CN101444647A - Polylactic acid membrane of surface-modified with microcapsule carrying hamocura and preparation method thereof - Google Patents
Polylactic acid membrane of surface-modified with microcapsule carrying hamocura and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a polylactic acid membrane of surface-modified with microcapsule carrying hamocura and a preparation method thereof, belonging to the field of biomaterial. The polylactic acid membrane consists of a polylactic acid membrane connected by a covalent bond and a microcapsule carrying hamocura, wherein, the microcapsule carrying hamocura is a three-membrane microcapsule which takes calcium alginate as a template and is provided the structure of poly-allylamine/hamocura/poly-allylamine. In the invention, the three-membrane microcapsule which is provided with the structure of poly-allylamine/hamocura/poly-allylamine and is prepared by employing the electrostatic layer-by-layer self-assembly technology reacts with the polylactic acid membrane after EDC/NHS to obtain the target product. The polylactic acid membrane of the invention is non-toxic and degradable, has good biocompatibility, nice mechanical property and stable and long-acting anticoagulation performance, can be stored and transported in the dry environment and widely used as anticoagulation material and drug release control material.
Description
Technical field
The present invention relates to a kind of utilization and carry polylactic acid membrane and the preparation method that the heparin surface of microcapsule is modified, belong to technical field of biological material.
Background technology
By surface modification to medical macromolecular materials, can improve blood compatibility on the one hand, also can keep its original good physical mechanical performance on the other hand.The method of material surface modifying comprises: (1) absorption or coating, technology is simple and effective but modified surface can not long-acting stable existence.(2) plasma, glow discharge and corona discharge technology are widely used but the surface grafting heterogeneity, and technology is difficult to amplify.(3) surface grafting polymerization can be fixed on material surface with specific functional group, has long-lasting.(4) surface molecular self assembly, molecule is spontaneous firmly to be adsorbed on a kind of ordered molecular assembly that the surface of solids forms by chemical bond.The method of these surface modifications can comprehensively be divided into covalency and non-covalent modification.Wherein, covalent modified is stable best, more can prolong life-span of bioactive molecule in field of medical materials, prevents metabolism and continuous activity.Therefore, utilize covalently bound biological components that macromolecule is carried out the research focus that modification becomes polymeric material field in recent years.
In the research of anticoagulant material, surface heparinization is direct and efficient ways.In human body, the cell that endotheliocyte etc. contact with blood can be secreted materials such as heparin sulfate or heparin, keeps blood not solidify in the circulation process.The viscous polysaccharide that heparin is made up of sulphuric acid D-glucamine and D-glucuronic acid need measure denier as the target anticoagulation medicine, and content is few among the human normal plasma, only 0.09mg/L.Its blood coagulation resisting function is mainly brought into play anticoagulation by Antithrombin III and Antithrombin II, activatory protein inhibitor, and wherein AT III accounts for 80%.
The anticoagulation function that utilizes heparin to improve medical macromolecular materials has had the history of decades, numerous experiments and clinical effectiveness have been affirmed the positive role of heparin to raising material anticoagulation function already, and result of study in recent years shows that heparin can reduce macromolecular material and get involved caused bacterial infection.Heparin can combine with medical macromolecular materials by the method for physics or chemistry.Physical method has simply, effective advantage, but effect duration is short.Physical method mainly contains physical blending (comprise surperficial blend and, homogeneous phase blend) and physical absorption (coating).Consider that from the effect of utilizing of heparin physical method is not ideal enough.Chemical method is by chemical bond heparin to be fixed on the material, heparin utilization rate height, and long-term effect is better.If directly heparin is fixed on material surface, can influence the activity of heparin.Generally be to adopt to connect spacerarm at material surface earlier, again heparin be fixed on the spacerarm.At present anticoagulation medicine mainly contains heparin, hirudin, Coumarins, and Antithrombin III, urokinase etc., and the method for chemical graft is destroyed the biological activity of medicine easily because harsh reaction condition.Therefore, demand developing a kind of method urgently, not only can keep the anticoagulant microbic activity and can make material have the anticoagulation function of slow release long-acting.
Microcapsule is the widely used method of medicine controlled releasing; and microcapsule can be encapsulated in bioactive substances such as enzyme, protein and hormone in the selection permeability film; form " bio-microcapsule ", also play a very good protection in the time of to the bioactive molecule controlled release.Polymer dielectric by two or more oppositely charged condenses on template core and forms, the microcapsule technology of i.e. self assembly layer by layer (layer-by-layer self-assembly), self-assembly method preparation condition gentleness layer by layer, microcapsule size, thickness and release are adjustable, and microcapsule structure and performance are various.
Polylactic acid is the degradable polymer material that second class can be used for human body through the FDA approval after polyglycolic acid.With respect to other synthetic macromolecular material, it has advantages such as excellent biological compatibility, degradable absorbability and certain mechanical strength.The present invention protects and controllable release anticoagulative substance by the microcapsule of introducing self assembly layer by layer, utilizes then covalently bound microcapsule to be fixed on the polylactic acid membrane material surface, has finally obtained to have the anticoagulant material of good resistance blood coagulation activity.
Summary of the invention
The object of the present invention is to provide a kind of utilization that is applied on the anticoagulation medical material to carry polylactic acid membrane of heparin surface of microcapsule modification and preparation method thereof.
Purpose of the present invention is realized by following technical scheme:
The polylactic acid membrane that the heparin surface of microcapsule is modified is carried in a kind of utilization of the present invention, form by a polylactic acid membrane and a year heparin microcapsule that covalent bond connects, wherein carrying the heparin microcapsule is with the calcium alginate template, has 3 tunic microcapsules of polyallylamine/heparin/polyallylamine structure.
Its constituent mass percentage ratio is as follows:
Polylactic acid membrane 90%～99%
Calcium alginate microsphere 0.1%～10%
Polyallylamine 0.001%～1%
Heparin 0.001%～1%
Described polylactic acid membrane thickness is 50～100 μ m, and the molecular weight of polylactic acid is 200～500Kd.
Described calcium alginate microsphere size 2～50 μ m carry heparin content 1～50pg/ microcapsule.
The method that the heparin surface of microcapsule is modified polylactic acid membrane is carried in a kind of utilization of the present invention, and its concrete preparation process is as follows:
Under step 2, the room temperature isobutyltrimethylmethane., (span) 85 of class of department and the 1%～4%wt sodium alginate aqueous solution mass ratio with 50:1:50～200:1:200 is mixed, ultrasonic emulsification 5～60min, add isobutyltrimethylmethane. and tween (Tween) 85 again, continue dropwise to add 10% wt CaCl then more than the ultrasonic emulsification 20min
2Solution fully stirs more than the 20min, centrifugally can obtain calcium alginate microsphere; Wherein the mixed liquor mass ratio is 1:2:200 after the isobutyltrimethylmethane. that adds once more and Tween 85 and the emulsifying, CaCl
2Compare 1:1 with the mixeding liquid volume behind the second emulsifying;
More than 5 minutes, wherein the mass ratio of polylactic acid membrane and NaOH solution is 1:1, reuse deionized water wash clean with the NaOH solution activation of 0.05%wt for step 4, polylactic acid membrane that the first step is prepared; In room temperature, the polylactic acid membrane that activation is good and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides (EDC)/N-hydroxy-succinamide (NHS) activate 10～120min in pH is acetic acid-sodium-acetate buffer of 4～7, obtain the polylactic acid membrane that the surface has carboxy intermediate.Wherein, the molar ratio of EDC/NHS is 1:1～1:8, and EDC/NHS is 1:1～1:5 with the quality of materials ratio of polylactic acid membrane.
Step 5, the microcapsule that the 3rd step was made pass through more than the triethylamine cleaning 5min of 99.5%wt, and wherein the mass ratio of microcapsule and triethylamine is 1:3～1:10; The polylactic acid membrane that microcapsule after the cleaning and the 4th step make with carboxy intermediate, at pH is 4～7 acetic acid-sodium-acetate buffer hatching 10～120min, and wherein the mass ratio of microcapsule, the polylactic acid membrane with carboxy intermediate and acetic acid-sodium-acetate buffer is 1:100:500～1:200:1000; The polylactic acid membrane that will take out afterwards after hatching uses dodecyl sodium sulfate (SDS) the aqueous solution shaking table of 10%wt to clean more than 5 minutes, and wherein the polylactic acid membrane of every 1g needs the SDS aqueous solution of 100ml to clean, and uses the deionized water wash clean at last, promptly gets target product.
The polylactic acid membrane that the heparin surface of microcapsule is modified is carried in a kind of utilization of the present invention, can be applicable to prepare the composite biological medical materials with efficient anticoagulant active, artificial blood vessel for example, blood contact materials such as cardiac valve.
Effective result:
The polylactic acid membrane that the heparin surface of microcapsule is modified is carried in utilization of the present invention, nontoxic, good biocompatibility, degradable, have the anticoagulation function of good mechanical performance and long stable effect, can stored dry and transportation, can be widely used in anticoagulant material and drug controlled release material.
Description of drawings
Year heparin surface of microcapsule current potential of Fig. 1 self assembly layer by layer;
The infrared spectrum comparison diagram that carries the heparin microcapsule of Fig. 2 self assembly layer by layer;
The polylactic acid membrane infrared spectrum comparison diagram of Fig. 3 polylactic acid membrane and covalently bound microcapsule.
The specific embodiment
The present invention is host material with the polylactic acid membrane, adopt the anticoagulation microcapsule of layer-by-layer preparation, adopt the catalytic covalent bond of EDC/NHS to connect, microcapsule is fixed on the polylactic acid membrane surface, obtain that mechanical property is good, anticoagulation function longer duration, active high polylactic acid membrane.
Of the present invention year heparin surface of microcapsule modified the preparation method of polylactic acid membrane, further specifies below in conjunction with embodiment:
1. the preparation of polylactic acid membrane: 5 kilograms of polylactic acid are put into preset temperature 140C, pressure 25MPa, film forming in the rustless steel injection molding machine of preset thickness 100 μ m.
2. the preparation of calcium alginate microsphere template: the span85 of isobutyltrimethylmethane. 50g, 1g and 1% (wt) sodium alginate aqueous solution 50g, mixed at room temperature, ultrasonic emulsification 20min adds the isobutyltrimethylmethane. of 1g and the Tween85 of 2g again, continue ultrasonic emulsification 20min, dropwise add 10% (wt) CaCl
2Solution, mixed liquor and 10% (wt) CaCl
2Volume ratio 1:1 fully stirs 20min, centrifugally can obtain calcium alginate microsphere.
3. adopt the static layer-by-layer, as template, polyallylamine as polyanion, prepares 3 tunic microcapsules with polyallylamine/heparin/polyallylamine structure as polycation, heparin with electronegative calcium alginate microsphere.Microcapsule capsule size, quality, a year heparin content do not limit.
4. carry the preparation of the covalently bound polylactic acid membrane of heparin microcapsule: the NaOH solution 5min that the polylactic acid membrane that the first step is prepared adopts 0.05% (wt), use the deionized water wash clean; Polylactic acid membrane that activation is good and EDC/NHS activate 15min with the ratio of 10:4:1 at acetic acid-sodium-acetate buffer of pH4.0, obtain the polylactic acid membrane that the surface has carboxy intermediate.
5. the microcapsule that the 3rd step was made cleans 5min through the triethylamine of 0.002M99.5% (wt); The polylactic acid membrane with carboxy intermediate that microcapsule and the 4th step make reacts 20min in acetic acid-sodium-acetate buffer of pH5.0, use 10% (wt) dodecyl sodium sulfate (SDS) shaking table to clean afterwards 5 minutes, use the deionized water wash clean at last, obtain target product.
Embodiment 2
1. the preparation of polylactic acid membrane: 5 kilograms of polylactic acid are put into preset temperature 150C, pressure 25MPa, film forming in the rustless steel injection molding machine of preset thickness 100 μ m.
2. the preparation of calcium alginate microsphere template: isobutyltrimethylmethane., span85 and 2% (wt) sodium alginate aqueous solution 50:1:50, mixed at room temperature, ultrasonic emulsification 30min adds isobutyltrimethylmethane. 1g and Tween852g again, continue ultrasonic emulsification 20min, dropwise add 10% (wt) CaCl
2Solution, mixed liquor and 10% (wt) CaCl
2Volume ratio 1:1 fully stirs 20min, centrifugally can obtain calcium alginate microsphere.
3. adopt the static layer-by-layer, as template, polyallylamine as polyanion, prepares 3 tunic microcapsules with polyallylamine/heparin/polyallylamine structure as polycation, heparin with electronegative calcium alginate microsphere.Microcapsule capsule size, quality, a year heparin content do not limit.
4. carry the preparation of the covalently bound polylactic acid membrane of heparin microcapsule: adopt the NaOH of 0.05% (wt) to activate 5min the polylactic acid membrane for preparing, use the deionized water wash clean; Polylactic acid membrane that activation is good and EDC/NHS are with the ratio of 10:5:1, and the acetic acid-sodium-acetate buffer activation 10min at pH5.0 obtains the polylactic acid membrane that the surface has carboxy intermediate.
5. the microcapsule that the 3rd step was made cleans 5min through the triethylamine of 0.002M99.5% (wt); The polylactic acid membrane with carboxy intermediate that microcapsule and the 4th step make reacted 30 minutes in acetic acid-sodium-acetate buffer of pH5.0.Use 10% (wt) dodecyl sodium sulfate (SDS) shaking table to clean afterwards 5 minutes, use the deionized water wash clean at last, obtain target product.
1. the preparation of polylactic acid membrane: 5 kilograms of polylactic acid are put into preset temperature 160C, pressure 25MPa, film forming in the rustless steel injection molding machine of preset thickness 50 μ m.
2. the preparation of calcium alginate microsphere template: isobutyltrimethylmethane. 150, span 85 2g and 2% (wt) sodium alginate aqueous solution 150g, mixed at room temperature, ultrasonic emulsification 40min adds isobutyltrimethylmethane. 1g and Tween852g again, continue ultrasonic emulsification 60min, dropwise add 10% (wt) CaCl
2Solution, mixed liquor and 10% (wt) CaCl
2Volume ratio 1:3 fully stirs 20min, centrifugally can obtain calcium alginate microsphere.
3. adopt the static layer-by-layer, as template, polyallylamine as polyanion, prepares 3 tunic microcapsules with polyallylamine/heparin/polyallylamine structure as polycation, heparin with electronegative calcium alginate microsphere.
4. carry the preparation of the covalently bound polylactic acid membrane of heparin microcapsule: adopt the NaOH of 0.05% (wt) to activate 5min the polylactic acid membrane for preparing, use the deionized water wash clean; Polylactic acid membrane that activation is good and EDC/NHS are with the ratio of 10:4:3, and the acetic acid-sodium-acetate buffer activation 20min at pH6.0 obtains the polylactic acid membrane that the surface has carboxy intermediate.
5. the microcapsule that the 3rd step was made cleans 5min through the triethylamine of 0.002M99.5% (wt); The polylactic acid membrane with carboxy intermediate that microcapsule and the 4th step make reacted 60 minutes in acetic acid-sodium-acetate buffer of pH6.0.Use 10% (wt) dodecyl sodium sulfate (SDS) shaking table to clean afterwards 5 minutes, use the deionized water wash clean at last, obtain target product.
Embodiment 4
1. the preparation of polylactic acid membrane: 5 kilograms of polylactic acid are put into preset temperature 170C, pressure 25MPa, film forming in the rustless steel injection molding machine of preset thickness 100 μ m.
2. the preparation of calcium alginate microsphere template: isobutyltrimethylmethane. 200, span 85 1g and 2% (wt) sodium alginate aqueous solution 200g, mixed at room temperature, ultrasonic emulsification 50min adds isobutyltrimethylmethane. 1g and Tween 85 2g again, continue ultrasonic emulsification 60min, dropwise add 10% (wt) CaCl
2Solution, mixed liquor and 10% (wt) CaCl
2Volume ratio 1:4 fully stirs 20min, centrifugally can obtain calcium alginate microsphere.
3. adopt the static layer-by-layer, as template, polyallylamine as polyanion, prepares 3 tunic microcapsules with polyallylamine/heparin/polyallylamine structure as polycation, heparin with electronegative calcium alginate microsphere.
4. carry the preparation of the covalently bound polylactic acid membrane of heparin microcapsule: adopt the NaOH of 0.05% (wt) to activate 5 minutes the polylactic acid membrane for preparing, use the deionized water wash clean; Polylactic acid membrane that activation is good and EDC/NHS are with the ratio of 10:4:4, and the acetic acid-sodium-acetate buffer activation 20min at pH6.0 obtains the polylactic acid membrane that the surface has carboxy intermediate.
5. the microcapsule that the 3rd step was made cleans 5min through the triethylamine of 0.002M 99.5% (wt); The polylactic acid membrane with carboxy intermediate that microcapsule and the 4th step make reacted 120 minutes in acetic acid-sodium-acetate buffer of pH7.0.Use 10% (wt) dodecyl sodium sulfate (SDS) shaking table to clean afterwards 5 minutes, use the deionized water wash clean at last, obtain target product.
Self assembly microcapsule process surperficial Zeta potential analysis (as Fig. 1) layer by layer of year heparin of above-mentioned acquisition and infrared spectrum characterization (as Fig. 2).The surface of microcapsule current potential shows clocklike positive and negative alternate, and current potential is more stable, illustrates that promptly PAH successfully is adsorbed onto on the sodium alginate colloid particle, and heparin also is adsorbed on the surface of PAH parcel colloidal particle.The surface of calcium alginate microsphere has stronger negative electricity, and this makes the PAH nanometer film of positively charged be adsorbed on the surface of calcium alginate microsphere, thereby microsphere surface electrically changes, and is electropositive.Electronegative heparin is adsorbed onto the surface of microsphere again, so positive and negative alternate takes place the electric charge of surface of microcapsule.The Infrared Characterization of the calcium alginate microsphere of sodium alginate, heparin and PAH/Hep is seen Fig. 2, at 1590cm
-1～1470cm
-1About be the characteristic peak of N-H and C-H, 1115cm
-1～1170cm
-1Be-SO
2-Characteristic peak, 1740cm
-1～1540cm
-1Be the characteristic peak of amide, show on the PAH film and contain amine groups that carbonyl group is contained on the sodium alginate surface.3000cm
-1The perpendicular peak at place is the air peak in the preparation sample.Sodium alginate has at 1590cm
-1～1470cm
-1About be the characteristic peak of N-H and C-H, PAH is at 2800cm
-1There is characteristic peak and the 2000cm of C=C at the place
-1About the phenyl ring characteristic absorption peak, heparin has 1115cm
-1～1170cm
-1Be-SO
2-Characteristic absorption peak, (PAH/Hep/PAH) the slight capsule of the calcium alginate of film has the characteristic peak of sodium alginate, heparin and PAH concurrently.
Observing through electromicroscopic photograph of year covalently bound polylactic acid membrane of heparin microcapsule of above-mentioned acquisition shows that polylactic acid membrane keeps smooth, and the form of microcapsule remains intact, and the microcapsule quantity on the polylactic acid membrane is greater than 0.1 ± 0.021/μ m
2
As Fig. 3, infrared spectrum shows 1570～1670cm
-1Between characteristic peak appears, illustrate to have amido link (amide I, 1550～1670cm
-1Amide II, 1500～1570cm
-1), 2300～2900cm
-1Between the characteristic peak of halogenation amino (PAH) appears.2700～3200cm
-1Between hydroxyl peak significantly reduce by 1620～1820cm
-1Between carbonyl peak also significantly reduce, carboxyl and amino generation condensation reaction be describeds.
Carry the clotting time experiment of the covalently bound polylactic acid membrane of heparin microcapsule:
To carry the small pieces that the covalently bound polylactic acid membrane precision of heparin microcapsule is cut into 3 * 5mm, place coagulo meter cuvette bottom, carry out the mensuration of prothrombin time (PT), thrombin time (TT) and activated partial thromboplastin time (APTT).As can be seen from Table 1: the blood clotting time of carrying the covalently bound polylactic acid membrane energy significant prolongation blood plasma of heparin microcapsule.
The clotting time (n=4, n promptly check multiple number of times) of the table 1 year covalently bound polylactic acid membrane of heparin microcapsule
Claims (4)
1, the polylactic acid membrane that the heparin surface of microcapsule is modified is carried in a kind of utilization, it is characterized in that: form by a polylactic acid membrane and a year heparin microcapsule that covalent bond connects, wherein carrying the heparin microcapsule is with the calcium alginate template, has 3 tunic microcapsules of polyallylamine/heparin/polyallylamine structure
Its constituent mass percentage ratio is as follows:
Polylactic acid membrane 90%～99%
Calcium alginate microsphere 0.1%～10%
Polyallylamine 0.001%～1%
Heparin 0.001%～1%.
2, the polylactic acid membrane that the heparin surface of microcapsule is modified is carried in a kind of utilization as claimed in claim 1, it is characterized in that: described polylactic acid membrane thickness is 50～100 μ m, the molecular weight of polylactic acid is 200～500Kd, calcium alginate microsphere size 2～50 μ m carry heparin content 1～50pg/ microcapsule.
3, the method that the heparin surface of microcapsule is modified polylactic acid membrane is carried in a kind of utilization, it is characterized in that concrete preparation process is as follows:
Step 1, with polylactic acid 140 ℃～180 ℃ of temperature, in injection molding machine, make the polylactic acid membrane that thickness is 50～100 μ m under the high-temperature and high-pressure conditions of pressure 20～25MPa;
Under step 2, the room temperature isobutyltrimethylmethane., span85 and the 1%～4%wt sodium alginate aqueous solution mass ratio with 50:1:50～200:1:200 is mixed, ultrasonic emulsification 5～60min, add isobutyltrimethylmethane. and Tween 85 again, continue dropwise to add 10%wt CaCl then more than the ultrasonic emulsification 20min
2Solution fully stirs more than the 20min, centrifugally can obtain calcium alginate microsphere; Wherein the mixed liquor mass ratio is 1:2:200 after the isobutyltrimethylmethane. that adds once more and Tween 85 and the emulsifying, CaCl
2Compare 1:1 with the mixeding liquid volume behind the second emulsifying;
Step 3, employing static layer-by-layer, as template, polyallylamine as polyanion, prepares 3 tunic microcapsules with polyallylamine/heparin/polyallylamine structure as polycation, heparin with electronegative calcium alginate microsphere;
More than 5 minutes, wherein the mass ratio of polylactic acid membrane and NaOH solution is 1:1, reuse deionized water wash clean with the NaOH solution activation of 0.05%wt for step 4, polylactic acid membrane that the first step is prepared; In room temperature, the polylactic acid membrane that activation is good and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides (EDC)/N-hydroxy-succinamide (NHS) activate 10～120min in pH is acetic acid-sodium-acetate buffer of 4～7, obtain the polylactic acid membrane that the surface has carboxy intermediate; Wherein, the molar ratio of EDC/NHS is 1:1～1:8, and EDC/NHS is 1:1～1:5 with the quality of materials ratio of polylactic acid membrane;
Step 5, the microcapsule that the 3rd step was made pass through more than the triethylamine cleaning 5min of 99.5%wt, and wherein the mass ratio of microcapsule and triethylamine is 1:3～1:10; The polylactic acid membrane that microcapsule after the cleaning and the 4th step make with carboxy intermediate, at pH is 4～7 acetic acid-sodium-acetate buffer hatching 10～120min, and wherein the mass ratio of microcapsule, the polylactic acid membrane with carboxy intermediate and acetic acid-sodium-acetate buffer is 1:100:500～1:200:1000; The polylactic acid membrane that will take out afterwards after hatching uses dodecyl sodium sulfate (SDS) the aqueous solution shaking table of 10%wt to clean more than 5 minutes, and wherein the polylactic acid membrane of every 1g needs the SDS aqueous solution of 100ml to clean, and uses the deionized water wash clean at last, promptly gets target product.
4, the polylactic acid membrane that the heparin surface of microcapsule is modified is carried in a kind of utilization of the present invention, it is characterized in that: be used to prepare the composite biological medical materials with efficient anticoagulant active.
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| CN101947212A (en) * | 2010-09-08 | 2011-01-19 | 华侨大学 | Micro-embedded medicament carrier and preparation method thereof |
| CN114870084A (en) * | 2015-05-27 | 2022-08-09 | 光州科学技术院 | Mixed hollow microcapsule, soft tissue stent comprising same and preparation method thereof |
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| CN101036809A (en) * | 2007-04-17 | 2007-09-19 | 孙勇 | Method for preparing heparin isinglass nanometer grain and heparin encapsulization heart closure device |
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| CN101947212A (en) * | 2010-09-08 | 2011-01-19 | 华侨大学 | Micro-embedded medicament carrier and preparation method thereof |
| CN114870084A (en) * | 2015-05-27 | 2022-08-09 | 光州科学技术院 | Mixed hollow microcapsule, soft tissue stent comprising same and preparation method thereof |
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