CN103372382A - Preparation method and device of treatment type microbubble ultrasound contrast agent - Google Patents
Preparation method and device of treatment type microbubble ultrasound contrast agent Download PDFInfo
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- CN103372382A CN103372382A CN2012101197164A CN201210119716A CN103372382A CN 103372382 A CN103372382 A CN 103372382A CN 2012101197164 A CN2012101197164 A CN 2012101197164A CN 201210119716 A CN201210119716 A CN 201210119716A CN 103372382 A CN103372382 A CN 103372382A
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Abstract
The invention discloses a flow channel, a device and a method for preparing a treatment type microbubble ultrasound contrast agent. The flow velocity of an inner membrane material is controlled to be between 10 and 50mu l/min, the flow velocity of an outer membrane material is controlled to be between 30 and 60mu l/min, working pressure of gas is controlled, and the diameter of microbubbles of the treatment type microbubble ultrasound contrast agent is controlled to be between 5 and 10mu m. The treatment type microbubble ultrasound contrast agent prepared by using the method is distributed in a single dispersion mode, and the size distribution concentricity of the microbubble is relatively high; and the verification shows that the treatment type microbubble ultrasound contrast agent has high gene bearing characteristic.
Description
Technical field
The present invention relates to the engineering in medicine field, especially relate to a kind of preparation method and device of micro air bubble ultrasonic contrast medium.
Background technology
Micro air bubble ultrasonic contrast medium (Microbubble Ultrasound Contrast Agents, mUCA) is a kind of suspension that contains the high concentration microbubble, and the average diameter of microbubble is less than 8 microns (μ m).Micro air bubble ultrasonic contrast medium is after peripheral vein injects human body, because microbubble presents different acoustic characteristics from surrounding tissue, thereby the echo that strengthens blood flow and surrounding tissue contrasts, and obviously improves ultrasonic image to the evaluation of tissue blood flow's perfusion.Micro air bubble ultrasonic contrast medium can reflect blood flow characteristics more accurately, sensitiveness and the specificity of diagnosis have been improved widely, further expanded simultaneously the Ultrasonic Diagnosis field, make the Ultrasonic Diagnosis technology at the aspects such as perfused tissue, inflammation detection and lesion detection of various internal organs, acquire widely studies and clinical application.In addition, also can at microbubble finishing targeting specific molecule or medicine, realize that molecule develops or drug therapy.
Studies show that recently, can make the microbubble generation cavitation effect that exists in tissue and the body fluid under the ultrasound wave irradiation, in the space that cell membrane produces a trafficability characteristic, thereby improve membrane passage, impel gene to enter cell, strengthened gene in intracellular transfection and expression.Thereby microbubble contrast can be used as the carrier of gene, medicine and the ability that can fix a point to discharge and tumor embolism treatment, be therapy of tumor breakthrough bottleneck problem, an a new direction is provided, and the therapeutic type micro air bubble ultrasonic contrast medium becomes the new focus of Medical research.
The microbubble contrast preparation method of present clinical use mainly contains acoustic cavitation, freeze drying, thermal current drying etc.The micro air bubble ultrasonic contrast medium AF0150 that produces such as U.S. Alliance drugmaker is the powder that adopts drying means to make, powder wherein contains surfactant, salt, buffer substance, powder is saturated and be stored in the airtight bottle with pfc gas, injects sterilized water during use and will form microvesicle.
The prepared microbubble size of said method is distributed and is concentrated, and must remove diameter greater than 8 microns microbubble in case blood vessel blockage is concentrated yet remaining microbubble still distributes, to such an extent as to cause very wide echo frequency.In addition, the thickness of each microbubble coating is also very inhomogeneous, and this echo reaction for microbubble also has a great impact.For realizing the treatment function of microbubble contrast, said method more can not satisfy microbubble as the requirement of the carrier of gene and medicine, can't make the therapeutic type micro air bubble ultrasonic contrast medium.
Therefore, we need a kind of new preparation method, and it is good and have a preferably therapeutic type micro air bubble ultrasonic contrast medium of gene bearer properties to prepare the distribution of sizes centrality.
Summary of the invention
First purpose of the present invention provides a kind of runner for preparing the therapeutic type micro air bubble ultrasonic contrast medium.
Second purpose of the present invention provides a kind of preparation facilities that comprises above-mentioned runner.
The 3rd purpose of the present invention provides uses above-mentioned preparation facilities, prepares the preparation method of described therapeutic type micro air bubble ultrasonic contrast medium.
For achieving the above object, main thought of the present invention is: utilize microflow control technique, prepare the microbubble of compound parcel function as the carrier of gene and/or medicine, realize the treatment function of microbubble contrast.And following technical scheme disclosed:
A kind of runner for the preparation of the therapeutic type micro air bubble ultrasonic contrast medium, described runner have a sprue, symmetrical two side runners, symmetrical two fluid intakes and fluid outlet;
Described sprue has and a bit focuses on position and an angle and focus on the position;
At described point focusing position, described sprue is the hourglass shape, has a minimum widith; Focus on the position in described angle, described side runner is angle and is connected with sprue.
Preferably, the Width of described sprue and side runner is 2:1; The width of described sprue is 100:7 ~ 100:20 with the ratio of the minimum widith of hourglass shape.Particularly preferably, the width of described sprue is 100 μ m, and the width of described side runner is 50 μ m, and the minimum widith of described hourglass shape is 7 ~ 20 μ m.
Preferably, focus on the position in described angle, the angular range between side runner and the sprue is between 60 ° ~ 90 °.
The material of described runner stream can be dimethyl silicone polymer (PDMS), and the employing etching method prepares and gets.
The present invention is a kind of device for the preparation of the therapeutic type micro air bubble ultrasonic contrast medium also, and described device comprises:
Above-mentioned arbitrary runner;
Gas source is connected with the point focusing position of described sprue;
Inner membrane material source, symmetrical both sides is connected with the point focusing position of described sprue by side runner;
Symmetrical both sides adventitia material source, the side runner that focuses on the position with the angle of described sprue is connected;
The described side runner that is connected with gas source is provided with control valve, is used for regulating pressure.
Preferably, use medical injection pump that the material in described inner membrane material source and the adventitia material source is injected described side runner.
The present invention also provides a kind of above-mentioned device of using, the method for preparing the therapeutic type micro air bubble ultrasonic contrast medium, by control inner membrane material and the flow velocity of outer membrane material and the operating pressure of gas, with the microbubble diameter control of described therapeutic type micro air bubble ultrasonic contrast medium at 5 ~ 10 μ m.
Preferably, by medical injection pump, with the flow control of described inner membrane material at 10 ~ 50 μ l/min, with the flow control of described outer membrane material at 30 ~ 60 μ l/min.
Preferably, by control valve described other operating pressure is controlled at 500 ~ 1000Pa.
Below some nouns that relate among the present invention are made an explanation.
Described hourglass shape refers to: wide centre, two ends is narrow, and change width is the shape of gradual change.
Described medical injection pump is that commercially available conventional equipment is arranged.
Described point focusing, angle focus on and belong to the flow focusing category.
Described fluid is the general name of liquids and gases, by a large amount of, constantly do warm-up movement and without the molecular composition of stable equilibrium position, its essential characteristic is not have certain shape and have flowability.
The present invention aims to provide equipment and the method for preparation therapeutic type micro air bubble ultrasonic contrast medium, for inner membrane material, the gentle body of outer membrane material all without specific (special) requirements, when concrete the use, can be according to required contrast preparation, choose the material of corresponding inner membrance and adventitia, and the kind of gas.
The therapeutic type micro air bubble ultrasonic contrast medium of the present invention's preparation shows a monodisperse distribution, and the distribution of sizes centrality of microbubble is relatively good, and through checking, described therapeutic type micro air bubble ultrasonic contrast medium has preferably gene bearer properties.
Description of drawings
Describe the present invention in detail below in conjunction with the drawings and specific embodiments:
Fig. 1 is the schematic diagram of the runner of preparation therapeutic type micro air bubble ultrasonic contrast medium.
Fig. 2 is the schematic diagram of the device of preparation therapeutic type micro air bubble ultrasonic contrast medium.
Fig. 3 is in preparation process, and microscope is to the observed image of runner 1.
Fig. 4 is the image of the prepared therapeutic type micro air bubble ultrasonic contrast medium that observes at microslide.
Fig. 5 is the microbubble distribution map of the prepared therapeutic type micro air bubble ultrasonic contrast medium that records through the laser particle analyzer.
Fig. 6 is the inverted fluorescence microscope figure of prepared therapeutic type micro air bubble ultrasonic contrast medium.
Fig. 7 is the ultrasonic development effect of prepared therapeutic type micro air bubble ultrasonic contrast medium.
The specific embodiment
Below in conjunction with embodiment the present invention is described in detail, embodiment is intended to explain and non-limiting technical scheme of the present invention.Moreover, the direction term of mentioning among the present invention, such as " on ", D score, 'fornt', 'back', " left side ", " right side ", " interior ", " outward ", " side " etc., only be the direction with reference to annexed drawings.Therefore, the direction term of use is in order to explanation and understands the present invention, but not in order to limit the present invention.
See also Fig. 1, the non-limiting example that shown in Figure 1 is for the preparation of the runner of therapeutic type micro air bubble ultrasonic contrast medium.In the present embodiment, described runner 1 has a sprue 11, several side runners 12.
Described runner 1 comprises point focusing position 13 and angle focuses on position 14.
At described point focusing position 13, described sprue 11 is the hourglass shape, has a minimum widith b
3Focus on position 14 in described angle, described side runner 12 is angle and is connected with sprue 11, and angle α scope is between 60 ° ~ 90 °.
In the present embodiment, the width b of described sprue 11
1Be 100 μ m, the width b of described side runner 12
2Be 50 μ m, the minimum widith b of described hourglass shape
3Be 7 μ m.The material of described runner stream can be dimethyl silicone polymer (PDMS), and the employing etching method prepares and gets.
Embodiment 2 is for the preparation of device and the preparation method of therapeutic type micro air bubble ultrasonic contrast medium
See also Fig. 2, the non-limiting example that shown in Figure 2 is for the preparation of the device of therapeutic type micro air bubble ultrasonic contrast medium.
Right-hand member is the outlet of fluid among the figure, and gas, inner membrane material and the flow direction of outer membrane material in runner see also the direction of arrow among Fig. 2.
In the present embodiment, gas source is connected with the point focusing position 13 of described sprue; Two inner membrane material sources are connected 13 by side runner 12 respectively and connect with the point focusing position of described sprue;
Two adventitia material sources are connected with the side runner 12 that the angle of described sprue focuses on position 14 respectively.
The width b of described sprue 11
1Be 100 μ m, the width b of described side runner 12
2Be 50 μ m, the minimum widith b of described hourglass shape
3Be 7 μ m.The material of described runner stream is dimethyl silicone polymer (PDMS), and the employing etching method prepares and gets.
In the present embodiment, the described runner that is connected with gas source is provided with the control valve (not shown), is used for regulating pressure.Described control valve can be the high accuracy control valve.
In the present embodiment, use the medical injection pump (not shown) that the material in described inner membrane material source and the adventitia material source is injected described side runner.
In the present embodiment, described gas adopts sulfur hexafluoride, and described inner membrane material adopts calf thymus DNA, and described adventitia adopts glycerine and Macrogol 2000 (PEG2000).By medical injection pump, the flow control of described inner membrane material at 10 μ l/min, at 30 μ l/min, is controlled at 500Pa by control valve with the operating pressure of described gas with the flow control of described outer membrane material.When concrete operations, medical injection pump and control valve be adjusted to designated parameter after, make each fluid inject simultaneously described device and get final product.
Embodiment 3
In the present embodiment, the width b of described sprue 11
1Be 100 μ m, the width b of described side runner 12
2Be 50 μ m, the minimum widith b of described hourglass shape
3Be 10 μ m.The material of described runner stream is dimethyl silicone polymer (PDMS), and the employing etching method prepares and gets.
Described gas adopts sulfur hexafluoride, and described inner membrane material adopts calf thymus DNA, and described adventitia adopts glycerine and Macrogol 2000 (PEG2000).By medical injection pump, the flow control of described inner membrane material at 30 μ l/min, at 50 μ l/min, is controlled at 800Pa by control valve with the operating pressure of described gas with the flow control of described outer membrane material.Preparation process is with embodiment 2.
Embodiment 4
In the present embodiment, the width b of described sprue 11
1Be 100 μ m, the width b of described side runner 12
2Be 50 μ m, the minimum widith b of described hourglass shape
3Be 20 μ m.The material of described runner stream can be dimethyl silicone polymer (PDMS), and the employing etching method prepares and gets.
Described gas adopts sulfur hexafluoride, and described inner membrane material adopts calf thymus DNA, and described adventitia adopts glycerine and Macrogol 4000 (PEG4000).By medical injection pump, the flow control of described inner membrane material at 50 μ l/min, at 60 μ l/min, is controlled at 1000Pa by control valve with the operating pressure of described gas with the flow control of described outer membrane material.Preparation process is with embodiment 2.
Embodiment 5 test experience
In preparation process, use microscope that runner 1 is observed, observed result is asked for an interview Fig. 3.Fig. 4 is the prepared therapeutic type micro air bubble ultrasonic contrast medium that observes on the microslide.Fig. 5 is the microbubble distribution map of the prepared therapeutic type micro air bubble ultrasonic contrast medium that records through the laser particle analyzer, and abscissa represents the radius of microbubble, and unit is nanometer; Ordinate represents the percentage that particle diameter distributes.Can be got by Fig. 4 and Fig. 5, use the prepared contrast preparation of the present invention and show a monodisperse distribution, the distribution of sizes centrality of microbubble is relatively good.
See also Fig. 6, Fig. 6 is the inverted fluorescence microscope figure of prepared therapeutic type micro air bubble ultrasonic contrast medium.As shown in Figure 6, use the prepared contrast preparation of the present invention and have preferably gene bearer properties.All be dissolved in solution by DNA behind the ultrasound destruction microbubble, the gene load-carry duty that calculates by formula 1.
Load-carry duty=
, wherein, DNA
wRefer to by solution D NA content behind the ultrasound destruction microbubble; DNA
1Refer to by dna content in the solution before the ultrasound destruction microbubble.
In the present embodiment, the DNA that records
wBe 88.2 μ g/ μ l, DNA
1Be 60 μ g/ μ l, calculate the gene load-carry duty 32% of gained.
See also Fig. 7, Fig. 7 is the ultrasonic development effect of prepared contrast preparation, as shown in Figure 7, uses the prepared contrast preparation of the present invention and has preferably ultrasonic development effect.
Comprehensive as can be known above-mentioned, the therapeutic type micro air bubble ultrasonic contrast medium of the present invention's preparation shows a monodisperse distribution, and the distribution of sizes centrality of microbubble is relatively good, and through checking, described therapeutic type micro air bubble ultrasonic contrast medium has preferably gene bearer properties.
The above only is preferred embodiment of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (8)
1. runner for the preparation of the therapeutic type micro air bubble ultrasonic contrast medium, described runner have a sprue, symmetrical two side runners, two fluid intakes and fluid outlet, it is characterized in that,
Described sprue has and a bit focuses on position and an angle and focus on the position;
At described point focusing position, described sprue is the hourglass shape, has a minimum widith; Focus on the position in described angle, described side runner is angle and is connected with sprue.
2. runner as claimed in claim 1 is characterized in that, the Width of described sprue and side runner is 2:1; The width of described sprue is 100:7 ~ 100:20 with the ratio of the minimum widith of hourglass shape.
3. runner as claimed in claim 2 is characterized in that, the width of described sprue is 100 μ m, and the width of described side runner is 50 μ m, and the minimum widith of described hourglass shape is 7 ~ 20 μ m.
4. runner as claimed in claim 2 is characterized in that, focuses on the position in described angle, and the angular range between side runner and the sprue is between 60 ° ~ 90 °.
5. the device for the preparation of the therapeutic type micro air bubble ultrasonic contrast medium is characterized in that, described device comprises:
Such as arbitrary described runner in the claim 1-4;
Gas source is connected with the point focusing position of described sprue;
Symmetrical inner membrane material source is connected with the point focusing position of described sprue by side runner;
Symmetrical adventitia material source, the side runner that focuses on the position with the angle of described sprue is connected;
The described side runner that is connected with gas source is provided with control valve, is used for regulating pressure.
6. device as claimed in claim 5 is characterized in that, uses medical injection pump that the material in described inner membrane material source and the adventitia material source is injected described side runner.
7. the method for the preparation of the therapeutic type micro air bubble ultrasonic contrast medium is characterized in that, uses such as claim 5 or 6 described devices, prepares described therapeutic type micro air bubble ultrasonic contrast medium;
Pass through medical injection pump, with the flow control of described inner membrane material at 10 ~ 50 μ l/min, with the flow control of described outer membrane material at 30 ~ 60 μ l/min, and the operating pressure of control gas, with the microbubble diameter control of described therapeutic type micro air bubble ultrasonic contrast medium at 5 ~ 10 μ m.
8. method as claimed in claim 7 is characterized in that, by control valve the operating pressure of described gas is controlled at 500 ~ 1000Pa.
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Cited By (4)
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|---|---|---|---|---|
| CN105772129A (en) * | 2016-03-04 | 2016-07-20 | 上海理工大学 | Integrated microfluidic device and method for preparing microdroplets |
| CN109152890A (en) * | 2016-03-02 | 2019-01-04 | 克劳斯贝医疗有限公司 | A kind of method and apparatus of echo conduit system |
| CN113521318A (en) * | 2021-07-29 | 2021-10-22 | 济南市中心医院 | Simethicone microbubble ultrasonic contrast agent and preparation method and application thereof |
| CN114599411A (en) * | 2019-08-26 | 2022-06-07 | 至点制药公司 | Cartridge for mixing liquids intended for in vivo use |
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| CN113521318A (en) * | 2021-07-29 | 2021-10-22 | 济南市中心医院 | Simethicone microbubble ultrasonic contrast agent and preparation method and application thereof |
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| CN103372382B (en) | 2016-03-30 |
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