CN111110929A - High-biosafety heart stent and manufacturing method thereof - Google Patents
High-biosafety heart stent and manufacturing method thereof Download PDFInfo
- Publication number
- CN111110929A CN111110929A CN202010094300.6A CN202010094300A CN111110929A CN 111110929 A CN111110929 A CN 111110929A CN 202010094300 A CN202010094300 A CN 202010094300A CN 111110929 A CN111110929 A CN 111110929A
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- Prior art keywords
- stent
- polylactic acid
- heart
- biosafety
- manufacturing
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Abstract
The invention discloses a high-biosafety heart stent and a manufacturing method thereof. Through the mode, the molecular weight of the polylactic acid can be adjusted, so that the polylactic acid has better mechanical property and degradation property; and the synergistic effect among the polylactic acid, the inorganic filler and the polyethylene glycol is utilized to effectively improve the strength of the prepared heart stent, so that the heart stent has proper degradation rate and higher biological safety. In addition, the high-biosafety heart stent prepared by the invention has higher radial strength, proper porosity and degradation time, and can meet the requirements of practical application.
Description
Technical Field
The invention relates to the technical field of heart stents, in particular to a high-biosafety heart stent and a manufacturing method thereof.
Background
The heart stent is a medical instrument commonly used in the heart interventional operation, has the function of dredging arterial blood vessels, and is often used for treating coronary heart disease. At present, heart stents are mainly classified into three types, namely metal stents, drug-coated stents and bioabsorbable stents. Wherein, the traditional metal stent and drug-coated stent can permanently exist in the blood vessel because of incomplete degradation, easily cause the problems of chronic injury of the blood vessel, intimal hyperplasia and the like, and cause the increase of risks of thrombus in the stent and restenosis in the stent; the biological absorbable stent can be dissolved in vivo after the stent effect is completed and absorbed by the organism, so that adverse effects caused by long-term storage of the stent in the body are avoided. Therefore, bioabsorbable stents are an important research direction in the current field of cardiac stents.
At present, the materials for preparing the bioabsorbable stent mainly comprise degradable polymers such as polylactic acid, polycaprolactone and polyglycolic acid, and degradable metal materials such as magnesium alloy and iron alloy. Among various materials, polylactic acid has excellent biocompatibility and good degradation performance and mechanical performance, so that the polylactic acid is widely applied. However, polylactic acid with different molecular weights and structures has larger performance difference, and the selection or preparation of polylactic acid suitable for the heart stent is still the focus of the current research.
The patent with publication number CN106963991A provides a modified degradable stent and a preparation method thereof, and the modified degradable stent has good mechanical strength, biocompatibility and biodegradability by compounding three polylactic acids, namely high molecular weight levorotatory polylactic acid, low molecular weight levorotatory polylactic acid and high molecular weight racemic polylactic acid, and shortens the degradation time while maintaining the mechanical strength of the high molecular weight levorotatory polylactic acid. However, because the raw materials used in the method are all polylactic acid, acidic substances generated in the metabolic process of the polylactic acid easily cause inflammatory reaction of the body; the strong hydrophobicity of the polylactic acid can influence the blood compatibility of the stent, and the risk of thrombus generation is increased; in addition, the stent prepared by the method still has the problems of insufficient strength and lower supporting force, is easy to retract in the vasoconstriction and dilation process, and has insufficient overall biological safety.
Based on the problem of insufficient biological safety brought by the polylactic acid stent, the problem is mainly solved by compounding polylactic acid with other materials at present, and the key of the current research is how to select a proper material to compound with polylactic acid to prepare the heart stent with proper performance and high biological safety.
In view of the above, there is a need to provide a cardiac stent with high biosafety and a manufacturing method thereof, in which polylactic acid is compounded with other materials to improve the strength of the cardiac stent, optimize the degradation time of the cardiac stent, and improve the biocompatibility of the cardiac stent, so that the manufactured cardiac stent has high biosafety.
Disclosure of Invention
The invention aims to solve the problems and provide a high-biosafety heart stent and a manufacturing method thereof, wherein polylactic acid with proper molecular weight is prepared by a lactide ring-opening polymerization method, so that the polylactic acid has better mechanical property and degradation property; and through preparing magnesium-doped tricalcium phosphate as an inorganic filler, the magnesium-doped tricalcium phosphate is uniformly mixed with polylactic acid under the action of polyethylene glycol, so that the strength and the hydrophilicity of the polylactic acid are effectively improved, and the prepared heart stent has higher supporting force and biological safety so as to meet the requirements of practical application.
In order to achieve the above object, the present invention provides a method for manufacturing a cardiac stent with high biosafety, comprising the steps of:
s1, preparing polylactic acid by a lactide ring-opening polymerization method, dissolving the polylactic acid in 1, 4-dioxane, and fully stirring for later use;
s2, dropwise adding a calcium nitrate solution into an ammonium hydrogen phosphate solution according to a preset molar ratio, fully stirring, adjusting the pH value of the solution to 8-10, and filtering, washing, drying and calcining after the product is completely separated out to obtain nano tricalcium phosphate;
s3, fully and uniformly mixing the nano tricalcium phosphate obtained in the step S2 and a preset amount of magnesium oxide through wet ball milling, drying and sintering the obtained mixture to obtain a sintered body, and grinding and sieving the sintered body to obtain an inorganic filler;
s4, adding polyethylene glycol with a preset amount and the inorganic filler obtained in the step S3 into the polylactic acid solution obtained in the step S1, fully stirring, heating and concentrating, and performing ball milling and uniform mixing to obtain printing slurry with a preset concentration;
s5, forming the printing slurry obtained in the step S4 into a heart stent by adopting a 3D printing technology, and freeze-drying the heart stent to obtain a porous heart stent; and (3) immersing the porous heart stent into a drug solution with a preset concentration, taking out and drying after sufficient immersion to obtain the high-biosafety heart stent.
Further, in step S1, the lactide ring-opening polymerization method for preparing polylactic acid includes the steps of:
s11, heating a levolactic acid monomer at 170 ℃ and 5kPa for dehydration under reduced pressure for 5h, adding 1wt% of stannous octoate as a catalyst, distilling lactide at 200 ℃ and 0.5kPa, and condensing to obtain crude lactide;
s12, washing and recrystallizing the crude lactide obtained in the step S11 in sequence to obtain purified levorotatory lactide;
s13, adding 1wt% of zinc acetylacetonate serving as a catalyst into the purified levorotatory lactide obtained in the step S12, heating to 130 ℃ in a nitrogen atmosphere, keeping the temperature for 12-36 hours, and performing ring-opening polymerization reaction; and centrifuging the product obtained by the ring-opening polymerization reaction, pouring supernatant into ice methanol, and filtering, washing and drying after the product is fully separated out to obtain the polylactic acid with the molecular weight of 40-70 ten thousand.
Further, in step S2, the preset molar ratio of the calcium nitrate solution to the ammonium hydrogen phosphate solution is 3: 2.
Further, in step S3, the mass ratio of the nano tricalcium phosphate to the magnesium oxide is (6-10): 1.
Further, in step S3, the sintering temperature of the sintering treatment is 1200-1400 ℃, and the sintering time is 1-3 h.
Further, in step S4, the mass ratio of the polylactic acid, the polyethylene glycol and the inorganic filler in the printing paste is 100 (0.2-0.6) to (10-30).
Further, in step S4, the predetermined concentration of the printing paste is 1.3-1.5 g/mL.
Further, in step S5, the concentration of the drug solution is 0.1 g/mL; the medicine is one or more of rapamycin, paclitaxel, heparin and aspirin.
In order to achieve the purpose, the invention also provides a high-biosafety heart scaffold which is prepared according to any one of the technical schemes.
Further, the radial strength of the high-biosafety heart scaffold is 196-254 kPa, the porosity is 23.0% -44.7%, and the degradation time is 12-24 months.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the invention, the polylactic acid with a proper molecular weight is prepared by a lactide ring-opening polymerization method, so that the problems of too low degradation rate caused by too high molecular weight of the polylactic acid and low strength caused by too low molecular weight of the polylactic acid are solved, and the prepared polylactic acid has better mechanical property and degradation property; meanwhile, the magnesium-doped tricalcium phosphate is prepared as the inorganic filler and is uniformly mixed with the polylactic acid under the action of the polyethylene glycol, so that the strength and the hydrophilicity of the polylactic acid are effectively improved, and the prepared heart stent has higher supporting force and biological safety so as to meet the requirements of practical application.
2. According to the invention, the nanometer tricalcium phosphate is prepared, and is mixed with the magnesium oxide and then sintered, so that magnesium in the magnesium oxide partially replaces calcium in the tricalcium phosphate by utilizing the chemical properties similar to those of magnesium element and calcium element, and the magnesium-doped tricalcium phosphate is obtained; the magnesium is doped to change the crystal structure of the tricalcium phosphate, so that the strength of the tricalcium phosphate can be improved, and the crystal structure of the tricalcium phosphate can be defected, thereby improving the specific surface area and the bioactivity of the tricalcium phosphate. In addition, the magnesium oxide remained after doping can also exist in the sintered body in the form of nano magnesium oxide, so that the antibacterial effect is achieved, and the biocompatibility of the inorganic filler is improved.
3. According to the invention, polyethylene glycol is blended with polylactic acid and inorganic filler, so that the excellent hydrophilic property of polyethylene glycol can be utilized to carry out hydrophilic modification on polylactic acid, the blood compatibility of the stent is improved, the generation of thrombus is reduced, and the prepared heart stent has higher biocompatibility; and hydroxyl contained in the polyethylene glycol and the polylactic acid can form hydrogen bonds, so that the polylactic acid is uniformly distributed, the compatibility of the polylactic acid and the inorganic filler is improved, the polylactic acid and the inorganic filler are uniformly mixed and tightly combined, and the mechanical property, the degradation property and the biological safety of the polylactic acid are improved by using the inorganic filler. The polylactic acid, the polyethylene glycol and the inorganic filler have synergistic effect, so that the prepared heart stent has higher strength, proper degradation rate and higher biological safety.
4. According to the invention, the heart stent is prepared by blending the polylactic acid and the inorganic filler, so that the alkaline degradation product of tricalcium phosphate in the inorganic filler can be utilized to neutralize the acidic degradation product of the polylactic acid, and the inflammatory reaction of an organism caused by acidic substances is avoided; the degradation time of the polylactic acid can be shortened by utilizing the relatively fast degradation rate of the tricalcium phosphate, the problem of late thrombosis caused by slow degradation of the prepared heart stent is avoided, and the biological safety of the stent is improved. In addition, the addition of the inorganic filler is also beneficial to improving the developing property of the prepared heart stent under X-ray, is convenient for observing and tracking the heart stent implanted into a body and ensures the use safety of a patient.
5. The heart stent prepared by the invention can be completely degraded, and degradation products are all absorbable substances harmless to human bodies, so that the biological safety is high; meanwhile, the prepared heart stent has a porous structure by a freeze-drying method, so that the drug loading capacity of the heart stent can be effectively improved, and the drugs can be slowly released in an organism, so that the biological safety of the stent is further improved.
Drawings
Fig. 1 is a schematic flow chart of a manufacturing method of a high biosafety heart scaffold provided by the invention.
Detailed Description
The following detailed description of the preferred embodiments of the present invention, taken in conjunction with the accompanying drawings, will make the advantages and features of the invention easier to understand by those skilled in the art, and thus will clearly and clearly define the scope of the invention. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without any inventive step, are within the scope of the present invention.
The invention provides a method for manufacturing a high-biosafety heart stent, which has the manufacturing flow shown in figure 1 and comprises the following steps:
s1, preparing polylactic acid by a lactide ring-opening polymerization method, dissolving the polylactic acid in 1, 4-dioxane, and fully stirring for later use;
s2, dropwise adding a calcium nitrate solution into an ammonium hydrogen phosphate solution according to a preset molar ratio, fully stirring, adjusting the pH value of the solution to 8-10, and filtering, washing, drying and calcining after the product is completely separated out to obtain nano tricalcium phosphate;
s3, fully and uniformly mixing the nano tricalcium phosphate obtained in the step S2 and a preset amount of magnesium oxide through wet ball milling, drying and sintering the obtained mixture to obtain a sintered body, and grinding and sieving the sintered body to obtain an inorganic filler;
s4, adding polyethylene glycol with a preset amount and the inorganic filler obtained in the step S3 into the polylactic acid solution obtained in the step S1, fully stirring, heating and concentrating, and performing ball milling and uniform mixing to obtain printing slurry with a preset concentration;
s5, forming the printing slurry obtained in the step S4 into a heart stent by adopting a 3D printing technology, and freeze-drying the heart stent to obtain a porous heart stent; and (3) immersing the porous heart stent into a drug solution with a preset concentration, taking out and drying after sufficient immersion to obtain the high-biosafety heart stent.
In step S1, the lactide ring-opening polymerization method for preparing polylactic acid includes the steps of:
s11, heating a levolactic acid monomer at 170 ℃ and 5kPa for dehydration under reduced pressure for 5h, adding 1wt% of stannous octoate as a catalyst, distilling lactide at 200 ℃ and 0.5kPa, and condensing to obtain crude lactide;
s12, washing and recrystallizing the crude lactide obtained in the step S11 in sequence to obtain purified levorotatory lactide;
s13, adding 1wt% of zinc acetylacetonate serving as a catalyst into the purified levorotatory lactide obtained in the step S12, heating to 130 ℃ in a nitrogen atmosphere, keeping the temperature for 12-36 hours, and performing ring-opening polymerization reaction; and centrifuging the product obtained by the ring-opening polymerization reaction, pouring supernatant into ice methanol, and filtering, washing and drying after the product is fully separated out to obtain the polylactic acid with the molecular weight of 40-70 ten thousand.
In step S2, the preset molar ratio of the calcium nitrate solution to the ammonium hydrogen phosphate solution is 3: 2.
In step S3, the mass ratio of the nano tricalcium phosphate to the magnesium oxide is (6-10): 1.
In step S3, the sintering temperature of the sintering treatment is 1200-1400 ℃, and the sintering time is 1-3 h.
In step S4, the mass ratio of the polylactic acid, the polyethylene glycol and the inorganic filler in the printing paste is 100 (0.2-0.6) to (10-30).
In step S4, the predetermined concentration of the printing paste is 1.3-1.5 g/mL.
In step S5, the concentration of the drug solution is 0.1 g/mL; the medicine is one or more of rapamycin, paclitaxel, heparin and aspirin.
The invention also provides a high-biosafety heart stent which is prepared according to any one of the technical schemes.
The radial strength of the high-biosafety heart scaffold is 196-254 kPa, the porosity is 23.0% -44.7%, and the degradation time is 12-24 months.
The present invention provides a highly biosafety cardiac stent and a method for manufacturing the same, which will be described below with reference to the following examples and accompanying drawings.
Example 1
The embodiment provides a manufacturing method of a high-biosafety heart stent, which comprises the following steps:
s1, preparing polylactic acid by a lactide ring-opening polymerization method, dissolving the polylactic acid in 1, 4-dioxane according to the mass-volume ratio of 1g:10mL, and fully stirring for later use;
the lactide ring-opening polymerization method for preparing the polylactic acid comprises the following steps:
s11, placing a levolactic acid monomer into a round-bottom flask, heating and dehydrating under reduced pressure for 5 hours at 170 ℃ under the condition of 5kPa, adding 1wt% of stannous octoate as a catalyst, distilling lactide at 200 ℃ under the condition of 0.5kPa, and condensing to obtain crude lactide;
s12, washing and recrystallizing the crude lactide obtained in the step S11 in sequence to obtain purified levorotatory lactide; the water washing process comprises the steps of putting the crude lactide into deionized water, quickly stirring and then carrying out suction filtration, so that dextrorotatory lactide and meso-lactide in the crude lactide can be removed; dissolving the washed crude lactide in ethyl acetate according to the mass-volume ratio of 2.5g:1mL, heating and stirring at 80 ℃ until the crude lactide is completely dissolved, naturally cooling to room temperature to separate out the dextrorotatory lactide crystal, and performing suction filtration and drying to obtain purified dextrorotatory lactide;
s13, adding 1wt% of zinc acetylacetonate as a catalyst into the purified levorotatory lactide obtained in the step S12, heating to 130 ℃ in a nitrogen atmosphere, keeping the temperature for 24 hours, and carrying out ring-opening polymerization reaction; and centrifuging the product obtained by the ring-opening polymerization reaction, pouring supernatant into ice methanol, and filtering, washing and drying after the product is fully separated out to obtain the polylactic acid with the molecular weight of 70 ten thousand.
S2, dripping 0.3mol/L calcium nitrate solution into 0.2mol/L ammonium hydrogen phosphate solution with the same volume, fully stirring, adjusting the pH value of the solution to 9, standing for 12 hours until the product is completely separated out, filtering, washing, drying, and calcining at 900 ℃ for 3 hours to obtain the nano tricalcium phosphate.
S3, fully and uniformly mixing the nano tricalcium phosphate obtained in the step S2 and a predetermined amount of magnesium oxide through wet ball milling, and enabling the mass ratio of the nano tricalcium phosphate to the magnesium oxide to be 8: 1; drying the obtained mixture, placing the dried mixture in a resistance furnace for sintering treatment, controlling the sintering temperature at 1300 ℃ and the sintering time at 2h to obtain a sintered body; and grinding the sintered body, and then sieving the ground sintered body with a 300-mesh sieve to obtain the inorganic filler.
S4, adding polyethylene glycol with a preset amount and the inorganic filler obtained in the step S3 into the polylactic acid solution obtained in the step S1, fully stirring, heating and concentrating, and performing ball milling and uniform mixing to obtain printing slurry with the concentration of 1.4 g/mL; the mass ratio of the polylactic acid to the polyethylene glycol to the inorganic filler in the printing paste is 100:0.4: 20.
S5, loading 3D model data of the heart stent to be printed to a drawing system by using a 3D printer, placing the printing slurry in a tray of the 3D printer, and starting printing to obtain the heart stent with the diameter of 1.5mm and the wall thickness of 150 micrometers; freeze-drying the heart scaffold for 48h at-50 ℃ under 10Pa to obtain a porous heart scaffold; and (3) immersing the porous heart stent into a rapamycin medicine solution with the concentration of 0.1g/mL, taking out and drying after immersing for 1h to obtain the high-biosafety heart stent.
The radial strength and the porosity of the high biosafety heart scaffold prepared in the embodiment are measured, the high biosafety heart scaffold is subjected to in-vitro simulated degradation, the degradation time in a simulated environment is converted into the actual in-vivo degradation time, and the weight loss rates of the heart scaffold after in-vivo degradation for 6 months, 12 months, 18 months and 24 months are tested, and the results are shown in table 1.
TABLE 1 Performance parameters of the high biosafety cardiac scaffolds prepared in example 1
As can be seen from the table 1, the high-biosafety heart stent prepared by the embodiment has higher radial strength and porosity, and can be completely degraded within 18 months, so that the blood vessel can be effectively supported in the early stage, the safety of the stent implantation part can be guaranteed by utilizing excellent drug loading capacity, the stent can be completely degraded after the blood vessel recovery capacity, the risks of thrombus and stent restenosis in the stent in the later stage can be effectively reduced, the high-biosafety heart stent has higher biosafety, and the requirements of practical application can be met.
Examples 2 to 5 and comparative example 1
Examples 2 to 5 and comparative example 1 each provide a method for manufacturing a cardiac stent with high biosafety, and are different from example 1 in that examples 2 to 5 change the time of the ring-opening polymerization reaction of step S13, thereby obtaining polylactic acids with different molecular weights; comparative example 1a polylactic acid was not prepared through step S1, but a commercially available high molecular weight l-polylactic acid having a molecular weight of 90 ten thousand was directly purchased. The ring-opening polymerization reaction time for each example and the molecular weight of the polylactic acid for each example and comparative example are shown in Table 2.
TABLE 2 Ring-opening polymerization time and molecular weight of polylactic acid in examples 2 to 5 and comparative example 1
| Examples | Ring opening polymerization reaction time (h) | Molecular weight of polylactic acid |
| Example 2 | 12 | 40 ten thousand |
| Example 3 | 18 | 60 ten thousand |
| Example 4 | 30 | 67 ten thousand |
| Example 5 | 36 | 65 ten thousand |
| Comparative example 1 | - | 90 ten thousand |
As can be seen from table 2, the molecular weight of the polylactic acid obtained increases and then decreases with the increase of the ring-opening polymerization reaction time, mainly because the polymerization and depolymerization processes of the ring-opening polymerization reaction are reversible, and the l-lactide rapidly undergoes ring-opening polymerization at the initial stage of the ring-opening polymerization reaction, and the molecular weight of the polylactic acid obtained gradually increases. The invention can make the molecular weight of the prepared polylactic acid be 40-70 ten thousand by controlling the ring-opening polymerization reaction time to be 12-36 h.
The radial strength, porosity and degradation performance of the high biosafety heart scaffold prepared in examples 2-5 and comparative example 1 were tested, and the results are shown in table 3.
TABLE 3 Performance of high biosafety cardiac scaffolds prepared in examples 2-5 and comparative example 1
It can be seen from table 2 and table 3 that the molecular weight of polylactic acid can be controlled by adjusting the time of the ring-opening polymerization reaction, so as to control the strength, porosity and degradation performance of the prepared cardiac scaffold with high biosafety.
Comparing examples 1-5 with comparative example 1, it can be seen that the radial strength of the prepared high biosafety heart scaffold is improved with the increase of the molecular weight of polylactic acid, but the porosity is reduced and the degradation speed is reduced. Compared with example 1, comparative example 1 has relatively high radial strength, but has low porosity, long degradation time, small drug loading, low biocompatibility, and the like, and easily causes the problems of thrombus in the stent, stent restenosis and the like in the later stage of the use of the stent. Therefore, in order to enable the high-biosafety heart stent to have comprehensive and excellent performance, the molecular weight of polylactic acid is preferably 40-70 ten thousand, and the prepared heart stent can have relatively high radial strength, porosity and appropriate degradation rate and has high biosafety.
Examples 6 to 9 and comparative example 2
Examples 6 to 9 and comparative example 2 respectively provide a method for manufacturing a cardiac stent with high biosafety, and compared with example 1, the differences are that the mass ratio of the nano tricalcium phosphate to the magnesium oxide in step S3 or the sintering temperature and the sintering time in the sintering treatment process are changed in examples 6 to 9; in comparative example 2, nano tricalcium phosphate was directly used as an inorganic filler, and the addition of magnesium oxide and the sintering process were not performed. The raw material mass ratios and sintering parameters for each example and comparative example are shown in table 4.
TABLE 4 raw material mass ratios and sintering parameters of step S3 in examples 6 to 9 and comparative example 2
The radial strength, porosity and degradation performance of the high biosafety heart scaffold prepared in examples 6-9 and comparative example 2 were tested, and the results are shown in table 5.
TABLE 5 Performance of high biosafety cardiac scaffolds prepared in examples 6-9 and comparative example 2
It can be seen from the combination of tables 4 and 5 that the strength, porosity and degradation of the prepared cardiac scaffold with high biosafety can be controlled by adjusting the relative content of magnesium oxide and the sintering parameters.
Comparing example 1 with examples 6-7, it can be seen that the increase of the relative content of magnesium oxide can improve the radial strength, porosity and degradation rate of the prepared heart scaffold with high biosafety. The main reason is that magnesium in the magnesium oxide can partially replace calcium in tricalcium phosphate, the doping amount of magnesium can be increased by increasing the content of magnesium oxide, so that the crystal structure change of tricalcium phosphate is increased, the strength of tricalcium phosphate can be improved, defects can be generated in the crystal structure of tricalcium phosphate, the specific surface area and the bioactivity of tricalcium phosphate are improved, the obtained heart stent has high radial strength, porosity and degradation rate, but the degradation rate is too high due to too high content of magnesium oxide, and the sufficient supporting effect is difficult to play. Therefore, the mass ratio of the nano tricalcium phosphate to the magnesium oxide is preferably (6-10): 1. In contrast, in comparative example 2, magnesium oxide is not used, and the radial strength, porosity and degradation rate of the high biosafety heart scaffold prepared by the method are obviously lower than those of the high biosafety heart scaffold prepared in example 1 of the invention, which indicates that the incorporation of magnesium oxide has an important influence on the improvement of the performance of the heart scaffold.
Comparing example 1 with examples 8-9, it can be seen that the increase of the sintering temperature and the extension of the sintering time can improve the radial strength of the prepared heart scaffold with high biosafety, and reduce the porosity and the degradation rate. Mainly because the increase of sintering temperature and the extension of sintering time can improve the compactness of the sintered body, thereby improving the radial strength of the heart stent, but the porosity and the degradation rate are relatively low. Therefore, in order to enable the prepared heart stent with high biological safety to have comprehensive and excellent performance, the sintering temperature of the sintering treatment is preferably 1200-1400 ℃, the sintering time is 1-3 h, and the heart stent prepared under the conditions can have relatively high radial strength, porosity and appropriate degradation rate and has high biological safety.
Examples 10 to 15 and comparative examples 3 to 4
Examples 10 to 15 and comparative examples 3 to 4 each provide a method for manufacturing a cardiac stent with high biosafety, and compared with example 1, the difference is that the mass ratio of polylactic acid, polyethylene glycol and an inorganic filler or the concentration of printing paste in step S4 is changed in examples 10 to 15; comparative example 3 no polyethylene glycol was added in step S4, and comparative example 4 no inorganic filler was added in step S4. The raw material mass ratios and printing paste concentrations for each example and comparative example are shown in table 6.
TABLE 6 raw material mass ratios and printing paste concentrations of step S4 in examples 10 to 15 and comparative examples 3 to 4
The radial strength, porosity and degradation performance of the high biosafety heart scaffolds prepared in examples 10-15 and comparative examples 3-4 were tested, and the results are shown in table 7.
TABLE 7 Performance of high biosafety cardiac scaffolds prepared in examples 10-15 and comparative examples 3-4
As can be seen from table 6 and table 7, the strength, porosity and degradation of the prepared cardiac scaffold with high bio-safety can be controlled by adjusting the contents of polylactic acid, polyethylene glycol, inorganic filler and solvent in the printing slurry.
Comparing example 1 with examples 10-13, it can be seen that the increase of the relative content of polyethylene glycol in the printing slurry can improve the radial strength of the prepared high biosafety heart scaffold, and reduce the porosity and degradation rate of the heart scaffold; while an increase in the relative amount of inorganic filler can increase the radial strength and degradation rate of the heart scaffold and decrease its porosity. The compatibility between the polylactic acid and the inorganic filler can be improved by increasing the polyethylene glycol, so that the polylactic acid and the inorganic filler are tightly combined, the radial strength of the heart stent is improved, but the porosity and the degradation rate are relatively low; the strength of the heart stent can be effectively improved by adding the inorganic filler, the degradation of the polylactic acid is promoted, and the degradation rate is improved. Therefore, in order to enable the prepared heart stent with high biological safety to have comprehensive and excellent performance, the mass ratio of the polylactic acid to the polyethylene glycol to the inorganic filler in the printing slurry is preferably 100 (0.2-0.6) to 10-30, and the heart stent prepared under the condition can simultaneously have relatively high radial strength, porosity and appropriate degradation rate and has high biological safety. In the comparative examples 3-4, because polyethylene glycol or inorganic filler is not added, the radial strength of the prepared heart stent is obviously lower than that of the heart stent prepared in the embodiment 1 of the invention, and the surface polyethylene glycol and the inorganic filler have important influence on the radial strength of the prepared heart stent, but the two have no influence.
Comparing example 1 with examples 14-15, it can be seen that the increase in the printing paste concentration can increase the radial strength of the prepared cardiac stent with high biosafety, and reduce the porosity and degradation rate thereof. Mainly because the printing slurry has higher concentration, the solvent content in the formed heart stent is lower, and the gaps formed after freeze drying are reduced, thereby improving the strength of the stent and reducing the degradation rate. Therefore, in order to enable the prepared heart stent with high biological safety to have comprehensive and excellent performance, the concentration of the printing slurry is preferably 1.3-1.5 g/mL, and the heart stent prepared under the condition can have relatively high radial strength, porosity and appropriate degradation rate and has high biological safety.
In conclusion, polylactic acid is prepared by a lactide ring-opening polymerization method, nano calcium phosphate and magnesium oxide are mixed and sintered to prepare an inorganic filler, the polylactic acid, polyethylene glycol and the inorganic filler are blended to prepare a printing slurry, a heart stent structure is formed by 3D printing, and the heart stent with high biosafety is obtained after freeze drying and dipping drug loading. Through the mode, the molecular weight of the polylactic acid can be adjusted, so that the polylactic acid has better mechanical property and degradation property; and the synergistic effect among the polylactic acid, the inorganic filler and the polyethylene glycol is utilized to effectively improve the strength of the prepared heart stent, so that the heart stent has proper degradation rate and higher biological safety. In addition, the high-biosafety heart stent prepared by the invention has higher radial strength, proper porosity and degradation time, and can meet the requirements of practical application.
It should be noted that, as will be understood by those skilled in the art, the pH of the reaction between the calcium nitrate solution and the ammonium hydrogen phosphate in step S2 may be 8 to 10, and the adjustment within this range does not affect the reaction and the sufficient precipitation of the product; in addition, the medicament in step S5 may be one or more of rapamycin, paclitaxel, heparin, aspirin, which may be adjusted according to the actual condition of the patient, and all fall within the protection scope of the present invention.
The above description is only for the purpose of illustrating the technical solutions of the present invention and is not intended to limit the same; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; all the equivalent structures or equivalent processes performed by using the contents of the specification and the drawings of the invention, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (10)
1. A method for manufacturing a heart stent with high biological safety is characterized by comprising the following steps:
s1, preparing polylactic acid by a lactide ring-opening polymerization method, dissolving the polylactic acid in 1, 4-dioxane, and fully stirring for later use;
s2, dropwise adding a calcium nitrate solution into an ammonium hydrogen phosphate solution according to a preset molar ratio, fully stirring, adjusting the pH value of the solution to 8-10, and filtering, washing, drying and calcining after the product is completely separated out to obtain nano tricalcium phosphate;
s3, fully and uniformly mixing the nano tricalcium phosphate obtained in the step S2 and a preset amount of magnesium oxide through wet ball milling, drying and sintering the obtained mixture to obtain a sintered body, and grinding and sieving the sintered body to obtain an inorganic filler;
s4, adding polyethylene glycol with a preset amount and the inorganic filler obtained in the step S3 into the polylactic acid solution obtained in the step S1, fully stirring, heating and concentrating, and performing ball milling and uniform mixing to obtain printing slurry with a preset concentration;
s5, forming the printing slurry obtained in the step S4 into a heart stent by adopting a 3D printing technology, and freeze-drying the heart stent to obtain a porous heart stent; and (3) immersing the porous heart stent into a drug solution with a preset concentration, taking out and drying after sufficient immersion to obtain the high-biosafety heart stent.
2. The method for manufacturing a cardiac stent with high biosafety according to claim 1, wherein: in step S1, the lactide ring-opening polymerization method for preparing polylactic acid includes the steps of:
s11, heating a levolactic acid monomer at 170 ℃ and 5kPa for dehydration under reduced pressure for 5h, adding 1wt% of stannous octoate as a catalyst, distilling lactide at 200 ℃ and 0.5kPa, and condensing to obtain crude lactide;
s12, washing and recrystallizing the crude lactide obtained in the step S11 in sequence to obtain purified levorotatory lactide;
s13, adding 1wt% of zinc acetylacetonate serving as a catalyst into the purified levorotatory lactide obtained in the step S12, heating to 130 ℃ in a nitrogen atmosphere, keeping the temperature for 12-36 hours, and performing ring-opening polymerization reaction; and centrifuging the product obtained by the ring-opening polymerization reaction, pouring supernatant into ice methanol, and filtering, washing and drying after the product is fully separated out to obtain the polylactic acid with the molecular weight of 40-70 ten thousand.
3. The method for manufacturing a cardiac stent with high biosafety according to claim 1, wherein: in step S2, the preset molar ratio of the calcium nitrate solution to the ammonium hydrogen phosphate solution is 3: 2.
4. The method for manufacturing a cardiac stent with high biosafety according to claim 1, wherein: in step S3, the mass ratio of the nano tricalcium phosphate to the magnesium oxide is (6-10): 1.
5. The method for manufacturing a cardiac stent with high biosafety according to claim 1, wherein: in step S3, the sintering temperature of the sintering treatment is 1200-1400 ℃, and the sintering time is 1-3 h.
6. The method for manufacturing a cardiac stent with high biosafety according to claim 1, wherein: in step S4, the mass ratio of the polylactic acid, the polyethylene glycol and the inorganic filler in the printing paste is 100 (0.2-0.6) to (10-30).
7. The method for manufacturing a cardiac stent with high biosafety according to claim 1, wherein: in step S4, the predetermined concentration of the printing paste is 1.3-1.5 g/mL.
8. The method for manufacturing a cardiac stent with high biosafety according to claim 1, wherein: in step S5, the concentration of the drug solution is 0.1 g/mL; the medicine is one or more of rapamycin, paclitaxel, heparin and aspirin.
9. A high biosafety heart stent, characterized in that: the cardiac stent with high biosafety is produced by the production method according to any one of claims 1 to 8.
10. The cardiac stent with high biosafety as set forth in claim 9, wherein: the radial strength of the high-biosafety heart scaffold is 196-253 kPa, the porosity is 23.0% -44.7%, and the degradation time is 12-24 months.
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