CN112007178A - Ultrasonic microbubble and preparation method thereof - Google Patents
Ultrasonic microbubble and preparation method thereof Download PDFInfo
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- CN112007178A CN112007178A CN202010876034.2A CN202010876034A CN112007178A CN 112007178 A CN112007178 A CN 112007178A CN 202010876034 A CN202010876034 A CN 202010876034A CN 112007178 A CN112007178 A CN 112007178A
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- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
The invention relates to the technical field of biomedical engineering, in particular to an ultrasonic microbubble and a preparation method thereof. The preparation method of the ultrasonic microbubble comprises the following steps: (1) the phospholipid dispersion is treated with an excess of H2S, after saturation, placing the saturated solution in a sealed container for sealed storage; (2) mixing hydrogen sulfide and perfluoropropane to obtain mixed gas, replacing headspace gas in a sealed container with excessive mixed gas, and oscillating to obtain the ultrasonic microbubble. The ultrasonic microbubble carrying hydrogen sulfide is simple and convenient to prepare and has good performanceGood stability and ultrasonic development effect, and can be triggered by ultrasonic waves to release hydrogen sulfide. The hs-MB damaged by ultrasonic has a protective effect on myocardial ischemia reperfusion injury, not only provides a new method for visual positioning and quantitative transmission of gas signal molecules, but also is beneficial to realizing diagnosis-treatment integration.
Description
Technical Field
The invention relates to the technical field of biomedical engineering, in particular to an ultrasonic microbubble and a preparation method thereof.
Background
Clinically, Reperfusion therapy for acute Myocardial infarction can effectively treat acute Myocardial infarction in most cases, but in the process of restoring Ischemia Myocardial blood flow Reperfusion, Myocardial damage can be caused by the acute Myocardial infarction, such as arrhythmia, Myocardial stunning, no-reflow phenomenon and even Myocardial infarction area enlargement, and the damage is called Myocardial Ischemia Reperfusion Injury (MIRI).
Currently, a large number of animal experiments and clinical studies have been devoted to exploring the control strategy for MIRI. These preventive strategies can be generalized to physical intervention (including ischemic preconditioning, post-ischemic conditioning, remote ischemic adaptation, cryotherapy, etc.) and pharmaceutical intervention.
Ischemic Preconditioning (Ischemic Preconditioning) is a method of repeating transient ischemia before prolonged ischemia to increase tolerance to prolonged ischemia. Animal experiments show that the ischemia pre-adaptation can reduce the myocardial infarction area, reduce the occurrence of reperfusion arrhythmia and protect the cardiac function; post-Ischemic conditioning (Ischemic Postconditioning) is an intervention to improve the tolerance of the myocardium to reperfusion injury by several transient reperfusion and ischemia before prolonged reperfusion following occlusion of the culprit's blood vessels. This method was found in a canine animal model to reduce myocardial infarct size by 44% when 3 cycles of transient reperfusion and transient ischemia (30 seconds each) were administered prior to ischemic myocardial reperfusion. In 2005, Staat et al observed the change in serum creatine kinase levels within 72h after reperfusion, and found that the myocardial infarction area of the adapted group patients after ischemia was reduced by 36%, and myocardial perfusion was significantly improved; remote Ischemic Conditioning (Remote Ischemic Conditioning) is usually performed in the upper arm by non-invasively blocking blood flow in the upper arm for 5 minutes with a cuff to cause transient ischemia, and then releasing the cuff to restore reperfusion, and repeating this for a number of cycles to exert cardioprotective effect. The 2010 Boker HE and the like research the protection effect of the remote ischemia adaptation on the myocardium in the PCI operation, and the follow-up visit lasts for 30 days, and the results show that compared with a control group, the limb repeated ischemia/reperfusion for 4 minutes and 5 minutes can save more infarcted myocardium; cryotherapy (Therapeutic hyperthermia) is another physical intervention to alleviate MIRI. Animal experiment research shows that reducing the temperature of the myocardium to 32-33 ℃ can reduce myocardial metabolism, relieve inflammatory reaction, resist platelet aggregation and reduce myocardial infarction area.
Pharmaceutical intervention is currently an important therapeutic approach to alleviate MIRI. With the progressive study of the pathogenesis of MIRI, it was found that drugs acting on specific targets in this mechanism have significant cardioprotective effects. These drugs can be roughly classified into two groups, one of which is a drug acting on the Reperfusion Injury Salvage Kinase (RISK) signal pathway, including adenosine, atrial natriuretic peptide, statins, erythropoietin, exenatide, and glucose-insulin-potassium (GIK); another class is drugs that protect mitochondrial function, such as cyclosporin A, nitrite, and TR040303, among others.
In contrast, a recent study found Hydrogen Sulfide (Hydrogen Sulfide, H)2S) is a third gas signaling molecule following carbon monoxide (CO) and Nitric Oxide (NO), plays an important biological role in the cardiovascular system, especially in the protection of MIRI. Knock-out of mouse CSE genes to reduce endogenous sulfuration in mouse myocardial ischemia-reperfusion modelThe generation of hydrogen will enlarge the myocardial infarction area, and the specific over-expression of CSE gene in mouse heart increases the generation of endogenous hydrogen sulfide to reduce myocardial infarction area and improve heart function, while exogenous H administration2S also has cardioprotective effect. Elrod et al, 2007, injected sodium sulfide (H) intracardially while restoring reperfusion 45 minutes after myocardial ischemia in mice2S donor), the results showed a 72% reduction in myocardial infarct area and a significant improvement in cardiac function. The result is further proved on the heart of a pig which is an animal model before clinic, Sodha NR and the like establish a myocardial ischemia reperfusion model of Yorkshire pigs, and after sodium sulfide is injected 10 minutes before ischemia, the apoptosis and inflammatory reaction are observed to be reduced, the myocardial infarction area is obviously reduced, and the heart function is improved. H2S has important regulatory effect on MIRI, and H is exogenously supplied2S is a very promising cardioprotective measure.
In the aspect of physical intervention, the acute myocardial infarction cannot be predicted in advance, and ischemia pre-adaptation needs to be intervened before ischemia, so that the clinical application and popularization of the myocardial infarction are limited; the PoST-ischemic adaptation showed no significant differences in myocardial infarct area, myocardial injury markers, ejection fraction, and cardiovascular events compared to conventional treatments in the 2014 postischemic study, while in one multicenter randomized controlled study (PoST), 700 cases of STEMI patients included: 1 was randomly assigned to the post-ischemic acclimation group and the conventional PCI group, and the post-ischemic acclimation failed to improve the ST-segment fallback level and the myocardial color grading 30 minutes after PCI, and no clinical prognosis improvement was observed in the 1-year follow-up results. In fact, in the emergency PCI of acute myocardial infarction, repeated balloon dilatation can aggravate the damage of local plaques, especially in patients with heavier thrombus load, further exacerbating the risk of distal embolism; prasad A and the like found in 2013 that the heart protection effect cannot be exerted by remote ischemic adaptation; the gill-MI study in 2014 randomly assigned 120 acute myocardial infarction patients to the conventional PCI group and the cryotherapy + PCI group, which rapidly brought the body temperature to 33 ℃ before PCI and continued until l hours after reperfusion, and magnetic resonance imaging results showed that cryotherapy failed to reduce the myocardial infarction area compared to the conventional PCI group;
for pharmaceutical intervention, thoughIn animal experiments, it was demonstrated that these drugs act on different signaling pathways to effectively alleviate MIRI, however, often with no beneficial results during clinical transformation. At present H2The administration method of S includes two methods of gas inhalation and donor administration. H2S is difficult to tolerate even by inhalation of very low concentrations of gas due to its unpleasant smelling of rotten eggs and its irritation to the respiratory tract. H2The common donors of S are sodium hydrosulfide and sodium sulfide, and the two donors can rapidly increase the H in vivo within seconds after being injected2S concentration, but it is difficult to maintain an effective concentration in local tissue for a long time due to its fast degradation rate. Most importantly, the different organ pairs H2S is sensitive and systemic administration may produce side effects including sharp fluctuations in blood pressure, central nervous system toxicity and respiratory depression. Therefore, a safe, effective, feasible and less side effects therapeutic means for improving reperfusion injury after myocardial ischemia is needed.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides an ultrasonic microbubble and a preparation method thereof. The ultrasonic microbubble can solve the problems of difficult intake, high degradation speed and low effective concentration of the existing gas inhalation mode in injection administration.
In order to achieve the purpose, the invention adopts the technical scheme that: a method for preparing ultrasound microbubbles, comprising the steps of:
(1) the phospholipid dispersion is treated with an excess of H2S, after saturation, placing the saturated solution in a sealed container for sealed storage;
(2) mixing hydrogen sulfide and perfluoropropane to obtain mixed gas, replacing headspace gas in a sealed container with excessive mixed gas, and oscillating to obtain the ultrasonic microbubble.
The ultrasonic microbubble is an ultrasonic contrast agent formed by wrapping a gas core by a biological shell, and can be used as a good carrier for transmitting genes, medicines and even therapeutic gases. The method has the advantages that on one hand, the medicine can be prevented from reacting with components in blood and being removed due to the fact that the medicine is wrapped by the biological shell, on the other hand, the microbubble can be destroyed only in the ultrasonic irradiation area to release the medicine, so that the whole body injection administration dosage can be reduced, the local medicine concentration is ensured, the whole body toxic and side effects are avoided, and the targeted administration is realized.
Due to H2S is a small molecule gas, which easily overflows microbubbles, and C3F8Is a macromolecular inert gas, and can increase the stability of the microvesicle.
Further, the phospholipid dispersion liquid in the step (1) is prepared by adding DPPC, DPPE-PEG5000 and DPPA into a solution containing propylene glycol, glycerol and sodium chloride, and stirring and dissolving in a water bath.
Further, the mole ratio of DPPC, DPPE-PEG5000 and DPPA is DPPC: DPP E-PEG 5000: DPPA ═ 10: 82: 8.
further, the temperature of the water bath is 60-80 ℃.
Further, the volume ratio of hydrogen sulfide to perfluoropropane is 4/0, 3/1, 2/2, 1/3 or 0/4.
Further, the volume ratio of hydrogen sulfide to perfluoropropane is 2/2.
To prepare a compound with higher stability and H2S-loading hs-MB, we explored H2S and C3F8The optimal mixing ratio is that when the volume ratio of hydrogen sulfide to perfluoropropane is 2/2, the ultrasonic microbubble H is prepared2The S loading was highest and stability was good.
Further, the oscillation time in the step (2) is 30-60 seconds.
The invention also provides an ultrasonic microbubble, which is prepared by the preparation method.
The invention has the beneficial effects that:
(1) the ultrasonic microbubble carrying hydrogen sulfide is simple and convenient to prepare, has good stability and ultrasonic development effect, and can be triggered by ultrasonic waves to release hydrogen sulfide.
(2) The hs-MB damaged by ultrasonic has a protective effect on myocardial ischemia reperfusion injury, not only provides a new method for visual positioning and quantitative transmission of gas signal molecules, but also is beneficial to realizing diagnosis-treatment integration.
(3) The invention can realize that the hydrogen sulfide gas can improve the reperfusion injury myocardium after ischemia in a targeted way by destroying the hydrogen sulfide gas-loaded ultrasonic microvesicle through ultrasonic guidance, and simultaneously has evaluation functions of comparing the myocardial perfusion effect after ultrasonic real-time observation and treatment and the like, thereby realizing the diagnosis-treatment integrated function.
Drawings
FIG. 1: ultrasound microbubble mediated H2S transmission schematic to mitigate myocardial ischemia reperfusion injury. US: ultrasonic waves; hs-MB: carrier H2S hydrogen sulfide microbubbles.
FIG. 2: appearance and morphological characteristics under a light lens of hs-MB loaded with mixed gas in different proportions, H2S and C3F8The ratios of (A), (B), (2/2), (C), (1/3), (D) and (0/4) are 4/0(A), (3/1 (B), (2/2 (C)), respectively.
FIG. 3: different H2S/C3F8The hydrogen sulfide content of the ultrasonic microvesicles constructed in proportion.
FIG. 4: the effect of the hydrogen sulfide microbubbles and the condition of the hydrogen sulfide microbubbles damaged by the ultrasound are observed in vivo. Left panel: an ultrasonic radiography before injecting hydrogen sulfide-carried microbubbles; the middle graph is as follows: sonography during hydrogen sulfide microbubble infusion; right panel: an ultrasonographic image after irradiation with low-frequency ultrasound (1.0MHz, 1.0MPa) was given. White arrows indicate ultrasonic pulse waves emitted by the ultrasonic cavitation therapy apparatus.
FIG. 5: the left cardiac function of each group of rats was compared. A: a rat left heart M-type hyperrepresentative diagram, wherein SHAM is a SHAM operation group, MIR is an ischemia reperfusion group, c-MB + US is an unloaded microbubble + ultrasonic irradiation group, and hs-MB + US is a hydrogen sulfide-loaded microbubble + ultrasonic irradiation group; B-E diagram: comparison of cardiac function, EDd: left ventricular end diastolic diameter; ESd: left ventricular end systolic diameter; and (3) LVFS: left ventricular minor axis shortening rate; LVEF: left ventricular ejection fraction, NS: there was no significant difference.
Detailed Description
To more clearly illustrate the technical solutions of the present invention, the following embodiments are further described, but the present invention is not limited thereto, and these embodiments are only some examples of the present invention.
EXAMPLE 1 preparation of Hydrogen sulfide-loaded microbubbles (hs-MB)
Preparing 5 kinds of H with different loading proportions by adopting a mechanical oscillation method2S and perfluoropropane (C)3F8) Ultrasonic microbubbles of a mixed gas.
According to a molar ratio of 10: 82: 8 weighing DPPC, DPPE-PEG5000 and DPPA, adding into solution containing propylene glycol, glycerol and 0.9% sodium chloride, stirring in 70 deg.C water bath for 15 min to dissolve completely to obtain phospholipid dispersion, respectively packaging 2m1 in 3ml glass bottles, and adding excessive H2And (5) sealing and storing after S is saturated. Hydrogen sulfide/perfluoropropane (H)2S/C3F8) The mixed gas is prepared according to different proportions by mixing according to the volume ratios of 4/0, 3/1, 2/2, 1/3 and 0/4. The headspace gas in the glass bottle was replaced with excess mixed gas, and the glass bottle was placed in a silver-mercury capsule blender (Hangzhou Zhongrun medical instruments Co., Ltd., China) and shaken for 50 seconds at 3200 times/minute to obtain 5 different hs-MB.
Example 2 microscopic examination of the morphology of microvesicles hs-MB
After the hydrogen sulfide-loaded microbubbles hs-MB were successfully prepared, the microbubbles were gently shaken, a drop of the microbubble solution was dropped onto a glass slide, the glass slide was covered, and the microbubbles were observed for morphology, size, and the like under a microscope (BX5l, OLYMPUS, Japan).
As shown in FIG. 2, the 5 hs-MB appeared uniformly milky; h2S/C3F8Microvesicles constructed for 2/2 (fig. 2C), 1/3 (fig. 2D) and 0/4 (fig. 2E) were visually indistinguishable; h2S/C3F8The microbubbles constructed for 4/0 (FIG. 2A) and 3/l (FIG. 2B) were lighter in color than the other three groups, H2S/C3F8The microbubbles at 4/0 (FIG. 2A) are particularly evident. All hs-MB under the microscope is in a complete spherical shape with a bright center and smooth shell, and has good dispersity and no obvious aggregation phenomenon; h2S/C3F8The microvesicles constructed for 2/2, 1/3 and 0/4 were uniform in morphology and no significant difference in number; h2S/C3F8The number of microbubbles constructed for 4/0 and 3/l was less than the other three groups, H2S/C3F8The 4/0 microbubbles were particularly pronounced.
Example 3 concentration and particle size distribution of microbubbles
The concentration and particle size distribution of the microbubbles were analyzed using a coulter counter. After hs-MB was prepared, the mixture was gently shaken, 20. mu.l of the sample was precisely transferred, diluted 5000-fold with physiological saline, and the concentration and particle size distribution of the microbubbles of hs-MB were measured by a Coulter counter (Multisizer III, USA). Standing in a 4 deg.C refrigerator, measuring the concentration and particle diameter of the microbubbles with Coulter counter after lh, 6 hr, 24 hr and 72 hr respectively, and evaluating the stability.
TABLE 1 change over time of hs-MB microbubble concentration loaded with different proportions of mixed gas
#P＜0.05，vs0h.
Results are shown in Table 1, H2S/C3F8The microbubble concentration at 4/0 began to decrease after 1 h. H2S/C3F8The microbubble concentration at 3/l started to decrease and progressively decreased after 6 h. H2S/C3F8The concentrations of microvesicles constructed for 2/2, 1/3 and 0/4 were unchanged for 72 h. This indicates H2S/C3F8Microvesicles constructed for 4/0 and 3/1 were less stable than H2S/C3F8Microvesicles constructed for 2/2, 1/3 and 0/4.
Example 4H in microvesicles2Determination of the S content
Taking a flask with the capacity of 1L, punching three holes on a rubber plug of the flask, and connecting the two holes with a pump-suction type hydrogen sulfide detector (SKY 2000-H)2S, Shenzhen Yunt science and technology Limited, China), one hole is connected with an injector for injecting hs-MB into the bottle, so that the whole device is ensured to be well sealed. Opening a switch of a pump suction type hydrogen sulfide detector, adding lml hs-MB into the flask, using ultrasonic irradiation to destroy the microbubbles, and recording H in the flask2S content in μmol/ml microbubbles.
The results are shown in FIG. 3, H2S/C3F8The microbubble hydrogen sulfide content of 2/2 is significantly higher than that of the other fourGroup (P)<0.05). According to microbubble concentration, microbubble stability and H2Parameter of S Loading, H2S and perfluoropropane as per 2: 2 mixing is the optimal ratio for the preparation of hs-MB.
Example 5 ultrasound disruption of hs-MB localized Transmission H2S
6X 10 of the tail vein of SD rat9And (2) pumping hs-MB at a speed of/(kg.h) for 30 minutes, and simultaneously placing an ultrasonic probe of the ultrasonic cavitation therapeutic instrument in the precordial region to transmit low-frequency ultrasonic waves to destroy microbubbles (the parameter conditions are set to be sine wave waveforms, the ultrasonic center frequency is 1.0MHz, the sound pressure is 1.0MPa, the duty ratio is 1.0%, the pulse repetition frequency is 100Hz, and the working/gap time is 3/9 seconds).
And (5) observing the imaging effect and the microbubble destruction condition of the hs-MB by contrast ultrasonic examination. An imaging probe (17L5) is placed beside an ultrasonic probe of the ultrasonic cavitation therapeutic apparatus for ultrasonic imaging, and is fixed on the precordial region of the rat by a bracket, and the position is kept unchanged in the experimental process after a satisfactory two-dimensional image section is obtained. Contrast ultrasound examination was performed using a Sequoia512 echocardiograph (Siemens, Germany), Contrast Pulse Sequence (CPS) imaging technique, with a probe transmit frequency of 7.0MHz and a mechanical index of 0.18. And observing the imaging effect after the hs-MB is infused and the damage condition of the ultrasonic cavitation therapeutic instrument to the microbubbles.
As a result, as shown in FIG. 4, after a satisfactory two-dimensional image of the heart was obtained, no enhanced visualization was seen in the CPS imaging mode. Myocardial development can be seen 3 +/-1 seconds after the hs-MB is injected intravenously, the myocardial development is gradually enhanced, the plateau phase is reached 12 +/-2 seconds later, and the hs-MB is filled uniformly and is clearly separated from surrounding tissues. The results show that hs-MB can reach myocardial tissues after intravenous injection, has good ultrasonic development capability and is beneficial to realizing H2And (4) visual conveying of S. The ultrasonic cavitation therapeutic apparatus is turned on to emit low-frequency ultrasonic waves to irradiate the precordial region of the rat, and the enhanced echo in the myocardial tissue is obviously weakened or even disappears, which indicates that hs-MB is damaged by the ultrasonic waves in the myocardial tissue.
Example 6 myocardial contrast ultrasonography Observation of myocardial perfusion
72 SD rats were randomly divided into 4 groups, which were grouped as follows:
(ii) SHAM group: after the operation the suture was not tightened and each rat was continuously pumped into physiological saline through the tail vein at a rate of 6ml/(kg h).
(ii) MIRI group: the suture was tightened for 30 minutes after the operation and saline was continuously pumped in through the tail vein at a rate of 6ml/(kg h).
c-MB + US group: suture was tightened for 30 minutes after surgery at 6X 10 via the tail vein9The speed/(kg h) was continuously pumped into the common ultrasound microbubbles (perfluoropropane core, Control Microbubble, c-MB). The rat precordial region is coated with a couplant, an ultrasonic probe of an ultrasonic cavitation therapeutic apparatus is placed in the rat precordial region, the parameter conditions are set to be sine wave waveforms, the ultrasonic central frequency is 1.0MHz, the sound pressure is 1.0MPa, the duty ratio is 1.0%, the pulse repetition frequency is l00Hz, the working/gap time is 3/9 seconds, and the treatment time is 30 minutes. During the injection of c-MB, the ultrasonic switch is turned on and ultrasonic waves are emitted.
hs-MB + US group: suture was tightened for 30 minutes after surgery at 6X 10 via the tail vein9The speed of individual/(kg h) is continuously pumped into hs-MB. The ultrasonic irradiation method and conditions were the same as those of the c-MB + US group. Intervention was initiated 5 minutes prior to resumption of ischemic myocardial reperfusion for 30 minutes. After 4 hours of reperfusion, 6 rats per group were treated with H&E staining and TUNEL staining, 6 additional rats were taken to measure the concentration of myocardial tissue MDA and SOD. Reperfusion is carried out for 24 hours, the rat is killed after the rat is subjected to echocardiography examination to evaluate the cardiac function, and the heart is taken out to be subjected to TTC/Evans blue double staining to detect myocardial ischemia and infarct size.
During the ultrasound in combination with microbubble intervention treatment, myocardial perfusion was observed using a Sequoia512 echocardiograph (with a 17L5 ultrasound probe) line-contrast sonography of the myocardium. The ultrasonic probe (17L5) is fixed on the precordial region of the rat by a bracket, and the position and the parameters are kept unchanged in the treatment process after the parameters are adjusted to obtain a satisfactory two-dimensional image section. And switching to a contrast pulse sequence imaging mode, wherein the transmitting frequency and the receiving frequency of the probe are respectively 7.0MHz and 14MHz, the mechanical index is 0.18, and observing the myocardial perfusion condition.
The results are shown in fig. 5, and 24 hours after the myocardial ischemia reperfusion injury model was made, the echocardiography examination was performed to examine the left cardiac function of the rat. Compared to the SHAM group, the left ventricular end-diastolic diameter (EDd) and the end-systolic diameter (ESd) of the MIRI group were significantly increased, and the left ventricular minor axis shortening rate (LVFS) and the Left Ventricular Ejection Fraction (LVEF) were significantly decreased. There were no significant differences between MIRI and c-MB + US groups ESd, EDd, LvFS and LVEF. Compared with the c-MB + US group, the hs-MB + US group has reduced ESd, and the LVFS and LVEF are obviously improved, but EDd has no significant difference.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (8)
1. A preparation method of ultrasonic microbubbles is characterized by comprising the following steps:
(1) the phospholipid dispersion is treated with an excess of H2S, after saturation, placing the saturated solution in a sealed container for sealed storage;
(2) mixing hydrogen sulfide and perfluoropropane to obtain mixed gas, replacing headspace gas in a sealed container with excessive mixed gas, and oscillating to obtain the ultrasonic microbubble.
2. The method according to claim 1, wherein the phospholipid dispersion liquid in the step (1) is prepared by adding DPPC, DPPE-PEG5000 and DPPA to a solution containing propylene glycol, glycerin and sodium chloride, and dissolving the mixture by stirring in a water bath.
3. The method of claim 2, wherein the molar ratio of DPPC, DPPE-PE G5000 and DPPA is DPPC: DPPE-PEG 5000: DPPA ═ 10: 82: 8.
4. the method of claim 2, wherein the temperature of the water bath is 60 to 80 ℃.
5. The method of claim 1, wherein the volume ratio of hydrogen sulfide to perfluoropropane is 4/0, 3/1, 2/2, 1/3, or 0/4.
6. The method according to claim 5, wherein the volume ratio of hydrogen sulfide to perfluoropropane is 2/2.
7. The method according to claim 1, wherein the shaking time in the step (2) is 30 to 60 seconds.
8. An ultrasound microbubble, characterized in that the ultrasound microbubble is prepared by the preparation method of any one of claims 1 to 7.
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