical device in Examples 1-3 and the comparative example. Example 28-day vascular stenosis rate (%) Example 1 0.7 Example 2 1.2 Example 3 0.5 Comparative Example 54.0 As can be seen from Table 2 above, in Examples 1-3, the vascular area stenosis rate was less than 1.5% after 28 days, while in the comparative example, the vascular area stenosis rate was as high as 54.0% after 28 days. This indicates that the medical devices in Examples 1-3 can significantly reduce the vascular area stenosis rate after 28 days, which helps to maintain the long-term patency of the lumen.

[0082] 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.

[0083] 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 vascular cross-linking agent, characterized in that, It includes a photosensitizer and an anti-inflammatory composition, wherein the mass ratio of the photosensitizer to the anti-inflammatory composition is 1:0.02 to 1:100; wherein, The anti-inflammatory composition comprises an anti-inflammatory drug and a thermosensitive hydrogel, wherein the mass ratio of the anti-inflammatory drug to the thermosensitive hydrogel is 1:1 to 1:

100.

2. The vascular crosslinking agent according to claim 1, characterized in that, The low critical dissolution temperature of the thermosensitive hydrogel is 32℃~43℃.

3. The vascular cross-linking agent according to claim 2, characterized in that, The lower critical dissolution temperature of the thermosensitive hydrogel is 37℃~42℃.

4. The vascular cross-linking agent according to any one of claims 1 to 3, characterized in that, The thermosensitive hydrogel is one or more of the following: poly(N-isopropylacrylamide), chitosan / β-glycerophosphate disodium composite gel, poloxamer, poly(DL-lactic acid)-poly(ethylene glycol)-poly(DL-lactic acid), and poly(DL-lactic acid)-poly(ethylene glycol).

5. The vascular crosslinking agent according to claim 1, characterized in that, The photosensitizer is 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.

6. The vascular crosslinking agent according to claim 1, characterized in that, The anti-inflammatory drug mentioned is at least one of dexamethasone, ulinastatin, rapamycin, aspirin, resveratrol, and celecoxib.

7. The vascular crosslinking agent according to claim 1, characterized in that, The anti-inflammatory composition further includes a carrier, which is one or more of the following: lecithin, hyaluronic acid, chitosan, polyvinylpyrrolidone, polyvinyl alcohol, shellac, gum arabic, poloxamer, phosphatidylethanolamine, phosphatidylserine, polypeptide dendrimer, albumin, silk fibroin, sericin, silk peptide, and casein.

8. 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 vascular crosslinking agent coating (20), which is prepared by the vascular crosslinking agent according to any one of claims 1 to 7, and the vascular crosslinking 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), 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 vascular crosslinking agent coating (20) is provided.

9. 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 vascular crosslinking agent, which is the vascular crosslinking agent according to any one of claims 1 to 7. The vascular crosslinking agent is delivered to the micropore (131) through the delivery channel (12) and sprayed out 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.

10. The medical device according to claim 9, 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).

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