Controllable dissolution microsphere preparation method based on sodium alginate and pectin

Abstract

The invention relates to the technical field of high polymer materials, and provides a controllable dissolution microsphere preparation method based on sodium alginate and pectin, which comprises the following steps: obtaining a sodium alginate solution and a pectin solution, mixing the sodium alginate solution and the pectin solution based on a first preset proportion, and uniformly stirring and mixing by using preset stirring equipment, mixing a pre-constructed calcium chloride aqueous solution and absolute ethyl alcohol based on a second preset proportion, uniformly stirring and mixing through stirring equipment to obtain a cross-linking agent solution, dropwise adding the mixed gel solution into the cross-linking agent solution through a preset dropwise adding method, obtaining mixed gel beads in the cross-linking agent solution, and drying the mixed gel beads in a drying oven to obtain the hydrogel. And washing the mixed microgel beads to obtain the controllably dissolved microspheres. The invention mainly aims to solve the problems that pectin microspheres are different in shape and low in mechanical strength and are not suitable for cell culture and sodium alginate microspheres are still long in dissolving time when the concentration of a dissolving agent is high, and meanwhile, the microspheres which are high in pelletizing rate and controllable in dissolution are prepared.

Description

Technical Field

[0001] The invention relates to a method for preparing controllably dissolvable microspheres based on sodium alginate and pectin, and belongs to the technical field of polymer materials. Background Art

[0002] Biopharmaceuticals usually use cells as production plants for large-scale cell culture, and the cultured cells produce target products such as monoclonal antibodies, viruses, and exosomes. Cell culture microsphere carriers are nanoscale particles with a three-dimensional structure that can provide support for the attachment and growth of adherent cells. Compared with traditional two-dimensional structure culture, the combination of cell culture microcarriers and bioreactors can achieve a large number of cell proliferation in a short period of time while maintaining their specific morphology and phenotype. However, the microcarriers currently sold on the market still have many shortcomings in scientific research and clinical applications. For example, after the cells grow and spread on the surface of the microspheres, the digested cells cannot be separated from the microspheres, resulting in a high cell loss rate when harvesting cells.

[0003] Pectin calcium gel has become one of the most studied biogels due to its easy preparation and good biocompatibility. It is widely used in the fields of drug delivery, heavy metal adsorption and cell immobilization. However, the prepared pectin calcium microspheres are not suitable for cell culture due to their different shapes and low mechanical strength. On the contrary, sodium alginate microspheres have good mechanical strength, but they require not only high concentrations of EDTA but also a very long action time (about 1-2 hours) to completely dissolve. For applications such as embedding cells, it is easy to damage cells, resulting in extremely low cell harvest rates. Among them, alginate and pectin are both natural polyanionic polysaccharides with similar structures, and can combine with divalent ions such as calcium and magnesium to form gels. Therefore, there is an urgent need for a method for preparing controllable dissolution microspheres based on sodium alginate and pectin that combines the advantages of sodium alginate and pectin. Summary of the invention

[0004] The present invention provides a method, device and computer-readable storage medium for preparing controllably dissolvable microspheres based on sodium alginate and pectin, the main purpose of which is to solve the problems that pectin microspheres have different shapes and low mechanical strength and are not suitable for cell culture, and that sodium alginate microspheres are difficult to dissolve, and at the same time, to prepare microspheres with high spherification rate and controllably dissolvable microspheres.

[0005] To achieve the above object, the present invention provides a method for preparing controllably dissolvable microspheres based on sodium alginate and pectin, comprising:

[0006] Obtaining sodium alginate solution and pectin solution as preparation raw materials, wherein the sodium alginate solution has a concentration of 1-3%, and the pectin solution has a concentration of 1-6%;

[0007] The sodium alginate solution and the pectin solution are mixed based on a first preset ratio, and are stirred and mixed uniformly using a preset stirring device to obtain a mixed gel solution, wherein the first preset ratio is a volume ratio, and the volume ratio of the mixed sodium alginate solution and the pectin solution is 4-1:1-4;

[0008] The pre-constructed calcium chloride aqueous solution and anhydrous ethanol are mixed based on a second preset ratio, and the mixture is stirred and mixed uniformly by the stirring device to obtain a cross-linking agent solution, wherein the calcium chloride aqueous solution has a concentration of 1-9% and is mixed with anhydrous ethanol in a second preset ratio, and the second preset ratio is mixed in a volume ratio of 1-6:1;

[0009] The mixed gel solution is dripped into the cross-linking agent solution by a preset dripping method, and mixed gel beads are obtained in the cross-linking agent solution, wherein the preset dripping method is a high-voltage electrostatic spray method, the flow rate used is 1-5 ml / min, the voltage is 2-20 KV, and the electrode distance is 2.5-5 cm;

[0010] The mixed microgel beads are washed to obtain controllably dissolving microspheres, wherein the mixed microgel beads are washed with sterile purified water, the diameter of the mixed microgel beads is 10-1000 um, and the shape is spherical or quasi-spherical.

[0011] Optionally, the mixed microgel beads can achieve controllable dissolution, and the method further comprises:

[0012] Take 1 ml of the controllably dissolvable microspheres and add 4-10 ml of the dissolving agent, and observe the dissolution of the controllably dissolving microspheres, and detect the dissolution of the mixed microgel beads, wherein the dissolving agent is EDTA or sodium citrate chelating agent, the concentration of the EDTA or sodium citrate is 4mM-20mM, and the dissolution time is 20s-3min.

[0013] Optionally, the mixed microgel beads have high mechanical strength, and the method further comprises:

[0014] 4 ml of the sterilized controllably soluble microspheres were extracted and added to 50 ml of culture medium, and then transferred to a 125 ml magnetic stirring bottle for stirring. The microsphere carriers were continuously stirred at a high speed of 40-80 rpm in the culture medium and could remain free of cracks or breakage for 30 days, thereby verifying that the prepared microspheres had high mechanical strength.

[0015] Optionally, before obtaining the sodium alginate solution and the pectin solution as preparation raw materials, the method further comprises:

[0016] Obtaining a test sample from the sodium alginate solution to obtain a sodium alginate solution sample;

[0017] Adding deionized water and solid sodium carbonate to the sodium alginate solution sample, and heating with stirring at 80-90° C. for 1.5-3 hours to obtain a mixed sodium alginate solution sample;

[0018] Centrifuging the mixed sodium alginate solution sample and retaining the supernatant to obtain the sodium alginate solution to be tested;

[0019] Add the sodium alginate solution to be tested into a reaction container, add concentrated hydrochloric acid and phloroglucinol colorimetric solution, shake well, and perform colorimetric reaction in a boiling water bath for 40-50 minutes to obtain a colorimetric reaction solution;

[0020] After the color development reaction solution is fixed to volume, the absorbance of the color development reaction solution is measured at a wavelength of 420-460nm, and the concentration of sodium alginate in the sodium alginate solution is calculated according to the standard curve. When the concentration of sodium alginate in the sodium alginate solution reaches the preset concentration requirement, the test is passed.

[0021] Optionally, the sodium alginate solution and the pectin solution are mixed based on a first preset ratio, and are stirred and mixed uniformly using a preset stirring device to obtain a mixed gel solution, comprising:

[0022] Obtaining the stirring speed and stirring time of the mixed gel solution;

[0023] The sodium alginate solution and the pectin solution are mixed based on a first preset ratio to obtain a mixed solution, and the mixed solution is stirred by starting the stirring device, and the stirring speed is gradually adjusted to the stirring speed, and the mixed solution is observed to see whether there is agglomeration and precipitation, and the stirring speed is adjusted according to whether there is agglomeration and precipitation;

[0024] Stirring for the stirring time, turning off the stirring device, and taking samples to check the uniformity of the mixed solution. When the uniformity of the mixed solution reaches a preset requirement, the mixed gel solution is obtained.

[0025] Optionally, washing the mixed microgel beads to obtain controllably dissolvable microspheres comprises:

[0026] Taking a preset volume of washing solution, placing the collected mixed microgel beads into the washing solution, gently stirring or shaking, and separating the solution from the microgel beads by filtering, and discarding the washing solution;

[0027] Repeat the above steps for a preset number of times until there are no more impurities in the washing solution, thereby obtaining initial controllably dissolvable microspheres;

[0028] The microsphere variation coefficient value of the initial controllably dissolvable microspheres is obtained by measuring the diameter of the initial controllably dissolvable microspheres, and when the microsphere variation coefficient value is less than a preset variation threshold, the controllably dissolvable microspheres are obtained.

[0029] Optionally, the obtaining the microsphere variation coefficient value of the initial controllably dissolvable microspheres by measuring the diameter of the initial controllably dissolvable microspheres comprises:

[0030] Optical photographs of the controllably dissolvable microspheres before and after washing were taken using an industrial microscope. When measuring the diameter of the microspheres, at least 100 microspheres were measured for each condition, and the coefficient of variation (CV) of the microspheres was calculated according to the following formula:

[0031]

[0032] in, is the average diameter of the controllable dissolution microspheres, d i is the diameter of the ith controllably dissolvable microsphere, and n is the number of the measured controllably dissolvable microspheres.

[0033] Optionally, the stirring device is a magnetic stirrer.

[0034] Optionally, before obtaining the microsphere variation coefficient value of the initial controllably dissolving microspheres by measuring the diameter of the initial controllably dissolving microspheres, the method further comprises:

[0035] The volume change rate of the initial controllably dissolvable microspheres before washing and after washing is calculated by the following formula:

[0036]

[0037] Wherein, V is the volume change rate of the initial controllably dissolving microspheres before and after washing, D a is the average diameter of the initial controllably dissolvable microspheres before washing, D b is the average diameter of the initial controllably dissolvable microspheres after washing;

[0038] When the volume change rate is greater than or equal to a preset volume change threshold, the washing time of the controllably dissolvable microspheres is reduced or a washing solution is reconfigured for the initial controllably dissolvable microspheres.

[0039] In order to solve the above problem, the present invention further provides an electronic device, the electronic device comprising:

[0040] at least one processor; and,

[0041] a memory communicatively connected to the at least one processor; wherein,

[0042] The memory stores instructions that can be executed by the at least one processor, and the instructions are executed by the at least one processor to implement the above-mentioned method for preparing controllable dissolution microspheres based on sodium alginate and pectin.

[0043] In order to solve the above problems, the present invention also provides a computer-readable storage medium, in which at least one instruction is stored. The at least one instruction is executed by a processor in an electronic device to implement the above-mentioned method for preparing controllable dissolution microspheres based on sodium alginate and pectin.

[0044] Compared with the problems described in the background technology, the present invention first obtains sodium alginate solution and pectin solution as preparation raw materials, wherein the sodium alginate solution has a concentration of 1-3%, and the pectin solution has a concentration of 1-6%. It can be seen that the present invention adopts a mixed solution of sodium alginate solution and pectin solution, rather than a single pectin solution or sodium alginate solution to prepare microspheres, thereby solving the problems that pectin microspheres have different shapes and low mechanical strength and are not suitable for cell culture, and that sodium alginate microspheres are difficult to dissolve. Thereafter, the sodium alginate solution and the pectin solution are mixed based on a first preset ratio, and are stirred and mixed uniformly using a preset stirring device to obtain a mixed gel solution, wherein the first preset ratio is a volume ratio, and the volume ratio of the mixed sodium alginate solution and the pectin solution is 4-1:1-4. It can be seen that in order to reflect the advantages of the two materials, the present invention sets a strict concentration standard. Then, the pre-constructed calcium chloride aqueous solution and anhydrous ethanol are mixed based on a second preset ratio, and are stirred and mixed uniformly by the stirring device to obtain a cross-linking agent solution, wherein the calcium chloride aqueous solution has a concentration of 1-9%, and is mixed with anhydrous ethanol in a second preset ratio, and the second preset ratio is mixed in a volume ratio of 1-6:1; in order to prepare microspheres with good shape, uniform particle size and high mechanical strength, a cross-linking agent solution of suitable concentration is prepared. Thereafter, the mixed gel solution is dripped into the cross-linking agent solution by a preset dripping method, and mixed gel beads are obtained in the cross-linking agent solution, wherein the preset dripping method is a high-voltage electrostatic spray method, the flow rate used is 1-5ml / min, the voltage is 2-20KV, and the electrode distance is 2.5-5cm. Finally, the mixed microgel beads are washed to obtain controllably dissolving microspheres, wherein the mixed microgel beads are washed by sterile purified water, the diameter of the mixed microgel beads is 10-1000um, and the shape is spherical or quasi-spherical. It can be seen that the present invention not only formulates specific conditions in the microsphere preparation process, but also considers the concentration of each component to be adjusted in combination with the actual situation and the performance requirements of the target product, thereby obtaining controllably dissolving microspheres that meet the experimental requirements. Therefore, the method, device, electronic device and computer-readable storage medium for preparing controllable dissolution microspheres based on sodium alginate and pectin proposed in the present invention mainly aim to solve the problems that pectin microspheres have different shapes and low mechanical strength and are not suitable for cell culture, and that sodium alginate microspheres are difficult to dissolve, and at the same time, prepare microspheres with high spherification rate and controllable dissolution. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 A schematic flow chart of a method for preparing controllably dissolvable microspheres based on sodium alginate and pectin provided in one embodiment of the present invention;

[0046] Figure 2 Optical microscopy images of controllable dissolution microspheres prepared at different voltages;

[0047] Figure 3This is an optical microscope image of calcium pectin microspheres prepared in Comparative Example 1;

[0048] Figure 4 This is an optical microscope image of the calcium alginate cross-linked microspheres prepared in Comparative Example 2;

[0049] Figure 5 An optical microscope image of the controllably dissolvable microspheres prepared in an embodiment of the present invention;

[0050] Figure 6 This is an optical microscope image of the stability and mechanical strength test of mixed microspheres prepared with 4% pectin and 1% sodium alginate in culture medium in Comparative Example 3;

[0051] Figure 7 Optical microscope images of the controllably dissolving microspheres prepared in an embodiment of the present invention in the experiment of determining the stability and mechanical strength in the culture medium;

[0052] Figure 8 A schematic diagram of the structure of an electronic device for implementing the method for preparing controllable dissolving microspheres based on sodium alginate and pectin provided in one embodiment of the present invention.

[0053] The purpose, features and advantages of the present invention will be further described with reference to the accompanying drawings in conjunction with the embodiments. DETAILED DESCRIPTION

[0054] It should be understood that the specific embodiments described herein are only used to explain the present invention, and are not used to limit the present invention.

[0055] The embodiment of the present application provides a method for preparing controllably dissolving microspheres based on sodium alginate and pectin. The execution subject of the method for preparing controllably dissolving microspheres based on sodium alginate and pectin includes but is not limited to at least one of the electronic devices such as a server and a terminal that can be configured to execute the method provided in the embodiment of the present application. In other words, the method for preparing controllably dissolving microspheres based on sodium alginate and pectin can be executed by software or hardware installed on a terminal device or a server device. The server includes but is not limited to: a single server, a server cluster, a cloud server or a cloud server cluster, etc.

[0056] Embodiment 1:

[0057] Reference Figure 1 FIG. 1 is a flow chart of a method for preparing controllably dissolving microspheres based on sodium alginate and pectin according to an embodiment of the present invention. In this embodiment, the method for preparing controllably dissolving microspheres based on sodium alginate and pectin comprises:

[0058] S1. Obtaining sodium alginate solution and pectin solution as preparation raw materials, wherein the sodium alginate solution has a concentration of 1-3%, and the pectin solution has a concentration of 1-6%.

[0059] It is understandable that when preparing microspheres using sodium alginate solution and pectin solution as raw materials, the advantages of both can be combined by adjusting the concentration and process during preparation. The embodiments of the present invention mainly solve the problems that the prepared calcium pectin microspheres have different shapes and low mechanical strength and are not suitable for cell culture, and that the prepared sodium alginate microspheres are difficult to dissolve, and when the embedded cells are harvested, the cells are easily damaged, resulting in a low cell harvest rate.

[0060] In the embodiment of the present invention, the sodium alginate solution is an important material in the preparation of cell microspheres, and has the advantages of low toxicity, mild ion crosslinking conditions, good biocompatibility and biodegradability. Micron-sized alginate microgel balls are often used to encapsulate living cells in drug research, tissue engineering and regenerative medicine. This microgel ball disperses cells in independent regions, providing an effective strategy for the study of cell metabolism. The pectin solution can also be used to prepare cell microspheres, and also has good biocompatibility and biodegradability. However, the pectin solution and the sodium alginate solution each have advantages and disadvantages when preparing cell microspheres, so it is necessary to use the two in combination to avoid the disadvantages of the two and highlight the advantages of the two.

[0061] Furthermore, before obtaining the sodium alginate solution and the pectin solution as the preparation raw materials, the method comprises:

[0062] Obtaining a test sample from the sodium alginate solution to obtain a sodium alginate solution sample;

[0063] Adding deionized water and solid sodium carbonate to the sodium alginate solution sample, and heating with stirring at 80-90° C. for 1.5-3 hours to obtain a mixed sodium alginate solution sample;

[0064] Centrifuging the mixed sodium alginate solution sample and retaining the supernatant to obtain the sodium alginate solution to be tested;

[0065] Add the sodium alginate solution to be tested into a reaction container, add concentrated hydrochloric acid and phloroglucinol colorimetric solution, shake well, and perform colorimetric reaction in a boiling water bath for 40-50 minutes to obtain a colorimetric reaction solution;

[0066] After the color development reaction solution is fixed to volume, the absorbance of the color development reaction solution is measured at a wavelength of 420-460nm, and the concentration of sodium alginate in the sodium alginate solution is calculated according to the standard curve. When the concentration of sodium alginate in the sodium alginate solution reaches the preset concentration requirement, the test is passed.

[0067] The reaction container may be a test tube, a centrifuge tube, a beaker, or other laboratory containers suitable for conducting the reaction, and the preset concentration requirement may be 1-3%.

[0068] It is understandable that in order to ensure that the concentration of the obtained pectin solution also meets the requirements, a method similar to the above-mentioned concentration determination method can be adopted for the pectin solution according to the characteristics of the pectin solution, so it will not be described in detail here.

[0069] S2. Mix the sodium alginate solution and the pectin solution based on a first preset ratio, and use a preset stirring device to stir and mix them evenly to obtain a mixed gel solution, wherein the first preset ratio is a volume ratio, and the volume ratio of the mixed sodium alginate solution and the pectin solution is 4-1:1-4.

[0070] It is understandable that the stirring device is a magnetic stirrer, which utilizes a rotating magnetic field to drive a magnetic stirrer, can achieve uniform mixing of liquids, and also has an adjustable stirring speed and heating function. When it is used to prepare a mixed gel solution of pectin gel solution and sodium alginate solution, it can ensure that the solution is uniformly mixed, providing a good foundation for subsequent microsphere preparation.

[0071] Furthermore, the sodium alginate solution and the pectin solution are mixed based on a first preset ratio, and are stirred and mixed uniformly using a preset stirring device to obtain a mixed gel solution, including:

[0072] Obtaining the stirring speed and stirring time of the mixed gel solution;

[0073] The sodium alginate solution and the pectin solution are mixed based on a first preset ratio to obtain a mixed solution, and the mixed solution is stirred by starting the stirring device, and the stirring speed is gradually adjusted to the stirring speed, and the mixed solution is observed to see whether there is agglomeration and precipitation, and the stirring speed is adjusted according to whether there is agglomeration and precipitation;

[0074] Stirring for the stirring time, turning off the stirring device, and taking samples to check the uniformity of the mixed solution. When the uniformity of the mixed solution reaches a preset requirement, the mixed gel solution is obtained.

[0075] Optionally, other stirring equipment may be used to stir the mixed solution of the sodium alginate solution and the pectin solution to obtain a mixed gel solution. Other technologies may also be used to achieve the same effect, which will not be described in detail again.

[0076] In other embodiments of the present invention, when the microspheres are prepared by using sodium alginate solution and pectin solution in other mixing ratios, the experimental phenomena shown in Table 1 below will be caused:

[0077]

[0078] Table 1

[0079] It can be seen that when the microspheres are prepared by using the 1% sodium alginate solution and the 2% pectin solution in the embodiment of the present invention, the problems that the prepared calcium pectin microspheres have different shapes and low mechanical strength and are not suitable for cell culture, and the prepared sodium alginate microspheres are difficult to dissolve, and the cells are easily damaged when the embedded cells are harvested, resulting in a low cell harvest rate can be solved.

[0080] Furthermore, the sodium alginate solution and the pectin solution may be mixed in other ratios, such as a mass ratio of 2:1.

[0081] S3. The pre-constructed calcium chloride aqueous solution and anhydrous ethanol are mixed based on a second preset ratio, and the mixture is stirred and mixed evenly by the stirring device to obtain a cross-linking agent solution, wherein the calcium chloride aqueous solution has a concentration of 1-9% and is mixed with anhydrous ethanol in a second preset ratio, and the second preset ratio is mixed in a volume ratio of 1-6:1.

[0082] It is understood that the crosslinker solution is a chemical solution used to form chemical bonds or physical entanglements between molecular chains, thereby improving the stability and mechanical properties of the material. The crosslinker prepared by calcium chloride aqueous solution and anhydrous ethanol plays a key crosslinking role when the sodium alginate solution and pectin solution are mixed to prepare microspheres. By forming calcium ion bridges with the carboxyl groups in sodium alginate and pectin, the mechanical strength and stability of the microspheres are enhanced. At the same time, the addition of ethanol helps to improve the surface tension, permeability and sphericity of the gelation bath, thereby preparing microspheres with good shape, uniform particle size and high mechanical strength, which are suitable for fields such as cell culture and tissue engineering.

[0083] Furthermore, the calcium chloride aqueous solution and anhydrous ethanol can be mixed in other proportions to prepare the crosslinker solution. However, when the calcium chloride aqueous solution and anhydrous ethanol are mixed in other proportions to prepare the crosslinker solution, the activity of the crosslinker solution may be changed, thereby changing the reaction efficiency and crosslinking density with the mixed gel solution, and also causing the physicochemical properties (such as viscosity and surface tension) of the crosslinker solution to change, affecting the formation and stability of the microspheres.

[0084] S4. Dropping the mixed gel solution into the cross-linker solution by a preset dropping method, and obtaining mixed gel beads in the cross-linker solution, wherein the preset dropping method is a high-voltage electrostatic spray method, the flow rate used is 1-5 ml / min, the voltage is 2-20 KV, and the electrode distance is 2.5-5 cm.

[0085] It should be understood that the process of dripping the mixed gel solution into the cross-linker solution to form gel beads is intended to quickly construct a stable three-dimensional gel structure through an ionic cross-linking reaction to prepare gel microspheres with specific release characteristics, biocompatibility and mechanical strength. These microspheres are widely used in drug delivery, cell encapsulation and tissue engineering to achieve controlled release and protection of bioactive molecules, while providing a form that is easy to operate, store and transport.

[0086] In other embodiments of the present invention, microspheres under different voltages were prepared by adjusting the voltage of the high voltage power supply, and the effect of voltage on the shape, particle size and distribution of the microspheres was investigated using an optical microscope and a laser particle size analyzer as shown in Table 2 and Figure 2 :

[0087]

[0088] Table 2

[0089] It is understandable that the table lists the experimental conditions for preparing microspheres under different voltages (KV) and the corresponding average particle size (μm). Figure 2 , we can intuitively see the effect of voltage change on the particle size of microspheres, providing a quantitative basis for understanding how voltage affects the microsphere preparation process.

[0090] Comparative Example 1

[0091] This embodiment is a method for preparing calcium pectin microspheres by dripping method, comprising the following steps:

[0092] (1) Preparing a pectin gel solution: preparing a 4% pectin solution, and stirring with a magnetic stirrer to completely dissolve the pectin solution;

[0093] (2) preparing a crosslinker solution: preparing a crosslinker solution by mixing a 3% calcium chloride aqueous solution and anhydrous ethanol, and stirring the crosslinker solution using a magnetic stirrer, wherein the volume ratio of the calcium chloride aqueous solution to the anhydrous ethanol is 1:1;

[0094] (3) preparing microsphere beads: dripping the pectin gel solution prepared in step 1 into the crosslinking agent solution prepared in step 2 by a dripping method to react and generate pectin microgel beads;

[0095] (4) Washing: To remove excess calcium chloride solution, the pectin microgel beads are washed 2-3 times with sterile purified water to obtain pectin calcium microspheres.

[0096] The prepared calcium pectin microspheres cannot be completely spherical, but have cracks or breakages. Figure 3 As shown:

[0097] It can be seen that the pectin calcium microspheres prepared by the dripping method have irregular shapes and uneven particle size distribution. Figure 3 As shown, it cannot become a complete spherical shape and has cracks or damage. If prepared by electrostatic spraying, the force that the gel solution needs to withstand is much greater than that of the dripping method, and the breakage is more serious. Therefore, the mechanical strength of pure pectin microspheres is far inferior to that of the microspheres prepared by mixing the two materials. It cannot withstand a certain mechanical stress. The stirring process must be carried out in cell culture. Therefore, pure pectin microspheres cannot be used for magnetic stirring bottle cell culture.

[0098] S5. Wash the mixed microgel beads to obtain controllably dissolvable microspheres, wherein the mixed microgel beads are washed with sterile purified water, the diameter of the mixed microgel beads is 10-1000 um, and the shape is spherical or quasi-spherical.

[0099] It should be understood that, optionally, the sterile purified water is used as a washing solution for washing the mixed microgel beads. Other technologies can achieve the same effect, which will not be described in detail here.

[0100] Furthermore, the washing of the mixed microgel beads to obtain controllably dissolvable microspheres comprises:

[0101] Step A, taking a preset volume of washing solution, placing the collected mixed microgel beads into the washing solution, gently stirring or shaking, and separating the solution from the microgel beads by filtering, and discarding the washing solution;

[0102] Step B, repeating the above step A for a preset number of times until there are no more impurities in the washing solution, thereby obtaining initial controllably dissolvable microspheres;

[0103] Step C, obtaining the microsphere variation coefficient value of the initial controllably dissolvable microspheres by measuring the diameter of the initial controllably dissolvable microspheres, and obtaining the controllably dissolvable microspheres when the microsphere variation coefficient value is less than a preset variation threshold.

[0104] It should be explained that after washing the mixed microgel beads to obtain controllably dissolvable microspheres, the method further comprises:

[0105] 4 ml of the sterilized controllably soluble microspheres were extracted and added to 50 ml of culture medium to obtain cell culture microsphere carriers, which were then transferred to a 125 ml magnetic stirring bottle for stirring. The cell culture microsphere carriers were continuously stirred at a high speed of 40-80 rpm in the culture medium and could remain free of cracks or breakage for 30 days, thereby verifying that the prepared microspheres had high mechanical strength.

[0106] In the embodiment of the present invention, the microspheres have a transparent spherical or spherical appearance.

[0107] It is understandable that the controllably dissolved microspheres are obtained by washing the mixed microgel beads and adding them to the culture medium for cell culture. This process not only provides a three-dimensional growth environment that simulates the extracellular matrix, but also verifies the efficiency and biocompatibility of the microspheres as cell culture carriers by adjusting the culture conditions and monitoring cell growth, thereby playing an important role in drug screening, tissue engineering, and regenerative medicine.

[0108] Further, the measuring the diameter of the initial controllably dissolvable microspheres to obtain the microsphere variation coefficient value of the initial controllably dissolvable microspheres comprises:

[0109] Optical photographs of the controllably dissolvable microspheres before and after washing were taken using an industrial microscope. When measuring the diameter of the microspheres, at least 100 microspheres were measured for each condition, and the coefficient of variation (CV) of the microspheres was calculated according to the following formula:

[0110]

[0111] in, is the average diameter of the controllable dissolution microspheres, d i is the diameter of the ith controllably dissolvable microsphere, and n is the number of the measured controllably dissolvable microspheres.

[0112] It should be understood that after washing the mixed microgel beads to obtain controllably dissolvable microspheres, the method further comprises:

[0113] Take 1 ml of the controllably dissolvable microspheres and add 4 ml of the dissolving agent, and observe the dissolution of the controllably dissolving microspheres, and detect the dissolution of the mixed microgel beads, wherein the dissolving agent is a chelating agent such as EDTA and sodium citrate, the concentration of the EDTA or sodium citrate is 4mM-20mM, and the dissolution time is 20s-3min.

[0114] It is understood that the dissolving agent can react or interact with the material in the microspheres, resulting in the disintegration or decomposition of the microsphere structure, thereby achieving controllable dissolution of the microspheres. In the embodiment of the present invention, EDTA (ethylenediaminetetraacetic acid) can be used as a dissolving agent. EDTA is a commonly used chelating agent that can form a stable complex with metal ions, and is therefore particularly useful in dissolving certain metal ion cross-linked microspheres (such as calcium cross-linked pectin microspheres).

[0115] Furthermore, before obtaining the microsphere variation coefficient value of the initial controllably dissolving microspheres by measuring the diameter of the initial controllably dissolving microspheres, the method further comprises:

[0116] The volume change rate of the initial controllably dissolvable microspheres before washing and after washing is calculated by the following formula:

[0117]

[0118] Wherein, V is the volume change rate of the initial controllably dissolving microspheres before and after washing, D a is the average diameter of the initial controllably dissolvable microspheres before washing, D b is the average diameter of the initial controllably dissolvable microspheres after washing;

[0119] When the volume change rate is greater than or equal to a preset volume change threshold, the washing time of the controllably dissolvable microspheres is reduced or a washing solution is reconfigured for the initial controllably dissolvable microspheres.

[0120] Comparative Example 2

[0121] This embodiment is a method for preparing calcium alginate cross-linked microspheres by high-voltage electrostatic spraying, comprising the following steps:

[0122] (1) Preparing a sodium alginate gel solution: stirring a 1% sodium alginate solution uniformly using a magnetic stirrer;

[0123] (2) preparing a crosslinker solution: mixing a 3% calcium chloride aqueous solution and anhydrous ethanol to prepare a crosslinker solution, and stirring the crosslinker solution with a magnetic stirrer, wherein the volume ratio of the calcium chloride aqueous solution to the anhydrous ethanol is 1:1;

[0124] (3) preparing microsphere gel beads: dropping the sodium alginate gel solution prepared in step 1 into the crosslinking agent solution prepared in step 2 by high-voltage electrostatic spraying to react and form sodium alginate microgel beads;

[0125] (4) Washing: To remove excess calcium chloride solution, wash with sterile purified water 2-3 times to obtain calcium alginate cross-linked microspheres;

[0126] The sodium alginate microgel beads prepared in step (3) have a diameter of 50-500um and a spherical or quasi-spherical shape; the flow rate of the high-voltage electrostatic spray in step (3) is 2.5ml / min and the voltage is 4.5KV.

[0127] Furthermore, the calcium alginate cross-linked microspheres prepared in Comparative Example 2 are completely spherical and have high mechanical strength. Figure 4 As shown:

[0128] The controllably dissolvable microspheres of alginate and pectin mixed by high-voltage electrostatic spraying in the embodiment of the present invention are also completely spherical and have high mechanical strength. Figure 5 shown.

[0129] According to Comparative Example 2 and the embodiments of the present invention, the prepared microspheres are all completely spherical and have high mechanical strength, so it is necessary to use a dissolving agent to conduct a controlled dissolution test on the prepared microspheres;

[0130] By taking 1 ml of the calcium alginate cross-linked microspheres prepared in Comparative Example 2 and adding 4-10 ml of the dissolving agent, it can be found that the calcium alginate cross-linked microspheres are not completely dissolved within 24 hours, while taking 1 ml of the controllably dissolving microspheres prepared in the embodiment of the present invention and adding 4-10 ml of the dissolving agent, the controllably dissolving microspheres are completely dissolved within 30 seconds to 2 minutes. Therefore, in order to prepare microspheres with controllably dissolving properties, it is necessary to mix the sodium alginate solution and the pectin solution.

[0131] Comparative Example 3

[0132] This example uses a mixed microsphere prepared with 4% pectin and 1% sodium alginate to test the stability and mechanical strength in a culture medium:

[0133] 4 ml of 4% pectin and 1% sodium alginate were used to prepare mixed microspheres, which were sterilized in 75% medical alcohol for 40 min, washed three times with sterile water, added with culture medium to 50 ml, transferred to a 125 ml magnetic stirring bottle and stirred at 60 rpm for 30 days. The obtained microsphere images are shown in the figure. Figure 6 As shown, the microspheres were partially cracked and broken.

[0134] In the present invention, 4 ml of 2% pectin and 1% sodium alginate prepared controllably soluble microspheres were sterilized in 75% medical alcohol for 40 min, washed three times with sterile water, added with culture medium to 50 ml, transferred to a 125 ml magnetic stirring bottle and stirred at 60 rpm for 30 days. The obtained microsphere images are as follows: Figure 7 As shown, the microspheres did not show cracks or breakage within 30 days.

[0135] Compared with the problems described in the background technology, the present invention first obtains sodium alginate solution and pectin solution as preparation raw materials, wherein the sodium alginate solution has a concentration of 1-3%, and the pectin solution has a concentration of 1-6%. It can be seen that the present invention adopts a mixed solution of sodium alginate solution and pectin solution, rather than a single pectin solution or sodium alginate solution to prepare microspheres, thereby solving the problems that pectin microspheres have different shapes and low mechanical strength and are not suitable for cell culture, and that sodium alginate microspheres are difficult to dissolve. Thereafter, the sodium alginate solution and the pectin solution are mixed based on a first preset ratio, and are stirred and mixed uniformly using a preset stirring device to obtain a mixed gel solution, wherein the first preset ratio is a volume ratio, and the volume ratio of the mixed sodium alginate solution and the pectin solution is 4-1:1-4. It can be seen that in order to reflect the advantages of the two materials, the present invention sets a strict concentration standard. Then, the pre-constructed calcium chloride aqueous solution and anhydrous ethanol are mixed based on a second preset ratio, and are stirred and mixed uniformly by the stirring device to obtain a cross-linking agent solution, wherein the calcium chloride aqueous solution has a concentration of 1-9%, and is mixed with anhydrous ethanol in a second preset ratio, and the second preset ratio is mixed in a volume ratio of 1-6:1; in order to prepare microspheres with good shape, uniform particle size and high mechanical strength, a cross-linking agent solution of suitable concentration is prepared. Thereafter, the mixed gel solution is dripped into the cross-linking agent solution by a preset dripping method, and mixed gel beads are obtained in the cross-linking agent solution, wherein the preset dripping method is a high-voltage electrostatic spray method, the flow rate used is 1-5ml / min, the voltage is 2-20KV, and the electrode distance is 2.5-5cm. Finally, the mixed microgel beads are washed to obtain controllably dissolving microspheres, wherein the mixed microgel beads are washed by sterile purified water, the diameter of the mixed microgel beads is 10-1000um, and the shape is spherical or quasi-spherical. It can be seen that the present invention not only formulates specific conditions in the microsphere preparation process, but also considers the concentration of each component to be adjusted in combination with the actual situation and the performance requirements of the target product, thereby obtaining controllably dissolving microspheres that meet the experimental requirements. Therefore, the method, device, electronic device and computer-readable storage medium for preparing controllable dissolution microspheres based on sodium alginate and pectin proposed in the present invention mainly aim to solve the problems that pectin microspheres have different shapes and low mechanical strength and are not suitable for cell culture, and that sodium alginate microspheres are difficult to dissolve, and at the same time, prepare microspheres with high spherification rate and controllable dissolution.

[0136] Embodiment 2:

[0137] like Figure 8 , which is a schematic diagram of the structure of an electronic device for implementing a method for preparing controllably dissolving microspheres based on sodium alginate and pectin provided by an embodiment of the present invention.

[0138] The electronic device 1 may include a processor 10, a memory 11, a bus 12 and a communication interface 13, and may also include a computer program stored in the memory 11 and executable on the processor 10, such as a program for preparing controllable dissolution microspheres based on sodium alginate and pectin.

[0139] The memory 11 includes at least one type of readable storage medium, and the readable storage medium includes a flash memory, a mobile hard disk, a multimedia card, a card-type memory (e.g., SD or DX memory, etc.), a magnetic memory, a disk, an optical disk, etc. The memory 11 may be an internal storage unit of the electronic device 1 in some embodiments, such as a mobile hard disk of the electronic device 1. The memory 11 may also be an external storage device of the electronic device 1 in other embodiments, such as a plug-in mobile hard disk, a smart memory card (Smart Media Card, SMC), a secure digital (Secure Digital, SD) card, a flash card (Flash Card), etc. equipped on the electronic device 1. Further, the memory 11 may also include both an internal storage unit of the electronic device 1 and an external storage device. The memory 11 may not only be used to store application software and various types of data installed in the electronic device 1, such as the code of the controllable dissolution microsphere preparation program based on sodium alginate and pectin, but also be used to temporarily store data that has been output or is to be output.

[0140] The processor 10 may be composed of an integrated circuit in some embodiments, for example, a single packaged integrated circuit, or a plurality of packaged integrated circuits with the same or different functions, including one or more central processing units (CPUs), microprocessors, digital processing chips, graphics processors, and combinations of various control chips, etc. The processor 10 is the control core (Control Unit) of the electronic device, and uses various interfaces and lines to connect various components of the entire electronic device, and executes or executes programs or modules stored in the memory 11 (such as a controllable dissolution microsphere preparation program based on sodium alginate and pectin, etc.), and calls data stored in the memory 11 to execute various functions of the electronic device 1 and process data.

[0141] The bus may be a peripheral component interconnect (PCI) bus or an extended industry standard architecture (EISA) bus, etc. The bus may be divided into an address bus, a data bus, a control bus, etc. The bus is configured to realize connection and communication between the memory 11 and at least one processor 10, etc.

[0142] Figure 8 Only an electronic device with components is shown, and those skilled in the art will understand that Figure 8 The structure shown does not constitute a limitation on the electronic device 1, and may include fewer or more components than shown in the figure, or combine certain components, or arrange the components differently.

[0143] For example, although not shown, the electronic device 1 may also include a power source (such as a battery) for supplying power to each component. Preferably, the power source may be logically connected to the at least one processor 10 through a power management device, so that the power management device can realize functions such as charging management, discharging management, and power consumption management. The power source may also include any components such as one or more DC or AC power sources, recharging devices, power failure detection circuits, power converters or inverters, power status indicators, etc. The electronic device 1 may also include a variety of sensors, Bluetooth modules, Wi-Fi modules, etc., which will not be repeated here.

[0144] Furthermore, the electronic device 1 may also include a network interface. Optionally, the network interface may include a wired interface and / or a wireless interface (such as a WI-FI interface, a Bluetooth interface, etc.), which is generally used to establish a communication connection between the electronic device 1 and other electronic devices.

[0145] Optionally, the electronic device 1 may further include a user interface, which may be a display, an input unit (such as a keyboard), or a standard wired interface or a wireless interface. Optionally, in some embodiments, the display may be an LED display, a liquid crystal display, a touch-sensitive liquid crystal display, and an OLED (Organic Light-Emitting Diode) touch device. The display may also be appropriately referred to as a display screen or a display unit, which is used to display information processed in the electronic device 1 and to display a visual user interface.

[0146] It should be understood that the embodiment is for illustration only and the scope of the patent application is not limited to this structure.

[0147] The controllably dissolvable microsphere preparation program based on sodium alginate and pectin stored in the memory 11 of the electronic device 1 is a combination of multiple instructions. When running in the processor 10, the following can be achieved:

[0148] Obtaining sodium alginate solution and pectin solution as preparation raw materials, wherein the sodium alginate solution has a concentration of 1-3%, and the pectin solution has a concentration of 1-6%;

[0149] The sodium alginate solution and the pectin solution are mixed based on a first preset ratio, and are stirred and mixed uniformly using a preset stirring device to obtain a mixed gel solution, wherein the first preset ratio is a volume ratio, and the volume ratio of the mixed sodium alginate solution and the pectin solution is 4-1:1-4;

[0150] The pre-constructed calcium chloride aqueous solution and anhydrous ethanol are mixed based on a second preset ratio, and are stirred and mixed evenly by the stirring device to obtain a cross-linking agent solution, wherein the calcium chloride aqueous solution has a concentration of 1-9% and is mixed with anhydrous ethanol in a second preset ratio, and the second preset ratio is mixed in a volume ratio of 1-6:1.

[0151] The mixed gel solution is dripped into the cross-linking agent solution by a preset dripping method, and mixed gel beads are obtained in the cross-linking agent solution, wherein the preset dripping method is a high-voltage electrostatic spray method, the flow rate used is 1-5 ml / min, the voltage is 2-20 KV, and the electrode distance is 2.5-5 cm;

[0152] The mixed microgel beads are washed to obtain controllably dissolving microspheres, wherein the mixed microgel beads are washed with sterile purified water, the diameter of the mixed microgel beads is 10-1000 um, and the shape is spherical or quasi-spherical.

[0153] Specifically, the specific implementation method of the processor 10 for the above instructions can refer to Figure 1 The description of the relevant steps in the corresponding embodiments will not be repeated here.

[0154] Furthermore, if the module / unit integrated in the electronic device 1 is implemented in the form of a software functional unit and sold or used as an independent product, it can be stored in a computer-readable storage medium. The computer-readable storage medium can be volatile or non-volatile. For example, the computer-readable medium can include: any entity or device capable of carrying the computer program code, a recording medium, a USB flash drive, a mobile hard disk, a magnetic disk, an optical disk, a computer memory, and a read-only memory (ROM).

[0155] The present invention further provides a computer-readable storage medium, wherein the computer-readable storage medium stores a computer program, and when the computer program is executed by a processor of an electronic device, the computer program can implement:

[0156] Obtaining sodium alginate solution and pectin solution as preparation raw materials, wherein the sodium alginate solution has a concentration of 1-3%, and the pectin solution has a concentration of 1-6%;

[0157] The sodium alginate solution and the pectin solution are mixed based on a first preset ratio, and are stirred and mixed uniformly using a preset stirring device to obtain a mixed gel solution, wherein the first preset ratio is a volume ratio, and the volume ratio of the mixed sodium alginate solution and the pectin solution is 4-1:1-4;

[0158] The pre-constructed calcium chloride aqueous solution and anhydrous ethanol are mixed based on a second preset ratio, and stirred and mixed evenly by the stirring device to obtain a cross-linking agent solution, wherein the concentration of the calcium chloride aqueous solution and the anhydrous ethanol are both 3%, and the second preset ratio is mixed to a volume ratio of 1:1;

[0159] The mixed gel solution is dripped into the cross-linking agent solution by a preset dripping method, and mixed gel beads are obtained in the cross-linking agent solution, wherein the preset dripping method is a high-voltage electrostatic spray method, the flow rate used is 1-5 ml / min, the voltage is 2-20 KV, and the electrode distance is 2.5-5 cm;

[0160] The mixed microgel beads are washed to obtain controllably dissolving microspheres, wherein the mixed microgel beads are washed with sterile purified water, the diameter of the mixed microgel beads is 10-1000 um, and the shape is spherical or quasi-spherical.

[0161] The modules described as separate components may or may not be physically separated, and the components shown as modules may or may not be physical units, that is, they may be located in one place or distributed on multiple network units. Some or all of the modules may be selected according to actual needs to achieve the purpose of the solution of this embodiment.

[0162] In addition, each functional module in each embodiment of the present invention may be integrated into one processing unit, each unit may exist physically separately, or two or more units may be integrated into one unit. The above-mentioned integrated unit may be implemented in the form of hardware or in the form of hardware plus software functional modules.

[0163] It is obvious to those skilled in the art that the present invention is not limited to the details of the above exemplary embodiments, and that the present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the present invention.

[0164] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the spirit and scope of the technical solution of the present invention.

Claims

1. A method for preparing controllable dissolution microspheres based on sodium alginate and pectin, characterized in that: The method comprises: Obtaining sodium alginate solution and pectin solution as preparation raw materials, wherein the sodium alginate solution has a concentration of 1-3%, and the pectin solution has a concentration of 1-6%; The sodium alginate solution and the pectin solution are mixed based on a first preset ratio, and are stirred and mixed uniformly using a preset stirring device to obtain a mixed gel solution, wherein the first preset ratio is a volume ratio, and the volume ratio of the mixed sodium alginate solution and the pectin solution is 4-1:1-4; The pre-constructed calcium chloride aqueous solution and anhydrous ethanol are mixed based on a second preset ratio, and the mixture is stirred and mixed uniformly by the stirring device to obtain a cross-linking agent solution, wherein the calcium chloride aqueous solution has a concentration of 1-9% and is mixed with anhydrous ethanol in a second preset ratio, and the second preset ratio is mixed in a volume ratio of 1-6:1; The mixed gel solution is dripped into the cross-linking agent solution by a preset dripping method, and mixed gel beads are obtained in the cross-linking agent solution, wherein the preset dripping method is a high-voltage electrostatic spray method, the flow rate used is 1-5 ml / min, the voltage is 2-20 KV, and the electrode distance is 2.5-5 cm; The mixed microgel beads are washed to obtain controllably dissolving microspheres, wherein the mixed microgel beads are washed with sterile purified water, the diameter of the mixed microgel beads is 10-1000 um, and the shape is spherical or quasi-spherical.

2. The method for preparing controllably dissolvable microspheres based on sodium alginate and pectin according to claim 1, characterized in that: The mixed microgel beads can achieve controllable dissolution, and the method further comprises: Take 1 ml of the controllably dissolvable microspheres and add 4-10 ml of the dissolving agent, and observe the dissolution of the controllably dissolving microspheres, and detect the dissolution of the mixed microgel beads, wherein the dissolving agent is EDTA or sodium citrate chelating agent, the concentration of the EDTA or sodium citrate is 4mM-20mM, and the dissolution time is 20s-3min.

3. The method for preparing controllably dissolvable microspheres based on sodium alginate and pectin according to claim 1, characterized in that: The mixed microgel beads have high mechanical strength, and the method further comprises: 4 ml of the sterilized controllably soluble microspheres were extracted and added to 50 ml of culture medium, and then transferred to a 125 ml magnetic stirring bottle for stirring. The microsphere carriers were continuously stirred at a high speed of 40-80 rpm in the culture medium and could remain free of cracks or breakage for 30 days, thereby verifying that the prepared microspheres had high mechanical strength.

4. The method for preparing controllably dissolvable microspheres based on sodium alginate and pectin according to claim 1, characterized in that: Before obtaining the sodium alginate solution and the pectin solution as the preparation raw materials, the method further comprises: Obtaining a test sample from the sodium alginate solution to obtain a sodium alginate solution sample; Adding deionized water and solid sodium carbonate to the sodium alginate solution sample, and heating with stirring at 80-90° C. for 1.5-3 hours to obtain a mixed sodium alginate solution sample; Centrifuging the mixed sodium alginate solution sample and retaining the supernatant to obtain the sodium alginate solution to be tested; Add the sodium alginate solution to be tested into a reaction container, add concentrated hydrochloric acid and phloroglucinol colorimetric solution, shake well, and perform colorimetric reaction in a boiling water bath for 40-50 minutes to obtain a colorimetric reaction solution; After the color development reaction solution is fixed to volume, the absorbance of the color development reaction solution is measured at a wavelength of 420-460nm, and the concentration of sodium alginate in the sodium alginate solution is calculated according to the standard curve. When the concentration of sodium alginate in the sodium alginate solution reaches the preset concentration requirement, the test is passed.

5. The method for preparing controllably dissolvable microspheres based on sodium alginate and pectin according to claim 1, characterized in that: The sodium alginate solution and the pectin solution are mixed based on a first preset ratio, and are stirred and mixed uniformly using a preset stirring device to obtain a mixed gel solution, including: Obtaining the stirring speed and stirring time of the mixed gel solution; The sodium alginate solution and the pectin solution are mixed based on a first preset ratio to obtain a mixed solution, and the mixed solution is stirred by starting the stirring device, and the stirring speed is gradually adjusted to the stirring speed, and the mixed solution is observed to see whether there is agglomeration and precipitation, and the stirring speed is adjusted according to whether there is agglomeration and precipitation; Stirring for the stirring time, turning off the stirring device, and taking samples to check the uniformity of the mixed solution. When the uniformity of the mixed solution reaches a preset requirement, the mixed gel solution is obtained.

6. The method for preparing controllably dissolvable microspheres based on sodium alginate and pectin according to claim 1, characterized in that: The step of washing the mixed microgel beads to obtain controllably dissolvable microspheres comprises: Taking a preset volume of washing solution, placing the collected mixed microgel beads into the washing solution, gently stirring or shaking, and separating the solution from the microgel beads by filtering, and discarding the washing solution; Repeat the above steps for a preset number of times until there are no more impurities in the washing solution, thereby obtaining initial controllably dissolvable microspheres; The microsphere variation coefficient value of the initial controllably dissolvable microspheres is obtained by measuring the diameter of the initial controllably dissolvable microspheres, and when the microsphere variation coefficient value is less than a preset variation threshold, the controllably dissolvable microspheres are obtained.

7. The method for preparing controllably dissolvable microspheres based on sodium alginate and pectin according to claim 6, characterized in that: The step of obtaining the microsphere variation coefficient value of the initial controllably dissolving microspheres by measuring the diameter of the initial controllably dissolving microspheres comprises: Optical photographs of the controllably dissolvable microspheres before and after washing were taken using an industrial microscope. When measuring the diameter of the microspheres, at least 100 microspheres were measured for each condition, and the coefficient of variation (CV) of the microspheres was calculated according to the following formula: in, is the average diameter of the controllable dissolution microspheres, d i is the diameter of the ith controllably dissolvable microsphere, and n is the number of the measured controllably dissolvable microspheres.

8. The method for preparing controllably dissolvable microspheres based on sodium alginate and pectin according to any one of claims 1 to 7, characterized in that: The stirring device is a magnetic stirrer.

9. The method for preparing controllably dissolvable microspheres based on sodium alginate and pectin according to claim 6, characterized in that: Before obtaining the microsphere variation coefficient value of the initial controllably dissolving microspheres by measuring the diameter of the initial controllably dissolving microspheres, the method further comprises: The volume change rate of the initial controllably dissolvable microspheres before washing and after washing is calculated by the following formula: Wherein, V is the volume change rate of the initial controllably dissolving microspheres before and after washing, D a is the average diameter of the initial controllably dissolvable microspheres before washing, D b is the average diameter of the initial controllably dissolvable microspheres after washing; When the volume change rate is greater than or equal to a preset volume change threshold, the washing time of the controllably dissolvable microspheres is reduced or a washing solution is reconfigured for the initial controllably dissolvable microspheres.

10. In order to solve the above problem, the present invention further provides an electronic device, the electronic device comprising: at least one processor; as well as, a memory communicatively connected to the at least one processor; wherein, The memory stores instructions that can be executed by the at least one processor, and the instructions are executed by the at least one processor to implement the above-mentioned method for preparing controllable dissolution microspheres based on sodium alginate and pectin.

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