CN115554263B - Composite structure microbubbles with double cavitation effect, cavitation method and preparation method - Google Patents

Composite structure microbubbles with double cavitation effect, cavitation method and preparation method Download PDF

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CN115554263B
CN115554263B CN202210855438.2A CN202210855438A CN115554263B CN 115554263 B CN115554263 B CN 115554263B CN 202210855438 A CN202210855438 A CN 202210855438A CN 115554263 B CN115554263 B CN 115554263B
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microbubble
phase
shell
cavitation
energy
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CN115554263A (en
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陈皓生
潘云帆
李永健
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Tsinghua University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

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Abstract

The embodiment of the application provides a microbubble with a double cavitation effect, a cavitation method and a preparation method thereof, wherein the microbubble comprises a microbubble shell; a gas core wrapped by a microbubble shell, wherein the microbubble shell and the gas core form a microbubble main body; phase change droplets carried by the microbubble shell; wherein the microbubble body is configured to cavitation at a first energy and the phase-change droplet is configured to cavitation at a second energy, the first energy being different from the second energy. According to the embodiment of the application, the phase change liquid drops are loaded on the microbubble shell, so that the microbubble has a double cavitation effect. When the microbubbles are matched with thrombolytic drugs to remove the thrombus, the permeability of the thrombolytic drugs can be improved, the thrombus removing effect is enhanced, and the thrombus removing efficiency is improved.

Description

Composite structure microbubbles with double cavitation effect, cavitation method and preparation method
Technical Field
The application relates to the technical field of biological pharmacy, in particular to a composite structure microbubble with double cavitation effect, a cavitation method and a preparation method.
Background
Cardiovascular and cerebrovascular embolism is one of the main diseases that endanger human life and health. Thrombolytic drugs are recommended by the American Society of Hematology (ASH) for the prevention of thrombosis and the treatment of embolism. Thrombolytic drugs can decompose thrombus by fibrinolysis, but have the problems of poor drug delivery efficiency and difficult thrombus penetration, and can lead to fatal bleeding events if the treatment time is increased.
In order to solve the problem of low drug delivery efficiency of thrombolytic drugs, one prior art proposes targeted controlled drug delivery, and targeted drug-carrying microbubbles perform thrombolysis through ultrasonic cavitation. Although the ultrasonically stimulated microbubbles can produce a stable and inertial cavitation effect to induce pore formation, they reside only on the outer shell of the thrombus, with low cavitation effect energy and small penetration.
In order to solve the problem of low drug delivery efficiency of thrombolytic drugs, another prior art uses nanoparticles (solid particles) which are considered to better enter the thrombus due to their small size, such as magnetic particles, nanoparticles, and nanodroplets, and have been used for thrombus formation treatment. However, the effect of nanoparticle penetration of the thrombus is not ideal due to lack of external energy drive and the filling of the inside of the thrombus with dense fibrin cores.
It should be noted that the foregoing description of the background art is only for the purpose of providing a clear and complete description of the technical solution of the present application and is presented for the purpose of facilitating understanding by those skilled in the art. The above-described solutions are not considered to be known to the person skilled in the art simply because they are set forth in the background of the application section.
Disclosure of Invention
In order to solve the problems noted in the background art and other similar problems, the embodiment of the application provides a composite structure microbubble with double cavitation effect, a cavitation method and a preparation method.
Embodiments of the first aspect of the present application provide a composite structure microbubble having a dual cavitation effect, comprising: a microbubble shell; a gas core surrounded by the microbubble shell, the microbubble shell and the gas core forming a microbubble body; and phase change droplets carried by the microbubble shell; wherein the microbubble body is configured to cavitation at a first energy and the phase-change droplet is configured to cavitation at a second energy, the first energy being different from the second energy.
In some embodiments, the first energy is a first ultrasonic frequency and the second energy is a second ultrasonic frequency, the first ultrasonic frequency being less than the second ultrasonic frequency.
In some embodiments, the first energy is a first sound pressure and the second energy is a second sound pressure, the first sound pressure being less than the second sound pressure.
In some embodiments, the gas core is an inert gas.
In some embodiments, the material of the microbubble shell comprises liposomes or/and proteins.
In some embodiments, the phase-change drip material comprises a fluorocarbon.
In some embodiments, the phase change droplets are carried in the shell of the microbubble shell or the phase change droplets are carried on the outer surface of the microbubble shell.
In some embodiments, a drug carried on the outer surface of the microbubble shell is also included.
In some embodiments, a drug is also included that is supported on the surface of the phase change droplet.
In some embodiments, magnetic nanoparticles are also included that are supported in the shell layer of the microbubble shell or on the outer surface of the microbubble shell.
In some embodiments, a drug loaded on the surface of the magnetic nanoparticle is also included.
In some embodiments, the radius of the microbubble body is 2um to 20um, and/or the radius of the phase change droplet is 200nm to 1000nm.
An embodiment of the second aspect of the present application provides a microbubble cavitation method, which is used for cavitation of the microbubbles according to the embodiment of the first aspect, and includes: step S100: applying first energy to the microbubbles until a first preset time is reached, so that cavitation of the microbubble body occurs; step S200: and applying second energy to the phase-change liquid drop until a second preset time is reached, so that cavitation of the phase-change liquid drop occurs.
In some embodiments, the second preset time is greater than the first preset time.
An embodiment of a third aspect of the present application provides a method for preparing a microbubble according to the embodiment of the first aspect, including: mixing and emulsifying the raw materials of the phase change liquid drops and the raw materials of the microbubble shell to obtain a microbubble precursor solution containing the phase change liquid drops; and mixing the gas with the microbubble precursor solution to wrap the gas by the microbubble precursor solution, thereby obtaining the microbubbles with gas cores wrapped in the microbubble shells and phase-change liquid drops contained in the microbubble shells.
In some embodiments, the mixing the gas with the microbubble precursor solution such that the gas is encapsulated in the microbubble precursor solution comprises: mixing the gas and the microbubble precursor solution using a membrane emulsifier; or mixing the gas and the microbubble precursor solution using a microfluidic cross-channel chip.
In some embodiments, further comprising: at least one of a surfactant, a drug, and magnetic nanoparticles is added to the microbubble precursor solution.
In some embodiments, further comprising: mixing the microbubbles with thrombolytic drug to load the drug on the outer surface of the microbubble shell.
The beneficial effects of the embodiment of the application include:
According to the embodiment of the application, the phase change liquid drops are loaded on the microbubble shell, so that the microbubble has a double cavitation effect. When the microbubbles are matched with thrombolytic drugs to remove the thrombus, the microbubble main body is cavitated by applying the first energy, the generated microjet drives the phase-change liquid drop to be injected into the thrombus, and the phase-change liquid drop is cavitated in the thrombus by applying the second energy, so that the flow field in the thrombus is changed and pores are generated in the thrombus, the permeability of the thrombolytic drugs is improved, the thrombolytic effect is enhanced, and the thrombus removal efficiency is improved.
Specific embodiments of the application are disclosed in detail below with reference to the following description and drawings, indicating the manner in which the principles of the application may be employed. It should be understood that the embodiments of the application are not limited in scope thereby. The embodiments of the application include many variations, modifications and equivalents within the spirit and scope of the appended claims.
Drawings
The accompanying drawings, which are included to provide a further understanding of embodiments of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the principles of the application. It is evident that the drawings in the following description are only some embodiments of the present application and that other drawings may be obtained from these drawings without inventive effort for a person of ordinary skill in the art. In the drawings:
FIG. 1 is a schematic diagram of a composite microbubble structure with dual cavitation effect according to an embodiment of the present application;
FIG. 2 is a schematic diagram of the application of a first energy to microbubbles in an embodiment of the application;
FIG. 3 is a schematic diagram of applying a second energy to a phase-change droplet in an embodiment of the application;
FIG. 4 is a schematic diagram of the structure of a drug-loaded microbubble according to an embodiment of the present application;
FIG. 5 is a schematic diagram of the structure of a drug-loaded microbubble according to another embodiment of the present application;
FIG. 6 is a flow chart of a microbubble cavitation method according to an embodiment of the present application;
FIG. 7 is a flowchart of a method for preparing a micro-fluid according to an embodiment of the present application;
FIG. 8 is a front view of a porous membrane of a membrane emulsifier employed in an embodiment of the application;
FIG. 9 is a side view of a porous membrane of the membrane emulsifier of FIG. 8;
FIG. 10 is a flowchart of a method for preparing a micro-fluid according to another embodiment of the present application.
Detailed Description
The foregoing and other features of the application will become apparent from the following description, taken in conjunction with the accompanying drawings. In the specification and drawings, there have been disclosed in detail specific embodiments of the application, illustrating some embodiments in which the principles of the application may be employed, it being understood that the application is not limited to the described embodiments, but, on the contrary, the application includes all modifications, variations and equivalents falling within the scope of the appended claims.
In the embodiments of the present application, the terms "first," "second," and the like are used to distinguish between different elements from what is referred to above, but do not denote a spatial arrangement or temporal order of the elements, and the elements should not be limited by these terms. The term "and/or" includes any and all combinations of one or more of the associated listed terms. The terms "comprises," "comprising," "including," "having," and the like, are intended to reference the presence of stated features, elements, components, or groups of components, but do not preclude the presence or addition of one or more other features, elements, components, or groups of components.
In embodiments of the application, the singular forms "a," an, "and" the "may include plural forms and should be construed broadly as" one "or" one type "and not as limited to the meaning of" one; furthermore, the term "the" should be interpreted to include both singular and plural forms, unless the context clearly indicates otherwise; furthermore, the term "according to" should be understood as "based at least in part on … …", and the term "based on" should be understood as "based at least in part on … …", unless the context clearly indicates otherwise; furthermore, the term "plurality" means two or more, unless otherwise indicated.
The following describes the implementation of the embodiment of the present application with reference to the drawings.
Example of the first aspect
Embodiments of the first aspect of the present application provide a composite structure microbubble with dual cavitation effects.
FIG. 1 is a schematic diagram of a composite microbubble structure with dual cavitation effect according to an embodiment of the present application; FIG. 2 is a schematic diagram of the application of a first ultrasonic frequency to microbubbles in an embodiment of the application; FIG. 3 is a schematic diagram of applying a second ultrasonic frequency to phase-change droplets in an embodiment of the application.
As shown in fig. 1, 2 and 3, the composite structure microbubble 100 with the double cavitation effect includes a microbubble shell 1, a gas core 2 and a phase-change liquid droplet 3. The gas core 2 is wrapped by the microbubble shell 1, and the microbubble shell 1 and the gas core 2 form a microbubble main body; the phase-change liquid droplet 3 is in a liquid state, the phase-change liquid droplet 3 is a nano-droplet capable of undergoing phase change, and the phase-change liquid droplet 3 is supported on the microbubble shell 1, in other words, the microbubble shell 1 is a carrier of the phase-change liquid droplet 3. In the case of a single microbubble, it has one microbubble body and a plurality/multitude of phase change droplets 3 distributed in the microbubble shell 1. Wherein the microbubble body is configured to cavitation at a first energy and the phase-change droplet 3 is configured to cavitation at a second energy, the first energy being different from the second energy.
When the thrombolytic drug is used, for example, when microbubbles are matched with thrombolytic drugs to remove the thrombus, first energy can be applied to the microbubbles so as to enable the microbubbles to generate cavitation (can be regarded as first cavitation of the microbubbles) to generate microjet, the microjet drives the phase-change liquid drops 3 to be injected into the thrombus, then second energy can be applied so as to enable the phase-change liquid drops 3 to generate phase change and cavitation (can be regarded as second cavitation of the microbubbles) in the thrombus, and the second cavitation enables flow fields in the thrombus to change and enables pores to be generated in the thrombus so as to improve the permeability of the thrombolytic drugs, enhance the thrombolytic effect and improve the thrombolytic efficiency.
The microbubbles of the embodiment of the application not only can be matched with thrombolytic drugs to remove thrombus, but also can be matched with tumor therapeutic drugs to carry out anti-tumor treatment, and can obviously enhance the therapeutic effect of the drugs.
According to the embodiment of the application, the phase-change liquid drop 3 is supported on the microbubble shell 1, so that the phase-change liquid drop 3 can smoothly reach a treatment part along with a microbubble main body; if the phase-change liquid droplet 3 is not carried in the microbubble shell 1, but a mixture of the phase-change liquid droplet 3 and the microbubble body (the phase-change liquid droplet 3 and the microbubble body are independent of each other) is introduced into a blood vessel, the nano-sized phase-change liquid droplet 3 is adhered and retained at the wall of the blood vessel, and cannot reach the treatment site, so that secondary cavitation cannot be realized.
According to the embodiment of the application, the phase-change liquid drops 3 are loaded in the microbubble shell 1, and jet flow generated by primary cavitation of microbubbles can drive the phase-change liquid drops 3 to permeate into thrombus, so that the permeation effect of the phase-change liquid drops 3 is enhanced; without the phase change droplet 3 being carried in the microbubble shell 1, the phase change droplet 3 hardly penetrates into the interior of the thrombus.
The microbubble shell 1 of the embodiment of the application enables the microbubbles to generate secondary cavitation by carrying the phase-change liquid drops 3 capable of generating phase change. The specific process of the second cavitation is as follows: the phase-change liquid drop 3 is subjected to phase change to form micron-sized bubbles, and the micron-sized bubbles are further cavitated, such as natural cavitation or cavitation under energy drive, so that the microbubbles have double cavitation effects. Because the phase change and cavitation of the phase change liquid drop 3 occur in the thrombus, the thrombus is loosened, the permeability of the medicine in the thrombus is effectively improved, and the thrombus removing effect is enhanced.
In some embodiments, the first energy is a first ultrasonic frequency and the second energy is a second ultrasonic frequency, the first ultrasonic frequency being less than the second ultrasonic frequency.
The method for determining the first ultrasonic frequency and the second ultrasonic frequency can be various, and one feasible method is a microbubble cavitation analysis method, which comprises the following steps:
A hydrophone is adopted to receive side scattering signals cavitated by microbubbles in different frequency ranges, and fast Fourier transform (Fast Fourier Transform, FFT) is carried out on the side scattering signals;
Then, harmonic signals and noise spectrums generated by microbubble cavitation are analyzed by using Matlab software of a computer, and super harmonics (1.5 f 0) and specific noise components (1.25 f 0 and 1.75f 0) in FFT spectrum signals are respectively proposed by using band-pass filtering. If the amplitude of the super-harmonic signal does not exceed the noise signal intensity by more than 3dB and the second harmonic signal exceeds the noise component intensity by 10dB, transient nulling is considered to be dominant, and the highest super-harmonic signal at the moment is calculated, so that the first ultrasonic frequency and the second ultrasonic frequency can be obtained.
In some embodiments, a more qualitative estimation method may be employed to determine the first ultrasonic frequency and the second ultrasonic frequency. For example, applying ultrasound at a specific frequency under a microscope, observing the response of the microbubbles, and thereby determining a first ultrasound frequency and a second ultrasound frequency.
In one possible technical solution, the first ultrasonic frequency is 20 kHz-1 MHz, preferably 300 kHz-1 MHz; the second ultrasonic frequency is 1MHz to 10MHz, preferably 1MHz to 2MHz.
In other embodiments, the first energy is a first sound pressure and the second energy is a second sound pressure, the first sound pressure being less than the second sound pressure.
In one possible technical scheme, the first sound pressure is 200 kPa-600 kPa, and the second sound pressure is 0.8 MPa-1.5 MPa.
In some embodiments, the gas core 2 is an inert gas, such as sulfur hexafluoride.
In some embodiments, the material of the microbubble shell 1 comprises liposomes or/and proteins.
In some embodiments, the material of the phase-change droplet comprises a fluorocarbon, such as perfluorocarbon.
In some embodiments, the phase change droplets 3 are carried in the shell layer of the microbubble shell 1, or the phase change droplets 3 are carried on the outer surface of the microbubble shell, wherein the former is a more preferred solution because the phase change droplets 3 carried in the shell layer of the microbubble shell 1 are less likely to detach from the microbubble shell 1, making the structure of the microbubble more stable before cavitation occurs.
In some embodiments, as shown in fig. 4, the microbubble 100 further includes a drug (such as thrombolytic drug) carried on the outer surface of the microbubble shell 1, in other words, the microbubble shell 1 is a microbubble shell carrying thrombolytic drug, when cavitation occurs in the microbubble body, the formed micro-jet can directly carry the thrombolytic drug to inject into the thrombus, so as to increase the penetration and release of the thrombolytic drug into the thrombus, thereby further enhancing the thrombolytic effect.
In some embodiments, as shown in fig. 5, the microbubbles 100 further comprise a drug (such as a thrombolytic drug) loaded on the surface of the phase-change droplet 3, in other words, the phase-change droplet 3 is a phase-change droplet loaded with a thrombolytic drug, preferably, the drug is located in the shell of the microbubble shell 1. When the phase-change liquid drop 3 cavitation occurs in the thrombus, the carried thrombolytic drug permeates in the thrombus, so that the permeation and release of the thrombolytic drug in the thrombus are improved, and the thrombus removing effect is further enhanced.
In some embodiments, as shown in fig. 5, the microbubbles 100 include a drug (such as thrombolytic drug) on the outer surface of the microbubble shell 1 and a drug (such as thrombolytic drug) on the surface of the phase-change droplet 3, so that the microbubbles have dual loading capability, the drug loading capacity and the drug release capacity of the microbubbles are further improved, and the thrombolytic effect is further enhanced.
In the above embodiment, the combination of the microbubble shell 1 or the phase-change droplet and the thrombolytic drug may be electrostatic adsorption or chemical co-bonding.
In the above embodiment, the thrombolytic drug may include at least one of urokinase, alteplase, and prim. Of course, other drugs, such as targeting proteins, which may be RGDs, CRECA, etc., may also be carried to treat tumors, as desired for treatment.
The embodiments of drug loading of the microbubbles provided by the present application are merely preferred embodiments, and it should be understood that the microbubbles 100 of the present application may be injected into a patient along with the drug without drug loading, in which case the dual cavitation effect of the microbubbles 100 may also enhance the permeation and release of the drug and enhance the therapeutic effect of the drug.
In some embodiments, as shown in fig. 5, the microbubble 100 further comprises magnetic nanoparticles 4 carried in the shell layer of the microbubble shell 1 or carried on the outer surface of the microbubble shell 1, in other words, the microbubble shell 1 is a microbubble shell carrying phase change droplets 3 and magnetic nanoparticles 4. The magnetic nanoparticles 4 in the microbubble shell 1 can enhance the B-ultrasound contrast effect. For example, the magnetic nanoparticles 4 may be iron oxide nanoparticles.
In this embodiment, the microbubbles 100 preferably further include a drug (such as thrombolytic drug) loaded on the surface of the magnetic nanoparticles 4, in other words, the magnetic nanoparticles 4 are drug-loaded nanoparticles, so as to further increase the drug loading rate of the microbubbles.
Further, the nanoparticle may further include a mesoporous nanoparticle, such as a mesoporous silica nanoparticle, where the pores of the mesoporous nanoparticle may be loaded with more thrombolytic drug by physical adsorption.
In some embodiments, the radius of the microbubble body is 2um to 20um.
In some embodiments, the radius of the phase change droplet 3 is 200nm to 1000nm.
However, the present application is not limited thereto, and the radii of the microbubble body and the phase-change droplet 3 may be set to other values according to actual needs, but the radii of the microbubble body and the phase-change droplet 3 are preferably controlled to be in the micrometer level, and the radii of the phase-change droplet 3 are preferably controlled to be in the nanometer level, so as to increase the loading of the phase-change droplet 3 in the microbubble shell 1.
Embodiments of the second aspect
Embodiments of the second aspect of the present application provide a microbubble cavitation method for double cavitation of the microbubbles 100 of the embodiment of the first aspect. Since the microbubbles 100 have been described in detail in the embodiment of the first aspect, the contents thereof are incorporated herein and the description thereof is omitted.
FIG. 6 is a flow chart of a microbubble cavitation method according to an embodiment of the present application. As shown in fig. 6, the microbubble cavitation method according to the embodiment of the present application includes:
step S10: applying first energy to the microbubbles until a first preset time is reached, so that cavitation of the microbubble body occurs, namely primary cavitation of the microbubbles;
step S20: and applying second energy to the phase-change liquid drop until a second preset time is reached, so that cavitation of the phase-change liquid drop, namely the second cavitation of microbubbles, occurs.
By adopting the microbubble cavitation method provided by the embodiment of the application, microbubbles are subjected to cavitation twice, and the permeability and the release amount of the therapeutic drug can be improved, so that the therapeutic effect of the drug is improved.
For a single microbubble, by applying a first energy and a second energy, it is possible to cause it to cavitate twice, i.e. double cavitation.
For a large number of microbubbles, since the first energy corresponding to different microbubbles may be different and the second energy corresponding to different microbubbles may be different, cavitation may be performed by alternately applying the first energy and the second energy multiple times, so that the microbubbles undergo double cavitation.
In some embodiments, the second preset time is greater than the first preset time, i.e., the second energy is applied for a time greater than the first energy, so that cavitation occurs for all or as many of the phase-change droplets in the microbubbles as possible. For example, the first preset time may be 1 minute and the second preset time may be 20 minutes.
Embodiments of the third aspect
An embodiment of the third aspect of the present application provides a method for preparing microbubbles of a composite structure having the double cavitation effect according to the embodiment of the first aspect. Since the microbubbles have been described in detail in the embodiments of the first aspect, the contents thereof are incorporated herein and the description thereof is omitted.
Fig. 7 is a flowchart of a method for preparing a micro-fluid according to an embodiment of the application. FIG. 10 is a flowchart of a method for preparing a micro-fluid according to another embodiment of the present application.
As shown in fig. 7, the method for preparing a micro-capsule according to the embodiment of the application includes:
Step S100: mixing and emulsifying the raw materials of the phase change liquid drops and the raw materials of the microbubble shell to obtain a microbubble precursor solution containing the phase change liquid drops;
step S200: mixing the gas and the microbubble precursor solution to wrap the gas by the microbubble precursor solution, thereby obtaining the microbubbles 100 in which the gas core 2 is wrapped in the microbubble shell 1 and the phase-change liquid drops 3 are contained in the microbubble shell 1.
In step S100, the raw material of the phase-change droplet 3 may be perfluorocarbon (PFP), and the raw material of the microbubble shell 1 may be liposome or protein, and in a specific operation, for example, perfluorocarbon is added to a liposome solution and is acoustically emulsified to obtain perfluorocarbon nanodroplets.
In some embodiments, as shown in fig. 8, 9, in the step 200, the gas G and the microbubble precursor solution S may be mixed using a membrane emulsifier having a porous membrane 5.
Specifically, pores 51 are densely distributed on a porous membrane 5 of the membrane emulsifier, a microbubble precursor solution S and a gas G are repeatedly cut by the pores 51 of the porous membrane 5 to form microbubbles 100 which are wrapped with gas cores 2 in a microbubble shell 1 and contain phase-change liquid droplets 3 in the microbubble shell 1, and the left and right arrows in fig. 8 indicate the direction of repeated cutting; the diameter of the initially formed microbubbles 100 is larger, and after repeated cutting of a single larger diameter microbubbles 100, a plurality of smaller diameter microbubbles 100 are formed, and the downward arrow in fig. 8 indicates that the larger diameter microbubbles 100 gradually decrease in diameter after repeated cutting through the porous membrane 5.
In other embodiments, in step 200, a microfluidic cross-channel chip may also be used to mix the gas and the microbubble precursor solution.
In particular, for example, microfluidic cross-channel chips may be injected with internal and external phase fluids. In this embodiment, the inner phase fluid is gas, the outer phase fluid is a microbubble precursor solution containing phase-change droplets, and the microbubbles 100 in which the gas core 2 is encapsulated in the microbubble shell 1 and the phase-change droplets 3 are contained in the microbubble shell 1 can be obtained by adjusting the flow rates or the air pressures of the inner phase fluid and the outer phase fluid.
In some embodiments, as shown in fig. 10, the method for preparing a micro-capsule further comprises:
Step S110: a drug (such as a thrombolytic drug or a targeting protein) is added to the microbubble precursor solution containing the phase-change droplets to covalently bind the two. In the concrete operation, the two materials can be mixed, stood for 30 minutes and then centrifuged to be resuspended.
In some embodiments, as shown in fig. 10, the method for preparing a micro-capsule further comprises:
Step S120: a surfactant is added to the microbubble precursor solution containing the phase change droplets to uniformly disperse the phase change droplets in the microbubble precursor solution. For example, by adding a fluorocarbon activator.
In some embodiments, as shown in fig. 10, the method for preparing a micro-capsule further comprises:
Step S130: magnetic nanoparticles and/or mesoporous nanoparticles are added to the microbubble precursor solution containing the phase-change droplets so as to obtain microbubbles containing the magnetic nanoparticles and/or mesoporous nanoparticles in the microbubble shell in step S200.
For the embodiment including the steps S110, S120 and S130, the present application is not limited to the sequence of the three steps, and the specific sequence may be determined according to the actual situation.
In some embodiments, as shown in fig. 10, the method for preparing a micro-capsule further comprises:
step S300: the microbubbles are mixed with a thrombolytic drug such that the outer surface of the microbubble shell carries the drug (e.g., thrombolytic drug or targeting protein).
While the application has been described in connection with specific embodiments, it will be apparent to those skilled in the art that the description is intended to be illustrative and not limiting in scope. Various modifications and alterations of this application will occur to those skilled in the art in light of the spirit and principles of this application, and such modifications and alterations are also within the scope of this application.
Preferred embodiments of the present application are described above with reference to the accompanying drawings. The many features and advantages of the embodiments are apparent from the detailed specification, and thus, it is intended by the appended claims to cover all such features and advantages of the embodiments which fall within the true spirit and scope thereof. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the embodiments of the application to the exact construction and operation illustrated and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope thereof.

Claims (17)

1. A composite structure microbubble having dual cavitation effects, comprising:
a microbubble shell;
a gas core surrounded by the microbubble shell, the microbubble shell and the gas core forming a microbubble body; and
The phase-change liquid drop loaded by the microbubble shell is a nano liquid drop, and the material of the phase-change liquid drop comprises fluorocarbon;
Wherein the microbubble body is configured to cavitation at a first energy to produce a jet for driving the phase-change droplet, the phase-change droplet configured to phase-change at a second energy to form micron-sized bubbles and cavitation, the first energy being different from the second energy.
2. The microbubble of claim 1, wherein said first energy is a first ultrasound frequency and said second energy is a second ultrasound frequency, said first ultrasound frequency being less than said second ultrasound frequency.
3. The microbubble of claim 1, wherein said first energy is a first sound pressure and said second energy is a second sound pressure, said first sound pressure being less than said second sound pressure.
4. The microbubble of claim 1 or 2, wherein said gas core is an inert gas.
5. The microbubble according to claim 1 or 2, wherein the material of the microbubble shell comprises liposomes or/and proteins.
6. The microbubble of claim 1 or 2, wherein the phase change droplet is supported in a shell of the microbubble shell or the phase change droplet is supported on an outer surface of the microbubble shell.
7. The microbubble of claim 1 or 2, further comprising a drug carried on an outer surface of said microbubble shell.
8. The microbubble of claim 1 or 2, further comprising a drug loaded on the surface of said phase change droplet.
9. The microbubble of claim 1 or 2, further comprising magnetic nanoparticles carried in the shell layer of the microbubble shell or on the outer surface of the microbubble shell.
10. The microbubble of claim 9, further comprising a drug supported on a surface of said magnetic nanoparticle.
11. The microbubble according to claim 1 or 2, characterized in that the radius of the microbubble body is 2-20 um and/or the radius of the phase-change droplet is 200-1000 nm.
12. A microbubble cavitation method for cavitation of microbubbles according to any of claims 1 to 11, comprising:
step S100: applying first energy to the microbubbles until a first preset time is reached, and cavitation is carried out on the microbubble bodies so as to generate jet flow for driving the phase-change liquid drops;
step S200: and applying second energy to the phase-change liquid drop until a second preset time is reached, so that the phase-change liquid drop is subjected to phase change to form micron-sized bubbles and cavitation.
13. A cavitation method according to claim 12, wherein the second preset time is greater than the first preset time.
14. A method for preparing a microbubble according to any one of claims 1 to 11, comprising:
mixing and emulsifying the raw materials of the phase change liquid drops and the raw materials of the microbubble shell to obtain a microbubble precursor solution containing the phase change liquid drops;
And mixing the gas with the microbubble precursor solution to wrap the gas by the microbubble precursor solution, thereby obtaining the microbubbles with gas cores wrapped in the microbubble shells and phase-change liquid drops contained in the microbubble shells.
15. The method of preparing of claim 14, wherein mixing the gas with the microbubble precursor solution such that the gas is encapsulated in the microbubble precursor solution comprises:
mixing the gas and the microbubble precursor solution using a membrane emulsifier; or alternatively
And mixing the gas and the microbubble precursor solution by adopting a microfluidic cross-shaped channel chip.
16. The method of manufacturing as set forth in claim 14, further comprising:
At least one of a surfactant, a drug, and magnetic nanoparticles is added to the microbubble precursor solution.
17. The method of manufacturing as set forth in claim 14, further comprising:
mixing the microbubbles with thrombolytic drug to load the drug on the outer surface of the microbubble shell.
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