CN116726235B - Monodisperse gas-carrying embolization microspheres and preparation method thereof - Google Patents
Monodisperse gas-carrying embolization microspheres and preparation method thereofInfo
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Abstract
本发明提供了一种单分散载气栓塞微球，该载气栓塞微球由聚合物外壳、包裹内聚合物外壳中的油相以及分散于聚合物外壳中的气核组成，所述聚合物外壳的材质为生物相容性的聚酰胺，所述油相为生物相容性的油相，该载气栓塞微球的粒径变异系数不超过5％。本发明还提供了基于微流控技术制备该单分散载气栓塞微球的制备方法。本发明通过在微流体装置中利用收集液中的二元胺与水包油包气乳液中的单体进行界面聚合反应实现了载气乳液的固化，解决了现有技术利用微流控技术制备的载气乳液难以甚至无法实现固化的问题，还可以解决现有技术依赖于光交交联对载气乳液进行固化而造成的载气微球具有较大生物毒性的问题。The present invention provides monodisperse gas-carrying embolic microspheres, comprising a polymer shell, an oil phase encapsulated within the polymer shell, and a gas core dispersed within the polymer shell. The polymer shell is made of a biocompatible polyamide, and the oil phase is a biocompatible oil phase. The particle size variation coefficient of the gas-carrying embolic microspheres does not exceed 5%. The present invention also provides a method for preparing the monodisperse gas-carrying embolic microspheres using microfluidic technology. The present invention solidifies the gas-carrying emulsion by performing an interfacial polymerization reaction between a diamine in a collection fluid and a monomer in an oil-in-water gas-in-water emulsion in a microfluidic device. This solves the problem of prior art gas-carrying emulsions prepared using microfluidic technology being difficult or even impossible to solidify. It also addresses the high biotoxicity of the gas-carrying microspheres caused by prior art reliance on photocrosslinking for solidification.
Description
Technical Field
The invention belongs to the technical field of biological medicines, relates to embolic microspheres and a preparation process thereof, and in particular relates to monodisperse carrier gas embolic microspheres and a preparation method thereof.
Background
Solid tumors develop to middle and late stages, often the operation is not resectable, and the embolism treatment is an alternative palliative treatment method, and the embolism treatment refers to that embolic materials are injected into blood vessels near the tumor through minimally invasive operation to block the blood supply of the tumor. Compared with common chemotherapy or radiotherapy, the embolism therapy can reduce side effects, improve patient compliance and improve treatment efficiency.
There are many embolic materials available for embolic therapy, early gelatin sponge particles, iodinated oil, etc., and as materials develop and progress, microspheres become the primary choice of embolic materials due to their unique spherical fluidity. The common embolic materials in the microspheres comprise polyvinyl alcohol (PVA), polylactic acid-glycolic acid copolymer (PLGA), calcium alginate, chitosan and the like, and the materials have good biocompatibility, are nontoxic, low in cost and rich in source, so that the embolic materials are widely applied in the biomedical field. At present, microspheres prepared from the materials can only be used as solid embolism or chemoembolization embolism. Recently, researches show that gases such as nitrogen have a good inhibition effect on tumors, and the nitrogen can form air embolism in the blood vessels near the tumors, so that the blood flow is better blocked, and the purpose of killing the tumors is achieved. The prior art research on carrier gas microspheres has focused mainly on how to load a gas into the microspheres and study their stability, and only a few studies have achieved curing of carrier gas microspheres. For example, glass microfluidic devices have been studied in which a water-in-oil gas-in-oil emulsion is formed by fluid shear force using carbon dioxide as a gas phase, water as a water phase, and silicone oil as an oil phase, but the emulsion prepared by this method cannot be crosslinked and can only exist in the form of an emulsion. There are also researches on using PDMS microfluidic devices, in which carrier gas microspheres are prepared by ultraviolet cross-polymerization using air as a gas phase, ethoxylated trimethylolpropane triacrylate (ETPTA) as an oil phase, and aqueous solutions as a water phase, but ETPTA used in the method has poor biocompatibility and cannot be used as an embolic material.
The micro-fluidic droplet forming technology can realize the generation and operation of bubbles and droplets in a micro-fluidic channel, and the bubbles and droplets generated on a micro-fluidic chip have good monodispersity, and the technology is expected to improve the monodispersity of carrier gas microspheres. At present, when a carrier gas microsphere is prepared by using a microfluidic technology, most of carrier gas microspheres are crosslinked by photopolymerization after uniform bubbles and liquid drops are prepared, but the carrier gas microsphere obtained by crosslinking has higher biotoxicity, and meanwhile, the carrier gas microsphere has the problems of extremely severe crosslinking conditions, lower gas encapsulation rate and the like, and is not suitable for embolism treatment.
Lu(Stabilization of carbon dioxide(CO2)bubbles in micrometer-diameter aqueous droplets and the formation of hollow microparticles.Rochester Institute of Technology,2016.) The microfluidic method is used to generate carbon dioxide double emulsion droplets in oil water, and evaporation is performed in the presence of Sodium Dodecyl Sulfate (SDS), polyvinyl alcohol (PVA) and/or Graphene Oxide (GO) particles dispersed in a double emulsion drip phase. The effect of bubble to droplet size ratio, PVA and graphene oxide concentration on CO 2 bubble stabilization upon water evaporation was studied, and it was found that thin shell particles with encapsulated CO 2 bubbles could be obtained under optimized conditions. However, the study also remained only at the emulsion stage, and curing of the carrier gas emulsion could not be achieved.
Therefore, if the existing preparation method based on the microfluidic technology is adopted, the novel preparation method of the carrier gas embolism microsphere is provided, the sphericity and the gas carrying capacity of the carrier gas embolism microsphere are ensured, the solidification of carrier gas emulsion is realized, the rapid continuous non-toxic preparation of the carrier gas embolism microsphere is realized, and positive significance is brought to the development of the carrier gas embolism microsphere and the better application in clinic.
Disclosure of Invention
Aiming at the problems that the existing carrier gas embolic microsphere is poor in monodispersity and incapable of being cured, and the preparation needs to be carried out by adopting toxic age, the invention provides the monodisperse carrier gas embolic microsphere and a preparation method thereof, so that the monodispersity of the carrier gas embolic microsphere is improved while the rapid continuous non-toxic preparation of the carrier gas embolic microsphere is realized.
In order to achieve the above purpose, the invention adopts the following technical scheme:
A monodisperse carrier gas embolism microsphere consists of a polymer shell, an oil phase in the polymer shell in a wrapping way and a gas nucleus dispersed in the polymer shell, wherein the polymer shell is made of biocompatible polyamide, the oil phase is biocompatible oil phase, and the particle size variation coefficient of the carrier gas embolism microsphere is not more than 5%.
In the technical scheme of the monodisperse carrier gas embolic microsphere, the polymer shell is formed by polymerization reaction of terephthaloyl chloride and diamine. Further, the diamine may be ethylenediamine or other diamines, for example, the polymer shell is terephthalamide formed by polymerization of terephthaloyl chloride and ethylenediamine.
In the above technical scheme of monodisperse carrier gas embolic microspheres, the material of the gas core may be oxygen, carbon dioxide, air, nitrogen, etc., wherein the effect of nitrogen on embolic treatment is better, therefore, the preferred material of the gas core is nitrogen.
In the technical scheme of the monodisperse carrier gas embolic microsphere, the biocompatible oil phase is edible vegetable oil, such as soybean oil, peanut oil, olive oil and the like.
In the technical scheme of the monodisperse carrier gas embolic microsphere, the particle size of the carrier gas embolic microsphere can be determined according to practical application requirements, and in general, the particle size of the carrier gas embolic microsphere is 200-700 mu m.
In the technical scheme of the monodisperse carrier gas embolic microsphere, the number of gas nuclei in the carrier gas embolic microsphere is at least 1, and the carrier gas embolic microsphere can generally contain 1-5 gas nuclei. Generally, when the number of gas nuclei is 1, the carrier gas embolic microsphere is spherical, and as the number of gas nuclei increases, the carrier gas embolic microsphere may take on a shape similar to a sphere, for example, as the number of gas nuclei increases, the carrier gas embolic microsphere may gradually change from a sphere to an ellipsoid.
The invention also provides a preparation method of the monodisperse carrier gas embolism microsphere, which comprises the following steps:
(1) Preparing oil phase, water phase fluid and collecting liquid
Preparing an oil phase fluid, namely dissolving terephthaloyl chloride and an oil-soluble surfactant into edible vegetable oil to obtain the oil phase fluid, wherein the mass ratio of the terephthaloyl chloride, the oil-soluble surfactant and the edible vegetable oil in the oil phase fluid is (0.01-0.1): 1;
Preparing an aqueous phase fluid, namely dissolving polyvinyl alcohol in water to obtain the aqueous phase fluid, wherein the mass ratio of water to the polyvinyl alcohol in the aqueous phase fluid is 1 (0.02-0.01);
Preparing a collecting liquid, namely dissolving diamine and polyvinyl alcohol into water to obtain the collecting liquid, wherein the mass ratio of the water to the polyvinyl alcohol to the diamine in the collecting liquid is 1 (0.02-0.1) (0.05-0.1);
(2) Preparation of Carrier gas embolic microspheres
Inputting a gas phase flow into a first-stage injection tube of a microfluidic device through a constant pressure pump, inputting an oil phase fluid into a second-stage injection tube of the microfluidic device, inputting a water phase fluid into a third-stage injection tube of the microfluidic device, inputting a collecting liquid into a fourth-stage injection tube of the microfluidic device, and forming a monodisperse gas-in-oil-in-water emulsion in the third-stage injection tube, wherein the gas-in-oil-in-water emulsion contacts the collecting liquid in the fourth-stage injection tube, and under the action of diamine in the collecting liquid, the terephthaloyl chloride in an oil phase of a gas-in-water emulsion liquid drop is initiated to undergo a surface polymerization reaction with diamine in the collecting liquid, and after sufficient interfacial polymerization reaction, the monodisperse gas-in-water emulsion is converted into monodisperse carrier gas plug microspheres;
(3) Washing
Washing with water to remove the monodisperse carrier gas embolism to obtain a collection liquid on the microsphere surface.
In the step (2) of the preparation method of the monodisperse carrier gas embolic microsphere, the pressure of the gas phase fluid can be controlled to be 90-180 mbar, the flow rate of the oil phase fluid is controlled to be 100-1000 mu L/h, and the flow rate of the water phase fluid is controlled to be 0.9-2.5 mL/h. The size, the number of gas nuclei and the size of the gas nuclei of the carrier gas embolic microsphere can be adjusted by adjusting the flow rates of the gas phase fluid, the oil phase fluid and the water phase fluid.
In the step (2) of the preparation method of the monodisperse carrier gas embolic microsphere, the time of interfacial polymerization reaction is controlled to be at least 5s. The specific interfacial polymerization time can be regulated and controlled according to the diameter of the carrier gas embolic microsphere, the strength of the carrier gas embolic microsphere and other requirements, and the interfacial polymerization time is generally controlled to be not more than 60 minutes.
In the step (2) of the preparation method of the monodisperse carrier gas embolic microsphere, after the gas-in-water-in-oil-in-gas emulsion is solidified in the four-stage injection tube through interfacial polymerization reaction, a container containing collection liquid can be adopted to collect output products from the tail end of the four-stage injection tube of the microfluidic device, and the solidified gas-in-water-in-oil-in-gas emulsion continuously generates interfacial polymer reaction in the container containing the collection liquid so as to regulate and control the mechanical property of the carrier gas embolic microsphere.
In the preparation method of the monodisperse carrier gas embolic microsphere, the mechanical properties of the carrier gas embolic microsphere can be adjusted by adjusting the pressure of the gas phase fluid and the time of interfacial polymerization reaction on the basis of meeting the defined composition of the water phase fluid, the oil phase fluid and the collecting liquid and the flow rates of the water phase fluid and the oil phase fluid.
In the preparation method of the monodisperse carrier gas embolic microsphere, the oil-soluble surfactant may be polyisobutylene bissuccinimide (T154), polyglyceryl ricinoleate, diethanolamide oleate, span20, span40, span60, span80 or Tween85.
In the preparation method of the monodisperse carrier gas embolic microsphere, the edible vegetable oil comprises at least one of soybean oil, peanut oil and olive oil.
In the preparation method of the monodisperse carrier gas embolism microsphere, when preparing aqueous phase fluid, polyvinyl alcohol is added into water, and is heated to 95-98 ℃ to dissolve the polyvinyl alcohol, so that the aqueous phase fluid is obtained.
In the preparation method of the monodisperse carrier gas embolism microsphere, when preparing the oil phase fluid, terephthaloyl chloride and an oil-soluble surfactant are added into edible vegetable oil and stirred until the terephthaloyl chloride and the oil-soluble surfactant are dissolved, thus obtaining the oil phase fluid, and the oil phase fluid is preferably prepared at present.
In the step (2) of the preparation method of the monodisperse carrier gas embolic microsphere, the adopted microfluidic device is a three-stage microfluidic device, the microfluidic device comprises a first-stage injection tube, a second-stage injection tube, a third-stage injection tube and a fourth-stage injection tube, the tail end of the first-stage injection tube is mutually connected with the head end of the second-stage injection tube, the tail end of the second-stage injection tube is mutually connected with the head end of the third-stage injection tube, the tail end of the third-stage injection tube is mutually connected with the head end of the fourth-stage injection tube, and the axes of the first-stage injection tube, the second-stage injection tube, the third-stage injection tube and the fourth-stage injection tube are positioned on the same straight line.
Further, in the step (2) of the preparation method of the monodisperse carrier gas embolic microsphere, the adopted microfluidic device has a size of the secondary injection tube larger than or equal to a size of the primary injection tube, a size of the tertiary injection tube larger than the size of the secondary injection tube, and a size of the quaternary injection tube larger than or equal to the size of the tertiary injection tube.
Further, in the step (2) of the preparation method of the monodisperse carrier gas embolic microsphere, the head end of the primary injection tube of the adopted microfluidic device is a gas phase inlet, two oil phase inlets are arranged on two sides of the head end of the secondary injection tube, a water phase inlet is arranged on two sides of the head end of the tertiary injection tube, and two collecting liquid inlets are arranged on two sides of the head end of the quaternary injection tube.
In the step (2) of the preparation method of the monodisperse carrier gas embolic microsphere, the channel size of the adopted microfluidic device is in the micron level, for example, the channel size can be in the range of 50-500 μm.
In the step (2) of the preparation method of the monodisperse carrier gas embolism microsphere, the microfluidic device is matched with a syringe pump for use, so that the control of the fluid flow of each phase can be realized.
In the invention, the formation mechanism of the monodisperse carrier gas embolic microsphere is as follows:
The invention takes the gas phase fluid of the carried gas (such as nitrogen), takes the edible vegetable oil (such as soybean oil) solution containing terephthaloyl chloride and oil-soluble surfactant as the oil phase fluid, takes the water solution of polyvinyl alcohol as the water phase fluid, inputs the gas phase fluid, the oil phase fluid and the water phase fluid into the first-stage, second-stage and third-stage injection tubes of the micro-fluidic device, forms the monodisperse oil-in-water gas-in-oil emulsion in the third-stage injection tubes of the micro-fluidic device, simultaneously inputs the collecting liquid into the fourth-stage injection tubes of the micro-fluidic device, takes the oil-in-water gas-in-oil emulsion formed in the third-stage injection tubes as the template, and changes the template into the fourth-stage injection tubes to contact with the collecting liquid. Because the collecting liquid is formed by dissolving diamine in the polyvinyl alcohol aqueous solution, the diamine dissolved in the polyvinyl alcohol aqueous solution can carry out interfacial polymerization reaction with terephthaloyl chloride in an oil phase at the oil-water interface of the gas-in-oil emulsion liquid drops, and the reaction process is shown in figure 1. Because the collecting liquid and the aqueous phase fluid are prepared based on the polyvinyl alcohol aqueous solution, diamine in the collecting liquid can be directly contacted with terephthaloyl chloride in the oil phase of the gas-in-oil-in-water emulsion liquid drops, and can rapidly initiate interfacial polymerization reaction after the collecting liquid and the aqueous phase fluid are contacted, and finally, the monodisperse gas-in-oil-in-water emulsion is solidified and converted into monodisperse carrier gas embolism microspheres.
Compared with the prior art, the technical scheme of the invention has the following beneficial technical effects:
1. The invention provides a monodisperse carrier gas plug microsphere and a preparation method thereof based on a microfluidic technology, and provides a preparation method of a monodisperse water-in-oil gas plug microsphere, which realizes the solidification of carrier gas emulsion by utilizing diamine in a collection liquid and a monomer in a water-in-oil-in-gas emulsion to carry out interfacial polymerization reaction in a microfluidic device, effectively solves the problem that the carrier gas emulsion prepared by the microfluidic technology in the prior art is difficult or even impossible to realize solidification, and simultaneously, the polymer shell of the carrier gas microsphere prepared by the invention and the oil phase and gas core entrapped in the polymer shell are biocompatible, so that the problem that the carrier gas microsphere prepared by solidifying the carrier gas emulsion by the photo-cross-linking technology in the prior art has larger biotoxicity can be solved.
2. The monodisperse carrier gas embolism microsphere provided by the method has the advantages of simple preparation process, low production cost and high reaction speed, can realize continuous production, and is favorable for realizing batch production. Meanwhile, the carrier gas embolism microsphere prepared by the method has uniform and controllable size, and the sizes of the carrier gas microsphere and the gas core can be flexibly regulated and controlled by regulating the flow of each phase of fluid and the pressure of the gas phase fluid. The mechanical property of the carrier gas embolism microsphere can be adjusted by changing the time of the interfacial polymerization reaction of the water and the oil, and the method has the characteristic of good adjustability and controllability.
3. When the carrier gas embolism microsphere is prepared by the method, the terephthaloyl chloride and diamine react to generate the polymer shell, and the edible vegetable oil and the gas core are wrapped by the polymer shell, so that the edible vegetable oil does not generate a crosslinking reaction, and the oil phase in the carrier gas embolism microsphere can well protect the gas core from being discharged.
4. The single-dispersion oil-in-water gas-in-water embolism microsphere provided by the invention is prepared based on edible vegetable oil, and because the edible vegetable oil is not crosslinked, the problems that gas is extruded by inward shrinkage during reaction so as to be discharged and the like do not exist, and the prepared carrier gas embolism microsphere has better strength. Meanwhile, the carrier gas embolism microsphere provided by the invention has uniform morphology and good monodispersity. The characteristics are that the existing carrier gas microspheres are difficult to achieve at the same time, so that the problems that the existing carrier gas microspheres cannot be crosslinked and solidified and are nonuniform in size can be solved, the carrier gas embolic microspheres can be better applied in clinical practice, and the safety of embolic treatment is improved.
Drawings
FIG. 1 is a schematic illustration of interfacial polymerization of terephthaloyl chloride and ethylenediamine in accordance with the present invention.
FIG. 2 is a schematic diagram of a PDMS microfluidic device according to the present invention, wherein the device comprises a 1-primary injection tube, a 1-gas inlet, a 2-secondary injection tube, a 2-1-oil inlet, a 3-tertiary injection tube, a 3-1-water inlet, a 4-quaternary injection tube, and a 4-1-collection liquid inlet.
FIG. 3 is a schematic illustration of interfacial polymerization curing of G/O/W emulsion droplets in a collection fluid of a four-stage syringe. FIG. 4 is an optical micrograph of a portion of the G/O/W emulsion prepared in example 1.
FIG. 5 (A) and (B) are graphs showing the diameter of the G/O/W emulsion droplet prepared in example 1 and the diameter of the gas core therein as a function of the gas flow rate and the aqueous phase fluid flow rate, wherein D drop represents the diameter of the G/O/W emulsion droplet, D gas represents the diameter of the gas core, and Q w represents the aqueous phase fluid flow rate.
FIG. 6 is a plot of the diameter of the droplets of the G/O/W emulsion prepared in the fourth set of experiments of example 1 and the diameter of the gas core therein as a function of the oil phase fluid flow rate, where D drop represents the diameter of the droplets of the G/O/W emulsion, D gas represents the diameter of the gas core, and Q o represents the oil phase fluid flow rate.
Fig. 7 is an optical photograph of a portion of carrier gas microspheres prepared in a fourth set of experiments in example 1.
FIG. 8 is a graph showing the coefficient of variation (Coefficient of variation, CV value) of the diameter of monodisperse carrier gas embolic microspheres prepared under different experimental conditions for the fourth set of experiments of example 1, the diameter of the microcarrier gas embolic microspheres on the abscissa.
FIG. 9 is a graph showing the relationship between the diameters of monodisperse carrier gas plug microspheres and G/O/W emulsion droplets prepared in the fourth experiment of example 1, wherein d p represents the diameter of the carrier gas plug microspheres and d e represents the diameter of the G/O/W emulsion droplets.
FIG. 10 is a graph showing the elastic properties of the carrier gas embolic microspheres prepared in example 2, wherein the graphs (A) and (B) are force-displacement relationships of the carrier gas embolic microspheres, respectively, and the elastic modulus of the carrier gas embolic microspheres is a function of test time.
FIG. 11 is an optical micrograph of a procedure for preparing droplets of a G/O/W emulsion of example 3 under different gas phase fluid pressure conditions.
FIG. 12 is an optical photograph of a portion of carrier gas embolic microspheres prepared in example 3.
Detailed Description
The monodisperse carrier gas embolic microsphere and the preparation method thereof according to the present invention are further described below by way of examples. It is to be noted that the following examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, since numerous insubstantial modifications and variations of the present invention may be made by those skilled in the art in light of the above teachings, and still fall within the scope of the invention.
In the following examples and comparative examples, the adopted microfluidic device is made of Polydimethylsiloxane (PDMS) material, and hereinafter referred to as PDMS microfluidic device, and the schematic channel structure of the microfluidic device is shown in fig. 2, and the microfluidic device comprises a first-stage injection tube 1, a second-stage injection tube 2, a third-stage injection tube 3 and a collecting liquid injection tube 4, wherein the head end of the first-stage injection tube 1 is a gas-phase inlet 1-1, the tail end of the first-stage injection tube is connected with the head end of the second-stage injection tube, two oil-phase inlets 2-1 connected with the second-stage injection tube are arranged on two sides of the head end of the second-stage injection tube 2, specifically, the oil-phase inlets are perpendicular to the second-stage injection tube, the tail end of the second-stage injection tube is connected with the head end of the third-stage injection tube, specifically, the two water-phase inlets 3-1 connected with the third-stage injection tube are arranged on two sides of the head end of the third-stage injection tube, specifically, the tail end of the third-stage injection tube is connected with the head end of the fourth-stage injection tube, the two collecting liquid inlets 4-1 are arranged on two sides of the head end of the fourth-stage injection tube, specifically, the two collecting liquid inlets are perpendicular to the head end of the third-stage injection tube is perpendicular to the head end of the third-stage injection tube, and the collecting liquid inlet is perpendicular to the head end of the third-stage injection tube.
In the microfluidic devices used in examples 1,2,3, 5 and comparative example 1, the heights of the primary syringe, the secondary syringe, the tertiary syringe and the quaternary syringe were all 100. Mu.m, the width of the primary syringe was 150. Mu.m, the width of the secondary syringe was 150. Mu.m, the width of the front section of the tertiary syringe was 200. Mu.m, the width of the rear section was 250. Mu.m, and the width of the quaternary syringe was 250. Mu.m.
In the microfluidic devices used in examples 4 and 6, the heights of the primary syringe, the secondary syringe, the tertiary syringe and the quaternary syringe were 100. Mu.m, the width of the primary syringe was 70. Mu.m, the width of the secondary syringe was 150. Mu.m, the width of the front section of the tertiary syringe was 200. Mu.m, the width of the rear section was 250. Mu.m, and the width of the quaternary syringe was 250. Mu.m.
Example 1
In this example, monodisperse carrier gas embolic microspheres were prepared as follows:
(1) Preparing oil phase, water phase fluid and collecting liquid
Preparing an oil phase fluid, namely dissolving terephthaloyl chloride and T154 into soybean oil to obtain an oil phase fluid, wherein the oil phase fluid is used at present, and the mass ratio of terephthaloyl chloride to T154 to soybean oil in the oil phase fluid is 0.05:0.04:1;
Preparing an aqueous phase fluid, namely adding polyvinyl alcohol into water, and heating to 95-98 ℃ to dissolve the polyvinyl alcohol to obtain the aqueous phase fluid, wherein the mass ratio of water to the polyvinyl alcohol in the aqueous phase fluid is 1:0.05;
preparing a collecting liquid, namely dissolving ethylenediamine and polyvinyl alcohol into water to obtain the collecting liquid, wherein the mass ratio of water to the polyvinyl alcohol to the ethylenediamine in the collecting liquid is 1:0.05:0.05.
(2) Preparation of monodisperse Carrier gas embolic microspheres
The PDMS microfluidic device with the structure shown in fig. 2 was used for the preparation.
The method comprises the steps of taking nitrogen as gas-phase fluid, inputting the gas-phase fluid into a first-stage injection tube of a microfluidic device through a gas-phase inlet by a constant-pressure pump, inputting the oil-phase fluid into a second-stage injection tube of the microfluidic device through the oil-phase inlet by an injection pump, inputting the water-phase fluid into a third-stage injection tube of the microfluidic device through the water-phase inlet by an injection pump, forming monodisperse gas-in-oil emulsion (G/O/W emulsion) in the third-stage injection tube, inputting the collecting liquid into a fourth-stage injection tube of the microfluidic device through a collecting liquid inlet by an injection pump, contacting the collecting liquid in the fourth-stage injection tube, and when ethylenediamine in the collecting liquid contacts terephthaloyl chloride in an oil phase of G/O/W emulsion liquid drops, initiating interfacial polymerization reaction of the G/O/W emulsion liquid drops to form polydimethyl ethylenediamine, wherein after polymerization for 5 seconds, the monodisperse G/O/W emulsion is converted into monodisperse carrier gas plug microspheres, collecting output products from the end of the fourth-stage injection tube by a container containing the collecting liquid, and separating solid and liquid.
In the preparation process, four groups of experiments are performed:
The first group of experiments controls the pressure of the gas phase fluid to be 107mbar, controls the flow rate of the oil phase fluid to be 650 mu L/h, and simultaneously controls the flow rates of the water phase fluid to be 1.5, 1.6, 1.7, 1.8 and 1.9mL/h respectively;
The second group of experiments controls the pressure of the gas phase fluid to be 120mbar, controls the flow rate of the oil phase fluid to be 650 mu L/h, and simultaneously controls the flow rates of the water phase fluid to be 1.5, 1.6, 1.7, 1.8 and 1.9mL/h respectively;
the third group of experiments controls the pressure of the gas phase fluid to be 107mbar, controls the flow rate of the water phase fluid to be 1.7mL/h, and simultaneously controls the flow rates of the oil phase fluid to be 550, 600, 650, 700 and 750 mu L/h respectively;
the fourth set of experiments controlled the pressure of the gas phase fluid to be 120mbar, the flow rate of the water phase fluid to be 1.7mL/h, and the flow rates of the oil phase fluid to be 550, 600, 650, 700 and 750. Mu.L/h respectively.
(3) Washing
Washing with pure water to remove the collected liquid on the surface of the monodisperse carrier gas plug microsphere obtained in the step (2), drying and preserving.
FIG. 4 is an optical micrograph of the G/O/W emulsion prepared under partial flow conditions of this example, and it can be clearly seen from FIG. 3 that the G/O/W emulsion and the gas core therein have good uniformity in size.
FIG. 5 is a graph showing the change in diameter of the G/O/W emulsion and the gas core therein according to the gas phase fluid pressure and the water phase fluid flow rate, and FIG. 6 is a graph showing the change in diameter of the G/O/W emulsion and the gas core therein according to the gas phase fluid pressure and the oil phase fluid flow rate. As can be seen from FIGS. 5 to 6, the diameters of the G/O/W emulsion droplets and the gas core therein can be controlled by adjusting the pressure of the gas phase fluid and the flow rates of the oil phase fluid and the water phase fluid.
Fig. 7 is an optical image of a portion of monodisperse carrier gas plug microsphere prepared in the fourth set of experiments of this example, i.e., an optical image of a carrier gas plug microsphere formed after curing of the G/O/W emulsion droplets of fig. 4. FIG. 8 shows the coefficient of variation (Coefficient of variation, CV values) of the diameters of monodisperse carrier gas embolic microspheres prepared under different experimental conditions in the fourth set of experiments of this example. As shown in figures 7-8, when the preparation conditions are consistent, the carrier gas embolic microsphere prepared by the method is spherical, has excellent sphericity, uniform size and good gas nucleus, and meanwhile, the CV value of the diameter of the carrier gas embolic microsphere prepared by the embodiment is not more than 4.25%, and is 2.25% -4.25%, which indicates that the carrier gas embolic microsphere prepared by the method has uniform size and morphology and good monodispersity.
FIG. 9 is a graph showing the relationship between the diameters of the carrier gas plug microspheres and the G/O/W emulsion droplets prepared in the fourth experiment, wherein the diameters of the carrier gas plug microspheres prepared in the fourth experiment under different conditions are 400-600 μm, and the diameters of the carrier gas plug microspheres are basically consistent with the diameters of the G/O/W emulsion droplets, which shows that the diameters are not obviously affected in the curing process.
Example 2
In this example, carrier gas embolic microspheres were prepared and tested for elasticity as follows:
(1) Preparing oil phase, water phase fluid and collecting liquid
The same internal phase fluid, external phase fluid and collection fluid as in example 1.
(2) Preparation of monodisperse Carrier gas embolic microspheres
The PDMS microfluidic device with the structure shown in fig. 2 was used for the preparation.
The method comprises the steps of taking nitrogen as gas-phase fluid, inputting the gas-phase fluid into a first-stage injection tube of a microfluidic device through a gas-phase inlet by a constant-pressure pump, inputting the oil-phase fluid into a second-stage injection tube of the microfluidic device through the oil-phase inlet by an injection pump, inputting the water-phase fluid into a third-stage injection tube of the microfluidic device through the water-phase inlet by an injection pump, forming monodisperse gas-in-oil emulsion (G/O/W emulsion) in the third-stage injection tube, inputting the collecting liquid into a fourth-stage injection tube of the microfluidic device through a collecting liquid inlet by an injection pump, contacting the collecting liquid in the fourth-stage injection tube, and when ethylenediamine in the collecting liquid contacts terephthaloyl chloride in an oil phase of G/O/W emulsion liquid drops, initiating interfacial polymerization reaction of the G/O/W emulsion liquid drops to form polydimethyl ethylenediamine, wherein after polymerization for 5 seconds, the monodisperse G/O/W emulsion is converted into monodisperse carrier gas plug microspheres, and collecting output products from the tail ends of the fourth-stage injection tube by a container containing the collecting liquid.
The pressure of the gas phase fluid was controlled to be 120mbar, the flow rate of the aqueous phase fluid was controlled to be 1.7mL/h, and the flow rate of the oil phase fluid was controlled to be 650. Mu.L/h. Meanwhile, five groups of experiments are carried out in the step, after products output from the tail end of the four-stage injection tube are collected by adopting a container containing collection liquid, carrier gas embolic microspheres continue to undergo interfacial polymerization reaction for a certain time in the container containing collection liquid, then solid-liquid separation is carried out, and the solidified carrier gas embolic microspheres are obtained after separation, wherein in the five groups of experiments, the time for the carrier gas embolic microspheres to undergo interfacial polymerization reaction in the container containing collection liquid is controlled to be 10,20,30,40 and 50 minutes respectively.
(3) Washing
Washing with pure water to remove the collected liquid on the surface of the monodisperse carrier gas plug microsphere obtained in the step (2), drying and preserving.
The elastic performance test is carried out on the carrier gas embolism microsphere prepared in the embodiment, the prepared embolism microsphere is placed in a water tank, the test is carried out by utilizing a microparticle strength tester, 10g of sensor is selected, the probe size is 1000 mu m, five groups of carrier gas embolism microsphere obtained by experiments through different interface polymer reaction times are compressed to obtain the force-displacement relationship, then analysis is carried out by utilizing a Hertz model to measure the elastic performance, and the results are respectively shown in two diagrams (A) and (B) in FIG. 10, so that the carrier gas embolism microsphere prepared in the embodiment has good mechanical performance.
Comparative example 1
In this example, the effect of the composition of the collection fluid on the preparation of carrier gas embolic microspheres was examined as follows:
(1) Preparing water phase, oil phase fluid and collecting liquid
The aqueous phase fluid and the oil phase fluid are the same as in example 1. Three different collections were prepared as follows.
Preparing a collection liquid A, namely dissolving polyvinyl alcohol into water to obtain the collection liquid A, wherein the mass ratio of the water to the polyvinyl alcohol in the collection liquid A is 1:0.03;
Preparing a collection liquid B, namely dissolving polyvinyl alcohol and SDS into water to obtain the collection liquid B, wherein the mass ratio of water to polyvinyl alcohol to SDS in the collection liquid B is 1:0.05:0.03;
the collection liquid C was prepared by using pure water as the collection liquid C.
(2) Preparation of Carrier gas embolic microspheres
The carrier gas embolic microspheres were prepared by the procedure of step (2) of example 2 by replacing the collection liquid in step (2) of example 1 with collection liquid A, collection liquid B and collection liquid C, respectively, to examine the influence of the composition of the collection liquid on the carrier gas embolic microspheres.
The pressure of the gas phase fluid is controlled to be 107mabr, the flow rate of the oil phase fluid is controlled to be 650 mu L/h, and the flow rate of the water phase fluid is controlled to be 1.5mL/h.
In the preparation process of the comparative example, it was found that when the collection liquid A was used instead of the collection liquid in the step (2) of example 1, the prepared monodisperse G/O/W emulsion was broken after entering the collection liquid, which may be caused by insufficient concentration of polyvinyl alcohol in the collection liquid A, when the collection liquid B was used instead of the collection liquid in the step (2) of example 1, the prepared monodisperse G/O/W emulsion was separated from the oil core due to greater traction of bubbles by SDS after entering the collection liquid, and thus gas encapsulation was not achieved, and when the collection liquid C was used instead of the collection liquid in the step (2) of example 1, G/O/W emulsion droplets were not sheared in the microfluidic device, and the subsequent preparation process was not performed.
As is clear from the combination of example 1 and comparative example 1, the formation, stability and crosslinking curing process of the composition G/O/W emulsion of the collection liquid have important effects, and the present invention has found that stable carrier gas embolic microspheres excellent in monodispersity can be formed only in the collection liquid of a specific composition and concentration.
Example 3
In this embodiment, monodisperse carrier gas plug microspheres carrying a plurality of gas nuclei are prepared as follows:
(1) Preparing oil phase, water phase fluid and collecting liquid
The same internal phase fluid, external phase fluid and collection fluid as in example 1.
(2) Preparation of monodisperse Carrier gas embolic microspheres
The PDMS microfluidic device with the structure shown in fig. 2 was used for the preparation.
The method comprises the steps of taking nitrogen as gas-phase fluid, inputting the gas-phase fluid into a first-stage injection tube of a microfluidic device through a gas-phase inlet by a constant-pressure pump, inputting the oil-phase fluid into a second-stage injection tube of the microfluidic device through the oil-phase inlet by an injection pump, inputting the water-phase fluid into a third-stage injection tube of the microfluidic device through the water-phase inlet by an injection pump, forming monodisperse gas-in-oil emulsion (G/O/W emulsion) in the third-stage injection tube, inputting the collecting liquid into a fourth-stage injection tube of the microfluidic device through a collecting liquid inlet by an injection pump, contacting the collecting liquid in the fourth-stage injection tube, and when ethylenediamine in the collecting liquid contacts terephthaloyl chloride in an oil phase of G/O/W emulsion liquid drops, initiating interfacial polymerization reaction of the G/O/W emulsion liquid drops to form polydimethyl ethylenediamine, wherein after polymerization for 5 seconds, the monodisperse G/O/W emulsion is converted into monodisperse carrier gas plug microspheres, collecting output products from the end of the fourth-stage injection tube by a container containing the collecting liquid, and separating solid and liquid.
In the preparation process, six groups of experiments are carried out, wherein each group of experiments controls the flow rate of the water phase fluid to be 1.7mL/h, the flow rate of the oil phase fluid to be 100 mu L/h, and each group of experiments controls the pressure of the gas phase fluid to be 134, 138, 142, 146, 148 and 150mbar respectively.
(3) Washing
Washing with pure water to remove the collected liquid on the surface of the monodisperse carrier gas plug microsphere obtained in the step (2), drying and preserving.
FIG. 11 is an optical micrograph of G/O/W emulsion droplets with different numbers of gas nuclei prepared in this example, wherein the first row corresponds to the case where the gas phase fluid pressures are 134, 138, 142mbar, respectively, from left to right, and the second row corresponds to the case where the gas phase fluid pressures are 146, 148, 150mbar, respectively. As can be seen from FIG. 11, when the flow rate of the aqueous phase fluid was 1.7mL/h, the flow rate of the oil phase fluid was 100. Mu.L/h, and the pressure of the gas phase fluid was 134mbar, the emulsion was prepared without gas core, which may be caused by the fact that the pressure of the gas phase fluid was too small under the flow rate conditions of the aqueous phase fluid and the oil phase fluid. Meanwhile, the G/O/W emulsion droplets in fig. 11 are converted into carrier gas embolic microspheres after solidification, which means that the number of gas nuclei in the carrier gas embolic microspheres can be adjusted by adjusting the pressure of the gas, and under the condition of the embodiment, at most 5 gas nuclei can be wrapped in one carrier gas embolic microsphere at the same time. FIG. 12 is an optical micrograph of a portion of a carrier gas embolic microsphere prepared in this example, wherein the first row corresponds to the case where the pressure of the gas phase fluid is 134, 138mbar, respectively, from left to right, and the second row corresponds to the case where the pressure of the gas phase fluid is 142, 146mbar, respectively, from left to right, wherein the flow rate of the water phase fluid is 1.7mL/h, the flow rate of the oil phase fluid is 100 μL/h, when the pressure of the gas phase fluid is 134mbar, no gas core is contained in the embolic microsphere prepared, and when the pressures of the gas phase fluid are 138, 142, and 146mbar, the carrier gas embolic microsphere prepared contains 1, 2, 3 gas cores.
Example 4
In this example, monodisperse carrier gas embolic microspheres were prepared as follows:
(1) Preparing water phase, oil phase fluid and collecting liquid
The aqueous phase fluid, the oil phase fluid and the collection liquid were the same as in example 1.
(2) Preparation of single-dispersed oil-in-water gas-in-water embolism microsphere
The preparation was performed using a PDMS microfluidic device having a structure as shown in fig. 2, which was substantially the same as that used in example 1, except that the width of the primary injection tube was 70 μm.
The method comprises the steps of taking nitrogen as gas-phase fluid, inputting the gas-phase fluid into a first-stage injection tube of a microfluidic device through a gas-phase inlet by a constant-pressure pump, inputting the oil-phase fluid into a second-stage injection tube of the microfluidic device through the oil-phase inlet by an injection pump, inputting the water-phase fluid into a third-stage injection tube of the microfluidic device through the water-phase inlet by an injection pump, forming monodisperse gas-in-oil emulsion (G/O/W emulsion) in the third-stage injection tube, inputting the collecting liquid into a fourth-stage injection tube of the microfluidic device through a collecting liquid inlet by an injection pump, contacting the collecting liquid in the fourth-stage injection tube, and when ethylenediamine in the collecting liquid contacts terephthaloyl chloride in an oil phase of G/O/W emulsion liquid drops, initiating interfacial polymerization reaction of the G/O/W emulsion liquid drops to form polydimethyl ethylenediamine, wherein after polymerization for 5 seconds, the monodisperse G/O/W emulsion is converted into monodisperse carrier gas plug microspheres, collecting output products from the end of the fourth-stage injection tube by a container containing the collecting liquid, and separating solid and liquid.
In this step, the flow rate of the aqueous phase fluid was controlled to be 1.7mL/h, the flow rate of the oil phase fluid was controlled to be 650. Mu.L/h, and the pressure of the gas phase fluid was controlled to be 120mbar.
(3) Washing
Washing with pure water to remove the collected liquid on the surface of the monodisperse carrier gas plug microsphere obtained in the step (2), drying and preserving.
Example 5
In this example, monodisperse carrier gas embolic microspheres were prepared as follows:
(1) Preparing oil phase, water phase fluid and collecting liquid
Preparing an oil phase fluid, namely dissolving terephthaloyl chloride and T154 into soybean oil to obtain an oil phase fluid, wherein the oil phase fluid is used at present, and the mass ratio of terephthaloyl chloride to T154 to soybean oil in the oil phase fluid is 0.1:0.08:1;
preparing an aqueous phase fluid, namely adding polyvinyl alcohol into water, and heating to 95-98 ℃ to dissolve the polyvinyl alcohol to obtain the aqueous phase fluid, wherein the mass ratio of water to the polyvinyl alcohol in the aqueous phase fluid is 1:0.1;
Preparing a collecting liquid, namely dissolving ethylenediamine and polyvinyl alcohol into water to obtain the collecting liquid, wherein the mass ratio of water to the polyvinyl alcohol to the ethylenediamine in the collecting liquid is 1:0.1:0.1.
(2) Preparation of monodisperse Carrier gas embolic microspheres
In the same manner as in the step (2) of example 1, the flow rate of the aqueous phase fluid was controlled to 2.5mL/h, the flow rate of the oil phase fluid was controlled to 1000. Mu.L/h, and the pressure of the gas phase fluid was controlled to 180mbar.
(3) Washing
Washing with pure water to remove the collected liquid on the surface of the monodisperse carrier gas plug microsphere obtained in the step (2), drying and preserving.
Example 6
In this example, monodisperse carrier gas embolic microspheres were prepared as follows:
(1) Preparing oil phase, water phase fluid and collecting liquid
Preparing an oil phase fluid, namely dissolving terephthaloyl chloride and T154 into soybean oil to obtain an oil phase fluid, wherein the oil phase fluid is used at present, and the mass ratio of terephthaloyl chloride to T154 to soybean oil in the oil phase fluid is 0.01:0.01:1;
Preparing an aqueous phase fluid, namely adding polyvinyl alcohol into water, and heating to 95-98 ℃ to dissolve the polyvinyl alcohol to obtain the aqueous phase fluid, wherein the mass ratio of water to the polyvinyl alcohol in the aqueous phase fluid is 1:0.02;
Preparing a collecting liquid, namely dissolving ethylenediamine and polyvinyl alcohol into water to obtain the collecting liquid, wherein the mass ratio of water to the polyvinyl alcohol to the ethylenediamine in the collecting liquid is 1:0.02:0.05.
(2) Preparation of monodisperse Carrier gas embolic microspheres
In the same manner as in the operation of step (2) of example 4, the flow rate of the aqueous phase fluid was controlled to be 0.9mL/h, the flow rate of the oil phase fluid was controlled to be 500. Mu.L/h, and the pressure of the gas phase fluid was controlled to be 90mbar.
(3) Washing
Washing with pure water to remove the collected liquid on the surface of the monodisperse carrier gas plug microsphere obtained in the step (2), drying and preserving.
Claims (8)
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