DE4305660C2 - Device and method for controlling the size distributions of gas or liquid bubbles in a liquid medium - Google Patents

Description

The generation of bubbles with a defined maximum size in certain liquids is on many Areas of greatest interest, for example in medicine, pharmaceuticals, but also in wide areas of the chemical industry, through the food industry to the metal industry. Applications in the field of solar energy are even conceivable.

Many techniques and processes for producing such bubbles have already been developed on a large number tested in liquids. All of these procedures are aimed at the best possible standardization of the Manufacturing process for reproducibility, as well as optimal control of the maximum Bubble size tries:

• - In some processes, the solution to the problem is by spraying gases with Helped with nozzles (e.g. OS 29 23 493). Here, the choice of Injector can achieve a very fine dispersion of the gas in the liquid, causing under other very small bubbles can arise. The attained bladder density of this The method is very high, but unfortunately the size variation of these bubbles is within such a broad spectrum that this method does not produce bubbles of a defined size can be.
• - The injection of gases through porous foam materials, causing the gas introduced is broken up into fine dispersions, especially in the "rinsing" of metal melts with the help of "purge gases" such. B. in laid-open specification No. 29 14 347 is described. Here, the effect of the purge gases proves to be more efficient, the smaller the bubbles introduced are. On the one hand, this method requires very expensive and fine ones Filter systems ("flushing stones"), on the other hand a very high pressure when the gas is injected. This required pressure becomes a serious problem once the bubble diameter is in the micrometer range be aimed for. In addition, a wide range of scatter can also be found here observe in the bubble diameters. If the desired sizes are the Micrometer range also makes it considerably more difficult to produce suitable porous materials Materials because, as is well known, a much smaller one to create a small bubble Gas outlet opening is required.
• - An improvement of the aforementioned method is described in the published patent application DE 31 29 234 A1 suggested. Before the gases are injected through a porous sink, one heats them to the temperature of the liquid in order to expand it later To prevent bubbles in the liquid. The resulting bubbles change accordingly not quite as strong after blowing into the liquid, but the rest remain problems mentioned above persist.  
• - The stirring of gases into the liquid by means of suitable devices, such as ultrasonic homogenizers (S. B. Feinstein, F. J. Ten Cate, W. Zwehl, K. Ong, G. Maurer, C. Tei, P. M. Shah, S. Meerbaum and E. Corday, "Two-Dimensional Contrast Echocardiography I. In Vitro Development and Quantitative Analysis of Echo Contrast Agents "J. Am. Coll. Cardiol., 1984, Vol. 3, pages 14-20) or rotor systems (cf. DE 33 17 312 A1) is very handy and quick to carry out as long as it is the stirred-in gas is the surrounding room air, but the scatter lies the bubble sizes, as with the aforementioned methods, within such a wide range, that an exact definition of the desired maximum bubble diameter, just is hopeless in the micrometer range. This is especially true in the manufacture of vesicles Ultrasound contrast media for medical diagnostics are not justifiable, because here one Changing the bubble size is an amplification of the ultrasound signal reflected by the bubble in the third power (B. F. Vandenberg, S. Feinstein, R. A. Kieso, M. Hunt and R. E. Kerber, "Myocardial risk area and peak gray level measured by contrast echocardiography: Effect of microbubble size and concentration, injection rate, and coronary vasodilation ", Am. Heart. J., 1988, Vol. 115, pages 733-739), which creates very annoying artifacts.
• - The generation of bubbles with the aid of high-intensity ultrasound, based on the cavitation phenomenon, is described in the published patent application DE 41 13 578 A1 (see also Spectrum of Science April 1969, pages 60-66). However, due to the high energy density of the necessary sound wave amplitude within the cavitation bubbles created, temperatures up to 5000 degrees Celsius occur depending on the type of gas (KS Suslick in "Ultrasound its chemical, biological and physical effects", editor KS Suslick, VCH publishing company, Weinheim 1988, page 130). At such high temperatures, sonochemical reactions, which are difficult to estimate, take place between the media, so that the use of this method in the pharmaceutical-medical field must be raised with the greatest concerns. There are harmful and aggressive connections such. B. H₂O₂.
  Another disadvantage of this method shows itself in the instability of the vesicles resulting from the negative pressure, which collapse again within a short time after the end of the sonification. B. is required in the manufacture of ultrasound contrast media in the medical field, not suitable.
• - As described in some places, the production of bubbles would also be very different Size (e.g. through injection nozzles) in liquids, followed by subsequent filtering out of the bubbles of a desired size using suitable filters. At this time-consuming (the bubble-containing liquid must be pressed very slowly through the filter to minimize mechanical damage to the bubbles of the correct size) and cumbersome method, however, the very low bubble yield comes to the fore. This has its cause on the one hand, due to the higher expenditure of time in the Coalescence from smaller bubbles to larger ones, on the other hand in mechanical destruction many bubbles of the desired size due to wall contact on the filter pores.  
• - Another method which is used, among other things, for dispersing and emulsifying of flowable materials or corresponding material mixtures is suitable from the Published specification DT 27 09 485 A1 known. This process uses ultrasonic longitudinal pressure vibrations, which in a suitably designed container in the Form used that due to multiple reflection of the ultrasonic vibrations a repeated passage of the sound waves through the Starting material results. The phenomena thus occurring favor one better dispersion effect. In this context, the positive is already mentioned Impact of the adjusted variation of the sound frequencies used. Also here, however, it has not yet been recognized what decisive influence besides the above Criteria also the targeted control of the sound energy used and thus the the resulting amplitude exerts a precise regulation of the entire process.

The invention is based on solving the following problems:

The invention is intended to enable the size distributions of bubbles (in particular of such in the micrometer range) with regard to their maximum diameter in bubble-laden liquids to steer specifically.

This problem is based on a resonance phenomenon in the context of enrichment Liquid with bubbles in a widely distributed size distribution and subsequent sonification treatment with ultrasound with the targeted selection of frequency f and sound energy E by the Features listed in claim 1 solved.

The advantage of the invention lies in the possibility of precisely controlling the maximum diameter the bubbles, which are still contained in the liquid after sonification, and in the Simplicity and economy of the procedure used.

Additional advantages:

• - The possible uses of the invention extend beyond medicine, far into the various branches of industry,
• - There are any upper and lower limits, as well as limited sections and areas in control the distributions of the bubble diameters extremely precisely,
• - easy to set up and handle,
• - contrary to the previously known methods, particularly quick and reliable implementation with optimal standardization, which is particularly important in medical diagnostics Meaning is
• - Very little manipulation with the sample medium is required, which also easily comply with the strictest sterility criteria,
• the invention is not limited to controlling the size distribution of gas bubbles, but is also quite different, in the sense of the claims liquid-containing bubble-like globular objects, such as B. liquid droplets, microorganisms or cellular structures applicable.

Additional refinements of the invention:

The variation of the coupling options of the sound source according to claims 2 and 15 enables the invention to be used in a wide variety of areas. So offers itself, for example, when using high-temperature-resistant airgels (J. Fricke, "Aerogele", Spectrum of Science, July 1988) the use in the processing of Metal melting.

The embodiment according to claim 3 is intended to take advantage of the wide-ranging capabilities of Ensure invention, which is not only the control of gas bubbles in liquids, but also on the control of mixtures of gas bubbles and liquid phases in one Obtain ambient medium of liquid phase (e.g. emulsions).

Claim 4 extends the area of application to any form of solid melts, such. B. an application in the degassing of molten metal is conceivable, in which it is of particular importance is the average for optimal use of the purging effect of the gases introduced Gas bubble diameter to obtain a maximum exchange surface of the gas bubbles if possible to keep low. This would be easy to achieve with the present invention.

In claim 5, the mainly planned field of application of the invention in the manufacture realized by diagnostic ultrasound contrast media. Here, the present solution the previously unsuccessful production of a uniformly contrasting agent for sonographic Representation of regions of the body that have been sound-homogeneous to date (e.g. myocardial capillary bed) on the enrichment of a contrast medium containing microbubbles in the local capillaries enable. The resulting contrast medium produces significantly fewer artifacts than the procedures used so far.

Claims 6 and 16 make it possible to make an exception in a simple and quick manner To achieve high bubble density when creating the starting substrate for sonification finally the desired higher bubble density in the resulting liquid is also achieved can be.

Claims 7 and 17 leave open the possibility of also passing the bubbles in the starting substrate the stirring in of surrounding gases (e.g. room air) or liquids with appropriate Facilities (e.g. ultrasonic homogenizer, whisk).

The embodiment according to claim 8 aims at the manufacture of medical Ultrasound contrast media is a medically safe gas for intravenous injection Use bubble production, which, such. B. with helium long ago from positive pressure ventilation known from deep sea divers, has the lowest possible solubility product in human blood. Blood saturated with helium ensures a longer half-life of the bubbles. It also increases the risk of toxic by-products from sonification chemicals Effects greatly reduced.

According to claims 9 and 18 (see Fig. 3) can be switched easily and efficiently as required between the selective destruction of bubbles only a certain critical diameter d _c or the elimination of all bubbles from a critical diameter d _c .

With the design according to claims 10 and 19 can be selected when choosing the appropriate Sound intensity when using multiple frequencies is now not just the upper bound or a control certain diameter in the bubble size distribution but rather it is possible any desired pattern in the size distribution of the bubbles in the sonicated liquid to create.

With an extension according to claims 11 and 20, z. B. an interference pattern through the generation of two ultrasonic waves interfering with each other generate in which the size distributions according to the selected frequencies and intensities the bubbles vary from place to place according to the interference pattern.

If the so-sonicated liquid is now also in accordance with claims 12 and 21 suddenly frozen in this state, a solid can be found in the micrometer range create definable bubble size distribution.

Claim 13 enables a further, extremely interesting field of application of the invention: since the mode of operation of the method relates primarily to the resonance vibration of an object with a certain critical diameter d _c , it is entirely possible to irradiate bubble-like globular structures as target objects, such as pathogenic ones Germs or cells of a certain size, which are also to be seen as liquid-containing bubbles within the meaning of claim 1.

In food production, ultrasound is used to sterilize dairy products successfully used for quite some time by destroying bacteria. Because the ultrasound sensitivities various cell forms (e.g. blood cells, protozoa, salmonella, pseudomonas, Escherichia Coli etc.) have been known for a long time, it would be with the present one Processes now also possible, targeted in vivo dangerous microorganisms or pathogenic cells certain size in body tissue or body fluids without surrounding cell structures to harm. This could well be used in a non-invasive extracorporeal ultrasound treatment of parasitic infections. So could be through the invention e.g. B. in liver abscesses by the magna form of Entamoeba histolytica. which with a Diameters of 20-30 microns have a significantly larger diameter than the surrounding cells Body tissue, this aggressive pathogen has no damage to the rest of the body tissue be selectively eliminated. But also in vivo areas of application in oncology non-invasive reduction of inoperable tumor metastases (if, as is often the case, tumor cell size and density clearly differ from the cell structure of the surrounding healthy tissue) or in the elimination of pathogenic tumor cells of a defined size from the bloodstream in certain Forms of leukemia are therefore quite possible. Furthermore, in vitro Versatile applications in the areas of microbiological research and industry offer, e.g. B. in the targeted separation of certain microorganisms from cell cultures or in the metered breaking open of cell structures with the aim, for. B. enzymes or chromophores isolate certain cells.  

The invention is illustrated below using exemplary embodiments and drawings.

It shows

Fig. 1 is a representation of the statistical size distributions of bubbles in a bubble laden liquid before (curve 1) and according to the invention Sonifikationsbehandlung (curve 2).

Fig. 2 shows the growth of smaller bubbles with the absorption of energy from the ultrasonic field up to the critical diameter d _c .

Fig. 3 shows the impact of the energy supplied to the amplitude of the resonant vibration of bubbles with the critical diameter d _c.

Fig. 4 expanded control options of the size distribution pattern of the bubbles when using different frequencies and intensities of ultrasound.

Fig. 5 shows an embodiment.

The following is an explanation of the invention with reference to the drawings according to structure and mode of operation:

Fig. 1 shows the principle of the invention become apparent from the characteristic of the individual stages of carrying out statistical size distributions of bubbles in a liquid. Bubbles with a statistically broad distribution of sizes are initially generated in the liquid as the starting substrate. This is done, for example, by introducing gases (e.g. compressed air) under pressure using a finely dispersing nozzle. Curve 1 describes the resulting size distribution pattern.

In order to limit the size distribution of the bubbles to an upper barrier, an ultrasound field is applied below, the frequency f of which is selected precisely such that bubbles from a critical diameter d _c resonate with the sound waves propagating in the liquid.

This critical diameter d _c is indirectly proportional to the first approximation of the frequency f of the sound (REApfel, "Acoustic Cavitation Prediction", J. Acoust. Soc. Am., 1981, Vol. 69, pages 1624-1633):

If the intensity of the sound is sufficiently high, all the bubbles burst whose diameter is greater than or equal to the critical diameter d _c . The result is now reflected in a size distribution pattern, as represented by curve 2.

The application of an ultrasound field selected in such a way accordingly results in a bubble size distribution whose maximum frequency is at a diameter which is just below the critical diameter d _c , as the observation shows.

The resulting products of the described process are smaller bubbles, which in turn absorb and grow energy from the sound field (AA Atchley in "Ultrasound its chemical, biological and physical effects", editor KS Suslick, VCH-Verlaggesellschaft, Weinheim 1988, page 52), until they again reach the critical diameter d _c and then finally burst again.

FIG. 2 shows the course of this process over time in milliseconds (X axis) in connection with the increase in the bubble diameter d (Y axis).

As can be seen in FIG. 3, not only the choice of the correct sound frequency f is important for the selection of the suitable ultrasonic field, but also the amount of the supplied energy in the form of the correct sound pressure is particularly important.

The present graphic describes the extent of the deflection (Y axis) of the respective bubble as a function of the respective bubble diameter in micrometers (X axis) at a given constant frequency f and two different sound energies E 1 and E 2. At a given frequency f under an applied energy E 1 only bubbles get whose diameter is close to the critical diameter d _c in such strong vibrations that the critical amplitude is exceeded. If this critical amplitude A _{c is} exceeded in the deflection of the bubble wall, the bubble can no longer withstand the mechanical stress and burst, which is the case with the example of the curve of E 1 for the bubbles of the critical diameter d _c , which means that bubbles are targeted have the critical diameter d _c removed from the liquid. If you increase the supplied energy, for example to the amount of E₂, then bubbles with a larger diameter than d _c exceed the critical amplitude A _c and are therefore destroyed.

In this way it is possible according to the inventive method in bubble-laden liquids not just to set an upper bound on the bubble size it contains, but it is possible to simply sort out unpleasant bubble sizes as required.

According to the principle just described can even, as shown in Fig. 4, after choosing the appropriate energy amounts E₁ and E₂ by using different frequencies f₁ and f₂, both upwards and downwards to sharply limited size ranges of the bubbles, which in the Liquid should remain, define, which would ensure absolute control of the size distributions in each direction.

Fig. 5 is a simple but proven embodiment for the implementation describes the method described in claim 1 in two steps:

• (A) First, by blowing helium from a pressure bottle ( 1 ) using a finely dispersing nozzle ( 2 ) into a vessel ( 3 ) with a suitable liquid (here a commercially available X-ray contrast medium), bubbles are formed in high density with a statistical spread of the size distribution between 2 and 100 microns in diameter. Here, the pressure of the inflowing gas can be controlled via the outlet valve ( 4 ) in such a way that control of both the bubble density and a rough control of the average bubble diameter is possible in advance.
• (B) The sonification treatment is then carried out, with the frequency generator ( 5 ) being able to regulate the frequency and energy parameters to the extent described above as desired. The ultrasonic transducer ( 6 ) is in turn built into the side wall of a container ( 7 ) which is filled with water for optimal coupling of the sound source to the medium to be sonicated. This coupling can also be used with gels or solids, e.g. B. at high temperatures with airgel. The container ( 3 ) with the bubble-containing liquid now only needs to be brought into the field of sound waves (as shown in the picture).

Claims (21)

1. A method for controlling the size distributions of gas or liquid bubbles in a liquid medium, characterized in that an ultrasound field is coupled in a suitable form to the liquid medium already loaded with bubbles, the sound frequencies and associated energies of which are selected such that bubbles with diameters, which are determined by these frequencies and energies come into resonance vibrations until they exceed the vibration amplitude A _c necessary for bursting and thus disintegrate into smaller bubbles. 2. The method according to claim 1, characterized, that for coupling the sound source, depending on the requirements, an impedance matching through liquids of different viscosity and temperature resistance, as well as solids (e.g. aerogels), suitable metals or plastic materials. 3. The method according to one or more of the preceding claims, characterized, that the size distributions of bubbles that consist of one or more gases or even one or several liquids can exist in a liquid medium according to the invention to be controlled. 4. The method according to one or more of the preceding claims, characterized, that as a liquid with which the starting substrate by loading with appropriate bubbles of the described method is formed, any solid melts (e.g. metal melts) be used. 5. The method according to one or more of the preceding claims, characterized, that known and tested for the production of medical ultrasound contrast media X-ray contrast media, human albumin or other suitable and intravenously compatible Liquids are used for the production of the starting substrate. 6. The method according to one or more of the preceding claims, characterized, that the loading of the liquid with bubbles of widely scattering size distribution as the starting substrate the described method by introducing a gas or a liquid under controllable pressure using a finely dispersing Nozzle takes place.   7. The method according to one or more of the preceding claims, characterized, that the generation of the starting substrate by stirring gases or liquids in Form of bubbles occurs in the liquid. 8. The method according to one or more of the preceding claims, characterized, that a noble gas (e.g. helium) is introduced as the gas to form the starting substrate. 9. The method according to one or more of the preceding claims, characterized in that the energy supplied can be selected so that the critical amplitude A _c , at which the bubbles burst, as required in a wide or only in a narrow range of the bubble size distribution is exceeded. 10. The method according to one or more of the preceding claims, characterized, that several frequencies with their associated energies at the same time or one after the other senses according to the invention are used. 11. The method according to one or more of the preceding claims, characterized, that by using multiple sound sources also multi-dimensional sound interference patterns are generated, which a location-dependent control of the size distribution of the bubbles enable. 12. The method according to one or more of the preceding claims, characterized, that from the bladder-containing liquid immediately after or during the ultrasound treatment by sudden cooling or polymerizing a solid with a defined size distribution the bubbles arise. 13. The method according to one or more of the preceding claims, characterized in that microorganisms or pathogenic cells with a certain critical diameter d _{c are destroyed} both in vivo in body tissue or body fluids, and in vitro in suitable media. 14. Device for controlling the size distributions of gas or liquid bubbles in a liquid medium, characterized in that a frequency generator with an ultrasound microphone is provided which generates an ultrasound field which is suitably coupled to the bubble-containing liquid medium and the sound frequencies and associated energies selected in this way are that bubbles with diameters, which are determined by these frequencies and energies, come into resonance vibrations until they exceed the vibration amplitude A _c necessary for bursting and thus disintegrate into smaller bubbles. 15. The device according to claim 14, characterized, that for coupling the sound source, depending on the requirements, an impedance matching through liquids of different viscosity and temperature resistance, as well as solids (e.g. aerogels), suitable metals or plastic materials. 16. The device according to one or more of the preceding claims, characterized, that a finely dispersing nozzle is provided with an upstream pressure reduction valve with the aid of which the liquid is loaded with bubbles with a broadly distributed size distribution as the starting substrate of the process described by the introduction of a gas or a liquid takes place under controllable pressure. 17. The device according to one or more of the preceding claims, characterized, that a special stirring system is provided for the production of the starting substrate by which gases or liquids are stirred into the liquid in the form of bubbles. 18. The device according to one or more of the preceding claims, characterized in that an ultrasonic frequency generator is provided with which the energy supplied can be selected so that the critical amplitude A _c , at which the bubbles burst, depending on the need in a wide or is only exceeded in a narrow range of the bubble size distribution. 19. The device according to one or more of the preceding claims, characterized, that one or more sound sources are present, with the help of which different frequencies with their associated energies simultaneously or successively in the sense of the invention be used. 20. The device according to one or more of the preceding claims, characterized, that multiple sound sources are provided for generating multi-dimensional sound interference patterns are, which allow a location-dependent control of the size distributions of the bubbles. 21. The device according to one or more of the preceding claims, characterized, that a cooling device, which is controlled by liquid nitrogen, is provided is through which from the bladder-containing liquid immediately after or during the Ultrasound treatment with sudden cooling a solid with a defined bubble size distribution arises.