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WO2003019174A1 - Procedes et appareils acoustiques pour identifier et traiter de maniere selective un systeme cellulaire - Google Patents

Procedes et appareils acoustiques pour identifier et traiter de maniere selective un systeme cellulaire Download PDF

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Publication number
WO2003019174A1
WO2003019174A1 PCT/CZ2001/000046 CZ0100046W WO03019174A1 WO 2003019174 A1 WO2003019174 A1 WO 2003019174A1 CZ 0100046 W CZ0100046 W CZ 0100046W WO 03019174 A1 WO03019174 A1 WO 03019174A1
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WO
WIPO (PCT)
Prior art keywords
differing
medium
cellular system
ultrasonic oscillations
measuring device
Prior art date
Application number
PCT/CZ2001/000046
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English (en)
Inventor
Serguei Nikolayevich Semenov
Original Assignee
Bertrust S.R.O.
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 Bertrust S.R.O. filed Critical Bertrust S.R.O.
Priority to PCT/CZ2001/000046 priority Critical patent/WO2003019174A1/fr
Publication of WO2003019174A1 publication Critical patent/WO2003019174A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/44—Processing the detected response signal, e.g. electronic circuits specially adapted therefor
    • G01N29/4409—Processing the detected response signal, e.g. electronic circuits specially adapted therefor by comparison
    • G01N29/4427—Processing the detected response signal, e.g. electronic circuits specially adapted therefor by comparison with stored values, e.g. threshold values
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/02—Analysing fluids
    • G01N29/036—Analysing fluids by measuring frequency or resonance of acoustic waves
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/22—Details, e.g. general constructional or apparatus details
    • G01N29/30—Arrangements for calibrating or comparing, e.g. with standard objects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2291/00—Indexing codes associated with group G01N29/00
    • G01N2291/01—Indexing codes associated with the measuring variable
    • G01N2291/014—Resonance or resonant frequency
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2291/00—Indexing codes associated with group G01N29/00
    • G01N2291/02—Indexing codes associated with the analysed material
    • G01N2291/024—Mixtures
    • G01N2291/02466—Biological material, e.g. blood
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2291/00—Indexing codes associated with group G01N29/00
    • G01N2291/02—Indexing codes associated with the analysed material
    • G01N2291/028—Material parameters
    • G01N2291/02836—Flow rate, liquid level
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2291/00—Indexing codes associated with group G01N29/00
    • G01N2291/10—Number of transducers
    • G01N2291/105—Number of transducers two or more emitters, two or more receivers

Definitions

  • the group of inventions relates to biotechnology, in particular, to microbiology and cell biology, and can be used for identification and treatment of various cellular systems in medicine, veterinary medicine, in timber and food industries and other fields of science and industry.
  • the interaction of ultrasound with biological medium is an object of numerous investigations and technological applications.
  • the ultrasound is a unique tool permitting, on the one hand, to determine characteristics of biological systems, and on the other hand, to produce a desired effect on them for the purposes of medicine and technology.
  • the term "ultrasound" in this description implies the acoustic waves in the frequency range from 1 kHz to hundreds of MHz.
  • One of the structural and functional units of biological medium is the cell, so assaying mechanisms of ultrasonic effect along with recommendations on the technology of said effect is the substance of many inventions. It should be taken into account that the* dimensions of biological systems are small, from tens of nanometers to fractions of micrometers. In most cases the systems have complex composition, structure and specific functions, which determine their responses to external stimuli.
  • the response of a biological structure depends on composition and physical condition of individual membrane components and on the parameters of the immediate environment of the membrane. That is, the response of a bio-membrane is determined by its molecular composition, the charge of polar groups of membrane molecules, the so-called "bound" water, the presence of various trans-membrane gradients and other factors. At that, an important characteristic of biological membranes is the surface pressure, and its evaluation allows obtaining a more complete information on the intra-cell processes (see, for example, SU 1465768 A1, Semenov S.N. et al. 15.03.1989) [1]. Besides, the biological structures display vital activity in liquid media, and constitute, to a certain extent, liquid media themselves. The media based on water in some concentration are characterized by the following acoustical parameters: the velocity of ultrasound not exceeding 1500 m/s and small attenuation in the kilohertz range of ultrasonic waves.
  • the "strong” ultrasound is generally used for disintegration of structures, production of emulsions and dispersions, and other technological purposes usually characterized by producing cavitation in liquid media. It is the cavitation that constitutes the source of high pressure necessary for the destructive physical and chemical treatment.
  • the "weak” ultrasound does not, as a rule, bring about physical or chemical transformations and is used for the purpose of measuring parameters of biological objects or affecting them without causing the irreversible biological destruction. For instance, there is a known method of ultrasonic treatment of biological structures in liquid suspensions.
  • the complex-shape oscillations are generated in the walls of a container with liquid suspension.
  • the biological structures are distributed over the length and the radius direction of the container according to the desired law (WO 91/13674 A1, Whitworth G., B01 D 43/00... , 19.09.1991) [2], which subsequently allows to make their selection.
  • Another method of the "weak" ultrasonic treatment may be used for agglutination of particles or cells via cross-bridging molecules in the immuno-agglutination assays. According to it, the biological suspension is placed in the field of standing ultrasonic waves, this resulting in sedimentation of its components (WO 93/19367 A2,
  • a device which implements the method for treating morbid cells in the living body by means of sonic and/or ultrasonic waves.
  • the ultrasonic radiation with natural frequency spectrum for the kind of cells being treated is used, which destroys said cells (EP 0774927 B1, Theuer E., A61 B 19/00, 19.08.1998) [5].
  • an acoustic tract is used comprising an electric generator connected to a wideband ultrasonic emitter.
  • the emitter generates in the examined medium ultrasonic oscillations, their spectrum being registered by an acoustic receiver connected to the spectrum analyzer.
  • the emitter can generate acoustic field of intensity up to 300 W/cm 2 and can operate in the pulse mode.
  • the invention provides a method for identification of frequencies of ultrasonic oscillations characterizing a certain type of biological cellular system (here, the biomembranes, for instance, the cytoplasmatic membranes). These frequencies, hereinafter called characteristic (natural) frequencies, are registered with the measuring system, possessing a complex type of natural resonances including also the natural oscillations of the cellular system. For the selective influence on a certain component, until its complete inactivation, it is proposed to subject the cellular system to ultrasonic oscillations on the characteristic frequencies and with the increased intensity compared to the one used in measurements of characteristic frequencies.
  • the claimed group of inventions unified by the common inventive idea, comprises acoustic methods for identification and selective influence on cellular systems, and an apparatus for application of the aforesaid methods.
  • the acoustical method of identification of a cellular system consists in generation of ultrasonic oscillations in the medium containing the cellular system, in registration and analysis of spectra of ultrasonic oscillations propagating through the aforesaid medium, and in determining the identification features of the cellular system in the spectra.
  • the method is characterized in that generation and registration of ultrasonic oscillations are performed with the measuring apparatus including the reference and the measuring channels connected according to differential scheme and balanced so that, if both channels contain the same medium, the output signal spectrum would have no resonance peaks.
  • the differential frequency spectrum natural for the examined medium with respect to the reference one, is registered, the resonance peaks are detected in the aforesaid frequency spectrum, and their respective frequencies are identified as the characteristic frequencies of the cellular system and/or its components in the examined medium.
  • the method can be characterized in that generation, reception and analysis of frequency spectra are performed in the frequency range from 10 kHz to 800 MHz.
  • the media containing cellular systems can be introduced into the measuring device in the form of mixtures based on aqueous solutions, mainly the physiological solution.
  • a flow-type measuring device can be employed.
  • the method can also be characterized in that the medium containing the cellular system is introduced into the measuring device in the form of an object of biological tissue.
  • the object of biological tissue used as the medium containing the cellular system is brought into acoustic bond with the measuring device placed outside and/or inside the aforesaid object of biological tissue.
  • the acoustical method of selective influence on a cellular system consists in generation of ultrasonic oscillations in the medium containing the cellular system and placed into a measuring device supplied with the means for regulation of frequency and intensity of ultrasonic oscillations.
  • the method can be characterized in that the ultrasonic oscillations in the medium containing the cellular system are generated on the characteristic frequencies of ultrasonic oscillations of the cellular system and/or its components in the examined medium, at that, the intensity of ultrasonic oscillations is chosen to be above the empirically found threshold value of intensity, causing the irreversible destruction of the cellular system or its components.
  • Another object of the claimed group of inventions is an apparatus for identification and selective treatment of cellular systems. It includes a measuring device for placing a medium containing cellular systems, which device comprises the means for generation and reception of ultrasonic oscillations, connected respectively to a generator of electric oscillations and a receiver with its output connected to the means for spectral analysis of ultrasonic oscillations and identification of characteristic frequencies.
  • the measuring device includes measuring units intended for the reference medium and the examined medium, the receiver has differential inputs.
  • the means for generation and reception of ultrasonic oscillations are embodied in the form of the wideband emitting and receiving piezoelectric transducers, the emitting ones being connected in parallel to the generator of electric oscillations, and the receiving ones related to the reference medium and the examined medium being connected to the differential inputs of the receiver.
  • the apparatus may include an electric generator embodied as a sweep generator and a controllable attenuator.
  • the piezoelectric transducers can be manufactured of ceramics on the basis of solid solutions of barium/lead zirconate/titanate, the measuring units for the reference medium and the examined medium can be manufactured in the form of cuvettes, in particular, the flow-type ones.
  • the emitting and receiving piezoelectric transducers can be placed outside and/or inside the object of biological tissue. BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a schematic drawing of the experiment and of the measuring apparatus
  • FIG. 2 shows experimental data obtained on the solutions: Graph A relates to the Bac. anthracoides culture; Graph B relates to the Bac. thurindiensis culture;
  • Graph C relates to the mixture of Bac. anthracoides + Bac. thurindiensis cultures
  • FIG. 3 shows the experimental dependence of the amplitude of the output signal (A) on concentration (C) for both cultures, measured on the natural frequencies.
  • FIG. 4 shows the experimental dependence of the characteristic-frequency signal amplitude on the time of ultrasonic treatment of the cellular system.
  • the apparatus comprises a measuring device including two channels, the reference one and the measuring one, being represented, for example, by the cuvettes 10, 12 of identical dimensions (their length along the direction of ultrasound propagation constituting 60 to 100 mm).
  • the ultrasonic transducers 101, 102, 121 and 122, constituting the measuring basis are placed.
  • the ultrasonic transducers 101 and 102 along with cuvette 10 form the reference acoustic tract; the ultrasonic transducers 121 and 122 along with cuvette 12 form the measuring tract and the tract for treating the cellular systems.
  • the object of measurement can be a cellular system, for example, suspension of cells placed into the cavity of cuvettes 10 and 12 and being in the acoustic contact with the aforesaid transducers 101 , 102, 121 and 122. If an object of biological tissue (either a biological object as a whole, or individual organ or else a fragment of an organ) is used as a medium containing the cellular system, the ultrasonic transducers 101 , 102, 121 and 122 are placed outside and/or inside the aforesaid object providing the acoustical bond with the latter.
  • an object of biological tissue either a biological object as a whole, or individual organ or else a fragment of an organ
  • the reversible ultrasonic transducers are used, permitting to effect both generation and registration of ultrasonic oscillations.
  • the known wideband piezoelectric ceramic transducers are used, embodied out of barium/lead zirconate/titanate solid solutions. Such transducers are easily accessible and are widely used for both scientific and applied purposes in the frequency range of 1 kHz to tens of MHz (cf., e.g., the monograph "Ultrasonic Transducers”/ ed. Y.Kikuchi. - Corona Publishing Company, LTD, Tokyo, 1969) [8].
  • Such piezoelectric transducers are peculiar in that they can be placed over the surface of a cuvette, for example, pasted up with the help of the compound. At the measurements of an object of biological tissue they can be fastened directly on the object or introduced into its bulk.
  • the measuring tract shall comprise a thermostatic system for the examined liquids and biological objects, while the cuvettes, for the convenience of manipulation, can be embodied as the flow-type ones and supplied with corresponding pumping systems (not shown in the FIG. 1).
  • the ultrasonic transducers are connected to the electrical generator 14 equipped with the means of frequency regulation (in the range from 10 kHz to 800 MHz) and of output power (from milliwatts to tens of Watts).
  • generator 14 may be a sweep generator equipped also with the controllable attenuator. Reception and registration of ultrasonic oscillations are carried out by means of the receiver 16 equipped with two differential inputs and functioning as a transducer amplifier. The output of the receiver 16 is connected to the input of the spectrum analyzer 18.
  • the transducers 101 and 121 are connected to generator 14 in parallel, while the transducers 102 and 122 are connected to the input of receiver 16 in opposite to provide the differential measurement mode.
  • the description of implementation of the proposed method is given below for the case of liquid media, the described routine, however, having no peculiarities in the case of a biological object.
  • the measuring system is considered ready for measurements when both cuvettes are filled with the same substance, for example, with physiological solution, and the output signal of spectrum analyzer 18 (the frequency response function of the measuring tract) does not show pronounced oscillations with respect to the "grass" while scanning the frequency of generator 14.
  • the methods of identification and selective effect provide for two procedures, differing, however, in technology and operating characteristics of ultrasonic field effect (cf. the above mentioned
  • the first procedure consists in identification of cellular systems. For this purpose, registration of frequency characteristics of the medium placed in cuvettes is carried out using the "weak" ultrasound mode on the known mixtures. The measured spectra are compared to the types of cellular systems, the acoustic "portrait" of the latter being determined.
  • the second procedure consists in using the acoustic "portraits", that is, the frequency characteristics registered according to the first procedure, for the selective treatment of cellular systems with ultrasound of higher intensity (the “strong” ultrasound mode). It is evident that the terms “weak” and 'strong” have no permanent meaning, however, taking into account the previous analysis along with subsequent explanations and recommendations, the choice of modes would not present any difficulties to the specialists.
  • a known cell culture for example, the Bac. anthracoides
  • known concentration of cells for example, 1.10 7 cells/ml
  • a known quantity, e.g. 20 ml, of the prepared cell culture is introduced into the measuring cuvette 12 and the corresponding frequency response function is registered with the spectrum analyzer 18 (see FIG. 2, A).
  • the peaks are detected in the aforesaid frequency response function, and the corresponding frequencies are identified as characteristic frequencies F-i, F 2 , inherent to the above mentioned known cell culture.
  • the concentration of the aforesaid known cell culture is increased (for example, by adding dosed quantities of the solution into the cuvette 12) and the dependence of signal amplitude on the concentration of cell culture is registered at the aforesaid characteristic frequencies F 1( F 2 (see FIG. 3).
  • the cuvettes 10 and 12 are filled with physiological solution.
  • Another known cell culture for example, the Bac. thurindiensis
  • known concentration for example, 1.10 7 cells/ml
  • the measurements entirely similar to those of A are conducted.
  • the results are shown in FIG. 2, B. In this case the Bac. thurindiensis cell culture can be demonstrated to have a single pronounced characteristic frequency F 3 .
  • concentration - amplitude dependence is linear. This circumstance can serve as a basis for quantitative determination of cell culture concentration in the unknown specimens by means of comparison with the reference.
  • a mixture of cultures examined in A and B is prepared. Further the same measurement procedure is followed as was used for individual cell cultures.
  • Cuvettes 10 and 12 are filled with physiological solution, then a known quantity of mixture of the Bac. anthracoides and the Bac. thurindiensis cultures is introduced into cuvette 12, and the peaks on the frequency response function are registered (see FIG. 2, C). It can be seen that the registered peak frequencies are equal to F 1 f F 2 and F 3 , i.e. the same values that were obtained separately in the experiments A and B.
  • the dependence of amplitude of the characteristic peak on the time of ultrasonic treatment of the cellular system is registered.
  • the FIG. 4 represents such dependence for one of the cell cultures, the Bac. thurindiensis, measured at the characteristic frequency F 3 .
  • the amplitude A of the output signal can be seen to diminish with the treatment time.
  • ultrasound of higher intensity is used (the above-mentioned "strong” ultrasound mode).
  • the threshold value of intensity of ultrasonic oscillations is empirically determined, which would not cause an irreversible destruction of the chosen cellular system or its components.
  • the intensity P treatmen t is chosen to be above the determined threshold value of the "weak" ultrasound intensity, which is usually applied at the acoustical spectroscopy of biological media.
  • the above-mentioned cellular system (within the framework of the experimental scheme of FIG. 1) is exposed to the ultrasound at one of the identified absorption frequencies.
  • the exposure is carried out at the frequency Fi (see FIG. 2).
  • the ultrasound intensity Ptreatment is set higher than that used for measurements:
  • the treatment is carried out for the predetermined time interval, preferably 15 minutes.
  • the method can be implemented with employing equipment and techniques known in biotechnology and ultrasonic technology.

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  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Pathology (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Acoustics & Sound (AREA)
  • Engineering & Computer Science (AREA)
  • Signal Processing (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Ultra Sonic Daignosis Equipment (AREA)

Abstract

L'invention a pour objet l'identification des fréquences d'oscillations ultrasonores caractérisant un certain type de structures cellulaires (par exemple les fréquences caractéristiques). Lesdites fréquences sont enregistrées au moyen d'un système de mesure caractérisé par un type complexe de résonances intrinsèques qui comprennent les oscillations naturelles à la fois du système cellulaire et du milieu agissant avec ce dernier. Dans le cadre d'une influence sélective sur un composant particulier desdits systèmes cellulaires, on expose lesdits systèmes cellulaires à des ondes ultrasonores d'une intensité notablement plus grande, à des fréquences caractéristiques précitées, jusqu'à ce que l'effet voulu (jusqu'à l'inactivation complète) soit produit. L'invention concerne le procédé ainsi que sa mise en oeuvre.
PCT/CZ2001/000046 2001-08-27 2001-08-27 Procedes et appareils acoustiques pour identifier et traiter de maniere selective un systeme cellulaire WO2003019174A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CZ2001/000046 WO2003019174A1 (fr) 2001-08-27 2001-08-27 Procedes et appareils acoustiques pour identifier et traiter de maniere selective un systeme cellulaire

Applications Claiming Priority (1)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8150633B2 (en) 2007-11-19 2012-04-03 Burke Timothy A Seafood physical characteristic estimation system and method

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003035A1 (fr) * 1987-10-02 1989-04-06 Public Health Laboratory Service Board Etude des proprietes de fluides
EP0774927A1 (fr) * 1993-04-24 1997-05-28 THEUER, Erich Dispositif de traitement de cellules morbides dans le corps vivant
WO1998001394A1 (fr) * 1996-07-04 1998-01-15 Eric Cordemans De Meulenaer Dispositif et procede de traitement d'un milieu liquide
US5952560A (en) * 1994-11-09 1999-09-14 Commonwealth Scientific And Industrial Research Organisation Particle property measurement
WO2000015097A2 (fr) * 1998-09-11 2000-03-23 Berkshire Laboratories, Inc. Techniques d'utilisation de l'energie acoustique et/ou acousto-electromagnetique de resonance pour detecter et/ou exercer un effet sur des structures

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003035A1 (fr) * 1987-10-02 1989-04-06 Public Health Laboratory Service Board Etude des proprietes de fluides
EP0774927A1 (fr) * 1993-04-24 1997-05-28 THEUER, Erich Dispositif de traitement de cellules morbides dans le corps vivant
US5952560A (en) * 1994-11-09 1999-09-14 Commonwealth Scientific And Industrial Research Organisation Particle property measurement
WO1998001394A1 (fr) * 1996-07-04 1998-01-15 Eric Cordemans De Meulenaer Dispositif et procede de traitement d'un milieu liquide
WO2000015097A2 (fr) * 1998-09-11 2000-03-23 Berkshire Laboratories, Inc. Techniques d'utilisation de l'energie acoustique et/ou acousto-electromagnetique de resonance pour detecter et/ou exercer un effet sur des structures

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EGGERS F ET AL: "BROAD-BAND ULTRASONIC MEASUREMENT TECHNIQUES FOR LIQUIDS", MEASUREMENT SCIENCE AND TECHNOLOGY, IOP PUBLISHING, BRISTOL, GB, vol. 7, no. 1, 1996, pages 1 - 19, XP000551465, ISSN: 0957-0233 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8150633B2 (en) 2007-11-19 2012-04-03 Burke Timothy A Seafood physical characteristic estimation system and method
US8457904B2 (en) 2007-11-19 2013-06-04 Timothy A. Burke Seafood physical characteristic estimation system and method
US8725424B2 (en) 2007-11-19 2014-05-13 Clearwater Seafoods Limited Partnership Seafood physical characteristic estimation system and method

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