CN103372382B - A kind of preparation facilities of therapeutic type micro air bubble ultrasonic contrast medium and method - Google Patents
A kind of preparation facilities of therapeutic type micro air bubble ultrasonic contrast medium and method Download PDFInfo
- Publication number
- CN103372382B CN103372382B CN201210119716.4A CN201210119716A CN103372382B CN 103372382 B CN103372382 B CN 103372382B CN 201210119716 A CN201210119716 A CN 201210119716A CN 103372382 B CN103372382 B CN 103372382B
- Authority
- CN
- China
- Prior art keywords
- runner
- sprue
- air bubble
- contrast medium
- micro air
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention discloses a kind of runner, the device and method of preparing therapeutic type micro air bubble ultrasonic contrast medium, by by the flow control of described inner membrane material at 10 ~ 50 μ l/min, by the flow control of described outer membrane material at 30 ~ 60 μ l/min, and control the operating pressure of gas, by the microbubble diameter control of described therapeutic type micro air bubble ultrasonic contrast medium at 5 ~ 10 μm.Therapeutic type micro air bubble ultrasonic contrast medium prepared by the present invention shows a monodisperse distribution, and the Size Distribution centrality of microbubble is relatively good, and through checking, described therapeutic type micro air bubble ultrasonic contrast medium has good gene bearer properties.
Description
Technical field
The present invention relates to 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 (MicrobubbleUltrasoundContrastAgents, mUCA) is a kind of suspension containing high concentration microbubble, and the average diameter of microbubble is less than 8 microns (μm).Micro air bubble ultrasonic contrast medium injects after human body through peripheral vein, because microbubble and surrounding tissue present different acoustic characteristics, thus strengthens the echo contrast of blood flow and surrounding tissue, obviously improves the evaluation that ultrasonic image pours into tissue blood flow.Micro air bubble ultrasonic contrast medium can reflect blood flow characteristics more accurately, greatly increase the Sensitivity and Specificity of diagnosis, further expanded Ultrasonic Diagnosis field simultaneously, ultrasonic diagnostic technique is made to detect in the perfused tissue of various internal organs, inflammation and in lesion detection etc., acquire studies and clinical application widely.In addition, also at microbubble finishing target-specific molecule or medicine, molecule development or drug therapy can be realized.
Nearest research shows, can make the microbubble generation cavitation effect existed in tissue and body fluid under ultrasound wave irradiation, on cell membrane, generation one is by the space of property, thus improves membrane passage, impel gene to enter cell, enhance gene in intracellular transfection and expression.Thus microbubble contrast also can carry out ability and the tumor embolism treatment of fixed point release as the carrier of gene, medicine, for therapy of tumor breakthrough bottleneck problem, provide a new direction, therapeutic type micro air bubble ultrasonic contrast medium becomes the new focus of Medical research.
The microbubble contrast preparation method of current Clinical practice mainly contains acoustic cavitation, freeze drying, thermal current drying etc.The micro air bubble ultrasonic contrast medium AF0150 produced as Alliance drugmaker of the U.S. is the powder adopting drying means to make, powder is wherein containing surfactant, salt, buffer substance, powder is saturated and be stored in sealed vials with pfc gas, and injecting sterilized water during use will form microvesicle.
Microbubble size prepared by said method is distributed and is not concentrated, and must remove diameter and be greater than the microbubble of 8 microns in case blood vessel blockage, but remaining microbubble still distributes and do not concentrate, to such an extent as to causes very wide echo frequency.In addition, the thickness of each microbubble coating is also very uneven, and this echo reaction for microbubble also has a great impact.For realizing the treatment function of microbubble contrast, said method more can not meet the requirement of microbubble as the carrier of gene and medicine, cannot obtain therapeutic type micro air bubble ultrasonic contrast medium.
Therefore, we need a kind of new preparation method, can prepare Size Distribution centrality good and have the therapeutic type micro air bubble ultrasonic contrast medium of good gene bearer properties.
Summary of the invention
First object of the present invention is to provide a kind of runner preparing therapeutic type micro air bubble ultrasonic contrast medium.
Second object of the present invention is to provide a kind of preparation facilities comprising above-mentioned runner.
3rd object of the present invention is to provide the above-mentioned preparation facilities of application, 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, and the microbubble of preparation compound parcel function, as the carrier of gene and/or medicine, realizes the treatment function of microbubble contrast.And following technical scheme is disclosed:
For the preparation of a runner for therapeutic type micro air bubble ultrasonic contrast medium, described runner has the outlet of a sprue, symmetrical two side runners, symmetrical two fluid intakes and fluid;
Described sprue has some focusing position and an angle and focuses on position;
At described point focusing position, described sprue is hour-glass in shape, has a minimum widith; Focus on position in described angle, described side runner is angularly connected with sprue.
Preferably, described sprue and the width of side runner are than being 2:1; The width of described sprue is 100:7 ~ 100:20 with the ratio of hourglass-shaped minimum widith.Particularly preferably, the width of described sprue is 100 μm, and the width of described side runner is 50 μm, and described hourglass-shaped minimum widith is 7 ~ 20 μm.
Preferably, focus on position in described angle, the angular range between side runner and sprue is between 60 ° ~ 90 °.
The material of described runner stream can be dimethyl silicone polymer (PDMS), adopts etching method preparation and obtains.
The present invention is a kind of device for the preparation of 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;
Symmetrical inner membrane material source, both sides, is connected with the point focusing position of described sprue by side runner;
Symmetrical outer membrane material source, both sides, the side runner focusing on position with the angle of described sprue is connected;
The described side runner be connected with gas source is provided with control valve, for regulating pressure.
Preferably, use medical injection pump that the material in described inner membrane material source and outer membrane material source is injected described side runner.
The present invention also provides a kind of and applies above-mentioned device, prepare the method for therapeutic type micro air bubble ultrasonic contrast medium, by controlling inner membrane material and the flow velocity of outer membrane material and the operating pressure of gas, by the microbubble diameter control of described therapeutic type micro air bubble ultrasonic contrast medium at 5 ~ 10 μm.
Preferably, by medical injection pump, by the flow control of described inner membrane material at 10 ~ 50 μ l/min, by the flow control of described outer membrane material at 30 ~ 60 μ l/min.
Preferably, by control valve, other operating pressure described is controlled at 500 ~ 1000Pa.
Below some nouns related in the present invention are made an explanation.
Describedly hourglass-shapedly to refer to: wide centre, two ends is narrow, and change width is the shape of gradual change.
Described medical injection pump has commercially available conventional equipment.
Described point focusing, angle focus on and belong to flow focusing category.
Described fluid is the general name of liquids and gases, by a large amount of, constantly make warm-up movement and the molecular composition without stable equilibrium position, its essential characteristic does not have certain shape and has mobility.
The present invention aims to provide equipment and the method for preparation therapeutic type micro air bubble ultrasonic contrast medium, for inner membrane material, outer membrane material and gas all without particular/special requirement, when specifically using, can according to required contrast preparation, choose the material of corresponding inner membrance and adventitia, and the kind of gas.
Therapeutic type micro air bubble ultrasonic contrast medium prepared by the present invention shows a monodisperse distribution, and the Size Distribution centrality of microbubble is relatively good, and through checking, described therapeutic type micro air bubble ultrasonic contrast medium has good gene bearer properties.
Accompanying drawing explanation
The present invention is described 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.
The image of the therapeutic type micro air bubble ultrasonic contrast medium obtained by Fig. 4 observes on microslide.
Fig. 5 is through the microbubble distribution map of the obtained therapeutic type micro air bubble ultrasonic contrast medium that laser particle analyzer records.
Fig. 6 is the inverted fluorescence microscope figure of obtained therapeutic type micro air bubble ultrasonic contrast medium.
Fig. 7 is the ultrasonic development effect of obtained therapeutic type micro air bubble ultrasonic contrast medium.
Detailed description of the invention
Be described in detail the present invention below in conjunction with embodiment, embodiment is intended to explain and non-limiting technical scheme of the present invention.Moreover, the direction term mentioned in the present invention, such as " on ", D score, "front", "rear", "left", "right", " interior ", " outward ", " side " etc., be only the direction with reference to annexed drawings.Therefore, the direction term of use is in order to illustrate and to understand the present invention, and is not used to limit the present invention.
embodiment 1 is for the preparation of the runner of therapeutic type micro air bubble ultrasonic contrast medium
Refer to Fig. 1, shown in Fig. 1 is the not limiting example of runner for the preparation 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 hour-glass in shape, has a minimum widith b
3; Focus on position 14 in described angle, described side runner 12 is angularly 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 μm, the width b of described side runner 12
2be 50 μm, described hourglass-shaped minimum widith b
3it is 7 μm.The material of described runner stream can be dimethyl silicone polymer (PDMS), adopts etching method preparation and obtains.
embodiment 2 is for the preparation of the device of therapeutic type micro air bubble ultrasonic contrast medium and preparation method
Refer to Fig. 2, shown in Fig. 2 is the not limiting example of device for the preparation of therapeutic type micro air bubble ultrasonic contrast medium.
In figure, right-hand member is the outlet of fluid, and gas, inner membrane material and the outer membrane material flow direction in runner refers to the direction of arrow in 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 respectively by side runner 12 with the point focusing position of described sprue and connect;
The side runner 12 that two outer membrane material sources focus on position 14 with the angle of described sprue is respectively connected.
The width b of described sprue 11
1be 100 μm, the width b of described side runner 12
2be 50 μm, described hourglass-shaped minimum widith b
3it is 7 μm.The material of described runner stream is dimethyl silicone polymer (PDMS), adopts etching method preparation and obtains.
In the present embodiment, the described runner be connected with gas source is provided with control valve (not shown), for regulating pressure.Described control valve can be high accuracy control valve.
In the present embodiment, use medical injection pump (not shown) that the material in described inner membrane material source and outer membrane 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, by the flow control of described inner membrane material at 10 μ l/min, by the flow control of described outer membrane material at 30 μ l/min, controlled at 500Pa by the operating pressure of control valve by described gas.When concrete operations, after medical injection pump and control valve are adjusted to designated parameter, make each fluid inject described device simultaneously.
embodiment 3
In the present embodiment, the width b of described sprue 11
1be 100 μm, the width b of described side runner 12
2be 50 μm, described hourglass-shaped minimum widith b
3it is 10 μm.The material of described runner stream is dimethyl silicone polymer (PDMS), adopts etching method preparation and obtains.
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, by the flow control of described inner membrane material at 30 μ l/min, by the flow control of described outer membrane material at 50 μ l/min, controlled at 800Pa by the operating pressure of control valve by described gas.Preparation process is with embodiment 2.
embodiment 4
In the present embodiment, the width b of described sprue 11
1be 100 μm, the width b of described side runner 12
2be 50 μm, described hourglass-shaped minimum widith b
3it is 20 μm.The material of described runner stream can be dimethyl silicone polymer (PDMS), adopts etching method preparation and obtains.
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, by the flow control of described inner membrane material at 50 μ l/min, by the flow control of described outer membrane material at 60 μ l/min, controlled at 1000Pa by the operating pressure of control valve by described gas.Preparation process is with embodiment 2.
embodiment 5 test experience
In preparation process, use microscope to observe runner 1, observed result asks for an interview Fig. 3.Fig. 4 is the obtained therapeutic type micro air bubble ultrasonic contrast medium that microslide observes.Fig. 5 is through the microbubble distribution map of the obtained therapeutic type micro air bubble ultrasonic contrast medium that laser particle analyzer records, and abscissa represents the radius of microbubble, and unit is nanometer; Ordinate represents the percentage of domain size distribution.Can be obtained by Fig. 4 and Fig. 5, the contrast preparation of application obtained by the present invention shows a monodisperse distribution, and the Size Distribution centrality of microbubble is relatively good.
Refer to Fig. 6, Fig. 6 is the inverted fluorescence microscope figure of obtained therapeutic type micro air bubble ultrasonic contrast medium.As shown in Figure 6, the contrast preparation of application obtained by the present invention has good gene bearer properties.All solution is dissolved in, the gene load-carry duty calculated by formula 1 by DNA after ultrasound destruction microbubble.
Formula 1
Load-carry duty=
, wherein, DNA
wrefer to by solution D NA content after ultrasound destruction microbubble; DNA
1refer to by DNA content in solution before ultrasound destruction microbubble.
In the present embodiment, the DNA recorded
wbe 88.2 μ g/ μ l, DNA
1be 60 μ g/ μ l, calculate the gene load-carry duty 32% of gained.
Refer to Fig. 7, Fig. 7 is the ultrasonic development effect of obtained contrast preparation, and as shown in Figure 7, the contrast preparation of application obtained by the present invention has good ultrasonic development effect.
Comprehensive above-mentioned known, therapeutic type micro air bubble ultrasonic contrast medium prepared by the present invention shows a monodisperse distribution, and the Size Distribution centrality of microbubble is relatively good, and through checking, described therapeutic type micro air bubble ultrasonic contrast medium has good gene bearer properties.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles 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., for the preparation of a runner for therapeutic type micro air bubble ultrasonic contrast medium, described runner has a sprue, two groups of side runners of symmetry, the fluid intake of two kinds of fluids and fluid outlet, it is characterized in that,
Described sprue has some focusing position and an angle and focuses on position;
At described point focusing position, described sprue is hour-glass in shape, has a minimum widith; Focus on position in described angle, described side runner is angularly connected with sprue.
2. runner as claimed in claim 1, is characterized in that, described sprue is 2:1 with the width ratio of side runner; The width of described sprue is 100:7 ~ 100:20 with the ratio of hourglass-shaped minimum widith.
3. runner as claimed in claim 2, it is characterized in that, the width of described sprue is 100 μm, and the width of described side runner is 50 μm, and described hourglass-shaped minimum widith is 7 ~ 20 μm.
4. runner as claimed in claim 2, is characterized in that, focus on position in described angle, the angular range between side runner and sprue is between 60 ° ~ 90 °.
5. for the preparation of a device for therapeutic type micro air bubble ultrasonic contrast medium, it is characterized in that, described device comprises:
As the runner as described in arbitrary in 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 outer membrane material source, the side runner focusing on position with the angle of described sprue is connected;
The described sprue be connected with gas source is provided with control valve, for regulating pressure.
6. device as claimed in claim 5, is characterized in that, use a medical injection pump that the material in described inner membrane material source and outer membrane material source is injected described side runner.
7. for the preparation of a method for therapeutic type micro air bubble ultrasonic contrast medium, it is characterized in that, apply device as claimed in claim 6, prepare described therapeutic type micro air bubble ultrasonic contrast medium;
By described medical injection pump, by the flow control of described inner membrane material at 10 ~ 50 μ l/min, by the flow control of described outer membrane material at 30 ~ 60 μ l/min, and control the operating pressure of gas, by the microbubble diameter control of described therapeutic type micro air bubble ultrasonic contrast medium at 5 ~ 10 μm.
8. method as claimed in claim 7, be is characterized in that, controlled at 500 ~ 1000Pa by the operating pressure of control valve by described gas.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210119716.4A CN103372382B (en) | 2012-04-23 | 2012-04-23 | A kind of preparation facilities of therapeutic type micro air bubble ultrasonic contrast medium and method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210119716.4A CN103372382B (en) | 2012-04-23 | 2012-04-23 | A kind of preparation facilities of therapeutic type micro air bubble ultrasonic contrast medium and method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103372382A CN103372382A (en) | 2013-10-30 |
| CN103372382B true CN103372382B (en) | 2016-03-30 |
Family
ID=49458596
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210119716.4A Active CN103372382B (en) | 2012-04-23 | 2012-04-23 | A kind of preparation facilities of therapeutic type micro air bubble ultrasonic contrast medium and method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103372382B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017151918A1 (en) * | 2016-03-02 | 2017-09-08 | Cross Bay Medical, Inc. | Method and apparatus of echogenic catheter systems |
| CN105772129A (en) * | 2016-03-04 | 2016-07-20 | 上海理工大学 | Integrated microfluidic device and method for preparing microdroplets |
| JP2022552070A (en) * | 2019-08-26 | 2022-12-15 | ソルスティス・ファーマシューティカルズ・ベー・フェー | Cartridges for mixing liquids intended for internal use |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0555498A1 (en) * | 1992-02-11 | 1993-08-18 | April Dynamics Industries 1990 Ltd. | A two-phase supersonic flow system |
| CN101837255A (en) * | 2009-03-17 | 2010-09-22 | 华东理工大学 | Method and device for preparing micro-bubbles |
| EP2277618A1 (en) * | 2006-02-15 | 2011-01-26 | Area 55, Inc. | Venturi apparatus |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE449449B (en) * | 1984-11-26 | 1987-05-04 | Bejaco Ab | PROCEDURE FOR INHIBITION OF FINE DISTRIBUTED LIQUID IN A GAS FLOW AND DEVICE FOR EXTENDING THE PROCEDURE |
| WO2006046202A1 (en) * | 2004-10-29 | 2006-05-04 | Koninklijke Philips Electronics N.V. | Apparatus and methods for the production of ultrasound contrast agents |
| ES2516818T3 (en) * | 2010-06-09 | 2014-10-31 | The Procter & Gamble Company | Fluid mixing unit and method for mixing a liquid composition |
-
2012
- 2012-04-23 CN CN201210119716.4A patent/CN103372382B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0555498A1 (en) * | 1992-02-11 | 1993-08-18 | April Dynamics Industries 1990 Ltd. | A two-phase supersonic flow system |
| EP2277618A1 (en) * | 2006-02-15 | 2011-01-26 | Area 55, Inc. | Venturi apparatus |
| CN101837255A (en) * | 2009-03-17 | 2010-09-22 | 华东理工大学 | Method and device for preparing micro-bubbles |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103372382A (en) | 2013-10-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zhang et al. | Extravascular gelation shrinkage-derived internal stress enables tumor starvation therapy with suppressed metastasis and recurrence | |
| Wu et al. | Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery | |
| Zhao et al. | Potential and problems in ultrasound-responsive drug delivery systems | |
| Gao et al. | Drug-loaded nano/microbubbles for combining ultrasonography and targeted chemotherapy | |
| Kwan et al. | Theranostic oxygen delivery using ultrasound and microbubbles | |
| Grainger et al. | Pulsed ultrasound enhances nanoparticle penetration into breast cancer spheroids | |
| Omata et al. | Effects of encapsulated gas on stability of lipid-based microbubbles and ultrasound-triggered drug delivery | |
| Hu et al. | Insonation of targeted microbubbles produces regions of reduced blood flow within tumor vasculature | |
| Owen et al. | Magnetic targeting of microbubbles against physiologically relevant flow conditions | |
| Mannaris et al. | Microbubbles, nanodroplets and gas-stabilizing solid particles for ultrasound-mediated extravasation of unencapsulated drugs: an exposure parameter optimization study | |
| CN103372382B (en) | A kind of preparation facilities of therapeutic type micro air bubble ultrasonic contrast medium and method | |
| Martz et al. | Precision manufacture of phase-change perfluorocarbon droplets using microfluidics | |
| Zhu et al. | Polydopamine-encapsulated perfluorocarbon for ultrasound contrast imaging and photothermal therapy | |
| Radhakrishnan et al. | Scavenging dissolved oxygen via acoustic droplet vaporization | |
| Lin et al. | Effects of focused ultrasound and microbubbles on the vascular permeability of nanoparticles delivered into mouse tumors | |
| Wang et al. | Guiding Drug Through Interrupted Bloodstream for Potentiated Thrombolysis by C‐Shaped Magnetic Actuation System In Vivo | |
| Klibanov | Ultrasound contrast: gas microbubbles in the vasculature | |
| Paris et al. | Ultrasound-activated nanomaterials for therapeutics | |
| Huang et al. | Ultrasound‐responsive microfluidic microbubbles for combination tumor treatment | |
| Talu et al. | Needle size and injection rate impact microbubble contrast agent population | |
| Faraji et al. | Electrokinetic convection-enhanced delivery of solutes to the brain | |
| Wang et al. | Experimental study of tumor therapy mediated by multimodal imaging based on a biological targeting synergistic agent | |
| Dixon et al. | In vitro sonothrombolysis enhancement by transiently stable microbubbles produced by a flow-focusing microfluidic device | |
| Lee et al. | Antitumor effects of intra-arterial delivery of albumin-doxorubicin nanoparticle conjugated microbubbles combined with ultrasound-targeted microbubble activation on VX2 rabbit liver tumors | |
| Yang et al. | pH-responsive hybrid platelet membrane-coated nanobomb with deep tumor penetration ability and enhanced cancer thermal/chemodynamic therapy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |