CN115845129A - Manufacturing process of large-size myocardial patch - Google Patents
Manufacturing process of large-size myocardial patch Download PDFInfo
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- CN115845129A CN115845129A CN202211557665.3A CN202211557665A CN115845129A CN 115845129 A CN115845129 A CN 115845129A CN 202211557665 A CN202211557665 A CN 202211557665A CN 115845129 A CN115845129 A CN 115845129A
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Abstract
The invention discloses a manufacturing process of a large-size myocardial patch, which comprises the following steps: (1) Screening water-soluble pore-forming agents with a certain particle size range, drying, and preparing a pore-forming agent bracket from the screened pore-forming agents by an alcohol immersion pressing method; (2) Filling the polymer solution into a pore-foaming agent bracket, and fully drying to remove the solvent to obtain a pore-foaming agent-polymer composite bracket; (3) Continuously slicing the pore-foaming agent-polymer composite scaffold by adopting a slicing machine to obtain a pore-foaming agent-polymer composite scaffold slice; (4) And (3) placing the pore-foaming agent-polymer composite scaffold sheet in deionized water, removing the pore-foaming agent, and then carrying out freeze drying to obtain the large-size myocardial patch with the communicated three-dimensional structure. The preparation process disclosed by the invention is high in stability and small in product shrinkage, and the prepared myocardial patch has better connectivity of internal holes.
Description
Technical Field
The invention relates to the technical field of biological materials, in particular to a manufacturing process of a large-size myocardial patch.
Background
In recent years, myocardial patches have made considerable progress in the treatment of myocardial infarction, heart failure, etc., and are considered as an effective therapeutic tool for improving ventricular remodeling. Compared with the traditional methods of medicine, cell therapy and the like, the myocardial patch can achieve the purposes of inhibiting left ventricular remodeling, relieving heart failure and improving or maintaining cardiac function by providing mechanical support for damaged myocardium, and on the other hand, the myocardial patch can be used as a carrier for carrying medicines, proteins and cells, so that the myocardial patch is a promising treatment scheme.
Common polymer/composite material myocardial patches are prepared by electrospinning, 3D printing, thermally induced phase separation, pore-forming method and the like.
The pore-forming agent method can stably prepare a three-dimensional structure with high porosity and high pore connectivity, and can well simulate the three-dimensional structure of the natural extracellular matrix. For example, as written in this group of subjects, chinese patent publication No. CN113425897A discloses a method for preparing an active oxygen-responsive degradable polyurethane heart patch for repairing myocardial infarction, and discloses an operation process for preparing a porous membrane as follows: dissolving polyurethane in tetrahydrofuran, dioxane or hexafluoroisopropanol, adding sodium chloride or gelatin particles into the polyurethane solution, pouring the solution into a polytetrafluoroethylene mold, and removing the solvent; and washing the sodium chloride or gelatin granules with water to obtain the polyurethane porous heart patch.
Although the small-size patch for small animal experiments is prepared from the materials, the preparation of the large-size and stable-quality polymer-based myocardial patch with practical application value is always a current research and development difficulty.
At present, only acellular matrix type myocardial patches prepared by Cormatrix Cardiovacular corporation of America are commercialized (reference: an off-the-shelf tissue heart muscle repair films and pigs, 2020), but the raw materials are expensive and the sources are single and limited. The synthesized myocardial patch has strong function controllability, wide raw material source and low cost, but has not been industrialized all the time.
Disclosure of Invention
The invention provides a manufacturing process of a large-size myocardial patch capable of being industrially produced, the quality controllability of a product prepared by the preparation process is high, and the connectivity of internal holes of the prepared myocardial patch is better.
The technical scheme of the invention is as follows:
a manufacturing process of a large-size myocardial patch comprises the following steps:
(1) Screening a water-soluble pore-foaming agent, drying, and pressing the screened pore-foaming agent into a pore-foaming agent bracket by an alcohol impregnation and compression method;
(2) Filling the polymer solution into a pore-foaming agent bracket, fully freezing and drying to remove the solvent to obtain a pore-foaming agent-polymer composite bracket;
(3) Continuously slicing the pore-foaming agent-polymer composite bracket by a machine to obtain a slice of a pore-foaming agent-polymer composite;
(4) Soaking the pore-foaming agent-polymer composite sheet in deionized water at 37-50 ℃, removing the pore-foaming agent, and then carrying out freeze drying to obtain the large-size myocardial patch with the communicated three-dimensional structure. Preferably, the pore-foaming agent is water-soluble protein particles; the size range of the sieved pore-foaming agent is 70-300 mu m.
Further, the pore-foaming agent is gelatin particles and/or collagen particles.
In the step (1), the pore-foaming agent screened out is pressed into a pore-foaming agent bracket by an alcohol dipping and pressing method, which comprises the following steps: drying pore-foaming agent at constant temperature, weighing a certain amount of pore-foaming agent particles according to the diameter of the needed bracket, pouring the pore-foaming agent particles into a mould for leveling, pouring alcohol water solution into the mould to immerse the pore-foaming agent particles, combining the moulds for one night, and putting the mould into an oven for drying to obtain the pore-foaming agent bracket with a certain thickness.
Further, the constant-temperature drying temperature is 25-40 ℃; the concentration of the alcohol water solution is 70-90%; the drying temperature of the oven is 40-70 ℃, and the drying time is 5-24 hours.
Under the condition, the bracket with moderate pore-foaming agent bonding strength and no scattering of the ultrasonic infiltration polymer solution can be prepared, and finally the myocardial patch with higher pore connectivity is obtained.
Furthermore, the pore-foaming agent bracket is a cylindrical pore-foaming agent bracket with the size of 40-100 mm and the thickness of 10-20 mm.
The polymer is a biocompatible polymer material. Preferably, the polymer is selected from Polycaprolactone (PCL), polypropylene Glycol Sebacate (PGS), polylactic acid-glycolic acid copolymer (PLGA), polylactic acid-co-caprolactone (PLCL), PC-3572D, PC-3555D, PC-3595A, PC-3585A and PC-3575A of Luborun Special chemical (Shanghai) Co., ltd, and the active oxygen-responsive degradable polyurethane.
The active oxygen-responsive degradable polyurethane can be prepared by a preparation method disclosed in Chinese patent document with publication number CN 113425897A.
The solvent of the polymer solution is at least one of 1, 4-dioxane, tetrahydrofuran and hexafluoroisopropanol; the concentration of the polymer in the polymer solution is 4 to 20wt%.
In the step (2), the polymer solution is filled into the pore-foaming agent bracket in the following mode: and immersing the stent into the polymer solution, and infiltrating by using a negative pressure method.
The infiltration conditions were: the infiltration temperature is 30-50 ℃, the infiltration time by the negative pressure method is 0.5-1 h, and the vacuum degree is 0.5-0.1 MPa.
The solvent removal mode in the step (2) is as follows: vacuum freeze drying at-40 deg.c for 12-24 hr.
In step (3), the slice thickness may be determined according to specific use conditions. Preferably, the thickness of the prepared pore-foaming agent-polymer composite bracket sheet is 0.5-1.2 mm.
Sectioning can be performed using a numerically controlled cryomicrotome. The slicing temperature is 0-37 ℃, the slicing speed is 20-200 mm/min, and the slicing angle is 1-6 ℃.
In the step (4), the freeze drying time is 12-36 h, and the freeze drying temperature is-40 to-20 ℃.
Compared with the prior art, the invention has the beneficial effects that:
(1) In the method disclosed in chinese patent publication No. CN113425897A, the pore-forming agent scaffold is not completely bonded, resulting in lower connectivity of partial pores inside the prepared myocardial patch, but the present invention makes the surface of the pore-forming agent slightly soluble by alcohol immersion-pressing method, and contacts and bonds, so as to improve connectivity of pores formed by the pore-forming agent, and when the connectivity of the pores inside the myocardial patch is higher during actual use, the present invention can improve transmission of nutrients and waste inside and outside the myocardial patch, and can better promote migration and growth of cells.
(2) According to the invention, the alcohol immersion pressing method is adopted to replace a pouring method to prepare the pore-foaming agent bracket, so that the dimensional stability of a thicker gelatin bracket can be improved, the dimensional error of a final patch product is reduced, the stability of a preparation process is improved, and the production period is greatly shortened.
(3) The invention adopts a vacuumizing mode to introduce the polymer solution, improves the infiltration capacity of the polymer solution on the pore-foaming agent bracket, removes air bubbles in the middle part, and ensures that the thicker pore-foaming agent bracket can be fully infiltrated, thereby improving the quality of the product.
(4) According to the invention, a machine slicing mode is adopted, and by controlling slicing parameters, the large-size myocardial patches can be produced in batches, so that the production efficiency is greatly improved, and the stability of the preparation process is improved.
Drawings
Fig. 1 is a myocardial patch prepared by the alcohol-immersion-slicing method in example 1;
fig. 2 is SEM images of cross sections of the myocardial patches prepared in example 1 and comparative example 1, in which (a) is example 1 and (b) is comparative example 1.
FIG. 3 is a schematic view of the mold used, wherein (a) is the upper mold cover and (b) is the lower mold groove.
Detailed Description
Example 1
A manufacturing process of a large-sized myocardial patch, as shown in fig. 1, comprises the following steps:
(1) Crushing and screening gelatin particles with the particle size of 100-200 mu m, drying for 6 hours at 37 ℃, pouring into a cylindrical mold with the diameter of 4cm, using 75% alcohol solution to immerse a pore-forming agent, combining the molds overnight, and drying in an oven for 5 hours at 50 ℃. A cylindrical gelatin stent with a diameter of 4cm and a thickness of 15mm was obtained.
(2) Filling a 10% tetrahydrofuran solution of PC-3572D (Lubomoisten) into the stent by a negative pressure method, wherein the temperature is 50 ℃, the time is 60 minutes, and the vacuum degree is 0.5MPa; removing the solvent by freeze drying after air is exhausted to obtain a pore-foaming agent-polymer compound, wherein the freeze drying temperature is-40 ℃, and the freeze drying time is 24 hours;
(3) The porogen-polymer composite scaffolds were cut into thin sections with a thickness of 0.6mm using a cryomicrotome, at a temperature of: 37 degrees, the slicing angle used is 1 degree, and the slicing speed is 100rpm/min (about 1mm of the two ends of the composite stent is discarded and not used);
(4) And (3) placing the pore-foaming agent-polymer compound slice in deionized water for constant-temperature ultrasonic treatment at the ultrasonic temperature of 50 ℃ for 20 minutes to remove the pore-foaming agent, and then freezing and drying the polymer slice to obtain the myocardial patch with the communicated three-dimensional structure, wherein the freeze-drying temperature is-40 ℃ and the freeze-drying time is 24 hours. The prepared myocardial patch is shown in fig. 1.
Example 2
A manufacturing process of a large-size myocardial patch comprises the following steps:
(1) Screening gelatin particles with the particle size of 70-150 mu m, drying at 30 ℃ for 12 hours, pouring the gelatin particles into a cylindrical mold with the diameter of 4cm, immersing a pore-forming agent in 90% alcohol solution, combining the molds overnight, and air-drying at normal temperature for 10 hours. Obtaining a cylindrical gelatin bracket with the diameter of 4cm and the thickness of 15 mm;
(2) Filling a 1, 4-dioxane solution of 10% PLCL (poly L-lactide-co-caprolactone, random copolymerization, proportion of 1) into a bracket by a negative pressure method, wherein the temperature is 37 ℃, the time is 30 minutes, and the vacuum degree is 0.3MPa; removing the solvent by freeze drying after air is exhausted to obtain a pore-foaming agent-polymer compound, wherein the freeze drying temperature is-40 ℃, and the freeze drying time is 16 hours;
(3) Cutting the porogenic agent-polymer compound into slices with the thickness of 1mm by using a slicer, wherein the slicing temperature is 20 ℃, the slicing speed is 60rpm/min, and the slicing angle is 2 ℃;
(4) And (3) placing the pore-foaming agent-polymer compound slice in deionized water for constant-temperature ultrasonic treatment at the ultrasonic temperature of 40 ℃ for 30 minutes to remove the pore-foaming agent, and then freezing and drying the polymer slice to obtain the myocardial patch with the communicated three-dimensional structure, wherein the freeze-drying temperature is-40 ℃ and the freeze-drying time is 36 hours.
Example 3
A manufacturing process of a large-size myocardial patch comprises the following steps:
(1) Crushing and screening gelatin particles with the particle size of 150-200 mu m, drying for 6 hours at 40 ℃, pouring into a cylindrical mold with the diameter of 6cm, immersing a pore-forming agent in 80% alcohol solution, combining the molds overnight, and drying in an oven at 70 ℃ for 2 hours. Obtaining a cylindrical gelatin bracket with the diameter of 6cm and the thickness of 15 mm;
(2) Filling 3595A (Lubomoisten) hexafluoroisopropanol solution with the concentration of 12% into the stent by an ultrasonic method, wherein the temperature is room temperature, the time is 120 minutes, and the vacuum degree is 0.1MPa; removing the solvent by freeze drying after air is exhausted to obtain a pore-foaming agent-polymer compound, wherein the freeze drying temperature is-80 ℃, and the freeze drying time is 24 hours;
(3) Cutting the porogenic agent-polymer compound into slices with the thickness of 1mm by using a slicer, wherein the slicing temperature is 0 ℃, the slicing speed is 120rpm/min, and the slicing angle is 4 ℃;
(4) And (3) placing the pore-foaming agent-polymer compound slice in deionized water for constant-temperature ultrasonic treatment at the ultrasonic temperature of 60 ℃ for 25 minutes to remove the pore-foaming agent, and then freezing and drying the polymer slice to obtain the myocardial patch with the communicated three-dimensional structure, wherein the freeze-drying temperature is-40 ℃ and the freeze-drying time is 48 hours.
Comparative example 1
The preparation method is disclosed in the patent document with the publication number CN 113425897A. The particle leaching method comprises the following steps: dissolving 3572D in dioxane to obtain 10% solution, adding gelatin particles of 180-250 μm in 50% volume, pouring the solution into polytetrafluoroethylene mold, removing solvent, and washing with water to obtain porous myocardial patch.
In the preparation method of comparative example 1, the porogen scaffold is not completely bonded, resulting in low connectivity of the pores in the interior of the prepared myocardium patch (as shown in (b) of fig. 2), while example 1 can improve the connectivity of the pores formed by the porogen by alcohol-soaking and pressing (as shown in (a) of fig. 2). In practical use, the high connectivity of the internal holes of the myocardial patch can improve the transmission of nutrients and wastes inside and outside the myocardial patch, and can better promote the migration and growth of myocardial cells.
The properties of the myocardial patches prepared in comparative example 1 and example 1 are shown in table 1:
TABLE 1
In the embodiment 1, a product with the patch shrinkage rate of almost 0 can be prepared by adopting an alcohol immersion pressing method, and meanwhile, the obtained patch has smaller modulus measurement error, so that the quality and the dimensional stability of the product are ensured, the process period is greatly shortened, and the production efficiency is improved.
The above-mentioned embodiments are intended to illustrate the technical solutions and advantages of the present invention, and it should be understood that the above-mentioned embodiments are only specific embodiments of the present invention, and are not intended to limit the present invention, and any modifications, additions, equivalents, etc. made within the scope of the principles of the present invention should be included in the scope of the present invention.
Claims (10)
1. The manufacturing process of the large-size myocardial patch is characterized by comprising the following steps of:
(1) Screening a water-soluble pore-foaming agent, drying, and pressing the screened pore-foaming agent into a pore-foaming agent bracket by an alcohol impregnation and compression method;
(2) Filling the polymer solution into a pore-foaming agent bracket, fully freezing and drying to remove the solvent to obtain a pore-foaming agent-polymer composite bracket;
(3) Slicing the pore-foaming agent-polymer composite bracket to obtain a slice of a pore-foaming agent-polymer composite;
(4) Soaking the pore-foaming agent-polymer composite sheet in deionized water at 37-50 ℃, removing the pore-foaming agent, and then carrying out freeze drying to obtain the large-size myocardial patch with the communicated three-dimensional structure.
2. The process for manufacturing a large-size myocardial patch according to claim 1, wherein the pore-forming agent is water-soluble protein particles; the size range of the sieved pore-foaming agent is 70-300 mu m.
3. The manufacturing process of the large-size myocardial patch according to claim 1, wherein in the step (1), the sieved pore-foaming agent is pressed into a pore-foaming agent bracket by an alcohol leaching and pressing method, and the manufacturing process comprises the following steps: and drying the pore-foaming agent at constant temperature, weighing a certain amount of pore-foaming agent particles according to the diameter of the required bracket, pouring the pore-foaming agent particles into a mold for leveling, pouring an alcohol water solution into the mold to immerse the pore-foaming agent particles, combining the molds overnight, and putting the molds into an oven for drying to obtain the thickness pore-foaming agent bracket.
4. The manufacturing process of the large-size myocardial patch according to claim 3, wherein the constant-temperature drying temperature is 25-40 ℃; the concentration of the alcohol water solution is 70-90%; the drying temperature of the drying oven is 40-70 ℃, and the drying time is 5-24 hours.
5. The manufacturing process of the large-size myocardial patch according to claim 1, wherein the polymer is selected from polycaprolactone, polytrimethylene sebacate, polylactic acid-glycolic acid copolymer, polylactic acid-co-caprolactone, reactive oxygen-responsive degradable polyurethane, PC-3572D, PC-3555D, PC-3595A, PC-3585A, and PC-3575A of luobo special chemical (shanghai) ltd.
6. The process for manufacturing a large-sized myocardial patch according to claim 1, wherein the polymer solution has a polymer concentration of 4 to 20wt%.
7. The manufacturing process of the large-size myocardial patch according to claim 1, wherein in the step (2), the polymer solution is filled into the pore-foaming agent bracket in a manner that: and immersing the stent into the polymer solution, and infiltrating by using a negative pressure method.
8. The manufacturing process of the large-size myocardial patch according to claim 7, wherein the infiltration conditions are as follows: the infiltration temperature is 30-50 ℃, the infiltration time by the negative pressure method is 0.5-1 h, and the vacuum degree is 0.5-0.1 MPa.
9. The manufacturing process of the large-size myocardial patch according to claim 1, wherein in the step (3), the slicing temperature is 0-37 ℃, the slicing speed is 20-200 rpm/min, and the slicing angle is 1-6 degrees; the thickness of the prepared pore-foaming agent-polymer composite bracket sheet is 0.5-1.2 mm.
10. The manufacturing process of the large-size myocardial patch according to claim 1, wherein in the step (4), the freeze-drying time is 12-36 h, and the freeze-drying temperature is-40 ℃ to-20 ℃.
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| CN113425897A (en) * | 2021-06-25 | 2021-09-24 | 浙江大学 | Active oxygen responsiveness degradable polyurethane heart patch for myocardial infarction repair and preparation method thereof |
| CN114191615A (en) * | 2021-12-21 | 2022-03-18 | 浙江大学 | Multilayer composite material for promoting repair of articular cartilage-calcified layer-subchondral bone and preparation method thereof |
-
2022
- 2022-12-06 CN CN202211557665.3A patent/CN115845129A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101176799A (en) * | 2007-12-06 | 2008-05-14 | 同济大学 | Method for preparing polyalcohol stephanoporate bracket for tissue project by poragen agglutinating filtering off method |
| US20110111004A1 (en) * | 2008-05-27 | 2011-05-12 | Davide Barbieri | Osteoinductive nanocomposites |
| CN113425897A (en) * | 2021-06-25 | 2021-09-24 | 浙江大学 | Active oxygen responsiveness degradable polyurethane heart patch for myocardial infarction repair and preparation method thereof |
| CN114191615A (en) * | 2021-12-21 | 2022-03-18 | 浙江大学 | Multilayer composite material for promoting repair of articular cartilage-calcified layer-subchondral bone and preparation method thereof |
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