Embolic member for peripheral arteriovenous vessels

Abstract

The invention discloses an embolism part for peripheral arteriovenous vessels, the embolism part comprises an anchoring part and a blocking part fixedly connected with the anchoring part, the blocking part adopts polyurethane shape memory foam, the expansion rate of the polyurethane shape memory foam is 50-100 times, and a preparation method of the polyurethane shape memory foam comprises the following steps: step 1, preparing a polyurethane shape memory foam material; the preparation method comprises the following steps: preparing a polyurethane acrylate prepolymer from macromolecular polyol, diisocyanate, a chain extender containing disulfide bonds, other micromolecular chain extenders and an acrylate end-capping reagent; and 2, uniformly mixing the polyurethane acrylate prepolymer, a foaming agent, a foaming promoter and a photoinitiator to obtain a foaming solution, and sequentially carrying out light curing and foaming on the foaming solution to obtain the polyurethane shape memory foam. According to the embolism part, the polyurethane shape memory foam is adopted as the blocking part, the blocking part applies radial acting force to the wall of the blood vessel all the time based on the expansion trend of the blocking part, and the blocking part and the anchoring part jointly act and can be stably maintained in the blood vessel.

Description

Technical Field

[0001] The present application relates to the technical field of medical devices, and in particular to an embolic device for peripheral arteries and veins. Background Art

[0002] Peripheral arteries and veins may have abnormal blood flow pathways. For example, in a peripheral arteriovenous fistula, an abnormal blood flow channel forms between the artery and vein. Another example is that venous valve insufficiency causes blood to flow backward, forming dilated and tortuous blood vessels. Another example is that arteries supply blood to tumors and cause them to grow.

[0003] In the above situation, it is necessary to achieve the treatment purpose by blocking the target blood vessel. In the existing technology, spring coils, liquid embolic agents and covered stents are usually used to achieve the purpose of blocking the target blood vessel, but these methods all have shortcomings.

[0004] The use of coils to occlude the target blood vessels is sensitive to hemodynamic effects, and high-flow fistulas are prone to coil displacement or detachment, leading to embolization failure or ectopic embolism (such as pulmonary embolism). When coils are used alone, the thrombosis rate is high, which may cause distal tissue ischemia or venous hypertension. The recanalization rate can reach 10%-30% with long-term use. The coils are also not adaptable enough to blood vessels. For tortuous blood vessels or fistulas with a diameter of >5mm, it is difficult for the coils to completely fill them, and tiny fistulas are likely to remain, which may compress adjacent nerves (such as the saphenous nerve) or venous valves, causing pain or venous insufficiency.

[0005] Liquid embolic agents are injected to block the target blood vessels. However, the polymerization time of liquid embolic agents is difficult to control accurately. Premature solidification may lead to catheter adhesion, or late solidification may cause accidental occlusion of normal blood vessels. They are vascular toxic and may induce chronic inflammatory reactions or vascular intimal hyperplasia. Some materials (such as gelatin sponge) can be absorbed in a relatively short period of time, resulting in a short-term embolic effect and the need for repeated treatment.

[0006] The use of covered stent implantation is prone to complications, with an in-stent restenosis rate as high as 17%-20%. Long-term anticoagulation therapy (such as aspirin + clopidogrel) is required, which increases the risk of bleeding. The stent release process may damage the vascular endothelium, causing dissection or perforation. The risk is especially high when it is used in calcified or tortuous blood vessels. The covered stent is sensitive to hemodynamic changes and may aggravate distal tissue ischemia or venous return obstruction. The stent needs to precisely match the blood vessel diameter (error ≤ 1mm), otherwise internal leakage or displacement is likely to occur, leading to fistula recurrence. Summary of the Invention

[0007] The present application provides an embolic device for peripheral arteries and veins, which uses polyurethane shape memory foam as a sealing part. By utilizing its high expansion rate, the occluding part can fill the blood vessel to be blocked after full expansion. The occluding part always applies radial force to the blood vessel wall based on its own expansion trend, and works together with the anchoring part to stably maintain it in the blood vessel and avoid the risk of displacement.

[0008] An embolic device for peripheral arteries and veins, the embolic device comprising an anchor and a sealing portion fixedly connected to the anchor, the sealing portion being made of polyurethane shape memory foam having an expansion rate of 50 to 100 times. A method for preparing the polyurethane shape memory foam comprises:

[0009] Step 1, preparing a polyurethane acrylate prepolymer using a macromolecular polyol, a diisocyanate, a disulfide bond-containing chain extender, other small molecule chain extenders, and an acrylate end-capping agent;

[0010] Step 2: The polyurethane acrylate prepolymer, acrylate monomer diluent, foaming agent, foaming aid, and photoinitiator are uniformly mixed to form a foaming liquid, and the foaming liquid is sequentially photocured and foamed to obtain the polyurethane shape memory foam.

[0011] Several optional methods are also provided below, but they are not intended to be additional limitations on the above-mentioned overall solution. They are merely further supplements or optimizations. Under the premise that there are no technical or logical contradictions, each optional method can be combined separately for the above-mentioned overall solution, or multiple optional methods can be combined.

[0012] Optionally, the macromolecular polyol is at least one of polycaprolactone (PCL) diol, polyglycolic acid (PGA) diol, polyhydroxybutyrate (PHB) diol, and polylactic acid (PLA) diol; and the diisocyanate is at least one of 1,6-hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), and L-lysine diisocyanate (LDI).

[0013] Optionally, the molar ratio of the hydroxyl group in the macromolecular polyol to the isocyanate group in the diisocyanate is 1:1.5-2.

[0014] Optionally, the total mass of the macromolecular polyol and the diisocyanate is A, the amount of the disulfide bond-containing chain extender is 0.5% to 5% of A, and the amount of the small molecule chain extender is 0 to 5% of A.

[0015] Optionally, in step 1, the macromolecular polyol and diisocyanate are first subjected to a first-stage chemical reaction, and then a chain extender is added to carry out a second-stage chemical reaction;

[0016] The reaction temperature of the first stage is 50-60°C, and the reaction time of the first stage is 3-5 hours;

[0017] The reaction temperature of the second stage is 70-80° C., and the reaction time of the second stage is 3-5 hours.

[0018] Optionally, in step 1, the disulfide bond-containing chain extender is 2-hydroxyethyl disulfide, the small molecule chain extender is at least one of 1,4-butanediol, ethylene glycol, and propylene glycol, and in step 2, the acrylate monomer diluent is at least one of isooctyl acrylate, lauryl acrylate, lauryl methacrylate, and isobornyl methacrylate.

[0019] Optionally, the anchoring member is a metal member, or the anchoring member is a hard polyurethane shape memory foam, and the expansion rate of the hard polyurethane shape memory foam is smaller than that of the polyurethane shape memory foam used as the blocking part.

[0020] Optionally, the developer is added in any step of preparing the rigid polyurethane shape memory foam.

[0021] Optionally, the blocking portion is cylindrical, the anchor is an expansion claw connected to at least one axial end of the blocking portion, or the anchor is a hard polyurethane shape memory foam block connected to at least one axial end of the blocking portion.

[0022] Optionally, the anchoring member is a hard polyurethane shape memory foam block, the anchoring member runs through the axial direction of the blocking portion, and forms radially expanding expansion portions at both axial ends of the blocking portion.

[0023] The embolic device for peripheral arteries and veins provided in this application uses polyurethane shape memory foam as the sealing part. It takes advantage of its high expansion rate to fill the blood vessels that need to be blocked after full expansion. The sealing part always applies radial force to the blood vessel wall based on its own expansion trend, and works together with the anchoring member to maintain stability in the blood vessel and avoid the risk of displacement. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is a schematic diagram of one embodiment of the embolic device for peripheral arteries and veins of the present application;

[0025] Figure 2 A schematic diagram of one embodiment of the embolic device for peripheral arteries and veins of the present application in a blood vessel;

[0026] Figure 3 This is a schematic diagram of the embolic device used in the peripheral arteriovenous blood vessels of the present application releasing part of the anchoring member in the blood vessel;

[0027] Figure 4This is a schematic diagram of the embolic device used for peripheral arteries and veins in the present application releasing a portion of the occluding portion within the blood vessel;

[0028] Figure 5 This is a schematic diagram of the embolic device used in the peripheral arteriovenous vessels of the present application after being released into the blood vessel;

[0029] Figure 6 This is a schematic diagram of another embodiment of the embolic device for peripheral arteriovenous vessels of the present application in a blood vessel;

[0030] Figure 7 A schematic diagram of another embodiment of the embolic device for peripheral arteriovenous vessels of the present application;

[0031] Figure 8 This is a schematic diagram of another embodiment of the embolic device for peripheral arteries and veins in the present application in a blood vessel.

[0032] In the figure: 1000, embolic member; 1100, anchoring member; 1200, occluding portion; 1300, developing point; 2000, catheter. DETAILED DESCRIPTION

[0033] The following will be combined with the drawings in the embodiments of this application to clearly and completely describe the technical solutions in the embodiments of this application. Obviously, the embodiments described are only part of the embodiments of this application, not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of this application.

[0034] In order to better describe and illustrate the embodiments of the present application, reference may be made to one or more drawings, but the additional details or examples used to describe the drawings should not be considered as limiting the scope of the invention of the present application, any of the currently described embodiments or preferred methods.

[0035] It should be noted that when a component is referred to as being "connected" to another component, it may be directly connected to the other component or there may be an intermediate component. When a component is referred to as being "disposed on" another component, it may be directly disposed on the other component or there may be an intermediate component.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application pertains. The terms used herein in the specification of this application are for the purpose of describing specific embodiments only and are not intended to limit this application.

[0037] See also Figure 1 、 Figure 6 、 Figure 7As shown, an embolic device 1000 for peripheral arteries and veins includes an anchor 1100 and a sealing portion 1200 fixedly connected to the anchor 1100. The sealing portion 1200 is made of polyurethane shape memory foam, and the expansion rate of the polyurethane shape memory foam is 50 to 100 times.

[0038] See also Figure 1 As shown, the blocking portion 1200 is approximately cylindrical, with ridges at both axial ends of the cylinder. The length L of the blocking portion 1200 is 10 to 20 mm, and the diameter D of the blocking portion 1200 is 3 to 15 mm.

[0039] The anchor 1100 can be made of metal. The anchor 1100 is an expansion claw connected to at least one axial end of the blocking portion 1200. Figure 1 As shown, both ends of the axial direction of the occluding part 1200 are provided with expansion claws. When the embolic member 1000 is delivered into the target blood vessel using the catheter 2000, the expansion claws are brought together and gathered in the catheter 2000. Figure 2 As shown, the expansion claws expand themselves in the blood vessel and exert force on the blood vessel wall to stabilize the position of the embolic member 1000. Figure 6 As shown, the expansion claw may be provided only at one section of the axial direction of the sealing portion 1200 .

[0040] The release process of the plug 1000 is shown in FIG. Figure 3 、 Figure 4 、 Figure 5 As shown, the expansion claw at one end of the blocking portion 1200 is first released from the catheter 2000 at the expected position, and the catheter 2000 is slowly withdrawn to release the blocking portion 1200 and the expansion claw at the other end of the blocking portion 1200.

[0041] See also Figure 1 、 Figure 2 As shown, a developing point 1300 may be provided on the metal anchoring member 1100 to observe the release position of the embolic member 1000 and its subsequent long-term position.

[0042] The anchoring member 1100 may also be a rigid polyurethane shape memory foam block connected to at least one axial end of the occluding portion 1200. The rigid polyurethane shape memory foam block utilizes its relatively hard texture to exert a force on the blood vessel wall to achieve anchoring. Figure 7 、 Figure 8As shown, anchor 1100 is a rigid polyurethane shape memory foam block. It extends axially through occluding portion 1200 and forms radially expanding expansion portions at both ends of the axial direction of occluding portion 1200. In the freely expanding state, the diameter D2 of occluding portion 1200 is larger than the diameter of the expansion portion, with D2 ranging from 3 to 15 mm. The central portion of anchor 1100 that extends through occluding portion 1200 is cylindrical, with a diameter D3 that is 1 to 8 mm smaller than D2. Figure 8 As shown, after the embolic piece 1000 is released in the blood vessel, the sealing portion 1200 of the embolic piece 1000 expands and applies radial force to the blood vessel, and the hard polyurethane shape memory foam block serving as the anchor 1100 expands radially at the same time and applies radial force to the blood vessel. The sealing portion 1200 is softer than the anchor 1100, which reduces the squeezing damage to the blood vessel wall when the embolic piece 1000 is firmly fixed in the blood vessel.

[0043] When the anchoring member 1100 is a rigid polyurethane shape memory foam and the sealing part 1200 is a polyurethane shape memory foam, the polyurethane shape memory foam can be prepared as a degradable material, which can be degraded within a certain period of time after being implanted into the blood vessel, thereby avoiding complications such as thrombosis and venous stenosis caused by long-term retention.

[0044] The polyurethane shape memory foam used in the anchoring member 1100 and the occluding portion 1200 has an appropriate porosity, which enables it to have better pushability, reach the target position, and remain stably in the blood vessel for a long time.

[0045] In the present application, the preparation method of the polyurethane shape memory foam comprises:

[0046] Step 1, preparing a polyurethane acrylate prepolymer using a macromolecular polyol, a diisocyanate, a disulfide bond-containing chain extender, other small molecule chain extenders, and an acrylate end-capping agent;

[0047] Step 2: The polyurethane acrylate prepolymer, acrylate monomer diluent, foaming agent, foaming aid, and photoinitiator are uniformly mixed to form a foaming liquid, and the foaming liquid is sequentially photocured and foamed to obtain the polyurethane shape memory foam.

[0048] The foaming liquid in this application is a viscous liquid and cannot be foamed directly. It needs to be light-cured to give it a relatively fixed shape before foaming can be carried out. After light-curing, a solid is obtained, and then foaming can be carried out. During the heating and foaming process, the disulfide bonds undergo bond exchange reactions. On the one hand, this can eliminate the resistance to foam volume expansion, and on the other hand, it can relieve internal stress and prevent cracking of the polyurethane during expansion, thereby increasing the expansion multiple of the polyurethane shape memory foam.

[0049] In step 1, other small molecule chain extenders refer to chain extenders other than disulfide bond-containing chain extenders. The disulfide bond-containing chain extender itself is also a small molecule chain extender, but is described separately due to its special effect on polyurethane shape memory foam. In addition to the disulfide bond-containing chain extender, other small molecule chain extenders can also be used to participate in the reaction of step 1.

[0050] For peripheral arteriovenous fistulas, polyurethane shape memory foam can be delivered to the tortuous fistula through a catheter. When triggered by body temperature, its volume expands by more than 100 times, tightly fitting the vascular cavity (including fistulas with a diameter of 5-15mm). The radial pressure of the polyurethane shape memory foam during expansion is only <0.1N / mm 2 (The traditional metal embolizer is 3-5N / mm 2 ), especially suitable for fragile blood vessels or adjacent nerve areas; the open-loop-closed-loop hybrid porous structure (pore size 50-500μm) of polyurethane shape memory foam can form a high surface area-to-volume ratio (about 2000cm 2 / g), significantly slowing down blood flow and inducing thrombosis.

[0051] For peripheral veins, polyurethane shape memory foam has a filling rate of up to 98% for blood vessels with a diameter of more than 5mm, which is significantly higher than the 70%-85% of traditional sclerosants; polyurethane shape memory foam has no metal artifacts, and the CT / MRI images after surgery are clear, allowing real-time monitoring of the embolization effect; polyurethane shape memory foam completes shape recovery within 5-10 seconds at body temperature, and no complex energy control equipment is required during surgery, and the operating efficiency is 50% higher than radiofrequency ablation (single segment requires 20 seconds); polyurethane shape memory foam material can expand to a preset shape when triggered by body temperature (about 37°C), closely fitting the anatomy of tortuous veins, avoiding the problem of incomplete embolization caused by irregular blood vessel morphology by traditional metal coils or sclerosants; the low radial force of polyurethane shape memory foam will not compress the vein wall or adjacent nerves during expansion, avoiding the risk of saphenous nerve burns in radiofrequency / laser ablation; the speed of endothelialization after polyurethane shape memory foam embolization is faster than that of traditional materials, and there is no thermal damage or thrombophlebitis.

[0052] For peripheral arteries, the radial force of polyurethane shape memory foam is <0.1N / mm 2 Avoid damage to the blood vessel wall, especially suitable for tortuous iliac artery / gluteal artery aneurysms, and reduce the blood vessel perforation rate to 0.5%.

[0053] To indicate the position of the embolic device within the vessel, a contrast agent is incorporated into the polyurethane shape memory foam at any step during its preparation. This contrast agent, such as metal powders (tungsten and tantalum), is commonly used in interventional procedures. This contrast agent does not participate in the chemical reactions of the polyurethane shape memory foam. After preparation, the contrast agent is evenly distributed throughout the polyurethane shape memory foam, indicating its location and degradation. Polyurethane shape memory foam is inherently radiopaque, eliminating artifacts during surgery and enabling clear assessment of aneurysm cavity reduction and thrombosis postoperatively. Contrast agent can also be incorporated into rigid polyurethane shape memory foam at any step during its preparation.

[0054] The macromolecular polyol is at least one of polycaprolactone (PCL) diol, polyglycolic acid (PGA) diol, polyhydroxybutyrate (PHB) diol, and polylactic acid (PLA) diol. The macromolecular polyol has a number average molecular weight of 200 to 2000, preferably 500 to 1000.

[0055] Macromolecular polyols provide flexible chain segments for polyurethane, which affect the hardness, resilience and hydrolysis resistance of polyurethane shape memory foam.

[0056] The diisocyanate is at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), and L-lysine diisocyanate (LDI).

[0057] L-lysine diisocyanate is biodegradable, and its degradation product is lysine. The degradation product will not lower the pH value of nearby tissues, will not cause inflammation, and has the advantages of being friendly to the surface and cell interface, easy to connect biological reagents, and having little non-biological specific effects.

[0058] The diisocyanate provides -NCO groups, which react with -OH groups of the polyol to form urethane bonds (-NHCOO-). The diisocyanate not only affects the reactivity but also acts as a hard segment in the molecular chain to affect the final properties of the material.

[0059] The disulfide bond-containing chain extender is 2-hydroxyethyl disulfide, and the small molecule chain extender is at least one of 1,4-butanediol, ethylene glycol, and propylene glycol.

[0060] The chain extender (including disulfide bond-containing chain extenders and small molecule chain extenders) is used to regulate the molecular weight and soft and hard segment ratio of the polyurethane acrylate prepolymer, thereby adjusting the performance of the polyurethane. The disulfide bond in the chain extender also has an important influence on the performance of the polyurethane shape memory foam.

[0061] The molar ratio of the hydroxyl group (-OH) in the macromolecular polyol to the isocyanate group (-NCO) in the diisocyanate is 1:1.5-2.

[0062] The molar ratio between the hydroxyl groups provided by the macromolecular polyol and the isocyanate groups provided by the diisocyanate is 1:1.5-2. If the ratio is too small, the molecular weight and viscosity of the polyurethane acrylate prepolymer may be too large, which is not conducive to the subsequent steps.

[0063] The total mass of the macromolecular polyol and diisocyanate is A, and the amount of the disulfide bond-containing chain extender is 0.5% to 5% of A. The amount of the small molecule chain extender is 0% to 5% of A. More preferably, the amount of the small molecule chain extender is 0.1% to 5% of A.

[0064] In step 1, the total molar number of hydroxyl groups in the macromolecular polyol, chain extender (including disulfide bond-containing chain extender and small molecule chain extender), and acrylate end-capping agent is m, the total molar number of isocyanate groups in the diisocyanate is n, and 1≤m / n≤1.1.

[0065] In step 1, the macromolecular polyol and diisocyanate first undergo a first-stage chemical reaction, and then a chain extender is added to carry out a second-stage chemical reaction.

[0066] The reaction temperature of the first stage is 50-60° C., and the reaction time of the first stage is 3-5 hours.

[0067] The reaction temperature of the second stage is 70-80° C., and the reaction time of the second stage is 3-5 hours.

[0068] After the second stage of reaction is completed, a capping agent is used for capping. The acrylate capping agent is hydroxyethyl acrylate (HEA). On the one hand, the capping agent is used to introduce acrylate groups to facilitate the subsequent UV curing process. On the other hand, the capping agent is used to react with unreacted isocyanate groups. The amount of the capping agent is used to ensure that the OH:NCO ratio in the system is between 1 and 1.1:1, that is, the molar ratio of hydroxyl groups to isocyanate groups in the system is 1:1, or the hydroxyl groups are slightly excessive.

[0069] The specific end-capping reaction process is as follows: after the second stage reaction is completed, a capping agent is added and the reaction is carried out at 70 to 80° C. for 30 to 60 minutes to complete the end-capping.

[0070] The viscosity of the polyurethane acrylate prepolymer is 500 to 3000 cP (centipoise). More preferably, the viscosity of the polyurethane acrylate prepolymer is 800 to 2000 cP (centipoise).

[0071] In step 2, a PLGA-PEG copolymer is added. PLGA-PEG can load drugs. After the drugs are loaded by PLGA-PEG, they are dispersed in the polyurethane shape memory foam. PLGA-PEG and the polyurethane shape memory foam form two phases. After being implanted in the target position, the drugs loaded by PLGA-PEG can be slowly released.

[0072] The molar ratio of PLGA to PEG in the PLGA-PEG is 8:2. PLGA-PEG is an amphiphilic block copolymer whose core structure is composed of hydrophobic PLGA segments and hydrophilic PEG segments covalently linked. The PLGA segments (hydrophobic core) are copolymerized from lactic acid (LA) and glycolic acid (GA) in an adjustable molar ratio, with common LA:GA ratios of 50:50 or 75:25. PLGA provides mechanical strength, biodegradability, and drug loading capacity, while degradation products (lactic acid / glycolic acid) can be metabolized by the body. The PEG segments are hydrophilic polyether chains that coat the surface of the PLGA core. PEG enhances water solubility, reduces immunogenicity, prolongs circulation time (escaping clearance through the reticuloendothelial system), and stabilizes the nanoparticles through steric hindrance. PLGA enhances drug loading and release capacity, while PEG optimizes hydrophilicity and stability, balancing drug loading efficiency with the need for long-term circulation. The molecular weight of PLGA is 5000-40000 Da, and the molecular weight of PEG is 1000-5000 Da.

[0073] The acrylate monomer diluent is one or more of small molecule acrylate monomers such as isooctyl acrylate (CAS: 29590-42-9), lauryl acrylate (CAS: 2156-97-0), lauryl methacrylate (CAS: 142-90-5), and isobornyl methacrylate (CAS: 7534-94-3), and the acrylate monomer diluent participates in the photocuring reaction.

[0074] The foaming agent is hydrazine benzenesulfonate or hydrazine p-toluenesulfonate. The decomposition temperature of hydrazine benzenesulfonate, that is, the foaming temperature, is 90-100° C., which is relatively low. This type of foaming agent can be used alone.

[0075] The foaming agent is azodicarbonamide, which has a high foaming temperature and needs to be used in conjunction with a foaming aid to reduce the foaming temperature to 150-160°C. The foaming aid can be zinc oxide and its derivatives, zinc stearate, zinc acetate, etc.

[0076] Using a large amount of foaming agent or foaming aid can increase the foaming speed and porosity, but the foaming speed should not be too high. It should be compatible with the expansion multiple of the polyurethane foam and the exchange rate of disulfide bonds. Too high a foaming speed can easily cause the resin to crack, and too low a foaming agent or foaming aid cannot achieve a higher expansion multiple.

[0077] The photoinitiator is diphenyl-(2,4,6-trimethylbenzoyl)phosphine oxide (ie, photoinitiator TPO) or bis(2,4,6-trimethylbenzoyl)phenylphosphine oxide (ie, photoinitiator 819).

[0078] The mass ratio of the polyurethane acrylate prepolymer to PLGA-PEG is 1:1-0.1.

[0079] The amount of the acrylic acid ester monomer diluent is 5% to 15% of the weight of the polyurethane acrylic acid ester prepolymer. The amount of the foaming agent is 1% to 10% of the weight of the polyurethane acrylic acid ester prepolymer.

[0080] The amount of the foaming auxiliary agent is 0% to 2% of the polyurethane acrylate prepolymer.

[0081] The dosage of the foaming auxiliary agent is 0.1% to 2% of the polyurethane acrylate prepolymer.

[0082] The amount of the photoinitiator used is 0.2% to 2% of the polyurethane acrylate prepolymer.

[0083] The foaming liquid is light-cured in the mold, the wavelength of the light source is 365nm to 405nm, the light curing time is 1 to 5 minutes, and the radiation power density of the light source is 10 to 20mW / cm 2 .

[0084] After light curing molding, foaming is carried out at 90-160°C for 10-30 minutes.

[0085] Benzenesulfonic acid hydrazine or p-toluenesulfonic acid hydrazine is used as a foaming agent, and foaming is carried out at 90-100° C. after light curing molding, and the foaming time is 10-30 minutes.

[0086] Azodicarbonamide is used as a foaming agent, and foaming is carried out at 150-160° C. after light curing molding, and the foaming time is 10-30 minutes.

[0087] The expansion rate of the rigid polyurethane shape memory foam used in the anchoring part is smaller than that of the polyurethane shape memory foam used as the sealing part. The expansion rate can be controlled by adjusting the amount of raw materials of the polyurethane memory foam, for example, reducing the amount of foaming agent.

[0088] The method further includes step 3, wherein the surface of the polyurethane shape memory foam is modified by using protamine, and the specific operation is as follows:

[0089] The polyurethane shape memory foam was immersed in a PBS solution of protamine for 30 to 60 minutes, and then washed with PBS to remove unabsorbed protamine and dried.

[0090] Protamine can improve the biocompatibility of polyurethane shape memory foam, wherein the pH of the protamine PBS solution is 7.4 and the concentration of the protamine is 0.1-0.5 mg / mL. The polyurethane shape memory foam is immersed in the protamine PBS solution at room temperature.

[0091] Example 1

[0092] A method for preparing polyurethane shape memory foam comprises the following steps:

[0093] (1) 0.1 mol, 200 g of polycaprolactone diol (Mn = 2000) and 0.2 mol, 31.64 g of 1,6-hexamethylene diisocyanate (HDI) were mixed uniformly, reacted at 50°C for 5 hours, 0.02 mol, 3.085 g of 2-hydroxyethyl disulfide were added and mixed uniformly, and then the temperature was raised to 70°C for reaction for 4 hours. 0.168 mol, 19.51 g of β-hydroxyethyl acrylate (HEA) (capping agent) was added and the reaction was continued at 70°C for 30 minutes to obtain a polyurethane acrylate prepolymer. The viscosity of the polyurethane acrylate prepolymer was 2600 cP.

[0094] (2) 100 g of polyurethane acrylate prepolymer, 15 g of isooctyl acrylate, 4 g of azodicarbonamide (foaming agent), 0.1 g of zinc oxide (foaming aid), and 0.5 g of diphenyl-(2,4,6-trimethylbenzoyl)phosphine oxide (photoinitiator TPO) were mixed evenly using a dispersion plate and used as a foaming liquid. The foaming liquid was injected into the mold for light curing. The wavelength of the light source for light curing was 365 nm, the light curing time was 3 minutes, and the radiation power density of the light source was 15 mW / cm 2 After light curing molding, the polyurethane shape memory foam was obtained by foaming at 150°C for 10 minutes.

[0095] Examples 2 to 6

[0096] The types of raw materials used in Examples 2 to 6 and Comparative Examples 1 to 2 are shown in Tables 1 and 2, the amounts of raw materials used are shown in Tables 3 and 4, and the reaction conditions are shown in Table 5. For matters not listed in the tables, the same raw materials and reaction conditions as in Example 1 were used.

[0097] Table 1

[0098]

[0099]

[0100] In Table 1, PCL-Diol is polycaprolactone diol (such as CAPA 2200A), PGA-Diol is polyglycolic acid diol (such as PGA-diol 2000), PHB-Diol is polyhydroxybutyrate diol (such as: PHB-diol1000M), PLA-Diol is polylactic acid diol (such as: PLD 2000).

[0101] Table 2

[0102]

[0103] Table 3

[0104]

[0105]

[0106] In Table 3, the dosage of the same substance is expressed in both mol and g. For example, the dosage of the macromolecular polyol in Example 2 is 0.1 mol, which is also 100 g.

[0107] Table 4

[0108]

[0109] In Table 4, the amounts of acrylate monomer diluent, foaming agent, foaming aid, and photoinitiator are based on 100 g of polyurethane acrylate prepolymer. For example, for Example 2, 12 g of acrylate monomer diluent, 7 g of foaming agent, 0.15 g of foaming aid, and 0.2 g of photoinitiator are used per 100 g of polyurethane acrylate prepolymer.

[0110] Table 5

[0111]

[0112]

[0113] Example 7

[0114] A method for preparing polyurethane shape memory foam comprises the following steps:

[0115] (1) 0.1 mol, 180 g of PHB-diol (Mn = 1800) and 0.2 mol, 31.64 g of 1,6-hexamethylene diisocyanate (HDI) were mixed uniformly and reacted at 60°C for 5 hours. 0.02 mol, 3.085 g of 2-hydroxyethyl disulfide and 0.02 mol, 1.522 g of propylene glycol were added and mixed uniformly. The mixture was heated to 80°C and reacted for 3 hours. 0.12 mol, 13.93 g of β-hydroxyethyl acrylate (HEA) was added and the mixture was continued to react at 80°C for 30 minutes to obtain a polyurethane acrylate prepolymer having a viscosity of 3500 cP.

[0116] (2) 100 g of polyurethane acrylate prepolymer, 10 g of isooctyl acrylate, 5 g of azodicarbonamide (foaming agent), 0.15 g of zinc oxide (foaming aid), and 1 g of photoinitiator 819 were mixed evenly using a dispersion plate and used as a foaming liquid. The foaming liquid was injected into the mold for light curing. The wavelength of the light source for light curing was 365 nm, the light curing time was 3 minutes, and the radiation power density of the light source was 15 mW / cm 2 After light curing molding, the polyurethane shape memory foam was obtained by foaming at 150°C for 15 minutes.

[0117] (3) The polyurethane shape memory foam was immersed in a PBS solution of protamine (pH 7.4, concentration 0.1 mg / mL) for 30 minutes, then washed with PBS to remove unabsorbed protamine and dried.

[0118] Example 8

[0119] A method for preparing rigid polyurethane shape memory foam comprises the following steps:

[0120] (1) 0.1 mol, 100 g of PCL-diol (Mn=830) and 0.2 mol, 42.05 g of TMHDI were mixed uniformly and reacted at 60°C for 4 hours. 0.005 mol, 0.77 g of 2-hydroxyethyl disulfide was added and mixed uniformly. The mixture was heated to 80°C and reacted for 4 hours. 0.20 mol, 23.22 g of β-hydroxyethyl acrylate (HEA) was added and the mixture was reacted at 80°C for 30 minutes to obtain a polyurethane acrylate prepolymer having a viscosity of 1500 cP.

[0121] (2) 100 g of polyurethane acrylate prepolymer, 15 g of lauryl methacrylate, 6 g of benzenesulfonic acid hydrazine (foaming agent), and 1.5 g of photoinitiator 819 were mixed evenly using a dispersion plate and used as a foaming liquid. The foaming liquid was injected into the mold for light curing. The wavelength of the light source for light curing was 365 nm, the light curing time was 5 minutes, and the radiation power density of the light source was 10 mW / cm 2 After light curing molding, the polyurethane shape memory foam was obtained by foaming at 100°C for 15 minutes.

[0122] (3) The polyurethane shape memory foam was immersed in a PBS solution of protamine (pH 7.4, concentration 0.1 mg / mL) for 30 minutes, then washed with PBS to remove unabsorbed protamine and dried.

[0123] Performance Characterization

[0124] The polyurethane shape memory foam prepared in each example was characterized, and the characterization results are shown in Table 4.

[0125] Table 4

[0126]

[0127]

[0128] The characterization of degradation time includes the following steps:

[0129] (1) Solution preparation

[0130] The steps for preparing a 20% H₂O₂ solution containing CoCl₂ are as follows: First, weigh 7.77 g of CoCl₂ into a beaker and dissolve it in 400 mL of distilled water. Next, dilute 400 mL of a 50% H₂O₂ aqueous solution with 200 mL of distilled water and add this to the CoCl₂ solution. Keep the H₂O₂ solution cold before dilution and addition. Allow the solution to stand for 10 minutes to reach room temperature before use.

[0131] (2) Sample preparation

[0132] The polyurethane shape memory foam prepared in the example was used to prepare cylindrical samples (with a diameter of 10 mm), and the samples were cut into 20 mm lengths. The mass of each sample was then recorded, and each sample was marked and sealed for storage.

[0133] (3) Degradation test steps

[0134] Completely immerse the polyurethane shape memory foam sample in a sealed container containing 30 mL of a 20% H2O2 solution containing CoCl2. Place the container in a 37°C oven. Change the solution every three days and remove the sample for cleaning, drying, and weighing. After weighing and drying, place it back in a sealed container with a new solution. Repeat this cycle until the sample disappears and finally record the degradation time.

[0135] The polyurethane foam prepared in Comparative Example 1 cracked during foaming. Comparative Example 1 did not contain a disulfide bond-containing chain extender or other small molecule chain extenders, and the prepolymer was not chain extended. After UV curing, the crosslinking density was too high and the Tg was also high, resulting in stress concentration during the foaming process, which was difficult to dissipate and caused the foam material to crack.

[0136] In the system of Comparative Example 2, the ratio of NCO:OH (hydroxyl groups are derived from macromolecular polyols, chain extenders, and acrylate end-capping agents) is too low, resulting in excessive viscosity of the prepolymer, uneven stirring and uneven heat dissipation during the preparation process, and affecting the uniformity of the reaction; at the same time, due to the excessive viscosity, it is difficult to discharge bubbles, the Tg of the obtained polyurethane foam is low, the supporting force of the pore wall is weakened, and the mechanical properties of the foam are easily deteriorated.

[0137] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0138] The above-described embodiments merely represent several implementation methods of the present application. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art could make various modifications and improvements without departing from the spirit of the present application, all of which fall within the scope of protection of the present application. Therefore, the scope of protection of the present patent application shall be determined by the appended claims.

Claims

1. An embolic device for peripheral arteries and veins, characterized in that: The embolic member includes an anchor and a blocking portion fixedly connected to the anchor. The blocking portion is made of polyurethane shape memory foam. The polyurethane shape memory foam has an expansion rate of 50 to 100 times. The preparation method of the polyurethane shape memory foam includes: Step 1, preparing a polyurethane acrylate prepolymer using a macromolecular polyol, a diisocyanate, a disulfide bond-containing chain extender, other small molecule chain extenders, and an acrylate end-capping agent; Step 2: The polyurethane acrylate prepolymer, acrylate monomer diluent, foaming agent, foaming aid, and photoinitiator are uniformly mixed to form a foaming liquid, and the foaming liquid is sequentially photocured and foamed to obtain the polyurethane shape memory foam.

2. The embolic device for peripheral arteries and veins according to claim 1, characterized in that: The macromolecular polyol is at least one of polycaprolactone diol, polyglycolic acid diol, polyhydroxybutyrate diol, and polylactic acid diol; the diisocyanate is at least one of 1,6-hexamethylene diisocyanate, trimethyl hexamethylene diisocyanate, and L-lysine diisocyanate.

3. The embolic device for peripheral arteries and veins according to claim 1, characterized in that: The molar ratio of the hydroxyl group in the macromolecular polyol to the isocyanate group in the diisocyanate is 1:1.5-2.

4. The embolic device for peripheral arteries and veins according to claim 1, characterized in that: The total mass of the macromolecular polyol and the diisocyanate is A, the amount of the disulfide bond-containing chain extender is 0.5% to 5% of A, and the amount of the small molecule chain extender is 0 to 5% of A.

5. The embolic device for peripheral arteries and veins according to claim 1, characterized in that: In step 1, the macromolecular polyol and diisocyanate first undergo a first-stage chemical reaction, and then a chain extender is added to carry out a second-stage chemical reaction; The reaction temperature of the first stage is 50-60°C, and the reaction time of the first stage is 3-5 hours; The reaction temperature of the second stage is 70-80° C., and the reaction time of the second stage is 3-5 hours.

6. The embolic device for peripheral arteries and veins according to claim 1, characterized in that: In step 1, the disulfide bond-containing chain extender is 2-hydroxyethyl disulfide, and the small molecule chain extender is at least one of 1,4-butanediol, ethylene glycol, and propylene glycol. In step 2, the acrylate monomer diluent is at least one of isooctyl acrylate, lauryl acrylate, lauryl methacrylate, and isobornyl methacrylate.

7. The embolic device for peripheral arteries and veins according to claim 1, characterized in that: The anchoring member is made of a metal member, or the anchoring member is made of a hard polyurethane shape memory foam, and the expansion rate of the hard polyurethane shape memory foam is smaller than that of the polyurethane shape memory foam used as the blocking part.

8. The embolic device for peripheral arteries and veins according to claim 1, characterized in that: The developer is added in any step of preparing the rigid polyurethane shape memory foam.

9. The embolic device for peripheral arteries and veins according to claim 1, characterized in that: The blocking portion is cylindrical, the anchor is an expansion claw connected to at least one axial end of the blocking portion, or the anchor is a hard polyurethane shape memory foam block connected to at least one axial end of the blocking portion.

10. The embolic device for peripheral arteries and veins according to claim 1, characterized in that: The anchoring member is a hard polyurethane shape memory foam block, which runs through the axial direction of the blocking portion and forms radially expanding expansion portions at both axial ends of the blocking portion.

Images