CN114602397B - Multi-cavity microsphere based on electronic injection method and preparation method thereof - Google Patents
Multi-cavity microsphere based on electronic injection method and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a multi-cavity microsphere based on an electronic injection method and a preparation method thereof. The preparation method of the invention comprises the following steps: firstly, preparing a coaxial needle containing a core layer channel and a shell layer channel; secondly, preparing a sodium alginate solution and one or more mixed solutions containing a load; respectively sucking the mixed liquid by using a syringe again, and pushing the mixed liquid into different nuclear layer channels of the coaxial needles; the shell layer channel is filled with sodium alginate solution without addition; finally, connecting the high-voltage power supply with the metal part of the coaxial needle; the microsphere receiving device is connected with a copper plate of the grounding wire, a pump and a high-voltage power supply are turned on, so that precursor solution with a partition layered structure formed at the outlet of the coaxial needle falls into the receiving device, and then the precursor solution is stirred and filtered to obtain a multi-chamber microsphere finished product. The multi-chamber microsphere with the core-shell structure is formed in one step, so that the loss of the loading components in the preparation process is reduced, the protection and confinement of the loading components are improved, the regulation and control of the release rate of the loaded medicine can be realized, and the method has advantages in industrial production.
Description
Technical Field
The invention relates to the technical field of biological material preparation, in particular to a multi-cavity microsphere based on an electronic spraying method and a preparation method thereof.
Background
The multi-chamber microsphere can load different drugs, cells or other factors in different spaces of a single microsphere, so that the multi-chamber microsphere has a great deal of important application prospect in the fields of multi-drug release, cell co-culture, multi-target detection and the like. At present, the micro-fluidic technology is a main means for preparing the multi-chamber microsphere, but the micro-fluidic method needs to use oil, an initiator, a surfactant and the like, which have a certain influence on the activity of a biological agent or a cell to be loaded, so that the application of the method in the biological field is limited.
In order to avoid the possible toxic effects of these oils, initiators, etc., new multi-chamber microsphere preparation methods have been explored, including electrospray, centrifugation, gas shearing, etc., which separate the fluid into micro-and even nano-sized microspheres by high-voltage electric fields, high-speed centrifugal forces, and high-pressure gas shearing forces, respectively, and can avoid the use of additional solvents, thus having great advantages in the loading of bioactive drugs or cells.
However, these methods also suffer from a number of disadvantages. The centrifugation method requires a special device, is difficult to popularize, and has low efficiency due to limited centrifuge tube capacity. The gas shearing principle has the disadvantage of possibly introducing pollution of gas origin and high cost. Although the electronic spraying method is simple and easy to obtain relative to equipment, the operation is simple and efficient, but the core-shell layered multi-chamber microspheres cannot be prepared by the existing three methods in one step. Meanwhile, the structural components of each chamber are not different when the existing multi-chamber microsphere is prepared, and the release speed of the loaded drugs in different chambers cannot be controlled.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a multi-cavity microsphere based on an electronic spraying method and a preparation method thereof. The invention prepares the multi-chamber microsphere with the core-shell layering by self-making coaxial needles and simultaneously forming the core layer and the shell layer channels by utilizing the coaxial needles and combining a high-voltage electric field, reduces the loss of loading components in the preparation process, improves the protection and confinement effects on the loading components, can realize the regulation and control on the release rate of the loading drugs, and has advantages in industrial production.
The technical scheme of the invention is as follows:
a method for preparing multi-chamber microspheres based on an electronic spray method, comprising the following steps:
(1) Preparing coaxial needles containing a nuclear layer channel and a shell layer channel;
(2) Adding one or more substances to be loaded into the sodium alginate solution respectively to obtain one or more mixed solutions containing the substances to be loaded;
(3) Respectively sucking the mixed solution containing one or more loads prepared in the step (2) by using a syringe, and pushing the mixed solution into different nuclear layer channels of the coaxial needle by using a push injection pump; the shell layer channel is filled with sodium alginate solution without addition;
(4) Connecting the metal needle body of the coaxial needle prepared in the step (1) by using a high-voltage power supply; the microsphere receiving device is connected with a copper plate of the grounding wire, the push injection pump and the high-voltage power supply are turned on, so that precursor solution with a zoned layered structure flowing out of the coaxial needle falls into the receiving device and then is crosslinked into spheres, and the finished product of the multi-chamber microsphere with the core-shell structure is obtained through filtration.
Further, in the step (1), the coaxial needle comprises a core layer channel and a shell layer channel, and the inlet of the shell layer channel is positioned on the side surface of the coaxial needle and is perpendicular to the core layer channel; the core layer channels include, but are not limited to, 2-8 channels, each of which is distributed in parallel.
Further, the preparation method of the coaxial needle comprises the following steps: a plurality of 30G metal plain-end needles are adopted to be arranged in parallel in the same direction and then fixed; the fixed flat needle passes through the T-shaped tee joint, the penetrating opening is sealed by resin glue or a rubber cap, the penetrating opening is connected with the flat needle, and the flat needle is communicated with the side hole of the tee joint to form a shell layer channel.
Further, the plurality includes, but is not limited to, 2 to 8 roots; when the number of the coaxial needles is more than 6, a supporting needle is arranged in the middle of the coaxial needles; so that the liquid can just evenly spread the supporting needle for a circle when flowing out of the needle. When the number of the support needles is 6, a 30G support needle is placed in the middle of the coaxial needles; when the number of the support needles is 8, a 25G support needle is placed in the middle of the coaxial needles;
further, the flat head needles are different in size according to the number of the flat head needles. Two plain ends needles adopt 19G needles, three plain ends needles adopt 19G needles, four plain ends needles adopt 18G needles, six plain ends needles adopt 16G needles, eight plain ends needles adopt 15G needles, and all needle tips are kept flush.
Further, in the step (2), the sodium alginate solution is prepared by dissolving sodium alginate in water, wherein the concentration of the sodium alginate solution is 0.5-2.5% (w/v).
Further, in step (2), the plurality includes, but is not limited to, 2 to 8; the substance to be loaded includes, but is not limited to, one or more of a drug, a cell, a bacterium.
Further, in the step (3), the pushing speed of the mixed liquid in the nuclear layer channel is 1.25-2.5 ml/h; the feeding speed of the sodium alginate solution without being added in the shell layer channel is 2.5-5 ml/h; the sodium alginate solution without addition is prepared by dissolving sodium alginate in water, and the concentration of the sodium alginate solution without addition is 0.5-2.0% (w/v). The concentration of the shell sodium alginate solution is less than or equal to the concentration of sodium alginate in the core-layer mixed solution.
Further, in the step (4), the voltage of the voltage power supply is 8-10 kv.
Further, in the step (4), the precursor solution is spherical liquid drops formed by high pressure of the sodium alginate solution in the shell layer channel and the solution in the core layer channel.
Further, in the step (4), the microsphere receiving device is filled with a calcium chloride solution, and the molar concentration of the calcium chloride solution is 0.1-0.25 mol/L; the distance between the liquid level of the calcium chloride solution and the outlet of the coaxial needle is 6-9 cm.
A multi-cavity microsphere prepared by the preparation method.
The beneficial technical effects of the invention are as follows:
(1) The preparation device is simple and easy to obtain, is simple and efficient to operate, does not need to introduce additional gas or liquid, prepares the multi-chamber microsphere with the core-shell layered in one step, reduces the loss of loading components in the preparation process, improves the protection and confinement effects on the loading components, can realize the regulation and control of the release rate of the loading drugs, and has advantages in industrial production.
(2) The electric spraying method adopted by the invention utilizes the phenomenon that charged liquid drops can be sprayed at a high speed under the action of a high-voltage electric field. The microsphere nuclear layer adopts coaxial needle system with same size, sodium alginate flows out of needle head and then converges with liquid in adjacent needle, under the action of high voltage electric field, forming evenly divided conical liquid drop and suspending at coaxial needle outlet, shell sodium alginate is wrapped outside nuclear layer, when liquid drop gravity and electrostatic force are greater than surface tension, liquid drop is separated from conical tip and accelerated to drop down, under the action of surface tension, calcium ion of calcium chloride in receiving device replaces sodium ion of sodium alginate, forming water-insoluble calcium alginate gel microsphere, reaction process is rapid, thereby realizing wrapping and fixing factor suspended in sodium alginate.
(3) Compared with the traditional preparation of the multi-chamber microsphere by the electric spraying method, the shell gel is formed outside the multi-chamber microsphere by a one-step method, is the multi-chamber microsphere with a core-shell structure, can reduce the loss of loaded drugs in the process of crosslinking sodium alginate drops and calcium chloride, particularly the drugs at the periphery of the drops, and can play a role in reinforcing the protection and confinement of loaded bioactive substances. Especially when loading probiotics, the existence of the shell sodium alginate can prevent the probiotics from escaping, and meanwhile, the probiotics can be prevented from being killed by some antibiotics. Meanwhile, the precursor solutions with different concentrations are used in each chamber, so that the release rates of the loaded medicines in each chamber are different, and the ordered release of the medicines is realized.
Drawings
FIG. 1 is a schematic diagram of the preparation of a four-chamber calcium alginate microsphere according to the present invention.
Detailed Description
The present invention will be described in detail below with reference to the drawings and examples.
Example 1:
a multi-chamber microsphere based on an electronic spray method, which can form a microsphere with a core-shell structure through one step. The preparation method comprises the following steps:
(1) Manufacturing a coaxial needle: two 30G metal plain-end needles are arranged in parallel in the same direction, and are fixed by quick-drying adhesive. The fixed coaxial needle passes through the T-shaped tee joint, the penetration opening is closed by a rubber cap, the penetration opening is externally connected with a 19G needle head, and the penetration opening is communicated with a side hole of the tee joint to form a shell layer channel. Keeping all needle tips flush. The coaxial needle comprises a nuclear layer channel and a shell layer channel, and the inlet of the shell layer channel is positioned on the side surface of the coaxial needle and is vertical to the nuclear layer channel; the nuclear layer channel comprises 2 channels, and all the channels are distributed in parallel.
(2) Sodium alginate is dissolved in deionized water according to 2% (w/v), stirred to be completely dissolved, and 1% polystyrene nano-microspheres with orange red and blue fluorescence are respectively and uniformly suspended in the sodium alginate. Polystyrene microspheres are added here to characterize the successful preparation of the microspheres.
(3) And (3) respectively sucking the solution prepared in the step (3) by a 10ml syringe, placing the solution on two push injection pumps, connecting the solution to a channel of a corresponding core layer, and connecting the channel of the core layer with 1% (w/v) sodium alginate solution without adding the sodium alginate solution (the sodium alginate solution is obtained by deionized water and stirring the sodium alginate solution).
(4) The output end of the high-voltage power supply is connected to the metal needle body of the coaxial needle, the voltage is 8kv, a dish serving as a receiving device is connected with a copper plate of the grounding wire, 0.2M calcium chloride is added into the dish, and the distance between the liquid level and the outlet of the coaxial needle is 9cm. The flow rate of sodium alginate in each cavity of the core layer is the same and is 2.5ml/h, and the flow rate of sodium alginate in the shell layer is 2.5ml/h. And (3) electrospraying the blend solution into a receiving device, and finally filtering to obtain the two-chamber calcium alginate gel microspheres.
Example 2:
a multi-cavity microsphere based on an electronic spray method can form a three-cavity microsphere with a core-shell structure through one step. The preparation method comprises the following steps:
(1) Manufacturing a coaxial needle: three 30G metal plain-end needles are arranged in parallel and tightly in the same direction, the cross section is triangular, and the quick-drying adhesive is fixed. The fixed coaxial needle passes through the T-shaped tee joint, the penetration opening is closed by a rubber cap, the penetration opening is externally connected with a 19G needle head, and the penetration opening is communicated with a side hole of the tee joint to form a shell layer channel. Keeping all needle tips flush. The coaxial needle comprises a nuclear layer channel and a shell layer channel, and the inlet of the shell layer channel is positioned on the side surface of the coaxial needle and is vertical to the nuclear layer channel; the nuclear layer channel comprises 3 channels, and all the channels are distributed in parallel.
(2) Sodium alginate is dissolved in deionized water according to 2% (w/v), stirred to be completely dissolved, and 1% polystyrene nano-microspheres with green, orange red and blue fluorescence are respectively and uniformly suspended in the sodium alginate. Polystyrene microspheres are added here to characterize the successful preparation of the microspheres.
(3) And (3) respectively sucking the solution prepared in the step (2) by a 10ml syringe, placing the solution on three push injection pumps, connecting the solution to a channel of a corresponding core layer, and connecting the channel of the core layer with 1% (w/v) sodium alginate solution without adding the sodium alginate solution (the sodium alginate solution is obtained by deionized water and stirring the sodium alginate solution).
(4) The output end of the high-voltage power supply is connected to the metal needle body of the coaxial needle, the voltage is 8kv, a dish serving as a receiving device is connected with a copper plate of the grounding wire, 0.2M calcium chloride is added into the dish, and the distance between the liquid level and the outlet of the coaxial needle is 9cm. The flow rate of sodium alginate in each cavity of the core layer is the same and is 2ml/h, and the flow rate of sodium alginate in the shell layer is 3ml/h. And (3) electrospraying the blend solution into a receiving device, and finally filtering to obtain the three-chamber calcium alginate gel microsphere.
Example 3:
a multi-chamber microsphere based on an electronic spray method can form a four-chamber microsphere with a core-shell structure by one step (shown in figure 1). The preparation method comprises the following steps:
(1) Manufacturing a coaxial needle: four 30G metal plain-end needles are arranged in parallel in the same direction, and are fixed by quick-drying adhesive. The coaxial needle passes through the T-shaped tee joint, the penetration opening is closed by a rubber cap, the penetration opening is externally connected with an 18G needle head, and the coaxial needle is communicated with a side hole of the tee joint to form a shell layer channel. Keeping all needle tips flush. The coaxial needle comprises a nuclear layer channel and a shell layer channel, and the inlet of the shell layer channel is positioned on the side surface of the coaxial needle and is vertical to the nuclear layer channel; the nuclear layer channel comprises 4 channels, and all the channels are distributed in parallel.
(2) Sodium alginate is dissolved in deionized water according to 2% (w/v), stirred to be completely dissolved, 1% polystyrene nano-microspheres with orange red and blue fluorescence are respectively uniformly suspended in the sodium alginate, and the polystyrene microspheres are added here to represent successful preparation of the microspheres.
(3) And (3) respectively sucking the solution prepared in the step (2) by a 10ml syringe, then placing the solution on two push injection pumps, connecting the two push injection pumps to channels of corresponding core layers, enabling red and blue fluorescent microspheres to be arranged at intervals, and connecting the channels of the core layers with 1% (w/v) sodium alginate solution without adding the sodium alginate solution (the sodium alginate solution is obtained by deionized water and stirring the sodium alginate solution).
(4) The output end of the high-voltage power supply is connected to the metal needle body of the coaxial needle, the voltage is 8kv, a dish serving as a receiving device is connected with a copper plate of the grounding wire, 0.2M calcium chloride is added into the dish, and the distance between the liquid level and the outlet of the coaxial needle is 9cm. The flow rate of sodium alginate in each cavity of the core layer is the same and is 2ml/h, and the flow rate of sodium alginate in the shell layer is 4ml/h. And (3) electrospraying the blend solution into a receiving device, and finally filtering to obtain the four-chamber calcium alginate gel microspheres.
Example 4:
a multi-chamber microsphere based on an electronic spray method, which can form a microsphere with a core-shell structure through one step. The preparation method comprises the following steps:
(1) Manufacturing a coaxial needle: 8 30G metal plain-end needles are arranged in parallel in the same direction, and are fixed by quick-drying adhesive. The fixed coaxial needle passes through the T-shaped tee joint, the penetrating opening is closed by a rubber cap, the penetrating opening is externally connected with a 15G needle head, and the penetrating opening is communicated with a side hole of the tee joint to form a shell layer channel. A25G support needle was placed in the middle of the coaxial needle to keep all the needle tips flush. The coaxial needle comprises a nuclear layer channel and a shell layer channel, and the inlet of the shell layer channel is positioned on the side surface of the coaxial needle and is vertical to the nuclear layer channel; the nuclear layer channel comprises 8 channels, and all the channels are distributed in parallel.
(2) Sodium alginate is dissolved in deionized water according to 2.5% (w/v), stirred to be completely dissolved, and 1% polystyrene nano-microspheres with orange red and blue fluorescence are respectively and uniformly suspended in the sodium alginate. The polystyrene microspheres are added here in the sense that: to characterize successful preparation of microspheres.
(3) And (3) respectively sucking the solution prepared in the step (2) by a 10ml syringe, placing the solution on two push injection pumps, connecting the solution to a channel of a corresponding core layer, and connecting the channel of the core layer with a non-added 2% (w/v) sodium alginate solution (the sodium alginate solution is obtained by deionized water of the sodium alginate solution and stirring the sodium alginate solution).
(4) The output end of the high-voltage power supply is connected to the metal needle body of the coaxial needle, the voltage is 10kv, a dish serving as a receiving device is connected with a copper plate of the grounding wire, 0.25M calcium chloride is added into the dish, and the distance between the liquid level and the outlet of the coaxial needle is 6cm. The flow rate of sodium alginate in each cavity of the core layer is the same and is 1.25ml/h, and the flow rate of sodium alginate in the shell layer is 5.0ml/h. And (3) electrospraying the blend solution into a receiving device, and finally filtering to obtain the eight-chamber calcium alginate gel microspheres.
Example 5:
a multi-chamber microsphere based on an electronic spray method, which can form a microsphere with a core-shell structure through one step. The preparation method comprises the following steps:
(1) Manufacturing a coaxial needle: 6 30G metal plain-end needles are arranged in parallel in the same direction, and are fixed by quick-drying adhesive. The fixed coaxial needle passes through the T-shaped tee joint, the penetrating opening is closed by a rubber cap, the penetrating opening is externally connected with a 16G needle head, and the penetrating opening is communicated with a side hole of the tee joint to form a shell layer channel. A30G support needle was placed in the middle of the coaxial needle to keep all the needle tips flush. The coaxial needle comprises a nuclear layer channel and a shell layer channel, and the inlet of the shell layer channel is positioned on the side surface of the coaxial needle and is vertical to the nuclear layer channel; the nuclear layer channel comprises 6 channels, and all the channels are distributed in parallel.
(2) Sodium alginate is dissolved in deionized water according to 0.5% (w/v), stirred to be completely dissolved, and 1% polystyrene nano-microspheres with orange red and blue fluorescence are respectively and uniformly suspended in the sodium alginate. The polystyrene microspheres are added here in the sense that: to characterize successful preparation of microspheres.
(3) And (3) respectively sucking the solution prepared in the step (2) by a 10ml syringe, placing the solution on two push injection pumps, connecting the solution to a channel of a corresponding core layer, and connecting the channel of the core layer with a sodium alginate solution of 0.5% (w/v) without adding the sodium alginate solution (the sodium alginate solution is obtained by deionized water of the sodium alginate solution and stirring the sodium alginate solution).
(4) The output end of the high-voltage power supply is connected to the metal needle body of the coaxial needle, the voltage is 8kv, a dish serving as a receiving device is connected with a copper plate of the grounding wire, 0.1M calcium chloride is added into the dish, and the distance between the liquid level and the outlet of the coaxial needle is 9cm. The flow rate of sodium alginate in each cavity of the core layer is the same and is 1.25ml/h, and the flow rate of sodium alginate in the shell layer is 3.5ml/h. And (3) electrospraying the blend solution into a receiving device, and finally filtering to obtain the six-chamber calcium alginate gel microsphere.
The preparation method of the invention needs to simultaneously meet the following conditions: the voltage of the high-voltage power supply is limited to 8-10 kv, and the distance between the liquid level and the coaxial needle outlet is 6-9 cm; the flow rate of sodium alginate in each cavity of the core layer is the same and is 1.25-2.5 mL/h, and the flow rate of sodium alginate in the shell layer is 2.5-5 mL/h; a needle is sleeved outside the 30G coaxial needle combination and used for wrapping shell sol, a 19G needle is adopted in the double chambers, a 19G needle is adopted in the three chambers, an 18G needle is adopted in the four chambers, a 16G needle is adopted in the six chambers, a 15G needle is adopted in the eight chambers, and the tips of all the needles are kept flush.
The foregoing results illustrate the principles and principal features of the invention and the advantages of the invention. The present invention is not limited to the embodiments described above, which are merely illustrative of the principles and advantages of the present invention. The present invention is capable of numerous modifications and variations without departing from the spirit of the invention and is intended to be included within the scope of the present invention.
Claims (7)
1. The preparation method of the multi-chamber microsphere based on the electronic spraying method is characterized by comprising the following steps of:
(1) Preparing coaxial needles containing a nuclear layer channel and a shell layer channel;
(2) Adding one or more substances to be loaded into the sodium alginate solution respectively to obtain one or more mixed solutions containing the substances to be loaded;
(3) Respectively sucking the mixed solution containing one or more loads prepared in the step (2) by using a syringe, and pushing the mixed solution into different nuclear layer channels of the coaxial needle by using a push injection pump; the shell layer channel is filled with sodium alginate solution without addition;
(4) Connecting the metal needle body of the coaxial needle prepared in the step (1) by using a high-voltage power supply; the microsphere receiving device is connected with a copper plate of a grounding wire, a push injection pump and a high-voltage power supply are turned on, so that precursor solution with a zoned layered structure flowing out of a coaxial needle falls into the receiving device and then is crosslinked into spheres, and a multi-chamber microsphere finished product with a core-shell structure is obtained through filtration;
in the step (1), the coaxial needle comprises a nuclear layer channel and a shell layer channel, wherein an inlet of the shell layer channel is positioned on the side surface of the coaxial needle and is perpendicular to the nuclear layer channel; the nuclear layer channels comprise, but are not limited to, 2-8 channels, and all the channels are distributed in parallel;
in the step (1), the preparation method of the coaxial needle comprises the following steps: a plurality of 30G metal plain-end needles are adopted to be arranged in parallel in the same direction and then fixed; the fixed plain end needle passes through the T-shaped tee joint, the penetrating opening is closed by resin glue or a rubber cap, the penetrating opening is connected with the plain end needle, and the plain end needle is communicated with the side hole of the tee joint to form a shell layer channel;
the plurality includes, but is not limited to, 2-8 roots; when the number of the support needles is more than 6, a support needle is placed in the middle of the coaxial needles, so that the support needles can be just uniformly distributed for one circle when liquid flows out of the needles;
the flat head needles are different in size according to the number of the flat head needles, two flat head needles adopt 19G needles, three flat head needles adopt 19G needles, four flat head needles adopt 18G needles, six flat head needles adopt 16G needles, eight flat head needles adopt 15G needles, and all needle tips are kept flush;
the object to be loaded comprises one or more of a drug, a cell and a bacterium;
according to the multi-chamber microsphere, precursor solutions with different concentrations are used in each chamber, so that the release rates of the loaded medicines in each chamber are different, and the ordered release of the medicines is realized.
2. The method according to claim 1, wherein in the step (2), the sodium alginate solution is prepared by dissolving sodium alginate in water, and the concentration of the sodium alginate solution is 0.5-2.5% (w/v).
3. The method of claim 1, wherein in step (2), the plurality includes, but is not limited to, 2 to 8; the substance to be loaded includes, but is not limited to, one or more of a drug, a cell, a bacterium.
4. The method according to claim 1, wherein in the step (3), the pushing speed of the mixed liquid in the core layer channel is 1.25-2.5 ml/h; the feeding speed of the sodium alginate solution without being added in the shell layer channel is 2.5-5 ml/h; the sodium alginate solution without addition is prepared by dissolving sodium alginate in water, and the concentration of the sodium alginate solution without addition is 0.5-2.0% (w/v).
5. The method according to claim 1, wherein in the step (4), the voltage of the high-voltage power source is 8 to 10kv.
6. The preparation method according to claim 1, wherein in the step (4), the microsphere receiving device is filled with a calcium chloride solution, and the molar concentration of the calcium chloride solution is 0.1-0.25 mol/L; the distance between the liquid level of the calcium chloride solution and the outlet of the coaxial needle is 6-9 cm.
7. A multi-chamber microsphere prepared by the method of any one of claims 1-6.
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