Classifications

• • 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
  • G01N33/487—Physical analysis of biological material of liquid biological material
  • G01N33/48707—Physical analysis of biological material of liquid biological material by electrical means
  • G01N33/48728—Investigating individual cells, e.g. by patch clamp, voltage clamp
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
  • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
  • B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
  • B01L3/502784—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
  • B01L3/502792—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics for moving individual droplets on a plate, e.g. by locally altering surface tension
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/06—Auxiliary integrated devices, integrated components
  • B01L2300/0627—Sensor or part of a sensor is integrated
  • B01L2300/0645—Electrodes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0809—Geometry, shape and general structure rectangular shaped
  • B01L2300/0819—Microarrays; Biochips
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/089—Virtual walls for guiding liquids
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/04—Moving fluids with specific forces or mechanical means
  • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
  • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
  • B01L2400/0427—Electrowetting
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
  • G01N15/10—Investigating individual particles
  • G01N2015/1022—Measurement of deformation of individual particles by non-optical means

Definitions

• the present invention relates to a method and a device for measuring the electrical activity of one or more biological cells and in particular to a device for measuring in parallel the electrical activity of a plurality of biological cells.
• WO04 / 038409 discloses a device for performing such measurements.
• This device is of the planar type, made of silicon.
• the chip implemented implements a system of conduits for the suction of fluids. More precisely, this device comprises channels intended to be connected to capillaries themselves connected to liquid suction means located outside the chip.
• the system is therefore complex, not compact.
• the aspirated volumes are difficult to control, and are important, of the order of a few microliters.
• the fluid volumes are conditioned by cavities, made for example of silicon or by the polymers forming the tightness of the lower and upper chambers.
• Each measurement site must therefore be individually filled with a solution suitable for measuring the electrical activity of the ion channels and comprising a cell suspension.
• the volume of fluid is, again, important and the miniaturization limited by the standards of dispensing equipment. This constraint also limits the possibilities of integration because each site must be accessible to means of macroscopic dispensation.
• WO 02/03058 discloses a device in which liquid samples are continuously transported in a channel and fed to a patch clamp measurement site. This site is itself equipped with suction ducts and pumps to position the volumes of fluid to be analyzed. All of these devices use channels and capillaries.
• fluid volumes are high, which is particularly disadvantageous when using very expensive products such as toxins or drugs or other active ingredients.
• connection difficulties problems of electrical insulation of the chambers, problems of sealing, and even of fragility in the case of capillaries.
• problems of clogging during aggregation or cell sedimentation There is therefore the problem of producing a more compact device, making it possible to work on smaller volumes of fluid, in particular of the order of a picoliter.
• transport type functions fluid volumes to be analyzed with the means for analyzing these fluids.
• the invention firstly relates to a method for analyzing a drop of a liquid medium comprising:
• the electrical activity measurement site is free of hydrophobic layer, and has a hydrophilic layer, as well as first and second means of measuring electrical activity, the first means of measuring electrical activity being arranged on the hydrophilic layer.
• the drop may be confined, at least during its displacement, between said hydrophobic surface and an upper substrate. Before deformation, the drop can be, or not, confined by the upper substrate.
• the displacement is obtained by activating a plurality of electrodes, located under the hydrophobic layer.
• the drops of liquid to be analyzed can be formed from one or more tanks.
• the invention also relates to a device for analyzing a drop of a liquid medium comprising:
• a first substrate comprising a hydrophobic layer
• a second substrate may be arranged opposite the hydrophobic layer, making it possible to form a closed configuration.
• This second substrate may further comprise a superficial hydrophobic layer, and optionally an electrode.
• the means for moving a drop, on the hydrophobic layer, by electrowetting advantageously comprise a plurality of electrodes under this hydrophobic layer.
• At least one site of analysis or measurement of electrical activity is free of hydrophobic layer, and has a hydrophilic layer, as well as means for measuring electrical activity.
• the first means of measurement of electrical activity are then arranged on the hydrophilic layer.
• a cover or a substrate may form with the device a chamber, in communication, through an orifice of the hydrophilic layer, with the surface of the hydrophobic layer.
• At least one of the sites for analyzing or measuring electrical activity may be surrounded by a portion of the hydrophobic layer.
• the drops may have a volume of between, for example, 1 ⁇ l and 10 ⁇ l.
• the measurement of electrical activity can be performed on a single cell contained in the drop. It can be a measurement on a cell channel.
• the drop may contain cells of different types or at least one type of cell and one type of toxin.
• At least one substance for example an active agent such as a drug, lyophilized is disposed in the path of the drop towards a measurement site.
• a mixture of the substance with the liquid of the drop can thus take place when the drop comes into contact with said substance. This mixture can then be taken to the measurement site.
• At least one reservoir may be provided for storing a liquid to be analyzed or whose electrical activity is to be measured. Means make it possible to form a drop of liquid from such a reservoir.
• at least one reservoir common to this plurality of analysis or measurement sites may be provided, to form drops that can be brought to different analysis sites. of this plurality of analysis sites.
• the invention also relates to a device comprising a matrix of electrophysiology measuring sites on a substrate provided with means for bringing to the measurement sites drops of liquid to be analyzed, for example drops of physiological buffer containing cells or drugs.
• the method of dispensing fluids implements a displacement of drops by dynamic electrowetting on a dielectric, as opposed to continuous flow displacements in discrete microfluidic channels.
• the invention relates to a method and a device for performing electrophysiological measurements, using a dynamic electrowetting of a very small quantity of reagents. Two to several tanks can be made.
• the pitch of these tanks may be that of a well plate. From these reservoirs, series of drops can be generated and routed, in a controlled way, to bring the cell suspensions to the measurement wells, in a first step and, secondly, the drugs whose impact is to be measured. on the behavior of ion channels.
• FIGS. 1A-1C represent the principle of displacement of drops, by electrowetting
• FIG. 2 represents a closed configuration of a device for moving drops
• FIGS. 3A and 3B show a mixed configuration of a device for moving drops
• FIGS. 4 and 5A-5B show a device for displacing drops, in which the upper cover is provided with an electrode,
• FIG. 6 represents a view from above of a device according to the invention, with several measurement sites,
• FIG. 7 represents a detailed view of a measuring site of a device according to the invention.
• FIGS. 8A-8D represent a well or a reservoir of liquid
• FIGS. 9A-9C represent steps of a process with freeze-dried drug.
• a device implements a device for moving or handling drops of liquid, by electrowetting, and means for measuring the electrical activity of the liquid, contained in these drops or cells contained in these drops.
• These means comprise a site, or a well, in which a measurement of this activity, using means of the electrodes type, will be achieved.
• a device according to the invention is shown schematically in plan view in FIG. 6. Measuring sites 24, 26, 28 are shown therein, arranged on or integrated in a plate 250 for handling and transporting drops by electro-jigging.
• the resulting device is compact, allowing the formation and delivery of small volumes of liquid to measurement sites therefore do not require means such as fluid suction ducts.
• FIGS. 1A-1C A first embodiment of a device for moving and handling drops implemented in the context of the invention, of the open system type, is illustrated in FIGS. 1A-1C.
• This embodiment implements a device for moving or handling drops of liquid based on the principle of 1 electrowetting on a dielectric. Examples of such devices are described in the article by MG Pollack, AD Shendorov, RB Fair, entitled “Electro-wetting-based actuation of droplets for integrated microfluidics", Lab Chip 2 (1) (2002) 96-101.
• Document FR-2 841 063 describes a device implementing, in addition, a catenary facing electrodes activated for displacement. The principle of this type of displacement is synthesized in FIGS. 1A-1C.
• a drop 2 rests on a network 4 of electrodes, from which it is isolated by a dielectric layer 6 and a hydrophobic layer 8 ( Figure IA). There is therefore a hydrophobic and insulating stack.
• hydrophobic nature of this layer means that the drop has a contact angle, on this layer, greater than 90 °.
• the electrodes 4 are themselves formed on the surface of a substrate 1.
• the counter-electrode 10 allows a possible displacement by electrowetting on the surface of the hydrophobic surface; it maintains an electrical contact with the drop during such a displacement.
• This counter-electrode can be either a catenary as in FR-2 841 063, or a buried wire or a planar electrode in the hood of a confined system (such a confined system is described below).
• a confined system such a confined system is described below.
• the electrodes 4-1, 4-2 serving only to spread or deform the drop where it has been deposited. .
• the drop may thus be optionally displaced step by step (FIG. 1C) on the hydrophobic surface 8 by successive activation of the electrodes 4-1, 4-2, etc., along the catenary 10.
• FIG. 2 represents another embodiment of a device for moving or handling drops that can be used in the context of the invention, of the closed or confined system type.
• reference numerals identical to those of Figures IA-IC y designate the same elements.
• This device further comprises an upper substrate 100, preferably also covered with a hydrophobic layer 108.
• This set may be optionally transparent, allowing observation from above.
• FIGS. 3A and 3B in which numerical references identical to those of FIG. 2 denote identical or similar elements, represent a mixed system for moving or handling drops, in which a drop 2 is initially in an open medium (FIG. 3A), the activation of electrodes 4-1, 4-2, 4-3 allowing a flattening of the drop (FIG. 3B), in a closed system, in an area where the system is provided with a hood, as illustrated above in connection with Figure 2.
• FIG. 4 represents a variant of the closed system, with a conductive cover 100, comprising an electrode or an array of electrodes 112, as well as a possible insulating layer 106 (the latter being optional) and a hydrophobic layer 108.
• the catenary 10 of the preceding figures is replaced, in this embodiment, by the electrode 112.
• the activation of this electrode 112 and the electrodes 4 makes it possible to move the droplet into the desired position and then to stretch or deform it .
• FIGS. 5A and 5B in which identical reference numerals to those of FIG. 4 designate identical or similar elements, represent a mixed system, in which a drop 2 is initially in open medium (FIG. 5A), the activation of electrodes 4-1, 4-2, 4-3 allowing flattening of the droplet (FIG. 5B), in a system closed, in an area where the system is provided with a hood, as illustrated above in connection with Figure 4.
• a device according to the invention may further comprise means which will make it possible to control or activate the electrodes 4, for example a PC-type computer and a relay system connected to the device or the chip, such as the relays 14 of the FIG. 1A, these relays being controlled by the PC type means.
• a PC-type computer for example a PC-type computer and a relay system connected to the device or the chip, such as the relays 14 of the FIG. 1A, these relays being controlled by the PC type means.
• the distance between a possible conductor 10 (FIGS. 1A-5B) on the one hand and the hydrophobic surface 8 on the other hand is, for example, between 1 ⁇ m and 10 ⁇ m or between 1 ⁇ m and 50 ⁇ m.
• This conductor 10 may be for example in the form of a wire diameter between 10 microns and a few hundred microns, for example 200 microns.
• This wire may be a gold or aluminum wire or tungsten or other conductive materials.
• two substrates 1, 100 are used (FIGS. 2-5B), they are separated by a distance between, for example, 10 ⁇ m and 100 ⁇ m or 500 ⁇ m.
• a drop of liquid 2 may have a volume between, for example, 1 picolitre and a few microliters, for example between 1 and 100 ⁇ l or 1 ⁇ l or 5 ⁇ l or 10 ⁇ l.
• each of the electrodes 4 will for example have a surface of the order of a few tens of ⁇ m 2 (for example 10 ⁇ m 2 ) up to 1 mm 2 , depending on the size of the drops to be transported, the spacing between adjacent electrodes being for example between 1 .mu.m and 10 .mu.m.
• the structuring of the electrodes 4 can be obtained by conventional methods of micro ⁇ technologies, for example by photolithography. Methods for producing chips incorporating a device according to the invention may be directly derived from the processes described in document FR-2 841 063.
• Conductors, and in particular conductors 110 may be made by depositing a conductive layer and etching of this layer in the appropriate pattern of conductors, before deposition of the hydrophobic layer 108.
• the electrodes may be made by deposition of a metal layer (for example a metal selected from Au, Al, ITO, Pt, Cr, Cu) by photolithography.
• a metal layer for example a metal selected from Au, Al, ITO, Pt, Cr, Cu
• the substrate is then covered with a dielectric layer, for example Si 3 N 4 or SiO 2 .
• a deposit of a hydrophobic layer is performed, such as a teflon deposit made by spinning.
• Such a device for moving drops can implement a two-dimensional array of electrodes that will allow, step by step, to move liquids in or on a plane, to mix them, to achieve complex protocols.
• a two-dimensional set (2D) of these catenaries can be realized above the 2D set of electrodes 4.
• this counter electrode can also have a two-dimensional structure.
• FIG. 6 represents a device according to the invention, with sites or measuring chambers.
• This device comprises firstly a two-dimensional device for moving and handling drops, for example of the type as explained above, and of which only the electrodes of the lower substrate are shown schematically and designated, again, by the reference 4 .
• References 22 and 21 denote several reservoirs, for example a cell reservoir 22 and one or more reservoir of drugs or active agents 21.
• active agent is used to designate a toxin or a drug.
• a single tank may in some cases be sufficient. It is also possible not to use a reservoir and to bring the volumes of liquid to be analyzed by other means, for example a pipette.
• the system may further comprise a single measurement site 26 or a plurality of sites 24, 26,
• the reservoirs 21, 22 are advantageously compatible with a format of well plates (8, 96, 384, 1586 wells). They are advantageously integrated into the device. An embodiment of these reservoirs will be given later in connection with FIGS. 8A-8D.
• Figure 7 shows a portion of the device of Figure 6, in the vicinity of a measuring well 26, in section along an axis AA '.
• the lower substrate is provided with its activation electrodes 4, while the upper substrate 100 is shown in a simplified manner, without its counter-electrode.
• the drop displacement structure described above is based on a substrate or a hydrophilic layer having a thickness of between 0.1 ⁇ m and 20 ⁇ m, for example a dielectric such as SiO 2 or Si 3 N 4.
• the electrodes for the movement by electrowetting may be performed on this layer 30.
• This substrate or this layer comprises an opening 31 with a diameter of a few ⁇ m, for example between 1 ⁇ m and 2 ⁇ m or 5 ⁇ m.
• This opening is for example made by lithography and selective etching.
• This substrate or this layer 30 rests on a substrate 32 of thickness for example between 100 ⁇ m and 1 mm, for example silicon or glass or in a polymer, which itself comprises an opening 33 wider than the opening 31.
• a substrate or a lower cover 34 for example polycarbonate or epoxy or a printed circuit defines with the substrate 32 a chamber 40 which may contain a liquid 42, in particular a conductive solution such as PBS ("phosphate buffered saline").
• a liquid 42 in particular a conductive solution such as PBS ("phosphate buffered saline").
• This liquid 42 may have been previously brought drop by electrowetting, as the drops 2 are thereafter in a measurement.
• a measuring electrode 261 on the rear face may be placed against the substrate 32 or against the substrate 30, so as to be in contact with a liquid 42 present in the cavity 40.
• This electrode will make it possible to apply, with the electrode 260 , a potential difference in the liquid medium 42 present in the cavity.
• Conductors not shown in the figure, used to apply the desired voltage between the two electrodes 260, 261. This voltage is for example driven or controlled by the means that can control or activate the electrodes 4, for example a PC-type computer with appropriate interfaces. These conductors will also make it possible to measure the voltage variation between the electrodes 260, 261 when a drop 2 of liquid is brought by electrowetting to the measurement site and is mixed with the liquid 42. This variation may be stored in storage means a device that will then allow process and analyze the data thus collected during the measurements.
• Patch clamp it is rather cells that are brought into a drop in a measurement site, the electrodes 260, 261 for measuring on an individual cell.
• calibrated drops 2 are made by dynamic electrowetting, in configuration
• the drops 2 move in a non-conductive medium 16, for example oil or air.
• the chambers or measurement sites 24, 26, 28 are first filled with physiological conductive solutions containing cells brought for example from the reservoir
• nano-drops of drugs are created, for example from the tanks 21, which is conveyed by electrowetting to the sites 240, 260, 280 measurement.
• the drops moved or brought may be composed of a conductive solution (buffer solution for the cells) or not.
• the drugs, or the active agents can be diluted in solutions of low conductivity (order of magnitude of a few mS / m, for example 1 mS / m) but the liquid of gout at the measuring site is a conductivity of magnitude 1 Siemens / m or between 0.5 Siemens / m and 2 Siemens / m.
• the electrodes 4 used for electrowetting, as well as the electrodes 260 used for the electrophysiology measurement, are on a dielectric membrane 1, the coating 6, 8 of which is hydrophobic and passive in the zones of displacement of the drops.
• the coating in fact: the layer 30 is hydrophilic and non-passive, the measurement electrode 260 being in contact with the liquid of the conductive solution 42. 2, brought to the measurement site 26, will modify the properties of the liquid located on this site.
• one or more measurement chambers are made or integrated in a device for transporting drops by electrowetting.
• the electrowetting allows to bring drops in these rooms.
• Pumping means provide a vacuum between the upper chamber and the lower chamber to capture a cell on the port 31.
• the cells are electro-washed in a droplet in one of the measurement chambers. While the cells sediment, the pressures between the chamber 40 and the part of the device located on the side of the electrodes 260 are modified; a Depression is thus created between the lower and upper chambers.
• the cells are then drawn to the (single) hole 31 of the dielectric membrane 30. Only one cell will finally be studied. Once the membrane of the cell on the hole 31, it deforms and then invaginates in the hole.
• the electrical resistance measured at the cell / dielectric contact 30 can then be of the order of Giga-Ohm. This resistance makes it possible to visualize, for example on a "patch" amplifier, currents of the order of the pico-ampere. These currents result from the passage of ions through the channel proteins of the cell.
• FIGS. 8A-8D show how a reservoir such as tanks 21 or reservoir 22 can be made.
• a liquid 200 to be dispensed is deposited in a well 120 of this device (FIG. 8A).
• This well is for example made in the upper cover 100 of the device.
• the lower part, shown schematically in FIGS. 8A-8D, is for example similar to the structure of FIGS. 1A-1C. If you do not use a configuration with a top cover, the open configuration allows the possibility of pouring a liquid such as oil over the entire surface. One can then dispense a drop and then move it by electrowetting.
• Electrodes 4-1, 4-2, 4-3 similar to the electrodes 4 for moving liquid drops, are shown in Figures 8A-8D.
• Activation of this series of electrodes 4-1, 4-2, 4-3 results in the spreading of a drop from well 120, and thus to a liquid segment 201 as shown in FIG. 8C.
• this liquid segment is cut off by deactivating one of the activated electrodes (electrode 4-2 in FIG. 8C). A drop 2 is thus obtained, as illustrated in FIG. 8D.
• a series of electrodes 4-1, 4-2, 4-3 are thus used to stretch liquid from the reservoir 120 into a finger 201 (FIGS. 8B and 8C) and then to cut this finger 201 of liquid (FIG. 8D) and form a drop 2 that can be taken to any measurement site as described above.
• This method can be applied by inserting electrodes such as the electrodes 4-1 between the reservoir 120 and one or more electrode 4-2 called the breaking electrode.
• the invention offers multiple advantages. It first allows for a single dispensing, from a reservoir, of drugs and cells, or any active agent, instead of a well-by-well dispensing as in the known planar patch clamp devices. It also allows the use of extremely small volumes of reagents, of the picoliter order (for example between 0.5 ⁇ l and 1 ⁇ l or 2 ⁇ l or 5 ⁇ l), with no dead volume, and control of the concentrations. In addition there is no evaporation which could influence the viability of the cells.
• the measurement zones are electrically isolated in the upper chamber and the lower chamber. There is electrical independence of the wells, which makes the test conditions (drugs, buffer and cells) strictly independent.
• buffer 42 and / or electrodes to study other channels than BK on wild or diseased cells.
• BKs are potassium channels, which can be over-expressed in genetically modified cells.
• the optimal conductive solution 42 results from taking into account the type of channels and the set of electrodes 260, 261 used.
• the toxins of interest will have an inhibitory or activating effect on the channel proteins. This effect can be reversible; for example, by decreasing the concentration of toxin in the conductive solution will progressively regain a channel activity (the number of inhibited channels will decrease).
• Another example of application consists of the possibility of loading on the chip lyophilized toxins stored in oil.
• a drop of buffer solution 2 will be brought on the lyophilized toxin to put it in solution.
• the drop of toxin thus created will be fused to another drop 2 containing the cells. So far the toxins were "brought" to the measuring chamber in drops from a fluid reservoir.
• Figures 9A-9C show steps of a process with freeze-dried drug.
• a lyophilized drug 39 is disposed in the path of a drop 2 towards a measurement site (FIG. 9A).
• a single lyophilized drug 39 is shown, but there may be several freeze-dried lozenges, of different natures.
• the drop will be oriented, for example by its path by electrowetting, to the selected pellet.
• the invention makes it possible to carry out a "patch-clamp" type measurement on a volume of the order of a picoliter (for example between 0.5 ⁇ l and 5 ⁇ l, for example 1 ⁇ l or 2 ⁇ l. pi), which is, by orders of magnitude, less than the volume required in known devices.
• a picoliter for example between 0.5 ⁇ l and 5 ⁇ l, for example 1 ⁇ l or 2 ⁇ l. pi
• Electrophysiological measurements according to the invention can be performed on cells such as oocytes, but also on biological particles in suspension or on lipid vesicles (such as liposomes) or on globules or bacteria or viruses or cell nuclei , or a mixture of these.
• the transportable active agents include strands of DNA / RNA or nucleotides or enzymes or proteins or parasites or bacteria or viruses or pollens or polymers or insoluble solid particles such as dielectric particles or conductive or magnetic or pigments or dyes or powders or polymer structures or insoluble pharmaceutical substances.

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