EP1351766B1 - Vorrichtung und verfahren zum dosieren kleiner flüssigkeitsmengen - Google Patents
Vorrichtung und verfahren zum dosieren kleiner flüssigkeitsmengen Download PDFInfo
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- EP1351766B1 EP1351766B1 EP02702254A EP02702254A EP1351766B1 EP 1351766 B1 EP1351766 B1 EP 1351766B1 EP 02702254 A EP02702254 A EP 02702254A EP 02702254 A EP02702254 A EP 02702254A EP 1351766 B1 EP1351766 B1 EP 1351766B1
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- EP
- European Patent Office
- Prior art keywords
- nozzle
- liquid
- opening
- channel
- media reservoir
- 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.)
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- 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
- B01L3/02—Burettes; Pipettes
- B01L3/0241—Drop counters; Drop formers
- B01L3/0268—Drop counters; Drop formers using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
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- 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
- B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
-
- 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
- B01L2300/0829—Multi-well plates; Microtitration plates
-
- 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
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
- B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
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- 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
- B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
- B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
- Y10T436/2575—Volumetric liquid transfer
Definitions
- the present invention relates to devices and method for dosing small amounts of liquid, and in particular to such devices and methods which for simultaneous, precise dosing of small or smallest amounts of liquid from several parallel channels are suitable.
- the precise dosage of fluid quantities is among other things in pharmaceutical and biotechnology research, For example, genomics, the high-throughput screening, combinatorial chemistry and the like, from significant importance. Such a dosage is for example necessary to use so-called microtiter plates (in English well-plate) with reagents.
- microtiter plates in English well-plate
- reagents for example necessary to use so-called microtiter plates (in English well-plate) with reagents.
- microtiter plates in English well-plate
- Devices and methods are known, of which the most common Air cushion pipettes, piston displacement pipettes with Valve control, piezoelectric pipettes and needle pipettes are.
- the devices mentioned are single-channel designed. You can partly but also in the grid too be arranged parallel channels.
- the highest reached Degree of parallelization currently stands at 384 channels some commercially available dosing volume devices above 0.5 ⁇ l.
- Known microdosing devices are disclosed in DE-A-19706513 and DE-A-19802368. These known devices are based on a functional principle in which a Acceleration to a liquid to be dosed within a pressure chamber is applied by a displacer.
- the pressure chamber has a fluid connection to an outlet opening and to a fluid reservoir.
- Actuating the displacement in these known devices a movement of the liquid through both the outlet opening as well as back into the reservoir.
- From DE-A-19913076 is a microdosing device known, through which a plurality of microdroplets on a Substrate can be applied, where there is an entire dosing is applied with an acceleration.
- This acceleration of the entire dosing head is inertia a relative acceleration between contained Fluid and dosing reached such that droplets ejected from respective nozzle openings of the dosing become.
- WO 00/62932 discloses methods and devices for metered dispensing of the smallest quantities of liquid, where discharge amounts in a range of 0.1 nl to 100 ul are called.
- capillary used to the at least one gas line connected via an outlet point is.
- a gas shock in the Gas line introduced so that in the capillary located between the opening point and the outlet opening Amount of liquid dosed out of the outlet opening becomes.
- This document also mentions the possibility the creation of a pipetting array using a Plurality of metering devices as described above are. Also in the dosing devices described in this document there is a reflux in the reservoir or in worst case may be air bubbles in the reservoir line ascend and clog those.
- a plate which has a plurality has the same penetrating recesses.
- the recesses have to a surface of the plate towards a large opening and to the opposite surface towards a small nozzle opening.
- Another metering device is known from WO 99/36176, the one liquid reservoir and one with the Liquid reservoir fluidly connected channel has.
- opposite channel walls of the channel are Formed openings, so that by applying a pressure on one of the openings located between the openings Liquid can be dispensed.
- US-A-5943079 discloses an ink jet printhead known, in which in a printhead a nozzle, a reservoir area and a nozzle connecting the reservoir and the reservoir area Cavity are structured. Adjacent to the Cavity is provided a piezoelectric plate, wherein by applying a pressure signal, a vibrating part of the piezoelectric Plate can be vibrated, so that a pressure wave occurs in the cavity. If the Pressure wave reaches a nozzle opening of the nozzle is thereby causes an ink ejection.
- the reservoir area is further by a membrane-like structure of a damping chamber separated, which has a vent.
- the object of the present invention is to devices and method for dosing small amounts of liquid to create a simple structure of a Microdosing device and also a simultaneous, precise dosage of small amounts of liquid allow multiple parallel channels.
- the operating principle of the microdosing device according to the invention and the dosing method of the invention small amounts of liquid is based on two points, for a simultaneous application of reservoir and Nozzle or nozzle channel with a force, so that a substantially the same pressure on them, and on the other hand a sufficient separation of the reservoir and the nozzle from each other through the connecting channel.
- Such Separation is more effective the higher the fluidic Resistance of the connection channel in relation to the fluidic Resistance of the nozzle channel is. Due to the fluidic Separation according to the invention is the maximum in the nozzle contained volumes, wherein after the dosing this volume of dosing automatically stops.
- the reservoir, the nozzle and the connecting channel are according to the invention preferably formed in a dosing head, wherein such a dosing preferably a plurality of Reservoirs, nozzles and connecting channels may have.
- a driving force on the entire imprinted liquid contained in the dosing head i. either the reservoir as well as the nozzle will be with the force applied. Therefore, and because of the fact that the pressure gradient via the connecting line is negligible, takes place According to the invention, no backflow into the reservoir.
- Both the reservoirs and the jets are in a grid arranged in the format of a microtiter plate equivalent. Furthermore, the reservoirs and the nozzles be arranged in a different grid, so that by a dosing a format conversion between the format of the reservoirs and that of the recipient Container, usually a microtiter plate, takes place.
- the used in the microdosing device according to the invention Dosing head can in a conventional known manner manufactured using micromechanical methods be made of, for example, silicon or plastic, for example, using an injection molding technique.
- the drive means from a pneumatic or hydraulic Drive unit having a pressure chamber, the fast with a gas or a liquid as a buffer medium can be filled to the required force to apply the reservoirs and nozzles.
- the reservoirs and the discharge end of the nozzles opposite end thereof formed in a surface of the dosing are preferably the reservoirs and the the discharge end of the nozzles opposite end thereof formed in a surface of the dosing, so that the entire first side of the dosing head or dosing head substrate can be charged with the driving force, only those in the nozzle, i. the nozzle channel and the nozzle opening, contained liquid is discharged and the metering process stops automatically as soon as it contains Liquid was discharged.
- This principle allows it, on a spatial separation of the areas in which the nozzles or reservoirs are arranged to dispense, resulting in significantly higher integration densities can be considered as having devices that are driving Force only on the back nozzle areas, not however acts on the reservoirs.
- the present invention thus provides devices and Processes with which liquids highly parallel, for example can be dispensed into a microtiter plate. Consequently the microdosing device according to the invention has a simple structure and still allows exact dosage, even in the realization of a highly integrated Dosing in which, for example, using 1536 nozzles should be dosed in parallel. According to the invention can such an exact dosage without the use of active or passive valves, as according to the state of Technique to be used partially, as both reservoir as well as nozzles are subjected to the force and the connection channel between them accordingly is designed.
- the present invention thus constitutes an essential one Improvement of dosing technology in the nanoliter range, the one highly parallel and therefore much faster metering of reagents in microtiter plates.
- the present invention allows a high degree of parallelization and integration density, for example 96, 384, 1536 or more doses simultaneously at a Pitch of 9.0 mm, 4.5 mm, 2.25 mm or less performed can be.
- the present allows Invention also adapt to formats outside the standard for microtiter plates.
- the present invention an extremely high accuracy of the dosage, the error in the dosing volume at typical Dosage amounts from 50 nl to 100 nl less than 5 nl.
- the non-contact delivery in the free jet is also a Carryover of media excluded.
- the device reformatations are carried out in parallel, for example, from a 384 format to a 1536 format.
- the present invention allows storage of Media in the dosing head, so that the step of the transfer from the storage unit that currently is typically a 96-well microtiter plate, for Dosing machines, which are currently arranged in parallel Air cushion pipettes or the like is, saved can be.
- dosed Volume largely independent of the physical Properties of the fluids used.
- the present Invention also enables the construction of a microdosing device, in which the dosing easily exchanged is, so that the drive means, in the Usually more complicated than the dosing itself, for a Variety of different dosing heads are used can. This is particularly advantageous that the entire first surface of the dosing head with the force is applied, so that here also at different Arrangement of reservoirs and nozzles in different Dosing heads no adjustment is necessary.
- microtiter plates comprise, as stated above, a variety of reservoirs, such as 96, 384, 1536 or more, where the pitches of the reservoirs corresponding to 9 mm, 4.5 mm, 2.25 mm, etc.
- the volume of the Reservoirs approximately 100 ⁇ l, 20 ⁇ l, 4 ⁇ l, etc. In these reservoirs become chemical or biochemical reactions carried out and analyzed the reaction products.
- the possibility for precise filling of microtiter plates with given quantities of liquid is therefore an indispensable Prerequisite for carrying out quantitative analyzes when using the smallest amounts of liquid, the present Invention just this option advantageous offers.
- microtiter plate In addition to the precise filling of the microtiter plate is also a fast, preferably simultaneous metered addition of reagents in all reservoirs of interest, as in general a high number of reactions in a microtiter plate be carried out simultaneously. It is advantageous when the entire process of filling and analysis The results can be automated so that per day several hundred microtiter plates can be processed and carried out a few thousand to one hundred thousand reactions can be.
- the present Invention due to their property of massively parallel and high-precision dosing of smallest fluid quantities in a special way, especially for the delivery of a Variety of different liquids in the different Reservoir of a microtiter plate.
- FIG. 1 shows a detail of a dosing head 2, the part of an embodiment of an inventive Microdosing is.
- the microdosing device further comprises a drive device, which in the in Fig. 1 illustrated embodiment, a pressure chamber 12, a housing 13 for the pressure chamber 12 and a device 14 for pressurizing the pressure chamber having.
- the device 14 may be a conventional pump or a compressed air valve with a corresponding supply line be to the pressure chamber 12.
- a vent 16 for Venting the pressure chamber 12 is provided.
- the pressure generating device 14 and the vent 16 are connected to a control device 18 which controls the same, to eject droplets from the nozzle 6.
- the nozzle shown there 6 a nozzle channel 20 and a nozzle opening 22, wherein the nozzle channel 20 has a larger cross section than the Nozzle opening 22 has.
- the nozzle opening 22 opposite Opening of the nozzle channel can as an operating opening be designated.
- the nozzle opening 22 is dimensioned in such a way that the surface tension of the liquid the nozzle opening 22 a leakage of the same in the idle state prevented.
- the nozzle channel 20 is designed so that he completely filled with fluid due to the capillary force is.
- the media reservoir 4 is on a first one Side of the dosing head 2, i. in a first Surface of the same formed, whereas the liquid delivery through the nozzle opening 22 on the opposite second side of the dosing.
- the herein as a nozzle designated unit is through the nozzle channel 20 and the Düsenausdorf réelle 22 formed and provides a fluid Connection between the first surface 24 and the second opposite surface 26 of the dosing 2.
- the connecting channel 10 connects the media reservoir 4 and the nozzle 6 in the embodiment shown in Fig. 1 at an orifice portion 28 in the lower region of the nozzle channel 20th
- FIG. 2 shows a network model of the dosing head shown in FIG. 1, where P A denotes the pressure difference between the upper side 24 and lower side 26 of the dosing head 2, which is generated by the force applied by the drive device 12, 13, 14. 2, the resistance R 2 represents the flow resistance of the connecting channel 10.
- P A denotes the pressure difference between the upper side 24 and lower side 26 of the dosing head 2, which is generated by the force applied by the drive device 12, 13, 14. 2
- the resistance R 2 represents the flow resistance of the connecting channel 10.
- he nozzle channel (22) can be divided into three sections, each of which a flow resistance can be assigned.
- the flow resistance R 11 is assigned to the section of the nozzle channel between the first side 24 of the dosing head 2 and the point of the junction of the connecting channel 10.
- the flow resistance R 12 of the nozzle channel is assigned to the portion between the point of the junction of the connecting channel 10 in the nozzle channel 20 and the nozzle opening 22.
- the flow resistance of the connecting channel 10 and the nozzle i. of the nozzle channel 20 and the nozzle opening 22, designed such that upon application one located in the media reservoir and the nozzle Liquid 8 with such a force that a substantially identical pressure on those in the media reservoir and the In the nozzle located liquid is applied, a volume flow in the connection channel 10 small compared to a volume flow in the nozzle 6 is.
- an exact dosage can be achieved if the flow resistance R 2 of the connection channel is made significantly larger than the total resistance of the nozzle channel.
- the connecting channel 10 at a distance from the first side 24 opens into the nozzle channel 20 so that a resistance R 11 can be defined already fulfilling the condition R 2 >> R 11 leads to a sufficiently good result.
- the greater the difference in resistance the greater the bandwidth of the different liquids which can be metered with sufficient accuracy using a corresponding metering device.
- the metered volume depends on the ratio of the two resistors. If one selects R 2 / R 11 ⁇ 10, then the dosed volume corresponds to the liquid volume contained in the nozzle with a systematic deviation of maximally 10%. This deviation is due to the fact that due to the pressure drop across the flow resistance R 11 at the junction of the connecting channel in the nozzle, a lower pressure prevails than on the top, ie the first side of the dosing or in the reservoir. This results in a pressure difference across the connecting channel, the size of which depends on the ratio of the flow resistances R 2 and R 11 , wherein an additional volume flow in the connecting channel is induced in the direction of the nozzle opening by this pressure difference.
- This volume flow or flow also contributes to the metered volume.
- the exact height of this systematic deviation depends on the details of the specific design of the connecting channel and nozzle channel. The deviation can be minimized by skillful, geometric design of the channels, in particular at their confluence. However, the proportion of this induced flow in the total flow through the nozzle or the nozzle opening can be estimated independently of these geometric details with the value R 11 / R 2 upwards. Due to the additional flow through the connecting channel, the dosing volume thus increases to a maximum of the (1 + R 11 / R 2 ) times the volume of the nozzle channel.
- the ratio of the flow resistances does not depend on the fluid's fluid properties, the accuracy and serviceability of the metering device is not affected.
- the exact ratio of the flow resistances is therefore not essential as long as R 11 ⁇ R 2 .
- the ratio of the flow resistances causes a systematic error, which can be compensated in the preparation of the metering devices.
- it does not cause a statistical error that would affect the reproducibility of the metering device.
- R 11 / R 2 as small as possible or R 2 / R 11 as large as possible, for example R 2 / R 11 > 100. This leads to excellent fluidic decoupling of nozzle and reservoir during a dosing process and the metered volume corresponds to the nozzle volume with a maximum deviation of 1%.
- FIG. 3A shows a generalized network model showing a microdosing device according to the invention, wherein in FIG. 3A the resistance R K represents the fluidic resistance of the connection channel between nozzle and reservoir, while the flow resistance R D represents the flow resistance of the entire nozzle consisting of the Resistance of the nozzle channel and the resistance of the nozzle opening represents.
- P A denotes the static or dynamic pressure generated by the respective drive unit.
- the resistance R K is to be chosen large in comparison to the flow resistance R D.
- the ratio of flow resistances to be chosen on an individual basis depends on the liquid to be dosed, again finding that the greater the difference in resistance, the greater the range of liquids that can be dosed with the same dosing device ,
- the present invention ensures that there is no backflow through the communication passage.
- Such reflux is the case with known metering systems, as described, for example, in the abovementioned publications DE-A-19706513, DE-A-19802368 or WO 00/62932.
- a network model as it applies to the metering devices shown in the above references is shown in Figure 3B. It can be seen that there is a backflow into the reservoir in any case at a pressurization PA, wherein the ratio of metered liquid flows back to the liquid flowing back into the reservoir of the ratio of the flow resistance R D and R K.
- the dosing head 2 which is usually a plurality of Reservoirs and nozzles, wherein in Fig. 1 because of sectional representation only a reservoir 4 and a nozzle 6 are shown, is first with the or filled with the liquids to be dispensed. This happens, by using, for example, commercially available pipetting machines the fluids in the reservoir (s) 4 are filled.
- the nozzle and nozzle opening 22 is dimensioned such that leakage of the liquid from the nozzle both on page 24 and on page 26 through the Surface tension of the same at rest prevented is.
- the dosing is 2 with a Drive unit connected, as shown in Fig. 1 schematically by the elements designated by the reference numerals 12 and 14 is shown.
- a Drive unit connected, as shown in Fig. 1 schematically by the elements designated by the reference numerals 12 and 14 is shown.
- the pressure generator 14 for example by opening corresponding Pneumatic valves, then in the pressure chamber 12th produces an overpressure that is even on the entire first Side of the dosing acts, i. the media reservoir 4 and the nozzle 6 are from the first side with a in essentially the same pressure applied.
- the pressure chamber 12 prevailing overpressure is on the Liquid 8 in the dosing 2 exerted a force.
- the liquid begins to flow out through the nozzle opening 22.
- An afterglow of liquid from the reservoir 4 is hereby largely prevented, provided that the pressure difference between the two ends of the connecting channel 10 negligible or reproducible, which is the case when the Flow resistance of the connecting channel 10 and the nozzle channel designed according to the above explanations are.
- the amount is a fluid flowing from the reservoir reproducible, even if the ratio of flow resistance of connecting duct and nozzle not big enough is to substantially prevent such after-flow.
- the liquid in the connecting channel remains substantially at rest, while liquid is ejected from the nozzle channel 20 through the nozzle opening 22.
- the whole in the nozzle amount of liquid through the nozzle opening 22nd are discharged, without that in the connecting channel moving liquid moves.
- the metered Liquid quantity determined exactly by the geometry of the nozzle. The dosage of the liquid stops from even if the nozzle is completely empty.
- a fluid volume equal to the total volume of the nozzle 6, are metered out of the nozzle opening 6.
- the initial state after switching off the drive device alternatively restored by two options become.
- a venting of the pressure chamber take place, for example, by that shown in Fig. 1 Valve 16.
- the pressure generating device using so-called 3/2-way pneumatic valves be designed to actively aerate to allow the pressure chamber by switching the valves.
- the drive unit is pure switching valves, i. 2/2-way pneumatic valves, may be after switching off the pressure supply the overpressure caused by a gas flow through the Remove the nozzles.
- the nozzle opening In the microdosing device according to the invention, it is to a clean break of the exiting liquid column the nozzle opening to achieve, advantageously, a sufficient to generate high pressure amplitude in the pressure chamber whose temporal change beyond beneficial within should be done in a very short time, so that a high dynamic the pressure change is achieved. Furthermore, it is in the design the dosing head and the drive unit favorable, when the liquid discharge within a short time, for example 10 milliseconds, completed while the fluid lines for the refills by capillary forces be designed so that this process very much slower, for example within 100 milliseconds. Thus, both effects are superimposed only insignificantly and the precision of the dosing volume is determined by the Capillary refilling not falsified.
- Fig. 4 is a schematic representation of an inventive Microdosing shown to the simultaneous application of microdroplets to appropriate Places 30 of a microtiter plate 32, which is a conventional Grid of reservoirs 30 may have, suitable is.
- the dosing head 2 the microdosing in the top 24 thereof a plurality of media reservoirs 4.
- the in Fig. 4 shown microdosing a drive device 40 for example, have a structure can, as explained below with reference to FIG. 5 becomes.
- Fig. 4 can simultaneously a plurality of microdroplets, for example be applied to a microtiter plate 32 by at the same time a plurality by means of the drive means 40 actuated by fluid reservoirs 4 with associated nozzles become.
- the dosing 2 preferably easily and automatically exchangeable, so that together with the same drive means 40 different dosing heads or dosing head substrates can be used as long as the outside dimensions the same match or the drive device is designed to be different with dosing head substrates Exterior dimensions cooperate.
- Fig. 5 is a cross-sectional view of an inventive Microdosing device with a plurality of media reservoirs 4, nozzles 6 and connecting channels 10, which in one Dosierkopfsubstrat 2 are formed shown.
- the drive device in turn includes a pressure chamber 12 with a corresponding housing 13.
- the housing can in suitable Be configured to attach to the To enable dosing head substrate 2, or the use allow a replaceable dosing 2.
- a diffuser 40 is provided for securing a uniform distribution of pressure over all reservoirs 4 and nozzles 6 are used.
- the one shown here pneumatic realization of the drive unit further comprises fast switching valves 42 and compressed air supply lines 44.
- Valves 42 are produced with high dynamics overpressure, through which a driving force on the fluids in is transferred to the dosing head, i. at the same time on the located in the media reservoirs 4 and the nozzles 6 Liquids.
- FIG. 6 is a plan view of a section of a dosing head, for parallel delivery of reagents in a 1536 microtiter plate can be used, shown wherein 24 media reservoirs 4, connection channels 10 and associated nozzles 6 are shown.
- the connection channels 10a has a shape as referred to below is explained on Fig. 9A.
- each one nozzle must be assigned a media reservoir, but here essentially freedom of choice exists that one or more media reservoirs provided can be connected to one or more nozzles can be, with a respective media reservoir over several Connecting lines to be connected to a nozzle can, a media reservoir over several connecting lines can be connected to multiple nozzles, and a nozzle over several connecting lines with several media reservoirs may be connected, as later with reference to FIGS. 10A to 10D will be explained in more detail.
- both the reservoirs as well as the nozzles arranged in a different grid be, so that by the dosing a format conversion between the format of the reservoirs and that of the receiving container takes place.
- This can be a conventional Pipetting device for filling a microtiter plate be used even if the pipetting device a different grid than the microtiter plate to be filled having.
- FIGS. 8A to 8D exemplary embodiments of nozzles formed in the dosing head of a microdosing device according to the invention will now be explained.
- the simplest embodiment of a nozzle 6a is shown in Fig. 8A, where the entire nozzle consists of a single channel of constant diameter.
- the resistors R 11 and R 12 which have been explained above with reference to FIG. 2, can be influenced within certain limits ,
- the nozzle 6 shown in Fig. 8B corresponds to the above with reference 1 illustrated nozzle, wherein by the subdivision the nozzle 6 in two sections different Diameter above or below the confluence point of the connection channel 10 due to the use of two Diameter and two lengths reached a variability which is a separate sizing of volume, flow resistance and holding capacity of the nozzle easier.
- a nozzle 6b is shown, which is divided into three sections is divided. Such a subdivision may under circumstances be advantageous if not only the dosing volume, but also the shape and / or dynamics of the ejected Beam are of importance.
- Fig. 8D shows a conical nozzle 6c.
- the diameter of the nozzle channel may be different than vary as a function of depth in FIGS. 8B to 8D.
- FIG. 9A shows a channel 10a which is at the top of the Dosing head is open.
- FIGS. 6 and 7 show embodiments of a dosing head used.
- This possibility of channel design allows also the operation of the microdosing according to the described principle and has advantages in terms a simple production and the advantage that Gas inclusions easily escape in the connecting channel can.
- Fig. 9B shows a sectional view of a dosing head substrate in the plane of the substrate.
- a media reservoir 4 and a nozzle 6 to recognize the over a curved channel 10B are interconnected.
- any gradients possible, where in particular meandering courses are used can increase the flow resistance between Media reservoir and nozzle to realize.
- the connecting channel between the media reservoir and nozzle can furthermore have any cross sections and does not necessarily have be rectangular.
- the Expand or contract the cross-section in the course of the channel also including, for example, two or more connection channels arranged between the same reservoir and the same nozzle could be.
- Fig. 9C Such a configuration is shown in Fig. 9C, at the channel is formed by three subchannels 10c. About that In addition, the channel does not have to be parallel to the surface of the Dosing head run, but can within the dosing have any course, with an oblique extending channel 10d is shown in Fig. 9D. Regarding of the channel is only to be noted that the same no establishes a direct connection to the bottom of the dosing head, but only over the nozzle. In addition, must the flow resistance of the connecting channel be greater as the flow resistance of the nozzle.
- Figs. 10A to 10D are different possibilities for arranging the fluidic components of the media reservoir, Connecting channel and nozzle in the dosing of the invention Microdosing represented.
- First is determine that not all mounted in a dosing Elements, such as media reservoirs, that must have the same dimension. The same applies to the Connecting channels and nozzles.
- nozzles that contain different volumes on the same dosing head be housed.
- Fig. 10A shows schematically a Dosierkopfab mustard, at a media reservoir 4 via four connecting channels 10th is connected to four nozzles 6.
- Fig. 10B there are two Media reservoir 4 via a respective connecting channel 10th connected to a nozzle 6.
- Fig. 10C an arrangement possible, in which all nozzles 6 from a single reservoir 4a, as shown in Fig. 10C.
- each nozzle 6 is connected via a connection channel 10 connected to an associated media reservoir 4 is.
- a drive device used in the invention can be represented.
- a piston 48 is provided to force in the direction of arrow 50 on the System liquid 46 exercise.
- any one Other displacer be provided by the one such force on media reservoir and nozzle is exercisable that in them a substantially identical pressure condition is produced.
- About the system fluid 46 is the force exerted on the liquid to be dosed, whereupon the Dosing takes place.
- Fig. 11B is the microdosing device after the discharge of the desired amount of liquid represented, wherein this amount of liquid through the displaced volume is determined.
- the system liquid 46 does not penetrate into the nozzle opening 22 and is not affected by capillary forces in pulled the same.
- the metered volume from the volume of the nozzle either only the nozzle channel or the nozzle channel and the nozzle opening, determined and is essentially independent of the Fluid properties.
- the present invention allows the exact delivery of, for example, about 50 nl in one single dosing with a suitable design of the channels and openings.
- the several Reservoirs of the dosing head used in the invention filled with identical or different liquids can be so that the simultaneous delivery of the same or different liquids is possible.
- the dosing heads used according to the invention produced by any conventional method can be.
- the dosing head micromechanical be made of silicon.
- the dosing head micromechanical be made of silicon.
- other known methods such as micro injection molding, hot stamping or those methods where individual layers are glued or laminated, in question.
- the metering device according to the invention can be used either as a metering device for the delivery of a through the geometric Volume of the nozzle channel predefined amount of liquid operated, or as a device with a smaller, but variable volume.
- the driving force which acts on the liquid, so long maintained until the entire contained in the nozzle Amount of liquid is ejected through the nozzle opening.
- the dosage stops in this case by itself, because due the vanishing pressure gradient across the connection channel no liquid is supplied.
- driving Force off before the liquid from the nozzle completely ejected.
- the metered amount of fluid can therefore either by the design, namely by the volume in the nozzle, or by the duration and the course of the drive unit be applied applied driving force.
- the metered amount of liquid in essential regardless of the physical properties the liquid, e.g. Viscosity and surface tension.
- the metered volume of affected by these parameters It is therefore recommended in the last case to perform a calibration to to achieve an exact dosage, since the dosage of different liquids with different viscosities takes different lengths.
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- Feeding, Discharge, Calcimining, Fusing, And Gas-Generation Devices (AREA)
- General Preparation And Processing Of Foods (AREA)
- Automatic Analysis And Handling Materials Therefor (AREA)
- Infusion, Injection, And Reservoir Apparatuses (AREA)
- Nozzles (AREA)
Description
- Fig. 1
- eine schematische Ansicht, teilweise im Querschnitt, einer erfindungsgemäßen Mikrodosiervorrichtung;
- Fig. 2
- ein Netzwerkmodell der in Fig. 1 gezeigten Mikrodosiervorrichtung;
- Fig. 3A
- ein verallgemeinertes Netzwerkmodell für das erfindungsgemäße Dosiersystem und Fig. 3B ein Netzwerkmodell für ein bekanntes Mikrodosiersystem;
- Fig. 4
- eine schematische Darstellung eines Ausführungsbeispiels einer erfindungsgemäßen Mikrodosiervorrichtung;
- Fig. 5
- eine Querschnittansicht eines weiteren Ausführungsbeispiels einer erfindungsgemäßen Mikrodosiervorrichtung;
- Fig. 6
- und 7 Draufsichten von Dosierköpfen, die bei einer erfindungsgemäßen Mikrodosiervorrichtung verwendbar sind;
- Fig. 8A bis 8D
- Querschnittansichten, die unterschiedliche Gestaltungen für Düsen bei der erfindungsgemäßen Mikrodosiervorrichtung zeigen;
- Fig. 9A bis 9D
- schematische Darstellungen, die unterschiedliche Gestaltungen des Verbindungskanals bei erfindungsgemäßen Mikrodosiervorrichtungen zeigen;
- Fig. 10A bis 10D
- schematische Draufsichten auf bei erfindungsgemäßen Mikrodosiervorrichtungen verwendbare Dosierkopfsubstrate bzw. Abschnitte derselben; und
- Fig. 11A und 11B
- schematische Querschnittansichten zur Veranschaulichung einer erfindungsgemäß verwendbaren Antriebseinrichtung.
Claims (15)
- Mikrodosiervorrichtung mit folgenden Merkmalen:einem Medienreservoir (4) zum Enthalten einer zu dosierenden Flüssigkeit (8), das eine Medienreservoiröffnung aufweist;einer Düse (6) mit einem Düsenkanal (20), der eine Ausstoßöffnung (22) und eine Betätigungsöffnung aufweist, wobei die Düse (6) über einen Verbindungskanal (10) mit dem Medienreservoir (4) verbunden ist und über den Verbindungskanal (10) mit der zu dosierenden Flüssigkeit (8) befüllbar ist; undeiner Antriebseinrichtung zum gleichzeitigen Beaufschlagen einer in dem Medienreservoir (4) und der Düse (6) befindlichen Flüssigkeit (8) mit einer solchen Kraft über die Medienreservoiröffnung und die Betätigungsöffnung bei einer Betätigung derselben, daß ein im wesentlichen identischer Druck auf die im Medienreservoir (4) und in der Düse (6) befindliche Flüssigkeit ausgeübt wird,
- Mikrodosiervorrichtung nach Anspruch 1, die einen Dosierkopf (2) aufweist, in dem das Medienreservoir (4) und die Düse (6) gebildet sind, wobei die Betätigungsöffnung und die Medienreservoiröffnung in der gleichen Oberfläche (24) des Dosierkopfs (2) gebildet sind.
- Mikrodosiervorrichtung nach Anspruch 2, bei der die Antriebseinrichtung eine Druckerzeugungseinrichtung (12, 13, 14) zum gleichzeitigen Ausüben eines im wesentlichen gleichmäßigen Drucks auf die Medienreservoiröffnung und die Betätigungsöffnung aufweist.
- Mikrodosiervorrichtung nach Anspruch 3, bei der die Antriebseinrichtung eine mit einem Puffermedium befüllbare Druckkammer (12) aufweist, wobei über das Puffermedium der Druck auf die Medienreservoiröffnung und die Betätigungsöffnung ausübbar ist.
- Mikrodosiervorrichtung nach einem der Ansprüche 1 bis 4, die mehrere Düsen und ein oder mehrere Medienreservoire aufweist, wobei die Antriebseinrichtung zum Betätigen der mehreren Düsen ausgelegt ist, wobei die mehreren Düsen mit einem oder mehreren Medienreservoiren über jeweils einen oder mehrere Verbindungskanäle fluidmäßig verbunden ist.
- Mikrodosiervorrichtung nach einem der Ansprüche 1 bis 5, die mehrere Medienreservoire (4) und eine oder mehrere Düsen (6) aufweist, wobei jedes Medienreservoir über jeweils einen oder mehrere Verbindungskanäle mit einer oder mehreren Düsenöffnungen fluidmäßig verbunden ist.
- Mikrodosiervorrichtung nach Anspruch 5 oder 6, bei der die mehreren Düsen (6) und/oder die mehreren Reservoire (4) in einem Raster angeordnet sind, das dem Format einer Mikrotiterplatte (32) entspricht.
- Mikrodosiervorrichtung nach Anspruch 7, bei der mehrere Medienreservoire (4) in einem ersten Raster angeordnet ist, und bei der mehrere Düsen (6) in einem zweiten Raster angeordnet ist, so daß zwischen Medienreservoiren und Düsen eine Formatumwandlung stattfindet.
- Mikrodosiervorrichtung nach einem der Ansprüche 1 bis 8, bei der die Düse (6) und der Verbindungskanal (10) derart ausgelegt sind, daß ohne Betätigung der Antriebseinrichtung eine Befüllung der Düse (6) aufgrund von Kapillarkräften aus dem Medienreservoir (4) über den Verbindungskanal (10) stattfindet.
- Verfahren zum Dosieren kleiner Flüssigkeitsmengen, mit folgenden Schritten:Befüllen zumindest einer Düse (6), die einen Düsenkanal (20) mit einer Ausstoßöffnung (22) und einer Betätigungsöffnung aufweist, über einen Verbindungskanal (10), der die Düse mit einem Medienreservoir (4), das eine Medienreservoiröffnung aufweist, fluidmäßig verbindet, mit einer zu dosierenden Flüssigkeit (8) aus dem Medienreservoir (4);gleichzeitiges Beaufschlagen der in dem Medienreservoir (4) und der Düse (6) befindlichen Flüssigkeit (8) über die Medienreservoiröffnung und die Betätigungsöffnung mit einer solchen Kraft, daß ein im wesentlichen identischer Druck auf die im Medienreservoir (4) und in der Düse (6) befindliche Flüssigkeit (8) ausgeübt wird,
- Verfahren nach Anspruch 10, bei dem der Schritt des Befüllens einen Schritt des Befüllens der Düse (6) aufgrund von Kapillarkräften in dem Verbindungskanal (10) und der Düse (6) aufweist.
- Verfahren nach Anspruch 10 oder 11, bei dem der Schritt des Beaufschlagens der in dem Medienreservoir (4) und der Düse (6) befindlichen Flüssigkeit mit einer Kraft den Schritt des gleichzeitigen Anlegens eines im wesentlichen gleichen Drucks an der Medienreservoiröffnung und der Betätigungsöffnung aufweist.
- Verfahren nach Anspruch 10 oder 11, bei dem der Schritt des Beaufschlagens der in dem Medienreservoir (4) und der Düse (6) befindlichen Flüssigkeit mit einer Kraft das Bewirken einer Volumenverdrängung an der Medienreservoiröffnung und der Betätigungsöffnung aufweist.
- Verfahren nach Anspruch 10 oder 11, bei dem der Schritt des Beaufschlagens der in dem Medienreservoir (4) und der Düse (6) befindlichen Flüssigkeit mit einer Kraft das Anlegen eines elektrischen oder magnetischen Feldes aufweist.
- Verfahren nach einem der Ansprüche 10 bis 14, bei dem der Schritt des Befüllens das Befüllen mehrerer Düsen (6) mit unterschiedlichen Flüssigkeiten aus mehreren Medienreservoiren (4) aufweist, und bei dem der Schritt des Beaufschlagens einen Schritt des Beaufschlagens der mehreren Düsen (6) und der mehreren Medienreservoire (4) gleichzeitig mit der Kraft aufweist, so daß gleichzeitig unterschiedliche Flüssigkeiten durch die Düsen (6) ausgestoßen werden.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10102152A DE10102152C1 (de) | 2001-01-18 | 2001-01-18 | Vorrichtung und Verfahren zum Dosieren kleiner Flüssigkeitsmengen |
DE10102152 | 2001-01-18 | ||
PCT/EP2002/000186 WO2002057015A2 (de) | 2001-01-18 | 2002-01-10 | Vorrichtung und verfahren zum dosieren kleiner flüssigkeitsmengen |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1351766A2 EP1351766A2 (de) | 2003-10-15 |
EP1351766B1 true EP1351766B1 (de) | 2005-09-07 |
Family
ID=7670982
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02702254A Expired - Lifetime EP1351766B1 (de) | 2001-01-18 | 2002-01-10 | Vorrichtung und verfahren zum dosieren kleiner flüssigkeitsmengen |
Country Status (6)
Country | Link |
---|---|
US (1) | US7396510B2 (de) |
EP (1) | EP1351766B1 (de) |
AT (1) | ATE303867T1 (de) |
AU (1) | AU2002235830A1 (de) |
DE (2) | DE10102152C1 (de) |
WO (1) | WO2002057015A2 (de) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10257004A1 (de) * | 2002-12-06 | 2004-06-17 | Steag Microparts Gmbh | Vorrichtung zur parallelen Dosierung von Flüssigkeiten |
US20050226771A1 (en) * | 2003-09-19 | 2005-10-13 | Lehto Dennis A | High speed microplate transfer |
US20050233472A1 (en) * | 2003-09-19 | 2005-10-20 | Kao H P | Spotting high density plate using a banded format |
DE102004006453B4 (de) * | 2004-02-05 | 2007-03-29 | Ing. Erich Pfeiffer Gmbh | Dosiervorrichtung |
DE102004006452B4 (de) | 2004-02-05 | 2006-04-20 | Ing. Erich Pfeiffer Gmbh | Mikrodosiervorrichtung |
WO2005079986A1 (en) | 2004-02-18 | 2005-09-01 | Applera Corporation | Multi-step bioassays on modular microfluidic application platforms |
DE102006047658B4 (de) | 2006-09-29 | 2009-03-19 | Ing. Erich Pfeiffer Gmbh | Mikrodosiervorrichtung für ein flüssiges Medium |
DE102007023014A1 (de) * | 2007-05-15 | 2008-11-27 | Kba-Metronic Ag | Verfahren und System zur Dosierung und zum Aufbringen einer Reagenzflüssigkeit |
CN109991035B (zh) * | 2017-12-29 | 2021-12-24 | 台达电子工业股份有限公司 | 微量取样装置 |
CN111617812B (zh) * | 2019-10-17 | 2021-12-03 | 北京京东方健康科技有限公司 | 微流控基板及其流体驱动方法、微流控装置 |
Family Cites Families (13)
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US4537231A (en) * | 1983-08-29 | 1985-08-27 | Becton, Dickinson And Company | Dispenser apparatus for simultaneously dispensing predetermined equal volumes of liquid including a disposable dispenser module |
JPH04232752A (ja) * | 1990-06-24 | 1992-08-21 | Lexmark Internatl Inc | インクジエツト・プリントヘツド及びインクジエツトのプリント方法 |
DE9011816U1 (de) * | 1990-08-14 | 1990-10-18 | Siemens Ag, 8000 Muenchen, De | |
US5593290A (en) * | 1994-12-22 | 1997-01-14 | Eastman Kodak Company | Micro dispensing positive displacement pump |
US5943079A (en) * | 1995-11-20 | 1999-08-24 | Brother Kogyo Kabushiki Kaisha | Ink jet head |
DE19648694C1 (de) * | 1996-11-25 | 1998-04-30 | Vermes Mikrotechnik Gmbh | Bidirektionale dynamische Mikropumpe |
DE19706513C2 (de) * | 1997-02-19 | 1999-06-17 | Hahn Schickard Ges | Mikrodosiervorrichtung und Verfahren zum Betreiben derselben |
US5957167A (en) * | 1997-12-18 | 1999-09-28 | Pharmacopeia, Inc. | Article for dispensing small volumes of liquid |
DE19802368C1 (de) * | 1998-01-22 | 1999-08-05 | Hahn Schickard Ges | Mikrodosiervorrichtung |
EP1069941A2 (de) * | 1998-04-09 | 2001-01-24 | INSTITUT FÜR DIAGNOSTIKFORSCHUNG GmbH AN DER FREIEN UNIVERSITÄT BERLIN | Verfahren und vorrichtung zur anfertigung von synthese- oder analysereihen |
DE19913076A1 (de) * | 1999-03-23 | 2000-10-19 | Hahn Schickard Ges | Vorrichtung und Verfahren zum Aufbringen von Mikrotröpfchen auf ein Substrat |
DE19917029C2 (de) * | 1999-04-15 | 2001-08-09 | Inst Mikrotechnik Mainz Gmbh | Verfahren und Vorrichtung zur dosierten Ausgabe von Flüssigkeitsmengen im Bereich von 0,1 nl bis 100 mul |
JP4399072B2 (ja) * | 1999-12-03 | 2010-01-13 | ノードソン株式会社 | 液状物の吐出装置 |
-
2001
- 2001-01-18 DE DE10102152A patent/DE10102152C1/de not_active Expired - Fee Related
-
2002
- 2002-01-10 US US10/250,607 patent/US7396510B2/en not_active Expired - Lifetime
- 2002-01-10 WO PCT/EP2002/000186 patent/WO2002057015A2/de not_active Application Discontinuation
- 2002-01-10 AU AU2002235830A patent/AU2002235830A1/en not_active Abandoned
- 2002-01-10 DE DE50204175T patent/DE50204175D1/de not_active Expired - Lifetime
- 2002-01-10 EP EP02702254A patent/EP1351766B1/de not_active Expired - Lifetime
- 2002-01-10 AT AT02702254T patent/ATE303867T1/de not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
US20040074557A1 (en) | 2004-04-22 |
WO2002057015A2 (de) | 2002-07-25 |
DE10102152C1 (de) | 2002-06-20 |
DE50204175D1 (de) | 2005-10-13 |
US7396510B2 (en) | 2008-07-08 |
AU2002235830A1 (en) | 2002-07-30 |
WO2002057015A3 (de) | 2002-12-05 |
EP1351766A2 (de) | 2003-10-15 |
ATE303867T1 (de) | 2005-09-15 |
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