WO2002016936A1 - Dispositif et procede d'etude a resolution locale de cellules et/ou de systemes cellulaires reticules et utilisation pour l'etude d'agents actifs au moyen d'un microphysiometre - Google Patents

Dispositif et procede d'etude a resolution locale de cellules et/ou de systemes cellulaires reticules et utilisation pour l'etude d'agents actifs au moyen d'un microphysiometre Download PDF

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Publication number
WO2002016936A1
WO2002016936A1 PCT/EP2001/009752 EP0109752W WO0216936A1 WO 2002016936 A1 WO2002016936 A1 WO 2002016936A1 EP 0109752 W EP0109752 W EP 0109752W WO 0216936 A1 WO0216936 A1 WO 0216936A1
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WIPO (PCT)
Prior art keywords
cells
light sources
cell
study
laps
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PCT/EP2001/009752
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German (de)
English (en)
Inventor
Jan Behrends
Michael George
Christian Kirchner
Wolfgang Parak
Markus Seitz
Bernhard Stein
Rainer Metzger
Original Assignee
Jan Behrends
Michael George
Christian Kirchner
Wolfgang Parak
Markus Seitz
Bernhard Stein
Rainer Metzger
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Application filed by Jan Behrends, Michael George, Christian Kirchner, Wolfgang Parak, Markus Seitz, Bernhard Stein, Rainer Metzger filed Critical Jan Behrends
Priority to AU2001289829A priority Critical patent/AU2001289829A1/en
Publication of WO2002016936A1 publication Critical patent/WO2002016936A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/305—Electrodes, e.g. test electrodes; Half-cells optically transparent or photoresponsive electrodes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/4833—Physical analysis of biological material of solid biological material, e.g. tissue samples, cell cultures
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5058—Neurological cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • the invention relates to a device and a method for the spatially resolved examination of networked cells and / or cell systems and their use for diagnostic applications and for the investigation of active substances.
  • LAPS light-addressable potentiometric sensor
  • Cytosensor ® microphysiometer In a known Cytosensor ® microphysiometer (see EP-A-0394406) are operated in parallel four or eight measuring chambers (LAPS). Each chamber is controlled by a separate light source and has an independent connection (channel) with which the photocurrent and thus the acidification or alkalization of the solution surrounding the cells is measured. This data is collected and individually converted into so-called 'raw data' by deriving the acidification / alkalization. Correspondingly continuously evaluable data is thus obtained for each chamber and each individual measuring channel. Each LAPS is illuminated by the light source from the bottom in its center. The spatial resolution in this configuration is approximately one millimeter (Nakao, M., S. Inoue, et al.
  • the object of the invention is to provide a device and a method for spatially resolved investigations of networked cells and / or cell compartments. This object is achieved with the features of the claims.
  • the invention is based on the basic idea of providing several light sources for a single measuring chamber of a microphysiometer.
  • the chip can be activated at several different (preferably four to eight or even 25 different) locations on the surface in this chamber, and thus on one LAPS each.
  • preferably four to eight or even 25 light sources, which serve to activate the chip are attached to the underside.
  • a reference electrode, a connection (channel) to the LAPS for measuring the photocurrent and a liquid supply or drainage system are provided for each chamber.
  • not all light sources are used or controlled simultaneously for the spatially resolved measurement.
  • the light sources are operated in a sequential cycle.
  • light source number 1 is activated first, so that the photocurrent at this time depends on the acidification or alkalization of the cells, which is on the LAPS within an area of approximately one square millimeter at the point illuminated by light source number 1.
  • Light source number 1 is operated until a complete photocurrent-voltage curve is recorded.
  • the switch is made to light source number 2, in which case the measured photocurrent depends on the acidification or alkalization of the cells which are located on the LAPS on the surface illuminated by light source number 2. This change continues until the last light source, preferably light source number 25. The cycle is then repeated, starting with the operation of light source number 1.
  • simultaneous or controlled activation of the light sources is provided (e.g. all light sources simultaneously or in individual groups (e.g. light sources No. 2, 4, 6, etc.)).
  • the photocurrent-voltage curves are recorded sequentially at all eight (or up to 25) points of the LAPS, under each of which one of the eight light sources is located.
  • the turning point that is to say a single data point, is then determined from each photocurrent voltage curve.
  • eight data points are determined in the individual channel used, which can be shown as so-called "raw data" on a display.
  • the first channel contains data points 1, 9, 17, ....
  • the second channel the Data points 2, 10, 18, ... etc., whereby data points 1 to 8 correspond to the first measurement cycle, data points 9 to 16 correspond to the next measurement cycle etc.
  • Each channel thus contains the time-dependent course of the inflection point of the photocurrent-voltage curve from a separately illuminated area of the LAPS.
  • the present invention thus enables the sequential examination at several (preferably up to 25) measuring points on the surface of a LAPS and thus of a channel, based on the configuration of the microphysiometer.
  • the present invention permits the specific observation of the metabolism of living cells, cell systems or cell compartments by determining the acidification or alkalization rates of the medium by the cells, which is achieved by time-resolved measurement of the pH with the technology of the light-addressable potentiometric sensor (LAPS) is.
  • the cells that can be used can be cell cultures (including bacterial or fungal cultures) or also fresh, animal, human (including biopsy material) or plant cell material.
  • the present invention is in a preferred embodiment with the known Cytosensor ® microphysiometer, so that thus the spatially resolved measurement of the acidification of the medium or Alkalleitersrate operable or coupled possible by for example cross-linked cell aggregates.
  • the spatially resolving measuring system has three aspects: 1) the integration of the multiple (for example eight) light sources in one measuring chamber; 2) the electronics for cyclical switching between the light sources; and 3) the software that splits and analyzes the measured data from one channel into several (preferably four to -25) channels.
  • the invention relates to a regulation for a) direct application of the cell cultures to the LAPS, b) possible structuring of the LAPS into sensitive and insensitive areas and c) an optimal stimulation system.
  • cells can be applied to specific carriers, which can have separated regions, in order to obtain a separation for the cells.
  • the cells can e.g. can be cultivated directly on the LAPS. This makes it possible to colonize different locations on the LAPS and the support with different cells.
  • Several different methods can be used to apply different spatially separated cultures:
  • the cell tissue pieces are applied to various points on the LAPS and, for example, fixed or allowed to grow there. It is crucial, for example, that the physiological function of the cells is full remain. In this way it can be ensured that the initially spatially separated cultures form contact points with one another by growth on the chip. In the case of isolated cell suspensions, these are applied in highly concentrated form at various points on the LAPS. To prevent mixing of the cell cultures during the adhesion phase (approx. 24 hours), the surface of the LAPS can be divided. For example, boundaries can be applied to the LAPS surface by thin lines made of a hydrophobic material. As a result, the locally applied cells remain in their respective compartments.
  • these lines have interruptions and are applied as thinly as possible so that cells or cell extensions can also grow over these lines after the adhesion.
  • the medium necessary for cultivation is added to the cells.
  • it is important that the ability of the cell to grow is maintained and that the cells from the different areas form contact points with one another or can interact in another way, for example via secretion of hormones or other signal substances.
  • the separation can e.g. B. be held so that it keeps the cells, which are applied selectively, completely and separately from one another over the duration of the measurement, or ensures that the cells grow together or migrate to one another.
  • a separating device which has several chambers can be placed on the chip during the adhesion phase and can be removed after the adhesion phase.
  • a device made of Teflon has proven particularly useful here.
  • cells can also be applied selectively by injecting them into a polymer gel (in particular agarose gel) by needles or pipettes, by reducing or restricting their mobility.
  • a polymer gel in particular agarose gel
  • the acidification is to be averaged over a particularly small area in order to examine particularly structured cell tissue associations, for example if only a small region of the cell association contains the cells of interest, this is possible with a pre-structured LAPS.
  • the LAPS can be divided into sensitive and non-sensitive areas in which no photocurrent flows by partial illumination with UV light.
  • a LAPS can be structured so that up to eight excellent areas of approximately one hundredth of a square millimeter can be represented. When one of the active areas is illuminated, the acidification rate averaged over the area of approximately one hundredth of a square millimeter can be determined.
  • the stimulation of the cells can be achieved in different ways. By adding an active ingredient to the supplied medium, global stimulation of all cells, e.g. possess a corresponding receptor, are triggered and determined.
  • local stimulation of certain cell areas is also possible in the invention. This can be done either by microinjection of an active ingredient, via a microcapillary at one point in the LAPS measuring chamber or by a voltage stimulus (ie a metallic stimulus microelectrode is integrated at one point of the LAPS) or by local application of mechanical pressure (e.g. by means of a pressure in the LAPS - Measuring chamber integrated micrometer screw) can be reached.
  • the device / method is used for the spatially resolved measurement of the metabolism of cells which are either functionally coupled or which have different properties (e.g. expression of different receptors) and remain functionally separate.
  • Coupled cell groups include synapses, gap and tight junctions, ie there is a flow of information (physical or chemical) between neighboring cells. Due to the coupling, there is the option of non-local stimulation.
  • the local electrical activity of coupled cell assemblies can be observed at the level of individual cells using the patch-clamp technique (Fitzsimonds, RM, H.-J. Song, et al. (1997), "Propagation of activity-dependent synaptic depression in simple neural networks ", Nature 388 (July 21): 439-448).
  • patch-clamp technique Fritzsimonds, RM, H.-J. Song, et al. (1997), “Propagation of activity-dependent synaptic depression in simple neural networks ", Nature 388 (July 21): 439-448).
  • extracellular techniques must be used for long-term stable measurements.
  • the extracellular electrical activity of brain sections can be monitored with the aid of extracellular microelectrodes in a spatially resolved manner (Egert, U., B. Schlosshauer, et al. (1998), "A novel organotypic long-term culture of the rat hippocampus on substrate-integrated multielectrode arrays ", Brain Research Protocols 2 (4): 229-242).
  • a corresponding system is commercially available, for example from the Natural Science Medical Institute (NMI) in Reutlingen.
  • NMI Natural Science Medical Institute
  • the acidification or alkalization of the medium surrounding the cells is measured by determining the pH.
  • this is possible for all types of cells.
  • the applications or examples described below can also be coupled with fields of field effect transistors.
  • the brain depicts highly complex compositions of coupled nerve cells that are divided into functional regions.
  • the nerve cells are networked with each other through synapses and can therefore communicate with each other.
  • Diseases such as epilepsy, have communicative dysfunctions on the cells.
  • This is investigated according to the invention as follows. Cuts or punch preparations from the affected regions are removed and adhered to various parts of the LAPS. After a few days, nerve cells from this area form cell processes (dendrites and axons) that spread along the LAPS. Through synapses, contacts are made between individual neurons, ie after several days the different regions are networked through synapses. For reasons of clarity, two stamping preparations (regions 1, 2) are used in this example.
  • the photocurrent caused by light source 1 or 2 analyzes the acidification of the cells from region 1 or 2. For example, Specifically stimulate cells from region 1. This can be either by adding an active ingredient in the supplied medium that acts specifically on the cells in region 1 or by local microinjection (micro perfusion) of an active ingredient in region 1 or by local electrical stimulation with a microelectrode from region 1.
  • the acidification rate or The metabolism of the cells from region 1 is then influenced within seconds to minutes and can then be read off. Since region 2 is coupled to region 1 via neuronal synapses, the altered metabolism in region 1 can also influence the metabolism of the cells in region 2. This can only take some time (minutes to seconds).
  • the device according to the invention enables the acidification rates of the two regions to be separated, measured in parallel and the complex interplay of the two networked regions to be examined in a long-term stable manner.
  • Example 2 Certain cell types such as Epithelial cells, cartilage and bone cells react to pressure.
  • the effect of non-local mechanical stress can be examined.
  • the piece of tissue to be examined can be cultivated on the surface of the LAPS.
  • part of the tissue pieces can be subjected to mechanical pressure, e.g. through a micrometer screw integrated locally in the chamber.
  • the possibility of spatially resolved measurement of the acidification rate enables long-term stability to be used to examine the metabolism of cells that are exposed to direct mechanical stress, as well as that of neighboring cells that are connected to them via gap or tight junctions.
  • Tumor cells react with a number of cells. This interaction can lead to cell proliferation, phagocytosis or cell death on the target cells.
  • Follicular cells etc.
  • the spatially resolved determination allows a direct comparison of the effectiveness of the medication.
  • the use of the invention is further preferred for studies for the spatially resolving detection of the secretion and secretion of messenger substances, ions and transmitters, for the detection of the interaction of the secreting cell and the receptive cell, i.e. the messenger receiving cell (e.g. insulin production), secretion and absorption by the recipient cell, or for studies on neuronal cells to demonstrate pre- and post-synaptic effects.
  • the secreting cell and the receptive cell i.e. the messenger receiving cell (e.g. insulin production), secretion and absorption by the recipient cell
  • neuronal cells e.g. the active substance post-synaptically - e.g. Dopamine.
  • control cells and recombinants e.g. cells equipped with a target protein for quick identification of an active substance.
  • the use of the invention is preferred for the spatially resolved, parallel investigation of effects of an active ingredient on cells which have different receptors (for example receptor proteins of a family with different subunit compositions) for the rapid determination of the receptor selectivity of the active ingredient. Furthermore, the use of the invention is preferred for spatially resolved studies for the detection of physiological effects which are triggered by the interaction of homogeneous or heterogeneous cell populations (eg cell type 1 acidifies medium, cell type 2 reacts to this acidification of cell type 1).
  • Also preferred is the use of the invention for determining the migration behavior of cells (determining the creep speed of the cells from a first position (i.e. above a first light source) to a second position 2 (e.g. formation of fruiting bodies, dictyostellium)).
  • position 1 is also preferred for the use of the invention for the examination of bacteria (position 1) to define the protective cover formed therefrom for spatially resolving detection by interaction with an adjacent cell in position 2 (for example Heliobacter pylori, determination of the width of the alkaline protective cover).
  • the use of the invention is preferred for (i) the determination of the amount of secretion and distance from substances which are released by a cell type 1 (position 1) and which can be interpreted in the further positions by using sensory reference cells (quality control); (ii) the investigation of neuronal primary cultures or neuronal thin tissue sections to demonstrate the interaction of neurons (normal state).
  • lesions By setting lesions (interrupting the neural connection) changes in the signal transmission in the spatially resolving area, for example from position 1 versus position 2, can be examined; (iii) the determination of differential nutrient media in terms of their cell specificity and adhesion specificity; (iv) determining the interaction of a specific substance with cells which have one (position 1), two (position 2), three or more (position 3) signal receivers for this substance, for example receptors, for determining the simultaneous and location-mediated specificity of the substance ; (v) determining cell-cell interaction of cells of the same type and cells of different types; (vi) the study of prokaryotes, eukaryotes and viruses; and (vii) use in drug screening, diagnostics, toxicity testing and quality control.
  • the invention will be explained with reference to the drawings. Show it:
  • Fig. 1 shows the basic structure of the device of a preferred one
  • FIG. 2 shows the sequential activation of the light sources; and FIG. 3 the electronic control of the device according to the invention. 4 shows a spatially resolved measurement of the reaction of Chinese Hamster Ovary (CHO).
  • FIG. 1 of the device 1 according to the invention four light sources LED 1 to LED 4 are shown. These are arranged below the measuring chamber 2 in order to generate the local photocurrent at the different positions.
  • the active ingredient is supplied or removed via inlet 6 or outlet 7.
  • a sawtooth-shaped voltage U (t) is applied between the bath electrode 3 and the back contact 10 and the photocurrent I is measured as a function of U (t).
  • U (t) serves as a trigger signal for the control device 8, which controls the light sources via corresponding connecting lines 9.
  • the device according to the invention illustrates the operation of the device according to the invention or the control of the light sources. As shown, the four LEDs arranged below the measuring chamber 2 are operated in sequence for the duration of a voltage ramp. After all four diodes have been activated in sequence, the measurement continues with the first diode. In this way, several measurement cycles are run through in succession.
  • the device according to the invention has a control circuit 8 for controlling the four LEDs as shown in FIG. 3.
  • FIG. 4 illustrates a spatially resolved measurement of the reaction of Chinese Hamster Ovary (CHO) cells to the active ingredient carbachol using an embodiment of the device according to the invention.
  • positions 1 and 3 cells of the wild type (without muscarinic receptor of type 1) and in positions 2 and 4 genetically manipulated cells (with muscarinic receptor of type 1) are applied Service. Only the latter react with an increase in the acidification rate when carbachol is added.

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Abstract

L'invention concerne un dispositif et un procédé d'étude à résolution locale de cellules et/ou de systèmes cellulaires réticulés et l'utilisation diagnostique de ces procédé et dispositif pour l'étude d'agents actifs.
PCT/EP2001/009752 2000-08-24 2001-08-23 Dispositif et procede d'etude a resolution locale de cellules et/ou de systemes cellulaires reticules et utilisation pour l'etude d'agents actifs au moyen d'un microphysiometre WO2002016936A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001289829A AU2001289829A1 (en) 2000-08-24 2001-08-23 Device and method for a local resolution study of cross-linked cells and/or cellsystems and a use for the study of active ingredients using a microphysiometer

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DE2000141596 DE10041596A1 (de) 2000-08-24 2000-08-24 Vorrichtung und Verfahren zum ortsaufgelösten Untersuchen vernetzter Zellen und/oder Zellsystemen und Verwendung für die Wirkstoffuntersuchung
DE10041596.2 2000-08-24

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102015003019A1 (de) * 2015-03-06 2016-09-08 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Verfahren und Vorrichtung zur optischen Detektion einer Bewegung in einer biologischen Probe mit räumlicher Ausdehnung
US10488400B2 (en) 2015-03-06 2019-11-26 Fraunhofer-Gesellschaft Zur Foerderung Der Angewandten Forschung E. V. Method and device for optical detection of a movement in a biological sample with a spatial extent

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