EP1075507A2 - Dispositif et procede pour exposer de maniere ciblee un echantillon biologique a des ondes acoustiques - Google Patents

Dispositif et procede pour exposer de maniere ciblee un echantillon biologique a des ondes acoustiques

Info

Publication number
EP1075507A2
EP1075507A2 EP99927719A EP99927719A EP1075507A2 EP 1075507 A2 EP1075507 A2 EP 1075507A2 EP 99927719 A EP99927719 A EP 99927719A EP 99927719 A EP99927719 A EP 99927719A EP 1075507 A2 EP1075507 A2 EP 1075507A2
Authority
EP
European Patent Office
Prior art keywords
sample
sample vessel
sound waves
sound
electroacoustic transducer
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.)
Withdrawn
Application number
EP99927719A
Other languages
German (de)
English (en)
Inventor
Thomas Hahn
Bernhard Kleffner
Hans Ruf
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Original Assignee
Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV filed Critical Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Publication of EP1075507A2 publication Critical patent/EP1075507A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N13/00—Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
    • C12M47/06—Hydrolysis; Cell lysis; Extraction of intracellular or cell wall material

Definitions

  • the invention relates to a device for the targeted application of a biological sample, preferably biological cell material or tissue samples, with sound waves with a sample vessel in which the biological sample is in suspended form, and with an electroacoustic transducer device which generates the sound waves and which is arranged outside the sample vessel is so that the sound wave is coupled into the sample through the sample vessel wall.
  • a biological sample preferably biological cell material or tissue samples
  • an electroacoustic transducer device which generates the sound waves and which is arranged outside the sample vessel is so that the sound wave is coupled into the sample through the sample vessel wall.
  • ultrasound lithotriptors are used to smash kidney and gallstones using ultrasound.
  • Ultrasound is also used for wound cleaning and phacoemulsification.
  • ultrasound is used, for example, for cleaning, drilling, milling and welding.
  • ultrasound emulsifiers Due to the disintegrating effect on biological structures, ultrasound emulsifiers have gained considerable importance in sample digestion. Ultrasonic emulsifiers of this type, so-called sonotrodes, often have rapid transformers which are arranged on electroacoustic transducers, such as, for example, Langevinsche or compound transducers. The electroacoustic transducers often have a piezoceramic as the active material, and they vibrate with an amplitude of, for example, 0.5 ⁇ m. With the help of the transformers, the initially very small amplitude is multiplied to, for example, over 500 ⁇ m.
  • the conventional design of the sound system does not prevent foam and aerosol formation, which reduce the reproducibility of the sound system.
  • DE 32 09 841 C2 shows an arrangement for embedding at least one tissue sample in paraffin.
  • the device provides a container into which different coupling fluids can be introduced, in which a tissue sample to be treated is inserted.
  • the device provides an ultrasound generator 61 on the bottom of the vessel, which couples ultrasound waves with a frequency of 35 kHz into the interior of the working vessel. With the selected frequencies, however, it is not possible to concentrate ultrasonic energy on the smallest sample volumes.
  • the known device also provides an arrangement of the ultrasound-generating unit both outside and inside the sample vessel, which is why it can be assumed that the problem of cross-contamination does not exist in this case.
  • the invention has for its object to provide a device for subjecting a biological sample, preferably biological cell material, to sound waves, with which an exact intensity dosage of the sound waves is possible for targeted excitation of biological effects. Measures are also to be taken to increase the energy input based on the limited sample volume. In addition to the above requirements, it should in particular be possible to miniaturize the size of the device in order to be able to carry out a large number of sample examinations.
  • the device according to the invention for the targeted application of a biological sample, preferably biological cell material, with sound waves, with a sample vessel in which the biological sample is in suspended form, and with an electroacoustic transducer device which generates the sound waves and is arranged outside the sample vessel, so that the Sound wave coupling into the sample through the sample vessel wall is further developed such that the electroacoustic transducer device generates sound waves with a frequency of at least 100 kHz, preferably from 500 kHz to 5 MHz, and that means are provided for focusing the sound waves that the sound waves onto concentrate a sample volume within the sample vessel of approximately 50 ⁇ l.
  • a biological sample preferably biological cell material
  • the electroacoustic transducer device is operatively connected to the sample vessel in such a way that the sound wave is coupled into the sample through the sample vessel wall and the electroacoustic transducer device is arranged outside the sample vessel. Since the sound is not radiated from the inside to the outside, as is the case with conventional ultrasonic emulsifiers in the sample, but is coupled in from the outside in, the sound intensity distribution can be restricted to the area of the sample, so that in conjunction with a higher center frequency, Loading range from more than 100 kHz, the influences can be controlled by interference of the sound waves reflected on the sample vessel wall. This allows an exact dosing of the sound intensities and precise excitation of certain biological effects in sample volumes down to 50 ⁇ l and below. Typical sample volumes in which biological effects are to be produced are approximately 100 ⁇ l.
  • the sound is coupled in through the bottom of the sample vessel, so that the majority of the sound waves pass through the sample in a focused manner from below and are reflected at the upper boundary layer with reduced reflection on the wall of the sample vessel.
  • a plane-parallel acoustic ⁇ / 4-wave transformer is preferably provided in the sample vessel wall.
  • the acoustic lens is preferably designed as a spherical acoustic lens and can be inserted into the sample vessel base or forms it completely.
  • the sound wave is preferably coupled into the sample vessel by means of structure-borne noise, in that a soft polymer element or a fluid-containing coupling element is provided between the electroacoustic transducer device and the sample vessel and is in direct contact with both or a fluid coupling.
  • such high-frequency sound waves can be focused on the smallest areas, their spatial Sound intensity distribution can be influenced exactly. It is possible with such high-frequency sound waves to focus the area of the maximum sound pressure on the center of the sample volume, thereby avoiding spraying on the surface (aerosol formation) and thus cross-contamination between neighboring samples.
  • the sound coupling to the sample vessel wall by means of structure-borne noise is also essentially loss-free, so that even small transducer devices are sufficient to generate sound. Since they are arranged outside the sample vessel, they can also be of a very simple design in order to be able to provide the sound frequency required for the ultrasound treatment of biological samples.
  • the ultrasound device according to the invention can therefore be miniaturized and can be used together with microtiter plate systems.
  • the sound wave coupling into the sample through the sample vessel wall is not subject to changing parameters, which makes it exactly reproducible. Precise reproducibility of the sound wave coupling is a prerequisite for precise dosing and automated sample processing, in which the sample vessel is automatically replaced or the biological sample in a sample vessel is automatically exchanged.
  • FIG. 1 shows an ultrasound device according to the invention in a perspective view together with a microtiter plate shown in the manner of an exploded view above the ultrasound device
  • FIG. 2 shows an electroacoustic transducer device which is used in the ultrasound device in FIG. 1, together with a section through a sample vessel of the microtiter plate from FIG. 1,
  • FIG. 3 shows an ultrasound device according to the invention with a piezoelectric composite, an electronic control device and a microtiter plate having several sample vessels,
  • 4a and 4b show an SEM image of a piezoelectric composite and a schematic perspective illustration of the composite
  • Figure 5a to 5e the manufacturing steps for producing a piezoelectric composite.
  • FIG. 1 A first exemplary embodiment of a device for the targeted exposure of a biological sample, preferably biological cell material, to sound waves is shown in FIG. 1.
  • This device has a flat base plate 1, which is provided with a rail 2 on each of two opposite side edges.
  • a crossmember 4 is mounted on the rails 2 and can be displaced in the longitudinal direction of the rail 2 (double arrow 5) and is driven by an electric motor (not shown) for displacement along the rail 2.
  • An electroacoustic transducer device 7 is displaceably arranged on the cross member 4 and can be moved back and forth along the longitudinal direction on the cross member 4 (double arrow 8) by a further electric motor (not shown).
  • the micro Titer plate 12 is a plastic plate with several recesses arranged in a regular grid, each of which forms a sample vessel 13 for receiving chemical and biological and in particular microbiological samples.
  • the microtiter plate 12 is placed on the device according to the invention, wherein it is carried by the side walls 10.
  • the electroacoustic transducer device 7 can be moved in the plane of the base plate in the x and y directions, so that the electromagnetic transducer device 7 can be arranged under all sample vessels 13 of the microtiter plate 12. This electroacoustic transducer device 7 is shown in side view in FIG.
  • the electroacoustic transducer 15 is preferably made of a piezoelectric, magnetostrictive and / or electrostrictive material that can convert electromagnetic waves into sound waves.
  • the body 14 enclosing the electroacoustic transducer 15 is slidably attached to the cross member 4 by means of a holder 17.
  • An acoustic lens 19 with a spherical surface 20 is arranged on the upward-facing end face of the body 14. With the aid of this acoustic lens 19, the sound waves emitted by the electroacoustic transducer 15 are bundled, as a result of which a sharply focused ultrasound beam is obtained.
  • a coupling element 22 for coupling the ultrasound beam into the sample vessel 13 is provided approximately in the center on the spherical surface 20 of the acoustic lens 19.
  • the coupling element 22 consists, for example, of a soft, loss-free polymer or can consist of a thin-walled plastic vessel filled with a fluid suitable for sound transmission.
  • Fluid suitable for sound waves is, for example, water or preferably degassed water.
  • the crossmember 4 is preferably provided with a tilting device (not shown) with which the electroacoustic transducer 15 with the coupling element 22 can be raised and pressed against the sample vessel 13, the coupling element 22 being in direct contact with the vessel bottom 24.
  • the microtiter plates are preferably formed from polymer materials which transmit sound well, such as polystyrene, polypropylene or polyethylene, the contact areas of the vessels 13 with the electroacoustic transducer device 7 - in the illustrated embodiment these being the vessel bottoms 24 - preferably being membrane-like, or in particular plane-parallel acoustic ⁇ / 4 - Form shaft transformers.
  • the vessel bottom 24 of the sample vessel 13 as an acoustic lens with a spherical surface instead of the acoustic lens 19 arranged in the electroacoustic transducer device 7.
  • the sound wave coupling into the sample contained in the sample vessel 13 takes place through the sample vessel wall, so that the sound is coupled in by means of structure-borne noise in exactly defined conditions.
  • This coupling by means of structure-borne noise has low losses, so that the sound intensity required for the treatment of the sample materials can be provided even with small electroacoustic transducers.
  • the electroacoustic transducer device 7 according to the invention does not come into direct contact with the sample material, so that it can be moved quickly between individual sample vessels 13 of a microtiter plate 12 without the risk of contamination.
  • the electro- acoustic transducer 15 can be miniaturized. Since the transducer does not come into contact with the sample material during coupling and can therefore be moved quickly between individual sample vessels 13 without an additional cleaning process, the ultrasound device according to the invention is ideally suited for automated ultrasound treatment of a large number of samples.
  • High-frequency ultrasound with a frequency of at least more than 100 kHz and in particular 500 kHz to 5 MHz is used as the ultrasound, since high-frequency sound can be focused on the smallest volumes, so that even sample volumes of approximately 50 ⁇ l can be sonicated separately.
  • the maximum sound pressure can be focused in the middle of the sample volume, as a result of which spraying on the surface (aerosol formation) and thus cross-contamination between sample materials of adjacent sample vessels 13 are avoided.
  • FIGS. 3 to 5e A further exemplary embodiment according to the invention of an ultrasound device for the targeted exposure of a biological sample to sound waves is shown schematically in FIGS. 3 to 5e.
  • this ultrasound device has a so-called piezoelectric 1-3 composite.
  • a multiplicity of individual sound transducers 30, which are each formed from a piezoelectric rod 35, are arranged in a regular, for example, square grid, their longitudinal extension being oriented perpendicular to the grid plane.
  • These individual sound transducers 30 are embedded in a polymer matrix 31 for mutual isolation and for transmission of the sound generated (FIGS. 4a, 4b).
  • Composites of this type are produced by the dice and fill process, with plane-parallel disks 33 being first cut out from a cuboid block of piezoelectric material on a base area 34 (FIG. 5b), and disks 33 in the next working step in the transverse direction to the first cutting direction can be cut into rods 35 standing on the base 34. These rods 35 are cast together with the base 34 into the polymer matrix 31 (FIG. 5d). Finally, the base 34 is worked off, for example by grinding. processes so that only the rods 35 remain as individual sound transducers 30 in the polymer matrix 31 and are connected to corresponding contact elements for the application of an electrical frequency signal. It is also possible to structure this electrode in the form of individual elements (ultrasound array).
  • An electrical control device for controlling the individual sound transducers 30 has a frequency generator 40, a phase shifter device 41 and a phase control device 42.
  • the frequency generator 40 generates an electrical frequency signal with a frequency of at least 100 kHz and in particular 500 kHz to 5 MHz.
  • This frequency signal is fed into the phase shifter device 41, which has a multiplicity of individual phase shifters, with which the phase of the incoming frequency signal can be changed, the phase shifter device 41 having a separate output for each individual sound transducer 30, so that one for each individual sound transducer 30 the other individual sound transducers 30 independent phase signal can be output.
  • the individual phase shifters are controlled by a phase control device 42.
  • a thin, disk-shaped coupling element 22 made of a soft, loss-free polymer or a plastic body filled with a fluid is preferably arranged on the electroacoustic transducer device 7. If the individual sound transducers 30 embedded in a polymer matrix 31 are used, the polymer matrix 31 itself can be used as a coupling element, that is to say that the individual sample vessels 13 are placed directly on the electroacoustic transducer device 7 designed as a composite.
  • a fluid as a coupling layer is also possible.
  • the electronic control of the individual sound transducers 30 arranged in a two-dimensional array permits both sequential and parallel sonication of the individual sample vessels 13.
  • This array arrangement of the individual sound transducers 30 also enables a further miniaturization of the ultrasound device with ideal, arbitrarily adjustable and rapidly changing intensity distributions , so that even complicated methods for applying samples to ultrasonic waves can be carried out simply, quickly and, above all, automatically.
  • the piezoelectric composites are particularly advantageous for the device according to the invention, since they allow effective, broadband sound generation and coupling, simple further processing and extensive adjustment of the electroacoustic properties.
  • array arrangements can also be produced in a conventional manner from piezoceramic elements or lead zirconate titanate elements, the electronics for controlling them being essentially the same.
  • a major advantage of the array arrangement is that a large number of samples, which are located in the sample vessels of a microtiter plate or another cartridge system, can be used with ultrasound sequentially or in parallel or in any other order without a relative movement between the sample vessels and the electroacoustic transducer device can be sonicated. Since no relative movement is necessary, the sample vessels do not have to be moved when treating multiple samples, which avoids cross-contamination, and it is not necessary to mechanically couple the electroacoustic transducer device to a sample vessel each time anew, which must be done very carefully to ensure that the to obtain the desired, reproducible coupling states.
  • the invention allows an exact, reproducible coupling of the sound waves into sample vessels, whereby the in the field intensities generated in the sample vessels can be precisely adjusted and metered. This allows specific chemical, biological or microbiological effects in the samples to be specifically stimulated. In addition, interference effects can be reduced or completely avoided by focusing on the smallest sample volumes.
  • Double arrow electroacoustic transducer device Double arrow electroacoustic transducer device

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  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Sustainable Development (AREA)
  • Molecular Biology (AREA)
  • Cell Biology (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Sampling And Sample Adjustment (AREA)

Abstract

L'invention concerne un dispositif pour exposer de manière ciblée un échantillon biologique, de préférence un matériau cellulaire biologique, à des ondes acoustiques. Ce dispositif comprend un récipient à échantillon dans lequel l'échantillon biologique est présent en suspension, ainsi qu'une unité de conversion électroacoustique produisant les ondes acoustiques, placée à l'extérieur du récipient à échantillon de sorte que l'injection des ondes acoustiques dans l'échantillon s'effectue à travers la paroi du récipient à échantillon. L'invention est caractérisée en ce que l'unité de conversion électroacoustique produit des ondes acoustiques à une fréquence d'au moins 100 kHz, de préférence comprise entre 500 kHz et 5 MHz, et en ce que des moyens servant à focaliser les ondes acoustiques concentrent ces dernières sur un volume d'échantillon d'environ 50 νl à l'intérieur du récipient à échantillon.
EP99927719A 1998-05-07 1999-04-23 Dispositif et procede pour exposer de maniere ciblee un echantillon biologique a des ondes acoustiques Withdrawn EP1075507A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19820466A DE19820466C2 (de) 1998-05-07 1998-05-07 Vorrichtung und Verfahren zur gezielten Beaufschlagung einer biologischen Probe mit Schallwellen
DE19820466 1998-05-07
PCT/DE1999/001233 WO1999058637A2 (fr) 1998-05-07 1999-04-23 Dispositif et procede pour exposer de maniere ciblee un echantillon biologique a des ondes acoustiques

Publications (1)

Publication Number Publication Date
EP1075507A2 true EP1075507A2 (fr) 2001-02-14

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EP99927719A Withdrawn EP1075507A2 (fr) 1998-05-07 1999-04-23 Dispositif et procede pour exposer de maniere ciblee un echantillon biologique a des ondes acoustiques

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Country Link
US (1) US6699711B1 (fr)
EP (1) EP1075507A2 (fr)
DE (1) DE19820466C2 (fr)
WO (1) WO1999058637A2 (fr)

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WO1999058637A2 (fr) 1999-11-18
DE19820466A1 (de) 1999-11-18
US6699711B1 (en) 2004-03-02
WO1999058637A3 (fr) 2000-01-27
DE19820466C2 (de) 2002-06-13

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