DE4305660A1 - Controlling size distribution of gas or liquid bubbles - by coupling ultrasound field to the liquid medium which contains the bubbles and using sound frequency and energy chosen to break the bubbles up into smaller bubbles - Google Patents

Abstract

A process for controlling the site distribution of gas or liquid bubbles in a liquid medium comprises coupling an ultra sound field to the bubble-contg. liq. medium and selecting the sound frequency and associated energy so that bubbles with diameters which can be determined at these frequencies and energies are set in resonance vibrations until they exceed the ocillation amplitude Ac necessary to break the bubbles up into smaller bubbles. The device for performing the process is also claimed. USE/ADVANTAGE - The prodn. of bubbles of defined max. size in certain liquids is important e.g. in medicine and pharmaceuticals and in other areas of the chemical industry, including th foodstuffs industry and metal industries. There are also possibilities for use in solar energy. The process enables the size of the bubbles to be exactly controlled both in terms of upper and lower limits and is simple. the process is rapid (important in life saving medical diagnoses) and the least possible manipulation of samples is necessary. Thus it is easy to work under the most stringent sterile conditions. the process can also be used to control particle size of liquid-contg. bubble-like globular objects, e.g. liquid droplets, microorganisms or cellular structures. It can be used to destroy microorganisms of a critical diameter. It can be used to produce bubble-contg. solids, by cooling melts contg. bubbles of defined size.

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, from the food industry to metallin industry. Applications in the field of solar energy are even conceivable.

There have been innumerable techniques and processes for producing such bubbles 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). This can be done by choosing the injection nozzle achieve a very fine dispersion of the gas in the liquid, thereby among other things, very small bubbles can also form. 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 "flushing" of metal melt 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 introduced bubbles 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 as soon as the bubble diameter in the Mi range should be sought. In addition, a wide range of scatter can also be found here observe in the bubble diameters. 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 is used to create a small bubble Gas outlet opening is necessary.
• - An improvement of the aforementioned method is in the published patent application DE 31 29 234 A1 suggested. Before the gases are injected through a porous sink, one heats them up 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 ultrasound 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 Echocardio graphy 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 large band wide, that an exact definition of the desired maximum bubble diameter, straight is hopeless in the micrometer range. This is especially true in the manufacture of vesicular neck term ultrasound contrast media for medical diagnostics 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 (KSSuslick in "Ultrasound its chemical, biological and physical effects", editor KSSuslick, VCH-Verlagsgesellschaft, Weinheim 1988 , Page 130). At such high temperatures, sonochemical reactions, which are difficult to estimate, occur 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. H ₂ O.
  Another disadvantage of this method shows itself in the instability of the vesicles formed from the negative pressure, which collapse again after a short time after the end of the sonification. B. in the production of ultrasound contrast media in the medical field he is required, not suitable.
• - As described in some places, the production of bubbles would also be very different Size (e.g. through injectors) in liquids, followed by a subsequent manufacture filtering out 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 ten) and cumbersome method, however, the very low bubble yield occurs in the front the reason. This has its causes 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.

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 wide distribution of sizes and subsequent sonification treatment with ultrasound with 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 through knife of 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 is important
• - 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 distributions of gas blow, but is also quite diverse, in the sense of the claims liquid-like bubble-like globular objects, such as Liquid droplets, Microorga nisms 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 aerogels (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 utilize the wide-ranging capabilities of the Ensure invention, which not only relates to the control of gas bubbles in liquids, but also on the control of mixtures of gas bubbles and rivers 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 great importance tion 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 sonography representation, previously sound-homogeneous body regions (e.g. myocardial capillary bed) on the enrichment of a microbubble-containing contrast medium in the local capillary enable vessels. The resulting contrast agent produces significantly less artifacts than the procedures used so far.

By claims 6 and 16, it is possible in a simple and quick manner, an exception to achieve high bubble density when creating the starting substrate for sonification where finally achieved the desired higher bubble density in the resulting liquid 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 agents, for the intravenous injection of medically harmless gas for Use bubble production, which, such. B. with helium long ago from positive pressure ventilation known from deep-sea divers, the lowest possible solubility product in human blood be sits. Blood saturated with helium ensures a longer half-life of the bubbles. In addition, the risk of the formation of toxic by-products from sonification chemistries effects are 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 adjustment, 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 distribution according to the selected frequencies and intensities lungs of the bubbles vary from place to place according to the respective 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 area 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 target bubble-like globular structures as targets, such as pathogenic 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. Since the Ultra sound sensitivities of various cell forms (e.g. blood cells, protozoa, salmonella, pseudo monads, Escherichia coli etc.) have been known for a long time, it would be with the present Processes are now also possible, targeted in vivo dangerous microorganisms or pathogenic cells certain size in body tissue or body fluids without surrounding cells damage structures. This could be used in a non-invasive way extracorporeal ultrasound treatment of parasitic infections. So through the inven dung z. B. in liver abscesses by the magna form of Entamoeba histolytica, which with a Diameters of 20-30 microns have a considerably larger diameter than the cells of the reverse body tissue, this aggressive pathogen has no damage to the rest of the body weaves can 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 at certain Accordingly, there are various forms of leukemia. Furthermore, would also 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.

Show it

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 illustrated by the typical of the individual stages of carrying out statistical size distributions of bubbles in a liquid. It creates the bubbles in the liquid as a starting substrate in a statistically wide distribution of sizes. This is done, for example, by introducing gases (e.g. compressed air) under pressure with 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 depends indirectly on the frequency f of the sound in a first approximation (REApfel, "Acoustic Cavitation Prediction", J. Acoust.Soc.Am., 1981, Vol. 69, pages 1624-1633):

If the sound intensity is sufficiently high, all bubbles with a diameter greater than or equal to the critical diameter d _{c will} burst. The result is now reflected in a size distribution pattern, as represented by curve 2 .

The application of an ultrasound field selected in this way thus results in a blas 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 energy from the sound field and grow (AAAtchley in "Ultrasound its chemical, biological and physical effects", editor KSSuslick, VCH-Verlaggesellschaft, Weinheim 1988, page 52), bis they in turn reach the critical diameter d _c and then finally burst again.

From Fig. 2, the time course of this process in milliseconds (X-axis) in conjunction with the increase in the bubble diameter d (Y-axis) can be seen.

As shown in FIG. 3, for the selection of the suitable ultrasound field, not only the choice of the necessary sound frequency f but also the amount of the supplied energy in the form of the correct sound pressure is of particular importance.

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 acoustic energies E ₁ and E ₂ . At a given frequency f below a supplied 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 for the bubbles of critical diameter d _c using the example of the curve of E ₁ , with which bubbles are deliberately created of the critical diameter d _c can be removed from the liquid. If the energy supplied is increased, for example, to the amount of E ₂ , then bubbles with a larger diameter than d _c also exceed the critical amplitude A _c and are therefore destroyed.

In this way it is possible according to the inventive method in bubble-laden liquid Not only do you have to set an upper bound on the bubble size it contains, it is possible to simply sort out unpleasant bubble sizes as required.

According to the principle just described, it is even possible, as shown in FIG. 4, to choose the appropriate energy amounts E ₁ and E ₂ by using different frequencies f ₁ and f ₂ , both upwards and downwards, to sharply limited size ranges of the bubbles define which should remain in the liquid, which would ensure absolute control of the size distributions in each direction.

Fig. 5 illustrates a simple but proven embodiment for carrying out 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 the X-ray contrast medium Ultravist ^R ) bubbles with a 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 regulated 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, the frequency and energy parameters being able to be regulated as desired using the frequency generator ( 5 ). 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 suitably coupled to your bubble-containing liquid medium, the sen sound frequencies and associated energies are selected so that bubbles, with diameters through them Frequencies and energies are determined, advise in 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 by liquids of different viscosity and temperature resistance, as well as by 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 more liquids can be controlled in a liquid medium the. 4. The method according to one or more of the preceding claims, characterized, that as the liquid for the starting substrate any solid melts (e.g. metal melt zen) can 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 can be 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, wide-spread size distribution as the output Substrate of the method described by the introduction of a gas or a liquid takes place under controllable pressure by means of a finely dispersing nozzle.   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 takes place 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 respective associated energies simultaneously or in succession be 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 control the size of the Bla enable sen. 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 bubble-containing solid with a defined Size distribution of the bubbles is created. 13. The method according to one or more of the preceding claims, characterized in that as liquid-containing bubbles microorganisms or pathogenic cells with a certain critical diameter d _c , both in vivo in body tissue or body fluids, as well as in vitro in suitable media, specifically destroyed will. 14. Device for controlling the size distributions of gas or liquid bubbles in a liquid medium, characterized in that a frequency generator is provided with an ultrasound microphone which generates an ultrasonic field which is suitably coupled to the bubble-containing liquid medium and its sound frequencies and associated energies are chosen 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 by liquids of different viscosity and temperature resistance, as well as by Solids (e.g. aerogels), suitable metals or plastic materials. 16. The device according to one or more of the preceding claims, characterized, that a fine dispersing nozzle is provided with an upstream pressure reduction valve with the help of loading the liquid with bubbles, wide-spread 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 needs in a wide or only is 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 respective associated energies can be used simultaneously or in succession. 20. The device according to one or more of the preceding claims, characterized, that several sound sources are pre-generated for the generation of multidimensional sound interference patterns are seen, which allow a location-dependent control of the size distributions of the bubbles chen. 21. The device according to one or more of the preceding claims, characterized, that a cooling device, which is controlled by liquid nitrogen, before is seen through which from the blistered liquid immediately after, or during the Ultrasound treatment with sudden cooling a solid with defined bubble sizes distribution arises.