Medical device and system, and preparation method

Abstract

Provided in the present invention are a medical device and system, and a preparation method. The medical device comprises a base body and a coating, wherein the base body can expand or retract in the radial direction thereof, the coating is arranged in at least a partial region of the outer surface of the base body, and the coating comprises a protein and a cross-linking agent. The base body can be a balloon body. After the base body is introduced into a diseased blood vessel, the protein can be cross-linked with the protein on a blood vessel wall under the action of the cross-linking agent, so as to form a "protein micro-scaffold" in situ to support the blood vessel wall, thus maintaining vascular gain, maintaining vascular dilatation size, and reducing the possibility of vascular restenosis.

Description

Medical device, system, and preparation method Technical Field

[0001] The present invention belongs to the technical field of medical devices, and specifically relates to a medical device and system, and a preparation method. Background Art

[0002] Atherosclerosis refers to the thickening of the arterial walls and narrowing of the lumen of the arteries that supply blood to various organs, including the heart, brain, and kidneys. It is a major cause of heart attacks and strokes. Currently, there are many treatment options for atherosclerosis, including balloon angioplasty and plaque resection with stents, with stent implantation being the most common treatment. However, as a long-term implant in the body, stent implantation still carries the risk of long-term restenosis and thrombosis.

[0003] The emergence of degradable stents has solved the risks of long-term implants in the body, but they are still foreign implants. Therefore, in the early stages of implantation, patients need to continue taking medication. In addition, the degradation of the artificial synthetic materials used in degradable stents will cause the matrix of the blood vessel wall to become acidic, which has the risk of expanding the inflammatory response and causing calcification. Drug-eluting balloons are another treatment method. Although their use does not have the problem of foreign body implantation, the drug delivery method only physically adheres the drug coating to the blood vessel wall. Because there is no vascular support, the drug is easily lost, making it difficult to maintain drug concentration for a long time. The treatment effect is poor and long-term lumen gain cannot be maintained. Percutaneous transluminal angioplasty (PTA) is another treatment method often used in patients with peripheral arterial disease (PAD), but its effect is not ideal due to vascular recoil and dissection.

[0004] Summary of the Invention

[0005] The purpose of the present invention is to provide a medical device, system and preparation method for better treating atherosclerosis.

[0006] To achieve the above objectives, the present invention provides a medical device comprising a substrate and a coating, wherein the substrate can expand or contract along its radial direction; the coating is arranged on at least a portion of the outer surface of the substrate, and the coating comprises a protein and a cross-linking agent.

[0007] Optionally, the cross-linking agent includes a photosensitive cross-linking agent, which undergoes a cross-linking reaction with the protein under light.

[0008] Optionally, the photosensitive crosslinker includes at least one of methylene blue, methylene green, rose bengal, riboflavin, proflavin, fluorescein, eosin, 4-amino-1,8-naphthalimide, 2,2'-((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(6-((2-(2-aminoethoxy)ethoxy)ethyl)amino)-1H-benzo[de]isoquinoline-1,3(2H)-dione) and salts thereof.

[0009] Optionally, the crosslinking agent includes a non-photosensitive crosslinking agent, and the coating further includes an isolator, wherein the isolator isolates the protein and the non-photosensitive crosslinking agent to prevent the protein from undergoing a crosslinking reaction with the non-photosensitive crosslinking agent.

[0010] Optionally, the non-photosensitive crosslinking agent includes a physical crosslinking agent and / or a chemical crosslinking agent, and the chemical crosslinking agent includes at least one of glutaraldehyde, polyepoxide, genipin, horseradish peroxidase, ammonium persulfate, terpyridyl ruthenium chloride, camphorquinone, and curcumin.

[0011] Optionally, the physical cross-linking agent includes at least one of tannic acid, pentagalloyl glucose, gallic acid ester, gallic acid, ellagic acid, proanthocyanidin, anthocyanidin, quercetin, xanthophyllin, catechin, and epicatechin.

[0012] Optionally, the protein includes at least one of humanized elastin, humanized collagen, human serum albumin, silk fibroin, and proteoglycan.

[0013] Optionally, the mass ratio of the protein to the cross-linking agent is 100:1-1:1.

[0014] Optionally, the substrate includes a main body; and the coating is provided on at least a portion of an outer surface of the main body.

[0015] Optionally, the coating covers the entire outer surface of the main body.

[0016] Optionally, the coating includes a plurality of sub-coatings, and the plurality of sub-coatings are arranged at intervals along the axial direction of the main body.

[0017] Optionally, the coating is a spiral structure surrounding the axis of the main body.

[0018] Optionally, the coating is a grid-like structure.

[0019] Optionally, the coating further comprises a drug.

[0020] Optionally, the matrix comprises a balloon or a stent.

[0021] To achieve the above-mentioned object, the present invention further provides a medical system, comprising the medical device and a catheter body as described above, wherein the base is sleeved on the outer peripheral surface of the distal end of the catheter body.

[0022] Optionally, the cross-linking agent includes a photosensitive cross-linking agent; the medical system also includes an optical fiber assembly, which is at least partially inserted into the catheter body, and the optical fiber assembly includes a light-emitting portion, which extends to the distal end of the catheter body, and the position of the light-emitting portion corresponds to the position of the base; the distal end of the catheter body is configured to allow light emitted by the light-emitting portion to irradiate the base.

[0023] Optionally, the light transmittance of the distal end of the catheter body is greater than 90%.

[0024] To achieve the above object, the present invention further provides a preparation method for preparing the medical device as described above, the preparation method comprising the following steps:

[0025] providing the substrate and a coating solution, wherein the coating solution includes a protein and a cross-linking agent;

[0026] applying the coating solution to at least a portion of the outer surface of the substrate;

[0027] The coating solution is dried, and the coating layer is formed.

[0028] Compared with the prior art, the medical device, system, and preparation method of the present invention have the following advantages:

[0029] The aforementioned medical device includes a substrate and a coating, wherein the substrate is capable of expanding or contracting in its radial direction; the coating is disposed on at least a portion of the outer surface of the substrate and comprises a protein and a crosslinking agent. The substrate, such as a balloon or stent, can be delivered into a human organ, such as a blood vessel, and the protein in the coating can penetrate the vessel wall. Furthermore, under the action of the crosslinking agent, the exogenous protein can undergo a cross-linking reaction with the collagen and elastin on the vessel wall to form a lattice-like crosslinked structure. This crosslinked structure has excellent mechanical properties and can serve as an in situ "protein microscaffold" to support the vessel, fix the vessel's size after expansion, and prevent severe vessel rebound when the substrate is withdrawn, thereby reducing the probability of restenosis within the vessel. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The accompanying drawings are provided for a better understanding of the present invention and are not intended to limit the present invention.

[0031] FIG1 is a schematic structural diagram of a medical balloon catheter provided according to one embodiment of the present invention;

[0032] FIG2 is a schematic diagram of a partial structure of a medical balloon catheter according to one embodiment of the present invention, in which the coating covers the entire outer surface of the main body of the balloon body;

[0033] FIG3 is a schematic diagram of a partial structure of a medical balloon catheter provided according to an embodiment of the present invention, in which the coating includes a plurality of sub-coatings spaced apart along the axial direction of the main body;

[0034] FIG4 is a schematic diagram of a partial structure of a medical balloon catheter provided according to an embodiment of the present invention, in which the coating is a grid-like structure;

[0035] FIG5 is a schematic diagram of a coating provided on a balloon body of a medical balloon catheter according to one embodiment of the present invention;

[0036] FIG6 is an AA cross-sectional view of the medical balloon catheter shown in FIG1 ;

[0037] FIG7 is a partial structural diagram of an optical fiber assembly of a medical balloon catheter according to one embodiment of the present invention;

[0038] FIG8 is a schematic diagram comparing the cross-sectional dimensions of blood vessels after the medical balloon catheters provided by Comparative Example 1, Comparative Example 2, Example 1, and Comparative Example 3 of the present invention are applied to the blood vessels. In the figure, a is a blood vessel using the medical balloon catheter provided by Comparative Example 1, b is a blood vessel using the medical balloon catheter provided by Comparative Example 2, c is a blood vessel using the medical balloon provided by Example 1, and d is a blood vessel using the medical balloon catheter provided by Comparative Example 3;

[0039] FIG9 is a photograph of a cross-section of a blood vessel of a medical catheter provided according to Comparative Example 1, Comparative Example 2, Example 1, and Comparative Example 3 of the present invention after staining. In the figure, a is a blood vessel using the medical balloon catheter provided in Comparative Example 1, b is a blood vessel using the medical balloon catheter provided in Comparative Example 2, c is a blood vessel using the medical balloon catheter provided in Example 1, and d is a blood vessel using the medical balloon catheter provided in Comparative Example 3.

[0040] [The accompanying drawings are marked as follows]: 100-catheter body, 110-inner tube, 111-guidewire cavity, 120-outer tube, 200-medical balloon, 210-balloon body, 211-main body, 212-joining part, 220-coating, 221-sub-coating, 300-light component, 310-light-emitting part, 311-optical fiber core, 312-scattering layer, 320-protective layer, 400-connector, 410-first interface, 420-second interface, 500-guide head, 600-developing element; 10-nozzle, 20-core shaft. DETAILED DESCRIPTION

[0041] The following describes the embodiments of the present invention through specific specific examples. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that the illustrations provided in this embodiment only illustrate the basic concept of the present invention in a schematic manner, and the drawings only show components related to the present invention rather than being drawn according to the number, shape and size of components during actual implementation. During actual implementation, the type, quantity and proportion of each component can be changed at will, and the component layout type may also be more complicated.

[0042] In addition, each embodiment described below has one or more technical features. However, this does not mean that users of the present invention must implement all technical features in any embodiment at the same time, or that they can only implement some or all technical features in different embodiments separately. In other words, as long as implementation is possible, those skilled in the art can, based on the disclosure of the present invention and depending on design specifications or implementation requirements, selectively implement some or all technical features in any embodiment, or selectively implement a combination of some or all technical features in multiple embodiments, thereby increasing the flexibility of the implementation of the present invention.

[0043] In this article, the terms "proximal" and "distal" refer to the relative orientation, position, and direction of components or actions relative to each other from the perspective of a doctor using the medical device. Although "proximal" and "distal" are not restrictive, "proximal" generally refers to the end of the medical device that is close to the doctor during normal operation, and "distal" generally refers to the end that first enters the patient's body.

[0044] The purpose of the present invention is to provide a medical system. After the base of the medical device is introduced into the human body and expanded, it can form a "protein microscaffold" in situ on the blood vessel wall. The "protein microscaffold" is used to support the blood vessel to maintain the expanded size of the blood vessel as much as possible, avoiding severe rebound of the blood vessel and the problem of restenosis caused by the blood vessel.

[0045] To make the objects, advantages, and features of the present invention more apparent, the present invention is further described below in detail with reference to the accompanying drawings. It should be noted that the drawings are greatly simplified and not to exact scale, and are intended solely to facilitate and clearly illustrate the embodiments of the present invention. The same or similar reference numerals in the drawings represent the same or similar components.

[0046] The medical system includes a medical device, which includes a substrate that can expand or contract along its radial direction. Typically, the substrate is, for example, a balloon body 210 (as shown in FIG1 ) or a stent. When the substrate is the balloon body, the medical device is a medical balloon, and the medical system can be a medical balloon catheter. Next, the medical system is described as a medical balloon catheter. Those skilled in the art can modify the following description to adapt it to the case where the substrate is a stent or other medical device capable of carrying a coating.

[0047] FIG1 is a schematic structural diagram of the medical balloon catheter. As shown in FIG1 , the medical balloon catheter includes a catheter body 100 and a medical balloon 200, wherein the catheter body 100 is formed with a filling agent flow channel. The medical balloon 200 includes a balloon body 210 and a coating 220, wherein the balloon body 210 is sleeved on the distal outer peripheral surface of the catheter body 100. The balloon body 210 has a filling cavity, which is connected to the filling agent flow channel. The coating 220 is disposed on at least a portion of the outer surface of the balloon body 210 and includes a protein and a crosslinking agent. The protein is used to crosslink with proteins on the blood vessel wall under the action of the crosslinking agent.

[0048] The medical balloon catheter can be used to treat atherosclerosis. In actual use, the medical balloon 200 is introduced into a diseased blood vessel in the human body. A filling agent is perfused into the filling lumen of the balloon body 210 through the filling agent flow channel, causing the balloon body 210 to expand, thereby placing the coating 220 on the outer surface of the balloon body 210 in close contact with the blood vessel wall. The protein in the coating 220, as an exogenous protein, can penetrate the blood vessel wall after a short release time of approximately 30-60 seconds, resulting in a high protein concentration in the area where the blood vessel wall contacts the coating 220. Those skilled in the art are aware that the blood vessel wall comprises the intima, the media, and the adventitia. The intima is lined with squamous endothelial cells, while the media is separated from the intima by an internal elastic lamina. The media is composed of alternating layers of elastic layers, elastic fibers, and smooth muscle cells, while the adventitia is composed of collagen and elastic fibers. In other words, the blood vessel wall contains elastin and extracellular matrix proteins. Proteins can undergo cross-linking reactions to form a grid-like structure with certain mechanical properties and the ability to be stretched. In other words, in embodiments of the present invention, the elastic fiber protein and extracellular matrix proteins on the blood vessel wall can be fully cross-linked with the exogenous proteins from the coating 220 under the action of the cross-linking agent to form a grid-like cross-linked structure. This cross-linked structure forms an in-situ "protein microscaffold." The "protein microscaffold" has good mechanical properties and can support the blood vessel after expansion by the medical balloon 200. To a certain extent, it can maintain the size of the expanded blood vessel, avoid blood vessel rebound caused by the retraction of the balloon body 210, maintain lumen gain, reduce or even avoid the occurrence of restenosis, and achieve the purpose of vascular remodeling. Not only that, this "protein microscaffold" will not degrade, and there is no problem of foreign implant residue.

[0049] In an embodiment of the present invention, the additional introduction of exogenous proteins through the coating 220 can increase the concentration of proteins in the area where the vascular wall contacts the coating 220, form more cross-linked products, and improve the mechanical properties of the formed "protein microscaffold", thereby effectively avoiding the problem of the "protein microscaffold" being unable to effectively support the vascular wall due to insufficient protein content in the vascular wall or insufficient protein distribution in certain parts, resulting in the cross-linking reaction not occurring or the cross-linking degree being insufficient.

[0050] Furthermore, because the coating 220 is artificially applied, a predetermined shape of the coating 220 can be formed on the outer surface of the balloon body 210 according to actual needs during the production phase. This allows the medical balloon 200 to regulate the protein concentration in different parts of the blood vessel wall after implantation. Typically, the protein concentration is higher in areas of the blood vessel wall that come into contact with the coating 220, while the protein concentration is lower in areas not in contact with the coating 220.

[0051] Specifically, as shown in Figure 1, the balloon body 210 includes a main body 211 and two joints 212 connected to the axial ends of the main body 211. The coating 220 is provided on at least a portion of the outer surface of the main body 211. It should be noted that when the substrate is a stent, the stent only includes the main body and does not include the joints.

[0052] More specifically, in some embodiments, as shown in FIG2 , the coating 220 covers the entire outer surface of the main body 211. Thus, the portion of the vascular wall corresponding to the main body 211 is in contact with the coating 220 and receives exogenous protein from the coating 220, resulting in a higher protein concentration. In other embodiments, as shown in FIG3 , the coating 220 includes a plurality of sub-coatings 221 spaced axially along the main body 211. In this case, the portion of the vascular wall in contact with each sub-coating 221 receives exogenous protein from the coating 220 and has a higher protein concentration, while the portion of the vascular wall corresponding to the area between two adjacent sub-coatings 221 is not in contact with the coating 220 and has a relatively lower protein concentration. In other embodiments, as shown in FIG4 , the coating 220 has a lattice-like structure, and the portion of the vascular wall corresponding to the mesh area is not in contact with the coating 220 and has a relatively lower protein concentration. In yet other embodiments, the coating 220 is a helical structure surrounding the main body 211. The portion of the vascular wall corresponding to the area between two turns of the helical structure is not in contact with the coating 220 and thus has a relatively low protein concentration. Applying the coating 220 to different areas of the outer surface of the main body 211 can result in different mechanical properties for the vascular microstent ultimately formed within the blood vessel.

[0053] The coating 220 is formed by drying a coating solution attached to the main body 211 of the balloon 210. The coating 220 solution includes the protein and the cross-linking agent, which are dissolved in a solvent under the action of ultrasound. The solvent includes, but is not limited to, at least one of ethanol, ethyl acetate, acetone, tetrahydrofuran, and water.

[0054] In the embodiment of the present invention, any suitable method can be used as needed to make the coating solution adhere to the balloon body 210. In a typical embodiment, a single nozzle printing method such as ultrasonic spray printing can be used. Specifically, as shown in FIG5 , before spraying, the balloon body 210 is first placed on a core shaft 20 located below the nozzle 10, and then the core shaft 20 is controlled to rotate to drive the balloon body 210 to rotate synchronously. The nozzle 10 is also controlled to move along the axial direction of the balloon body 210 and spray the coating solution to perform printing and spraying. It is understood that the entire printing and spraying process can be controlled by a computer, and the rotation speed of the mandrel 20, the movement speed of the nozzle 10, and the spraying speed of the nozzle 10 can be preset through programming, so that the coating solution is sprayed onto the main body 211 along a preset path, thereby adhering to the entire outer surface of the main body 211, or forming a plurality of rings on the outer surface of the main body 211 at intervals along the axial direction of the main body 211, or forming a grid-like structure on the main body 211, or forming a spiral structure on the main body 211. In other words, different program settings can be used according to actual needs to form coatings 220 with different patterns on the main body 211, and ultimately obtain vascular microstents with different mechanical properties on the blood vessel wall.

[0055] Of course, in other implementations, the coating solution may be directly attached to the main body 211 of the balloon 210 by dipping.

[0056] The proteins used in the embodiments of the present invention include, but are not limited to, at least one of humanized elastin, humanized collagen, human serum albumin, silk fibroin, and proteoglycans. Silk fibroin, as a natural protein macromolecule, has excellent biosafety and degradability, an ordered molecular structure, and good mechanical properties. When forming a grid-like cross-linked structure, it can achieve better orientation of the cross-linked structure and better mechanical properties. Therefore, in the embodiments of the present invention, the protein preferably includes silk fibroin.

[0057] Optionally, the crosslinker comprises a photosensitive crosslinker. The term "photosensitive crosslinker" refers to a crosslinker that can undergo a crosslinking reaction with proteins under illumination. In other words, the crosslinker not only crosslinks proteins but also acts as a photosensitizer, activating under illumination to generate free radicals that initiate the crosslinking reaction.

[0058] Alternatively, the crosslinker includes a non-photosensitive crosslinker, meaning a crosslinker that can directly crosslink with proteins without illumination. In this embodiment of the present invention, the protein and the crosslinker are expected to crosslink on the vascular wall, rather than in vitro. To this end, the coating 220 preferably further includes a separator that isolates the protein and the non-photosensitive crosslinker to prevent them from crosslinking in vitro.

[0059] In an optional implementation, the protein, the separator and the cross-linking agent together form a coating solution, but the separator is wrapped on the outer surface of the protein. In this implementation, the separator is roughly a microsphere or microcapsule structure, which can effectively encapsulate the protein. The microspheres and the microcapsules can be prepared using existing technologies, for example, the microspheres are prepared using an emulsification solvent volatilization method, and the microcapsules can be prepared using an in-situ polymerization method. Alternatively, in another optional implementation, the coating 220 is a multi-layer structure, for example, three layers, namely a first layer structure, a second layer structure and a third layer structure, wherein the first layer structure includes the protein but does not include the non-photosensitive cross-linking agent, the second layer structure includes the separator, and the third layer structure includes the non-photosensitive cross-linking agent but does not include the protein, and the second layer structure is located between the first layer structure and the third layer structure. In this implementation, it is only necessary to configure each layer structure solution separately and form each layer structure in sequence, which is simpler to implement. It should be noted that, after entering the blood vessel, the separator should be capable of decomposing, dissolving, or degrading under the action of body fluids, thereby allowing the protein to contact the non-photosensitive crosslinker and undergo a crosslinking reaction. Optionally, the separator includes, but is not limited to, sustained-release materials such as phospholipids, starch, polylactic acid, chitosan, etc.

[0060] It should also be noted that, in some embodiments, the crosslinking agent includes both the photosensitive crosslinking agent and the non-photosensitive crosslinking agent.

[0061] It is understood that the crosslinking agent is divided into a physical crosslinking agent and a chemical crosslinking agent. The physical crosslinking agent includes at least one of tannic acid, pentagalloyl glucose, gallic acid ester, gallic acid, ellagic acid, proanthocyanidin, anthocyanidin, quercetin, xanthophyllin, catechin, and epicatechin. The chemical cross-linking agent includes at least one of glutaraldehyde, polyepoxide, genipin, methylene blue, methylene green, rose bengal, riboflavin, proflavin, fluorescein, eosin, horseradish catalase, 4-amino-1,8-naphthalimide, 2,2'-((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(6-((2-(2-aminoethoxy)ethoxy)ethyl)amino)-1H-benzo[de]isoquinoline-1,3(2H)-dione) and its salts, ammonium persulfate, terpyridine ruthenium chloride, camphorquinone, and curcumin.

[0062] Typically, the physical crosslinker is the non-photosensitive crosslinker. A portion of the chemical crosslinker is the non-photosensitive crosslinker, and the other portion is the photosensitive crosslinker. Specifically, among the chemical crosslinkers, methylene blue, methylene green, rose bengal, riboflavin, proflavin, fluorescein, eosin, 4-amino-1,8-naphthalimide, 2,2'-((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(6-((2-(2-aminoethoxy)ethoxy)ethyl)amino)-1H-benzo[de]isoquinoline-1,3(2H)-dione) is the photosensitive crosslinker.

[0063] Those skilled in the art know that riboflavin is vitamin B2, which has the effect of reducing inflammatory response and improving blood supply to the core shaft. Therefore, in the embodiment of the present invention, it is preferred that the cross-linking agent includes riboflavin.

[0064] In the coating solution, the mass ratio of the protein to the cross-linking agent is set as needed, usually 100:1-1:1, for example, 100:1, 90:1, 80:1, 70:1, 65:1, 55:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1, 1:1, etc.

[0065] In a further improved solution, the coating 220 further includes drugs. The type of the drugs is selected according to actual needs, such as anti-proliferative drugs, anti-inflammatory drugs, anti-inflammatory drugs, anti-proliferative drugs, antibacterial drugs, anti-tumor drugs, anti-mitotic drugs, cytostatic drugs, cytotoxic drugs, anti-osteoporosis drugs, anti-angiogenic drugs, anti-restenosis drugs, microtubule inhibitory drugs, anti-metastasis drugs, anti-thrombotic drugs, etc. Specific drugs include, but are not limited to, dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine and aminosalicylic acid, acemetacin, aescin, aminopterin, antifungal, arsenic trioxide, aristolochic acid, aspirin, scutellaria, ginkgo biloba, endostatin, angiostatin, angiopeptin, monoclonal antibodies capable of blocking smooth muscle cell proliferation, levofloxacin, paclitaxel, docetaxel, hydroxycamptothecin, vinblastine, vincristine, doxorubicin, 5-fluorouracil , cisplatin, thymidine kinase inhibitor antibiotics (especially actinomycin-D), hormones, antibody cancer drugs, bisphosphonates, selective estrogen receptor modulators, strontium ranelate, cyclosporine A, cyclosporine C, brefeldin A, vascular endothelial growth factor, angiogenin, recombinant proteins, stem cells, rapamycin and its derivatives, rapamycin derivatives include but are not limited to zotarolimus, everolimus, biolimus, 7-O-desmethylrapamycin, temsirolimus, and defossilolimus.

[0066] Since the medical balloon catheter can be used to treat atherosclerosis, the coating 220 may further include drugs for preventing or improving coronary microcirculation disorders. This type of drug includes but is not limited to at least one of statins (such as ACEI / ARB), ranolazine, metoprolol, adenosine, nitrates, sodium nitroprusside, verapamil, nicorandil, and alprostadil.

[0067] As mentioned above, the crosslinking agent in the coating 220 may include a photosensitive crosslinking agent, which needs to be activated under light. In this case, as shown in Figures 1, 6 and 7, the medical balloon catheter also includes an optical fiber assembly 300, and the distal end of the optical fiber assembly 300 has a light-emitting portion 310. The optical fiber assembly 300 is at least partially inserted into the catheter body 100, and the light-emitting portion 310 extends to the distal end of the catheter body 100, and the position of the light-emitting portion 310 corresponds to the position of the balloon body 210. The distal end of the catheter body 100 is configured to allow the light emitted by the light-emitting portion 310 to irradiate the balloon body 210, so that the photosensitive crosslinking agent is activated under light and generates free radicals, which trigger the crosslinking reaction of the protein. According to actual needs, the axial length of the light-emitting portion 310 is selected between 1mm and 50mm.

[0068] In an embodiment of the present invention, the optical fiber assembly 300 is preferably a cylindrical diffuse optical fiber, which can provide lateral divergent light. In a specific embodiment, the optical fiber assembly 300 includes an optical fiber core 311, the distal end of which extends to the distal end of the catheter body 100 and corresponds to the position of the balloon body 210. The optical fiber assembly 300 also includes a scattering layer 312, which is located at least at the light-emitting portion 310 and is uniformly attached to the outer circumferential surface of the optical fiber core 311. The scattering layer 312 includes a matrix material and scattering particles uniformly dispersed in the matrix material. The scattering particles can scatter the light emitted by the optical fiber core 311 to provide circumferentially uniform divergent light.

[0069] In this embodiment of the present invention, the diameter of the optical fiber core 311 is 0.05 mm to 1 mm. The thickness of the scattering layer 312 is 0.1 mm to 0.5 mm. The matrix material includes, but is not limited to, rubber, and the scattering particles include, but are not limited to, nano-titanium dioxide. It should be noted that when the scattering layer 312 is located only on the light-emitting portion 310, the optical fiber assembly 300 also includes a protective layer 320, which is attached to the outer circumference of the optical fiber core 311 and located proximal to the scattering layer 312.

[0070] Further, please refer to Figure 6, the catheter body 100 includes an inner tube 110 and an outer tube 120, wherein the inner tube 110 is partially inserted into the outer tube 120, and the distal end of the inner tube 110 extends from the distal end of the outer tube 120. The space between the inner surface of the outer tube 120 and the inner surface of the inner tube 110 constitutes the filler flow channel. The distal end of the outer tube 120 is sealedly connected to the joint 212 at the proximal end of the balloon body 210 so that the filler flow channel is in communication with the filling cavity of the balloon body 210. The inner tube 110 has an optical fiber channel (not marked in the figure), and the optical fiber assembly 300 is at least partially inserted into the optical fiber channel of the inner tube 110. The distal end of the inner tube 110 is configured to allow light to pass through. Optionally, the inner tube 110 is entirely made of a transparent polyethylene material, so that the light transmittance of the inner tube 110 is greater than 90%, allowing the light emitted by the light emitting portion 310 to pass through.

[0071] In addition, similar to the prior art, the inner tube 110 is further provided with a guidewire cavity 111, which axially penetrates the inner tube 110 and is parallel to the optical fiber channel. A guidewire inlet 101 is also formed on the proximal side wall of the catheter body 100, and the guidewire inlet 101 is communicated with the guidewire cavity 111 for passing a guide wire. In addition, the medical balloon catheter also includes a connector 400, which is connected to the proximal end of the catheter body 100 and includes a first interface 410 and a second interface 420. The first interface 410 is communicated with the filler flow channel and is used to connect to a filler such as a syringe. The second interface 420 is used to communicate with the inner tube 110 and can be used for the proximal end of the optical fiber assembly 300 to pass through. Furthermore, the medical balloon catheter also includes a guide head 500 and a developing element 600. The guide head 500 is connected to the distal end of the inner tube 110 and is located on the distal side of the medical balloon 200. It is also connected to the distal end of the optical fiber assembly 300. The guide head 500 is typically a tapered structure with an inner diameter that gradually decreases from the proximal end to the distal end, thereby facilitating guidance of the distal end of the medical balloon catheter as it travels within a blood vessel. The developing element 600 is disposed on the inner tube 110 and corresponds to the position of the medical balloon 200, allowing for visualization under X-rays to facilitate positioning of the medical balloon 200.

[0072] Furthermore, an embodiment of the present invention also provides a preparation method for preparing the medical device as described above. The preparation method comprises the following steps:

[0073] First, the substrate is provided, which can expand or contract along its radial direction, such as the balloon 210. Also, the coating solution is provided, which includes a protein and a cross-linking agent.

[0074] Next, the coating solution is sprayed onto at least a portion of the outer surface of the balloon body 210 .

[0075] Finally, the coating solution is dried to form the coating layer 220 .

[0076] Next, this article introduces the preparation method of the medical balloon through Example 1, and illustrates the therapeutic effect of the medical balloon catheter provided by the embodiment of the present invention through comparison between Example 1 and a comparative example.

[0077] In Example 1, the cross-linking agent used is riboflavin, the protein used is silk fibroin, and the mass ratio of silk fibroin to riboflavin is 10:1.

[0078] First, a coating solution is provided. Specifically, riboflavin and silk fibroin are added to a solvent and dissolved by ultrasound. In this embodiment, the solvent is a mixture of ethyl acetate and acetone, with a mass ratio of ethyl acetate to acetone of 3:1.

[0079] Next, the coating solution is applied to the outer surface of the main body 211 of the balloon 210 by ultrasonic spraying, and the coating solution completely covers the outer surface of the main body 211 .

[0080] Then, the coating solution was dried at room temperature for 24 hours to dry and solidify to form the coating 220 .

[0081] In this embodiment, a total of six medical balloons 200 are prepared, which are labeled as medical balloon No. 1, medical balloon No. 2, medical balloon No. 3, medical balloon No. 4, medical balloon No. 5 and medical balloon No. 6. The specifications of each medical balloon are shown in Table 1 below.

[0082] The silk fibroin and riboflavin in the coating 220 of the six medical balloons 200 were quantitatively measured. The results are shown in Table 1. The density of the silk fibroin loaded in the coating 220 was calculated to be approximately 0.13 mg / mm 2 The density of the loaded cross-linker is about 0.012 mg / mm 2 .

[0083] The medical balloon catheter is obtained by assembling the medical balloon 200, the catheter body 100, and the optical fiber assembly 300. The performance of the medical balloon catheter is tested.

[0084] First, a target blood vessel is provided. The target blood vessel is a porcine right iliac artery, whose surface tissue is removed. The porcine right iliac artery has a length of 1 cm, a vessel wall thickness of 2 mm, and an inner diameter of 5 mm.

[0085] The medical balloon catheter is prepared by taking the medical balloon 200 No. 1, wherein the medical balloon 200 is compressed and gripped.

[0086] The medical balloon 200 is introduced into the target vessel, and a filling agent is injected into the filling lumen of the balloon body 210 through the first interface 410 to inflate the balloon body 210, allowing the coating 220 to contact the vessel wall of the target vessel. In this step, the overexpansion ratio of the balloon body 210 is 125%. The overexpansion ratio refers to the ratio of the diameter of the balloon body 210 after expansion to the initial diameter of the target vessel (i.e., the diameter of the target vessel before treatment with the medical balloon 200).

[0087] Then, the light emitting portion 310 of the optical fiber assembly 300 emits laser light and irradiates the coating 220 . The wavelength of the laser light is 450 nm, the power is 1 W, and the irradiation time is 60 s.

[0088] Subsequently, the filling agent is discharged and the medical balloon 200 is withdrawn from the target blood vessel.

[0089] Afterwards, the wall thickness and inner diameter of the target blood vessel were measured, as shown in Table 2, and the target blood vessel was photographed, as shown in FIG8 c.

[0090] Finally, the target blood vessel was immersed in formalin for a certain period of time and histochemically stained, and then photographed, as shown in FIG9 c.

[0091] Comparative Example 1

[0092] This comparative example differs from Example 1 in that the coating 220 includes silk fibroin but does not include riboflavin. The procedures for treating a target blood vessel using the medical balloon catheter provided in this comparative example are identical. The parameters of the target blood vessel before and after treatment are shown in Table 2. A photograph of the target blood vessel after treatment with the medical balloon catheter provided in this comparative example and before histochemical staining is shown in Figure 8(a), and a photograph after histochemical staining is shown in Figure 9(a).

[0093] Comparative Example 2

[0094] This comparative example differs from Example 1 in that the optical fiber assembly 300 is not used to irradiate the coating 220 during treatment of the target vessel. The method for preparing the medical balloon catheter provided in this comparative example is identical to that provided in the example. The parameters of the target vessel before and after treatment are shown in Table 2. A photograph of the target vessel after treatment with the medical balloon catheter provided in this comparative example and before histochemical staining is shown in Figure 8(b), and a photograph after histochemical staining is shown in Figure 9(b).

[0095] Comparative Example 3

[0096] This comparative example differs from Example 1 in that the coating 220 includes riboflavin but not silk fibroin. The procedure for treating a target blood vessel using the medical balloon catheter provided in this comparative example is identical. The parameters of the target blood vessel after treatment are shown in Table 2. A photograph of the target blood vessel after treatment with the medical balloon catheter provided in this comparative example and before histochemical staining is shown in Figure 8(d), and a photograph after histochemical staining is shown in Figure 9(d).

[0097] Table 1

[0098] Table 2

[0099] As shown in Figures 8 and 9 , after treatment of the target vessel by the medical balloon catheter provided in Example 1 of the present invention, the cross-section of the target vessel exhibits a significant darkening of the protein, and the protein fibers exhibit a tendency to be oriented along the vessel's circumference. In contrast, the cross-sections of the target vessels treated with the medical balloon catheters provided in Comparative Examples 1 and 2 exhibited a lighter protein color and less pronounced fiber orientation. The cross-sections of the target vessel treated with the medical balloon catheter provided in Comparative Example 3 exhibited a slight darkening of the protein color and some fiber orientation, but the color was lighter than that of Example 1, and the orientation was less pronounced. This demonstrates that, when the medical balloon catheter provided in Example 1 of the present invention treats the target vessel, the protein on the coating 220 is able to deposit and orient on the vessel wall, forming an in situ "protein microscaffold." Furthermore, Table 2 shows that, compared with Comparative Examples 1 and 2, the inner diameter of the target vessel treated with the medical balloon catheter provided in Example 1 of the present invention increases, and the vessel wall becomes thinner, indicating that the "protein microscaffold" effectively supports the vessel wall, maintains the vessel wall in an expanded state, and reduces the possibility of restenosis. Compared with Comparative Example 3, it can be found that the medical balloon catheter provided in Example 1 has a more obvious effect on increasing the inner diameter of the target blood vessel. This is because the additional protein is introduced through the coating, the protein content is increased, and the cross-linking reaction occurs fully, thereby effectively forming a "protein microscaffold" with sufficient support strength, avoiding the problem of insufficient support force of the protein microscaffold and inability to effectively support the blood vessel wall.

[0100] In summary, the protein in the coating of the medical balloon of the medical balloon catheter provided by the embodiment of the present invention can undergo a cross-linking reaction with the protein of the blood vessel wall through the action of a cross-linking agent, thereby forming a "protein microscaffold" in situ. The mechanical properties of the "protein microscaffold" are used to support the expanded blood vessel, thereby maintaining the blood vessel in an expanded state and reducing restenosis of the blood vessel.

[0101] While the present invention is disclosed above, it is not limited thereto. Those skilled in the art may make various modifications and variations to the present invention without departing from the spirit and scope of the present invention. Thus, the present invention is intended to encompass such modifications and variations as long as they fall within the scope of the claims and their equivalents.

Claims

1. A medical device, characterized in that: The invention comprises a substrate and a coating, wherein the substrate can expand or contract along its radial direction; the coating is arranged on at least a part of the outer surface of the substrate, and the coating comprises protein and a cross-linking agent.

2. The medical device according to claim 1, characterized in that: The cross-linking agent includes a photosensitive cross-linking agent, and the photosensitive cross-linking agent undergoes a cross-linking reaction with the protein under light.

3. The medical device according to claim 2, characterized in that: The photosensitive crosslinking agent includes at least one of methylene blue, methylene green, rose bengal, riboflavin, proflavin, fluorescein, eosin, 4-amino-1,8-naphthalimide, 2,2'-((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(6-((2-(2-aminoethoxy)ethoxy)ethyl)amino)-1H-benzo[de]isoquinoline-1,3(2H)-dione) and salts thereof.

4. The medical device according to claim 1, characterized in that: The crosslinking agent includes a non-photosensitive crosslinking agent, and the coating layer further includes an isolator, wherein the isolator isolates the protein and the non-photosensitive crosslinking agent to prevent the protein from undergoing a crosslinking reaction with the non-photosensitive crosslinking agent.

5. The medical device according to claim 4, characterized in that: The non-photosensitive crosslinking agent includes a physical crosslinking agent and / or a chemical crosslinking agent, and the chemical crosslinking agent includes at least one of glutaraldehyde, polyepoxide, genipin, horseradish catalase, ammonium persulfate, terpyridine ruthenium chloride, camphorquinone, and curcumin.

6. The medical device according to claim 5, characterized in that: The physical cross-linking agent includes at least one of tannic acid, pentagalloylglucose, gallic acid ester, gallic acid, ellagic acid, proanthocyanidin, anthocyanidin, quercetin, xanthocyanin, catechin, and epicatechin.

7. The medical device according to claim 1, characterized in that: The protein includes at least one of humanized elastin, humanized collagen, human serum albumin, silk fibroin, and proteoglycan.

8. The medical device according to claim 1, characterized in that: The mass ratio of the protein to the cross-linking agent is 100:1-1:

1.

9. The medical device according to claim 1, characterized in that: The substrate comprises a main body; the coating is arranged on at least a portion of the outer surface of the main body.

10. The medical device according to claim 9, characterized in that: The coating covers the entire outer surface of the main body.

11. The medical device according to claim 10, characterized in that: The coating layer includes a plurality of sub-coating layers, and the plurality of sub-coating layers are arranged at intervals along the axial direction of the main body.

12. The medical device according to claim 10, characterized in that: The coating is a helical structure surrounding the axis of the main body.

13. The medical device according to claim 10, characterized in that: The coating layer is a grid-like structure.

14. The medical device according to claim 1, characterized in that: The coating also includes a drug.

15. The medical device according to claim 1, characterized in that The matrix includes a balloon or a stent.

16. A medical system, characterized in that: The invention comprises a medical device and a catheter body as claimed in any one of claims 1 to 15, wherein the base body is sleeved on the outer peripheral surface of the distal end of the catheter body.

17. The medical system according to claim 16, characterized in that: The cross-linking agent includes a photosensitive cross-linking agent; the medical system also includes an optical fiber assembly, which is at least partially inserted into the catheter body, and the optical fiber assembly includes a light-emitting portion, which extends to the distal end of the catheter body, and the position of the light-emitting portion corresponds to the position of the substrate; the distal end of the catheter body is configured to allow light emitted by the light-emitting portion to irradiate the substrate.

18. The medical system according to claim 17, characterized in that: The light transmittance of the distal end of the catheter body is greater than 90%.

19. A method for preparing the medical device according to any one of claims 1 to 15, characterized in that: The preparation method comprises the following steps: Providing the substrate and a coating solution, wherein the substrate can expand or contract along its radial direction, and the coating solution comprises a protein and a cross-linking agent; applying the coating solution to at least a portion of the outer surface of the substrate; The coating solution is dried, and the coating is formed.

Images