Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a developing biodegradable medical polyurethane foam and a preparation method thereof, so as to solve the problem of poor performance of an embolic material in the prior art.
The technical scheme for solving the technical problems is as follows: a developing biodegradable medical polyurethane foam and a preparation method thereof are provided, and the developing biodegradable medical polyurethane foam comprises the following steps:
(1) Uniformly mixing a developing material and isocyanate, adding polyol and a catalyst, uniformly stirring, adding a dispersing agent and water, and stirring to form a stable suspension system;
(2) Polymerizing the suspension system obtained in the step (1) for the first time, polymerizing for the second time, cooling, centrifuging, cleaning and drying to obtain the developing polyurethane microsphere;
(3) Mixing the developed polyurethane microsphere prepared in the step (2), isocyanate and part of polyol, stirring for prepolymerization, then adding the rest of polyol, catalyst, silicone oil, foaming agent and water, and performing polymerization foaming and heat treatment on the obtained mixture to obtain an intermediate;
(4) And (3) soaking the intermediate obtained in the step (3) by adopting a pore-forming agent to perform pore-forming, and then cleaning and drying to obtain the developing biodegradable medical polyurethane foam.
Based on the technical scheme, the invention can also be improved as follows:
Further, in the step (1), the mass ratio of the developing material, isocyanate, polyol, catalyst, dispersant and water is 1-30:5-70:5-70:0.1-5:0.2-2:100.
The beneficial effects of adopting the further technical scheme are as follows: the proportion can form stable cross-linked polyurethane microspheres containing developing materials, and the developing strength can be regulated and controlled by changing the proportion.
Further, in the step (1), the mass ratio of the developing material, isocyanate, polyol, catalyst, dispersant and water is 8:55:27:1.8:1.5:100.
Further, in the step (1), the developing material is tantalum nano particles, bismuth subcarbonate, bismuth oxychloride, bismuth oxide, barium sulfate or tungsten.
Further, in the step (1), the isocyanate is at least one of hexamethylene diisocyanate, trimethylhexamethylene diisocyanate, isophorone diisocyanate, hydrogenated xylylene diisocyanate, lysine ethyl ester diisocyanate, toluene diisocyanate, and methylene diphenyl diisocyanate.
Further, in the step (1), the polyol is at least one of polycaprolactone diol, polylactic acid diol, polyglycolic acid diol, polycaprolactone triol, polylactic acid triol, polyglycolic acid triol, polycaprolactone tetrol, polylactic acid tetrol, polyglycolic acid tetrol, polycarbonate diol, polyethylene glycol, polytetrahydrofuran diol, polyhexamethylene ether diol, butanediol, propylene glycol, triethanolamine, hydroxypropyl ethylenediamine, glycerol, pentaerythritol, trimethylolethane, and tris (hydroxymethyl) aminomethane.
Further, in step (1), the catalyst is an organometallic catalyst.
Further, in the step (1), the catalyst is an organotin-based catalyst or an organobismuth-based catalyst.
Further, the organotin-based catalyst is at least one of stannous octoate, dibutyltin dilaurate, dibutyltin diacetate and dibutyltin dilauryl sulfide.
Further, the organobismuth catalyst is at least one of bismuth laurate, bismuth isooctanoate and bismuth neodecanoate.
Further, in the step (1), the dispersing agent is at least one of cellulose, polyvinylpyrrolidone, polyvinyl alcohol and hydroxyl modified cellulose.
Further, in the step (1), the stirring speed at the time of forming a stable suspension is 500 to 2000rpm.
Further, in the step (2), the polymerization is carried out for 2.5 to 3.5 hours at the temperature of 40 to 60 ℃ to finish the first polymerization process.
Further, in the step (2), the polymerization is carried out at 50 ℃ for 3 hours, thereby completing the first polymerization process.
Further, in the step (2), the polymerization is carried out for 7 to 9 hours at the temperature of 75 to 85 ℃ to finish the second polymerization process.
Further, in the step (2), the polymerization is carried out at 80 ℃ for 8 hours, and the second polymerization process is completed.
Further, in step (2), centrifugation and washing are repeated, and then drying is performed.
Further, in the step (3), the mass ratio of the developing polyurethane microsphere to the isocyanate to the polyol to the catalyst to the silicone oil to the foaming agent to the water is 1-30:30-80:10-80:0.1-5:1-15:0.1-15:0.5-5.
Further, in the step (3), the mass ratio of the developing polyurethane microsphere to the isocyanate to the polyol to the catalyst to the silicone oil to the foaming agent to the water is 10:40:42:1.3:4.1:0.3:2.3.
Further, in the step (3), the mass ratio of the partial polyol to the remaining polyol is 70:30.
Further, in the step (3), the isocyanate is at least one of hexamethylene diisocyanate, trimethylhexamethylene diisocyanate, isophorone diisocyanate, hydrogenated xylylene diisocyanate, lysine ethyl ester diisocyanate, toluene diisocyanate, and methylene diphenyl diisocyanate.
Further, in the step (3), the polyol is at least one of polycaprolactone diol, polylactic acid diol, polyglycolic acid diol, polycaprolactone triol, polylactic acid triol, polyglycolic acid triol, polycaprolactone tetrol, polylactic acid tetrol, polyglycolic acid tetrol, polycarbonate diol, polyethylene glycol, polytetrahydrofuran diol, polyhexamethylene ether diol, butanediol, propylene glycol, triethanolamine, hydroxypropyl ethylenediamine, glycerol, pentaerythritol, trimethylolethane, and tris (hydroxymethyl) aminomethane.
Further, in step (3), the catalyst is an organometallic catalyst.
Further, in the step (3), the catalyst is an organotin-based catalyst or an organobismuth-based catalyst.
Further, the organotin-based catalyst is at least one of stannous octoate, dibutyltin dilaurate, dibutyltin diacetate and dibutyltin dilauryl sulfide.
Further, the organobismuth catalyst is at least one of bismuth laurate, bismuth isooctanoate and bismuth neodecanoate.
Further, in the step (3), the foaming agent is at least one of dichloromethane, chloroform and acetone.
Further, in the step (3), the mixture was stirred for 24 hours to perform the prepolymerization.
Further, in the step (3), the mixture is stirred for 22 to 26 hours to perform the prepolymerization.
Further, in the step (3), the polymerization foaming is carried out for 7.5 to 8.5 hours and the heat treatment is carried out for 1.8 to 2.2 days at the temperature of 75 to 85 ℃.
Further, in the step (3), the foaming was performed for 8 hours at 80℃and the heat treatment was performed for 2 days.
Further, in the step (4), the volume ratio of the pore-forming agent is 1:4-6:3-5 of sodium hydroxide, isopropanol and water.
Further, in the step (4), the volume ratio of the pore-forming agent is 1:5:4, a mixture of sodium hydroxide, isopropanol and water.
Further, in the step (4), the extrusion soaking is carried out for 4-6min, and the hole making process is completed.
Further, in the step (4), the mixture is extruded and soaked for 5min.
The invention also provides a developing biodegradable medical polyurethane foam which is prepared by adopting the method.
The invention also provides application of the developing biodegradable medical polyurethane foam in preparation of vascular embolic materials.
The invention has the following beneficial effects:
1. According to the invention, the developer and polyurethane are firstly prepared into polyurethane developing microspheres with a core-shell structure, and then the microspheres are added into polyurethane prepolymer to prepare the polyurethane foam material with the developing function through co-foaming. The foam material can develop and track in minimally invasive intervention so as to confirm whether the material reaches a target position, can quickly form thrombus to complete a plugging effect after implantation, can continuously develop and reflect the real state and the plugging effect of the material, simultaneously facilitates the review of prognosis, is degraded by a body and is non-toxic and metabolized later, achieves the purposes of confirmation in operation, tracking after operation and prognosis diagnosis, and is suitable for plugging filling materials of cardiovascular diseases.
2. According to the invention, the inorganic particles are coated by the polymer microspheres and the in-situ blending mode are utilized, so that the influence of the inorganic particles on polyurethane foaming, including density, pore diameter and porosity, is effectively avoided by a two-step method, and the influence on the self-expansion performance of the foam is reduced to the greatest extent.
3. The method of the present invention is equally applicable to other examples using polymeric materials as implants instead of metals, and the developer may be replaced depending on the implantation site and purpose.
Detailed Description
The principles and features of the present invention are described below with reference to the drawings, the examples are illustrated for the purpose of illustrating the invention and are not to be construed as limiting the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1:
a developing biodegradable medical polyurethane foam, the preparation method comprises the following steps:
(1) Uniformly mixing a developing material (tantalum nano particles) and isocyanate (hexamethylene diisocyanate), then adding polyalcohol (lactic acid triol and triethanolamine with the mass ratio of 25:2) and a catalyst (stannous octoate), uniformly stirring, and then adding a dispersing agent (cellulose) and water, and stirring at a high speed of 1000rpm to form a stable suspension system;
wherein the mass ratio of the developing material, isocyanate, polyol, catalyst, dispersant and water is 8:55:27:1.8:1.5:100;
(2) Polymerizing the suspension system obtained in the step (1) for 3 hours at 50 ℃ for the first time, polymerizing for 8 hours at 80 ℃ for the second time, cooling, centrifuging to obtain a solid phase by solid-phase separation, cleaning, repeating centrifuging and cleaning, and vacuum drying the obtained solid phase to obtain the developing polyurethane microsphere;
(3) Mixing the developed polyurethane microsphere prepared in the step (2), isocyanate (hexamethylene diisocyanate) and part of polyol (lactic acid triol and triethanolamine with the mass ratio of 40:2), stirring for 24 hours for pre-polymerization, then rapidly adding the rest polyol (the mass ratio of part of polyol to rest polyol is 70:30), catalyst (bismuth laurate), silicone oil, foaming agent (methylene dichloride) and water, mixing, transferring to an 80 ℃ oven for polymerization foaming for 8 hours, and continuously performing heat treatment for 2 days to obtain an intermediate;
Wherein the mass ratio of the developing polyurethane microsphere to the isocyanate to the polyol to the catalyst to the silicone oil to the foaming agent to the water is 10:40:42:1.3:4.1:0.3:2.3;
(4) And (3) extruding and soaking the intermediate obtained in the step (3) for 5min by adopting a pore-forming agent (a mixture of sodium hydroxide, isopropanol and water in a volume ratio of 1:5:4) to perform pore-forming, and then cleaning by adopting water, isopropanol and deionized water in sequence, and drying to obtain the developing biodegradable medical polyurethane foam.
Example 2:
a developing biodegradable medical polyurethane foam, the preparation method comprises the following steps:
(1) Uniformly mixing a developing material (bismuth subcarbonate) and isocyanate (trimethyl hexamethylene diisocyanate), then adding a polyol (polycaprolactone diol) and a catalyst (bismuth neodecanoate), uniformly stirring, then adding a dispersing agent (cellulose) and water, and stirring at a high speed of 500rpm to form a stable suspension system;
Wherein the mass ratio of the developing material, isocyanate, polyol, catalyst, dispersant and water is 1:5:5:0.1:0.2:100;
(2) Polymerizing the suspension system obtained in the step (1) for 2.5 hours at 60 ℃ for the first time, polymerizing for 7 hours at 85 ℃ for the second time, cooling, centrifuging to obtain a solid phase by solid-phase separation, cleaning, repeating centrifuging and cleaning, and vacuum drying the obtained solid phase to obtain the developing polyurethane microsphere;
(3) Mixing the developed polyurethane microsphere prepared in the step (2), isocyanate (trimethyl hexamethylene diisocyanate) and part of polyol (polycaprolactone diol), stirring for 22 hours for prepolymerization, then rapidly adding the rest polyol (the mass ratio of the part polyol to the rest polyol is 70:30), catalyst (dibutyl tin dilaurate) silicone oil, foaming agent (methylene dichloride) and water, mixing, transferring to a 75 ℃ oven for polymerization foaming for 8.5 hours, and continuously performing heat treatment for 2.2 days to obtain an intermediate;
Wherein, the mass ratio of the developing polyurethane microsphere to the isocyanate to the polyol to the catalyst to the silicone oil to the foaming agent to the water is 1:30:10:0.1:1:0.1:0.5;
(4) And (3) extruding and soaking the intermediate obtained in the step (3) for 4min by adopting a pore-forming agent (a mixture of sodium hydroxide, isopropanol and water in a volume ratio of 1:4:3) to perform pore-forming, and then cleaning by adopting water, isopropanol and deionized water in sequence, and drying to obtain the developing biodegradable medical polyurethane foam.
Example 3:
a developing biodegradable medical polyurethane foam, the preparation method comprises the following steps:
(1) Uniformly mixing a developing material (bismuth oxychloride) and isocyanate (methylene diphenyl diisocyanate), then adding a polyol (polyethylene glycol) and a catalyst (dibutyltin dilaurate), uniformly stirring, then adding a dispersing agent (cellulose) and water, and stirring at a high speed of 2000rpm to form a stable suspension system;
Wherein the mass ratio of the developing material, isocyanate, polyol, catalyst, dispersant and water is 30:70:70:5:2:100;
(2) Polymerizing the suspension system obtained in the step (1) for 3 hours at 50 ℃ for the first time, polymerizing for 8 hours at 80 ℃ for the second time, cooling, centrifuging to obtain a solid phase by solid-phase separation, cleaning, repeating centrifuging and cleaning, and vacuum drying the obtained solid phase to obtain the developing polyurethane microsphere;
(3) Mixing the developed polyurethane microsphere prepared in the step (2), isocyanate (methylene diphenyl diisocyanate) and part of polyol (polyethylene glycol), stirring for 26 hours for prepolymerization, then rapidly adding the rest of polyol (the mass ratio of part of polyol to rest of polyol is 70:30), catalyst (dibutyltin diacetate) silicone oil, foaming agent (methylene dichloride) and water, mixing, transferring to an oven at 85 ℃ for polymerization foaming for 7.5 hours, and continuously performing heat treatment for 1.8 days to obtain an intermediate;
wherein, the mass ratio of the developing polyurethane microsphere to the isocyanate to the polyol to the catalyst to the silicone oil to the foaming agent to the water is 30:80:80:5:15:15:5, a step of;
(4) And (3) extruding and soaking the intermediate obtained in the step (3) for 6min by adopting a pore-forming agent (a mixture of sodium hydroxide, isopropanol and water in a volume ratio of 1:6:5) to perform pore-forming, and then cleaning by adopting water, isopropanol and deionized water in sequence, and drying to obtain the developing biodegradable medical polyurethane foam.
Comparative example 1:
A non-developable biodegradable medical polyurethane foam, the preparation method comprising the steps of:
The steps (1) - (2) are not included, and the developing microsphere is not added in the step (3), and the rest is the same as in the example 1.
Comparative example 2:
a developing biodegradable medical polyurethane foam, the preparation method comprises the following steps:
The development material was directly added to step (3) without steps (1) - (2), and foam preparation was performed, with the remainder being the same as in example 1.
Test examples
1. ETM tests were performed on the polyurethane foams of example 1 and comparative examples 1-2, and the results are shown in FIGS. 1-3.
As can be seen from fig. 1 to 3, the polyurethane foam added with the developing microspheres of the present invention is substantially identical in pore size and distribution to the undeveloped polyurethane foam of comparative example 1, whereas the polyurethane foam directly added with the inorganic particles of comparative example 2 is uneven in pore size distribution and significantly reduced in pore size.
2. The polyurethane foam prepared in example 1 was subjected to development detection under X-ray, and the specific detection method was Micro-CT. The results are shown in FIG. 4.
As can be seen from fig. 4, the polyurethane foam of the present application has X-ray visibility.
3. The performance of the polyurethane foams of example 1 and comparative examples 1-2 was examined, and the results are shown in Table 1.
TABLE 1 Performance parameters
As can be seen from Table 1, after the developing microsphere is added, compared with the undeveloped foam prepared by the one-step method of comparative example 1, the pore diameter and the mechanical property of the foam are not greatly different, which indicates that the developing microsphere of the invention does not obviously cause the loss of the foam property; in comparative example 2, the foaming process is affected by directly adding an inorganic developing material, so that the foam pore size distribution is seriously uneven, the foam density and the mechanics are obviously affected, and the application of the foam is limited.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.