CN113498777A - Emulsion type organ preservation solution and preparation method thereof - Google Patents
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0205—Chemical aspects
- A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
- A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0236—Mechanical aspects
- A01N1/0242—Apparatuses, i.e. devices used in the process of preservation of living parts, such as pumps, refrigeration devices or any other devices featuring moving parts and/or temperature controlling components
- A01N1/0247—Apparatuses, i.e. devices used in the process of preservation of living parts, such as pumps, refrigeration devices or any other devices featuring moving parts and/or temperature controlling components for perfusion, i.e. for circulating fluid through organs, blood vessels or other living parts
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Abstract
The invention discloses an emulsion organ preservation solution and a preparation method thereof, the emulsion organ preservation solution comprises an oil phase component and a water phase component, the oil phase component comprises fluorocarbon oxygen carrying agent, emulsifier and lactic acid, the water phase component comprises osmotic pressure regulator, buffer salt, electrolyte and carbonate, and the volume ratio of the oil phase component to the water phase component is 1: (3-20); and mixing the oil phase and the water phase by a micro-fluidic method or a micro-jet high-pressure homogenization method to prepare the emulsion organ preservation solution with proper particle size, high stability and high oxygen carrying capacity. The emulsion type organ preservation solution can prolong the preservation time of organs and improve the preservation quality of organs.
Description
Technical Field
The invention belongs to the field of medical materials, and particularly relates to an emulsion type organ preservation solution and a preparation method thereof.
Background
With the development of the current organ transplantation technology, the preservation technology of organs is more and more emphasized, the high-quality donor organ is the precondition for the success of the organ transplantation operation, and the preservation technology of organs is the cornerstone of the organ transplantation. Organ transplantation entails the transplantation of a living organ, which is required to maintain intact anatomy and viability from the time of its removal from the donor until its major blood vessels are connected to the patient's blood vessels. However, once any organ loses its blood supply, the cells do not receive the necessary oxygen and nutrients and die in a short period of time at normal temperature. Therefore, it is necessary to try to maintain the activity of the isolated organ for a long time.
The most common form of organ preservation is known as lavage of excised donor organs with organ preservation solutions and static cryopreservation. At present, commonly used organ preservation solutions comprise UW solution, HTK solution, Euro-Collins solution, Celsior solution and the like, and the preservation mechanism is to maintain the ion concentration and the osmotic pressure. For example, UW solution can be stored for 12 hours in kidney or 8 hours in liver, is a well-known standard liver, pancreas and kidney storage solution, is widely used at home and abroad, but is high in viscosity and is not suitable for being matched with perfusion equipment. The HTK liquid has good buffering performance, outstanding performance in inhibiting tissue acidification, low viscosity and easy diffusion, and has the clinical effect equivalent to that of the UW liquid.
It is worth noting that current organ preservation solutions have no oxygen support function, which limits the effective preservation time of the organ. Whether stored statically cryogenically or by normothermic perfusion, metabolism in the organ is not completely halted. Even at 4 ℃, the transplanted organ still has 5% to 15% of the normal body temperature metabolic level. Therefore, an ideal organ preservation solution should provide sufficient oxygen supply to the tissues. Therefore, the development of an organ preservation solution capable of efficiently maintaining oxygen supply to the preserved organ is of great significance in prolonging the preservation time of the organ and improving the preservation quality.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides the emulsion type organ preservation solution which can prolong the preservation time of organs and improve the preservation quality.
The invention also provides a preparation method of the emulsion type organ preservation solution.
According to one aspect of the present invention, there is provided an emulsion-type organ preservation solution comprising an oil phase component and an aqueous phase component, the oil phase component comprising fluorocarbon-based oxygen carriers, emulsifiers, and lactic acid, the aqueous phase component comprising osmotic pressure regulators, buffer salts, electrolytes, and carbonates, the volume ratio of the oil phase component to the aqueous phase component being 1: (3-20).
According to a preferred embodiment of the present invention, at least the following advantages are provided: the fluorocarbon oxygen carrying agent in the emulsion type organ preservation solution is dispersed in a water phase as an oil phase, the oil phase supplies oxygen, and a plurality of solutes in the water phase maintain the ion concentration and osmotic pressure, so that the emulsion type solves the problem of stable dispersion of water-insoluble fluorocarbon in a water-based environment; the emulsion type organ preservation solution provides enough energy for emulsion formation by utilizing the gas production reaction of lactic acid and carbonate, and obtains emulsion with smaller and more uniform emulsion drop particle size distribution; the emulsion type organ preservation solution has high oxygen carrying content, and can prolong the preservation time of organs and improve the preservation quality.
In some embodiments of the invention, the fluorocarbon-based oxygen carrier is selected from at least one of perfluorooctyl bromide, perfluorodecyl bromide, perfluorodecalin, perfluorotripropylamine, perfluoromethylcyclohexylpiperidine, perfluorotributylamine, perfluorooctyl dichloride, and perfluorobutyl ethylene; and/or the emulsifier is selected from at least one of soybean lecithin and egg yolk lecithin; and/or the osmolality adjusting agent is selected from at least one of mannitol and glycerol; and/or the buffer salt is selected from at least one of histidine, histidine hydrochloride, tryptophan and potassium hydrogen 2-ketoglutarate; and/or the electrolyte is selected from at least one of sodium chloride, potassium chloride, magnesium chloride, calcium chloride and magnesium sulfate; and/or the carbonate is selected from at least one of sodium bicarbonate and sodium carbonate.
In the invention, the fluorocarbon oxygen carrying agent is a fluorocarbon compound, and the phospholipid emulsifier with good biological safety is adopted, so that the oxygen carrying agent is ensured to be stably dispersed in a nano-scale liquid drop form.
In some preferred embodiments of the present invention, the oil phase components are prepared by mixing (100 to 200): (1-10): (10-30): 1 of perfluorooctyl bromide, perfluorodecane bromide, an emulsifier and lactic acid; more preferably, the oil phase component consists of perfluorooctyl bromide, perfluorodecyl bromide, an emulsifier and lactic acid in a mass ratio of 155:3:20:1
In some embodiments of the present invention, the molar ratio of carbonate to lactic acid is (0.5-3): 1.
in some preferred embodiments of the present invention, the concentration of the carbonate in the aqueous phase is 0.01 to 0.03 mol/L.
In some preferred embodiments of the invention, when the carbonate is sodium bicarbonate, the concentration of sodium bicarbonate in the aqueous phase is 0.01-0.03 mol/L and the molar ratio of sodium bicarbonate to lactic acid is (1.5-3): 1; more preferably, the concentration of the sodium bicarbonate in the aqueous phase is 0.015mol/L with a molar ratio of sodium bicarbonate to lactic acid of 2: 1.
In some preferred embodiments of the invention, when the carbonate is sodium carbonate, the concentration of sodium carbonate in the aqueous phase is 0.01-0.02 mol/L and the molar ratio of sodium carbonate to lactic acid is (1.5-3): 2.
In some embodiments of the present invention, the average particle size of the emulsion-type organ preservation solution is 50 to 200 nm.
In some embodiments of the present invention, the emulsion-type organ preservation solution has an osmotic pressure of 290 to 320mOsm/kg H2O, pH 6.8 to 7.4, viscosity at 37 ℃ 100 to 230s-1。
In some embodiments of the present invention, the concentration of sodium ions is in the range of 0.01 to 0.03mol/L, the concentration of potassium ions is in the range of 0.005 to 0.015mol/L, the concentration of magnesium ions is in the range of 0.001 to 0.003mol/L, the concentration of calcium ions is in the range of 0.000005 to 0.000015mol/L, the total concentration of histidine and histidine hydrochloride is in the range of 0.05 to 0.15mol/L, the concentration of tryptophan is in the range of 0.0005 to 0.002mol/L, the concentration of mannitol is in the range of 0.01 to 0.03mol/L, the concentration of glycerol is in the range of 0.01 to 0.15mol/L, and the concentration of lecithin is in the range of 0.04 to 0.08 mol/L.
In some preferred embodiments of the invention, the potassium ion concentration is 0.009mol/L, the magnesium ion concentration is 0.002mol/L, the calcium ion concentration is 0.000008mol/L, the histidine concentration is 0.09mol/L, the histidine-containing hydrochloride concentration is 0.009mol/L, the tryptophan concentration is 0.001mol/L, the mannitol concentration is 0.015mol/L, and the glycerol concentration is 0.152 mol/L.
According to still another aspect of the present invention, there is provided a method for preparing an emulsion-type organ preservation solution, comprising the steps of: preparing an oil phase: uniformly mixing a fluorocarbon oxygen carrying agent, an emulsifier and lactic acid; preparing an aqueous phase: preparing an electrolyte, a buffer salt, an osmotic pressure regulator and a carbonate into an aqueous solution; and uniformly mixing the oil phase and the water phase by a micro-fluidic method or a micro-jet high-pressure homogenization method to obtain the emulsion type organ preservation solution.
The preparation method according to a preferred embodiment of the present invention has at least the following advantageous effects: the preparation method of the invention disperses the fluorocarbon oxygen-carrying agent in the aqueous solution containing suitable electrolyte, osmotic pressure regulator and buffer salt by the microfluidic mixing or the microfluidic high-pressure homogenization technology to obtain the emulsion type organ preservation solution, solves the problem of stable dispersion of water-insoluble fluorocarbon in the aqueous environment, is beneficial to maintaining the oxygen and nutrient supply of the preserved organ, and can be used for organ preservation in organ transplantation such as liver and the like.
In some embodiments of the invention, the microfluidic method comprises controlling the oil phase and the water phase to flow into the microchannel respectively through a microfluidic system, wherein the total flow rate is 3-8 mL/min, and the flow rate ratio of the oil phase to the water phase is 1 (3-20).
In some preferred embodiments of the present invention, the microfluidic mixing conditions are a total flow rate of 4-6 mL/min, and a flow rate ratio of the oil phase to the aqueous phase is 1 (8-12); more preferably, the microfluidic mixing conditions are such that the total flow rate is about 5mL/min and the ratio of flow rates of the oil phase and the aqueous phase is about 1: 10.
In some preferred embodiments of the invention, the microfluidic system is a NanoAssemblrTMA platform. NanoAssembblrTMThe platform is a microfluidic nano-particle manufacturing system, and the nano-emulsion with proper particle size and stable emulsion property can be prepared by mixing an oil phase and a water phase by the microfluidic technology of the system.
In some preferred embodiments of the present invention, the temperature of the reaction system of the microfluidic system is 15-30 ℃; more preferably, the reaction system temperature is about 25 ℃.
In some embodiments of the present invention, the microfluidics high-pressure homogenization process uses a pressure of 1000 to 2000bar and a cycle of 3 to 8 times.
In some preferred embodiments of the present invention, the microfluidics high-pressure homogenization method specifically comprises the following steps: mixing the oil phase and the water phase according to the volume ratio of 1:10, shearing at 10000rpm for 10min to obtain primary emulsion, homogenizing by a micro-jet high-pressure homogenizer at the pressure of 1500bar, circulating for 5 times, controlling the temperature at 25 ℃ to obtain fluorocarbon emulsion, and measuring the particle size distribution of the nano emulsion by dynamic light scattering, wherein the average particle size is 103.0nm, the polydispersity index is 0.106, the pH value is 7.2, and the osmotic pressure is 300 mmol/L.
Drawings
The invention is further described with reference to the following figures and examples, in which:
FIG. 1 is a particle size distribution diagram of the emulsion of fluorocarbon emulsion in example 1 of the present invention;
FIG. 2 is a distribution diagram of the particle size of the emulsion of fluorocarbon emulsion in example 2 of the present invention;
FIG. 3 is a graph showing the oxygen content of fluorocarbon milk of example 1 of the present invention and a control fluorocarbon milk prepared in comparative example 1;
FIG. 4 is the ATP content in the liver of rats 48 hours (4 ℃) after oxygen loading of fluorocarbon milk in example 1 of the present invention;
FIG. 5 is a graph showing the levels of aspartate Aminotransferase (AST) in the liver of rats after 48 hours (4 ℃) of storage after oxygen loading of fluorocarbon milk in example 1 of the present invention;
FIG. 6 is a graph showing Lipid Peroxide (LPO) levels in the liver of rats after 48 hours (4 ℃) of storage after oxygen loading with fluorocarbon milk in example 1 of the present invention.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention. The test methods used in the examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are commercially available reagents and materials unless otherwise specified.
In the present invention, the prepared emulsion-type organ preservation solution is an emulsion whose main component is a fluorocarbon-based oxygen carrier, and thus will be referred to in the following examples or comparative examples or by the name of fluorocarbon emulsion.
Example 1
The preparation method of the emulsion type organ preservation solution comprises the following specific steps:
(1) respectively preparing an oil phase and a water phase:
the oil phase preparation method comprises the following steps: 186g of perfluorooctyl bromide, 3.5g of perfluorodecane bromide, 2g of lactic acid and 44g of lecithin were weighed and sufficiently mixed and dissolved by ultrasonic oscillation.
The water phase preparation method comprises the following steps: pure water is used as a solvent, and solutes comprise 0.02mol/L sodium bicarbonate, 0.009mol/L potassium chloride, 0.002mol/L magnesium chloride, 0.000008mol/L calcium chloride, 0.009mol/L histidine hydrochloride, 0.0022mol/L potassium 2-oxoglutarate hydrogen, 0.09mol/L histidine, 0.001mol/L tryptophan, 0.015mol/L mannitol and 0.14mol/L glycerol, and are fully dissolved.
(2) Preparing fluorocarbon emulsion by a micro-fluidic method: using nanoAssemblmbrTMAnd (3) controlling the oil phase and the water phase to flow into the micro-channel respectively by the platform, controlling the flow rate ratio of the oil phase to the water phase to be 1:10, the total flow rate to be 5mL/min, controlling the temperature of the reaction system to be 25 ℃, and collecting the product at the outlet of the micro-channel to obtain the fluorocarbon emulsion. The fluorocarbon emulsion is used as emulsion type organ preservation solution for preserving organs.
Example 2
The preparation method of the emulsion type organ preservation solution comprises the following specific steps:
(1) respectively preparing an oil phase and a water phase:
the oil phase preparation method comprises the following steps: 186g of perfluorooctyl bromide, 3.5g of perfluorodecane bromide, 2g of lactic acid and 44g of lecithin were weighed and sufficiently mixed and dissolved by ultrasonic oscillation.
The water phase preparation method comprises the following steps: pure water is used as a solvent, and solutes comprise 0.02mol/L sodium bicarbonate, 0.009mol/L potassium chloride, 0.002mol/L magnesium chloride, 0.000008mol/L calcium chloride, 0.009mol/L histidine hydrochloride, 0.0022mol/L potassium 2-oxoglutarate hydrogen, 0.09mol/L histidine, 0.001mol/L tryptophan, 0.015mol/L mannitol and 0.14mol/L glycerol.
(2) Preparing fluorocarbon emulsion by a micro-jet high-pressure homogenization method: mixing the oil phase and the water phase according to the volume ratio of 1:10, shearing at 10000rpm for 10min to obtain primary emulsion, and homogenizing by a micro-jet high-pressure homogenizer at the pressure of 1500bar, circulating for 5 times, and controlling the temperature at 25 ℃ to obtain the fluorocarbon emulsion. The fluorocarbon emulsion is used as emulsion type organ preservation solution for preserving organs.
Comparative example
This example prepared an emulsion-type organ preservation solution, which was different from example 1 in that lactic acid was not added to the oil phase and carbonate was not added to the water phase, and other specific processes and preparation processes were completely identical to those of example 1. A control fluorocarbon emulsion was prepared.
Test examples
The performance of the fluorocarbon milk prepared in examples 1-2 and comparative example 1 was tested in this test example. Wherein:
first, particle size and emulsion property test:
the fluorocarbon emulsion of example 1 was measured for particle size distribution by dynamic light scattering, and as shown in fig. 1, the average particle size was 88.5nm, the polydispersity index was 0.268, and the stability was good (average particle size after autoclave sterilization was 98.5nm, PDI 0.323). The pH of the fluorocarbon emulsion is about 7.2, and the osmotic pressure is about 300 mmol/L.
The comparative fluorocarbon emulsion of the comparative example has overlarge drops, the average particle size is 520.5nm, the polydispersity is 0.10, the stability is poor, the particle size is more than 1 micron after room temperature, and delamination and emulsion breaking occur. Therefore, if a combination of sodium bicarbonate and lactic acid is not used, an emulsion having an appropriate particle size and stable properties cannot be obtained. The gas-generating reaction of lactic acid and carbonate is utilized to provide enough energy for the formation of the emulsion, and the emulsion with smaller and more uniform emulsion drop particle size distribution is obtained.
The fluorocarbon emulsion of example 2 was measured by dynamic light scattering to determine the nano-emulsion particle size distribution, mean particle size 103.0nm, polydispersity index 0.106, and the test results are shown in fig. 2. The pH was determined to be about 7.2 and the osmotic pressure was determined to be about 300 mmol/L.
Secondly, testing the oxygen content:
the tube openings connected with the oxygen tanks are respectively arranged 2cm below the liquid level of the fluorocarbon milk of example 1, the control fluorocarbon milk of the comparative example, and pure water or HTK liquid, and the gas is inflated for 15 minutes under the condition of ensuring the continuous bubbles. The oxygen content of each sample was measured with an InPro 6860i optical oxygen sensor, zeroed with a saturated solution of sodium bisulfite, 100% with freshly prepared saturated dissolved oxygen pure water, and the oxygen content data obtained from the test are shown in fig. 3. The results show that the fluorocarbon emulsion of example 1 has good oxygen carrying capacity, and the oxygen content is 1421.7 +/-100.2 mg/L, which is significantly higher than that of the control fluorocarbon emulsion or HTK liquid.
Thirdly, testing the preservation effect of the organs:
the fluorocarbon milk of example 1 was sterilized by filtration through a 220nm filter, then oxygen-loaded under the above conditions, and model organs (livers from healthy rats) to be preserved were immersed therein and stored at 4 ℃ for 48 hours, and the same experimental procedures were performed using HTK solution as a control, and then ATP content (results are shown in fig. 4), aspartate Aminotransferase (AST) level (results are shown in fig. 5), and Lipid Peroxide (LPO) level (results are shown in fig. 6) in the livers were measured, respectively. The results show that the stored liver with fluorocarbon milk of example 1 can significantly improve the quality of the stored organs, as shown by higher ATP content and lower aspartate aminotransferase and lipid peroxide content, compared to HTK fluid storage.
The invention disperses fluorocarbon oxygen carrying agent in aqueous solution containing proper electrolyte, osmotic pressure regulator and buffer salt by micro-fluidic method or micro-jet high-pressure homogenization method to obtain fluorocarbon emulsion, and prepares the emulsion organ preservation solution with proper grain size, high stability and high oxygen carrying capacity.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the gist of the present invention. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Claims (10)
1. An emulsion type organ preservation solution is characterized by comprising an oil phase component and a water phase component, wherein the oil phase component comprises fluorocarbon oxygen carrying agent, emulsifier and lactic acid, the water phase component comprises osmotic pressure regulator, buffer salt, electrolyte and carbonate, and the volume ratio of the oil phase component to the water phase component is 1: (3-20).
2. The emulsion-type organ preservation fluid according to claim 1, wherein the fluorocarbon-based oxygen carrier is at least one selected from the group consisting of perfluorooctyl bromide, perfluorodecyl bromide, perfluorodecalin, perfluorotripropylamine, perfluoromethylcyclohexylpiperidine, perfluorotributylamine, perfluorooctyl dichloride and perfluorobutyl ethylene; and/or
The emulsifier is at least one of soybean lecithin and egg yolk lecithin; and/or
The osmotic pressure regulator is selected from at least one of mannitol and glycerol; and/or
The buffer salt is selected from at least one of histidine, histidine hydrochloride, tryptophan and potassium hydrogen 2-ketoglutarate; and/or
The electrolyte is selected from at least one of sodium chloride, potassium chloride, magnesium chloride, calcium chloride and magnesium sulfate; and/or
The carbonate is selected from at least one of sodium bicarbonate and sodium carbonate.
3. The emulsion-type organ preservation solution according to claim 2, wherein the oil phase comprises the following components in a mass ratio of (100-200): (1-10): (10-30): 1 perfluorooctyl bromide, perfluorodecane bromide, an emulsifier and lactic acid.
4. The emulsion-type organ preservation solution according to claim 1, wherein the molar ratio of the carbonate to the lactic acid is (0.5-3): 1.
5. the emulsion-type organ preservation solution according to claim 1, wherein the average particle size of the emulsion-type organ preservation solution is 50 to 200 nm.
6. The method of claim 1The emulsion organ preservation solution is characterized in that the osmotic pressure of the emulsion organ preservation solution is 290-320 mOsm/kg H2O, pH 6.8 to 7.4, viscosity at 37 ℃ 100 to 230s-1。
7. The emulsion-type organ preservation solution according to claim 1, wherein the concentration of sodium ions is in the range of 0.01 to 0.03mol/L, the concentration of potassium ions is in the range of 0.005 to 0.015mol/L, the concentration of magnesium ions is in the range of 0.001 to 0.003mol/L, the concentration of calcium ions is in the range of 0.000005 to 0.000015mol/L, the total concentration of histidine and histidine hydrochloride is in the range of 0.05 to 0.15mol/L, the concentration of tryptophan is in the range of 0.0005 to 0.002mol/L, the concentration of mannitol is in the range of 0.01 to 0.03mol/L, the concentration of glycerol is in the range of 0.01 to 0.15mol/L, and the concentration of lecithin is in the range of 0.04 to 0.08 mol/L.
8. A method for preparing the emulsion-type organ preservation solution according to any one of claims 1 to 7, comprising the steps of:
preparing an oil phase: uniformly mixing a fluorocarbon oxygen carrying agent, an emulsifier and lactic acid;
preparing an aqueous phase: preparing an electrolyte, a buffer salt, an osmotic pressure regulator and a carbonate into an aqueous solution;
and uniformly mixing the oil phase and the water phase by a micro-fluidic method or a micro-jet high-pressure homogenization method to obtain the emulsion type organ preservation solution.
9. The preparation method according to claim 8, wherein the microfluidics method comprises controlling the oil phase and the water phase to flow into the microchannel respectively through a microfluidics system, the total flow rate is 3-8 mL/min, and the flow rate ratio of the oil phase to the water phase is 1 (3-20).
10. The method according to claim 8, wherein the microfluidics high-pressure homogenization is performed at a pressure of 1000 to 2000bar and a cycle of 3 to 8 times.
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| 郑志风等: "携氧剂最新进展", 《化学世界》 * |
| 郭莎莎等: "新型心脏保存液研究进展", 《中国分子心脏病学杂志》 * |
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