EP1099483A1 - Distribution de gouttelettes de liquide - Google Patents

Distribution de gouttelettes de liquide Download PDF

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Publication number
EP1099483A1
EP1099483A1 EP00650123A EP00650123A EP1099483A1 EP 1099483 A1 EP1099483 A1 EP 1099483A1 EP 00650123 A EP00650123 A EP 00650123A EP 00650123 A EP00650123 A EP 00650123A EP 1099483 A1 EP1099483 A1 EP 1099483A1
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EP
European Patent Office
Prior art keywords
valve
droplet
boss
dispensing assembly
dispensing
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.)
Granted
Application number
EP00650123A
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German (de)
English (en)
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EP1099483B1 (fr
Inventor
Igor Shvets
Sergei Makarov
Juergen Osing
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Allegro Technologies Ltd
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Allegro Technologies Ltd
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Publication date
Priority claimed from EP19990650106 external-priority patent/EP1099484B1/fr
Application filed by Allegro Technologies Ltd filed Critical Allegro Technologies Ltd
Priority to EP20000650123 priority Critical patent/EP1099483B1/fr
Publication of EP1099483A1 publication Critical patent/EP1099483A1/fr
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05C—APPARATUS FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05C11/00—Component parts, details or accessories not specifically provided for in groups B05C1/00 - B05C9/00
    • B05C11/10—Storage, supply or control of liquid or other fluent material; Recovery of excess liquid or other fluent material
    • B05C11/1002—Means for controlling supply, i.e. flow or pressure, of liquid or other fluent material to the applying apparatus, e.g. valves
    • B05C11/1034—Means for controlling supply, i.e. flow or pressure, of liquid or other fluent material to the applying apparatus, e.g. valves specially designed for conducting intermittent application of small quantities, e.g. drops, of coating material
    • 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
    • B01L3/0265—Drop counters; Drop formers using valves to interrupt or meter fluid flow, e.g. using solenoids or metering valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B1/00—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means
    • B05B1/02—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to produce a jet, spray, or other discharge of particular shape or nature, e.g. in single drops, or having an outlet of particular shape
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B1/00—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means
    • B05B1/30—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to control volume of flow, e.g. with adjustable passages
    • B05B1/3013—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to control volume of flow, e.g. with adjustable passages the controlling element being a lift valve
    • B05B1/302—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to control volume of flow, e.g. with adjustable passages the controlling element being a lift valve with a ball-shaped valve member
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B1/00—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means
    • B05B1/30—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to control volume of flow, e.g. with adjustable passages
    • B05B1/3033—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to control volume of flow, e.g. with adjustable passages the control being effected by relative coaxial longitudinal movement of the controlling element and the spray head
    • B05B1/304—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to control volume of flow, e.g. with adjustable passages the control being effected by relative coaxial longitudinal movement of the controlling element and the spray head the controlling element being a lift valve
    • B05B1/3046—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to control volume of flow, e.g. with adjustable passages the control being effected by relative coaxial longitudinal movement of the controlling element and the spray head the controlling element being a lift valve the valve element, e.g. a needle, co-operating with a valve seat located downstream of the valve element and its actuating means, generally in the proximity of the outlet orifice
    • B05B1/3053—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to control volume of flow, e.g. with adjustable passages the control being effected by relative coaxial longitudinal movement of the controlling element and the spray head the controlling element being a lift valve the valve element, e.g. a needle, co-operating with a valve seat located downstream of the valve element and its actuating means, generally in the proximity of the outlet orifice the actuating means being a solenoid

Definitions

  • the present invention relates to a dispensing assembly for liquid droplets of the type comprising a dispenser, having a main bore communicating with the nozzle having a nozzle bore terminating in a dispensing tip and delivery means for moving liquid to the dispenser and from there through the bore to form a droplet on the exterior of the tip and then to cause a droplet to fall off therefrom.
  • the invention is further concerned with a method of dispensing a droplet from such a dispenser.
  • the present invention is generally related to liquid handling systems and in particular to systems for dispensing and aspirating small volumes of reagents. It is particularly directed to a high throughput screening, polymerase chain reaction (PCR), combinatorial chemistry, microarraying, medical diagnostics and other similar tasks.
  • PCR polymerase chain reaction
  • the typical application for such a fluid handling system is in dispensing small volumes of reagents, e.g. 1 ml and smaller and in particular volumes around 1 microliter and smaller. It is also directed to the aspiration of volumes from sample wells so that the reagents can be transported between the wells.
  • the invention relates also to microarray technology, a recent advance in the field of high throughput screening. Microarray technology is being used for applications such as DNA arrays: in this technology the arrays are created on glass or polymer slides.
  • the fluid handling system for this technology is directed to dispensing consistent droplets of reagents of submicrolitre volume.
  • the present invention is also directed to medical diagnostics e.g. for printing reagents on a substrate covered with bodily fluids for subsequent analysis or alternatively for printing bodily fluids on substrates.
  • a dispensing system for ink jet applications is to deliver droplets of a fixed volume with a high repetition rate.
  • the separation between individual nozzles should be as small as possible so that many nozzles can be accommodated on a single printing cartridge.
  • the task is simplified by the fact that the mechanical properties of the liquid dispensed namely ink are well defined and consistent. Also in most cases the device used in the ink jet applications does not need to aspire the liquid through the nozzle for the cartridge refill.
  • HTS High Throughput Screening
  • the system should be capable of handling a variety of reagents with different mechanical properties e.g. viscosity. Usually these systems should also be capable of aspiring the reagents through the nozzle from a well. On the other hand there is not such a demanding requirement for the high repetition rate of drops as in ink jet applications.
  • Another requirement in the HTS applications is that cross contamination, between different wells served by the same dispensing device, be avoided as much as possible.
  • the most common method of liquid handling for the HTS applications is based on a positive displacement pump such as described in US Patent Specification No. US 5,744,099 (Chase et al).
  • the pump consists of a syringe with a plunger driven by a motor , usually a stepper or servo-motor.
  • the syringe is usually connected to the nozzle of the liquid handling system by means of a flexible polymer tubing.
  • the nozzle is typically attached to an arm of a robotic system which carries it between different wells for aspiring and dispensing the liquids.
  • the syringe is filled with a system liquid such as water.
  • the system liquid continuously extends through the flexible tubing into the nozzle down towards the tip.
  • the liquid reagent which needs to be dispensed fills up into the nozzle from the tip. In order to avoid mixing of the system liquid and the reagent and therefore cross-contamination, an air bubble or bubble of another gas is usually left between them.
  • the plunger of the syringe is displaced. Suppose this displacement expels the volume ⁇ V of the system liquid water from the syringe.
  • the front end of the system liquid filling the nozzle is displaced along with it.
  • the system liquid is virtually incompressible. If the inner volume within the flexible tubing remains unchanged, then the volume ⁇ V displaced from the syringe equals the volume displaced by the moving front of the system liquid in the nozzle.
  • the volume of the air bubble is small it is possible to ignore the variations of the bubble's volume as the plunger of the syringe moves.
  • the back end of the reagent is displaced by the same volume ⁇ V in the nozzle, and therefore the volume ejected from the tip is the same ⁇ V.
  • the pump works sufficiently accurately if the volume ⁇ V is much greater than the volume of the air bubble.
  • the volume of the air bubble changes as the plunger of the syringe moves. Indeed in order to eject a drop from the tip, the pressure in the tubing should exceed the atmospheric pressure by an amount determined by the surface tension acting on the drop before it detaches from the nozzle. This is discussed in more detail below.
  • the pressure in the tubing increases and after the ejection, it decreases.
  • the volume of the air or gas bubble changes during the ejection of the droplet and this adds to the error of the accuracy of the system.
  • the accuracy is determined significantly by the ratio of the volumes of the air bubble and the liquid droplet. The smaller this ratio is the better the accuracy. For practical reasons it is difficult to reduce the volume of the air or gas bubble to below some one or two microlitres and usually it is considerably greater than this.
  • this method with two liquids separated by an air or gas bubble and based on a positive displacement pump is not well suited for dispensing a small volume of the order of 1 microlitre or lower.
  • accuracy there are also additional limitations on accuracy when sub-microlitre volumes need to be dispensed.
  • the flexible tubing filled with the system liquid bends and consequently its inner volume changes. Therefore, as the arm moves, the front end of the system liquid in the nozzle moves to some extent even if the plunger of the syringe does not. This adds to the error of the volume dispensed.
  • Other limitations are discussed in Graig et al referred to above. Examples of such positive displacement pumps are shown in US Patent Specification No. 5744099 (Chase et al). Similarly the problems of dispensing drops of small volume are also described and discussed in U.S. Patent Specification Nos. 4574850 (Davis) and 5035150 (Tomkins).
  • U.S. Patent Specification No. 5741554 (Tisone) describes another method of dispensing submicrolitre volumes of fluids for biomedical application and in particular for depositing bodily fluids and reagents on diagnostic test strips.
  • This method combines a positive displacement pump and a conventional solenoid valve.
  • the positive displacement pump is a syringe pump filled with a fluid to be dispensed.
  • the pump is connected to a tubing. At the other end of the tubing there is a solenoid valve located close to the ejection nozzle.
  • the tubing is also filled with the fluid to be dispensed.
  • the piston of the pump is driven by a motor with a well-defined constant speed.
  • the speed determines the flow rate of the fluid from the nozzle provided the solenoid valve is opened frequently enough and the duty cycle between opening and closing of the valve is long enough.
  • the solenoid valve is actuated with a defined repetition rate.
  • the repetition rate of the valve and the flow rate of the pump determine the size of each drop. For example, if the pump operates at a flow rate of 1 ⁇ l per second and the repetition rate is 100 open-close cycles per second, then the size of each drop is 10 nl. This method is suitable for dispensing of large number of identical droplets.
  • the solenoid valve As the solenoid valve is normally not used as a disposable element due to its high cost, the used portion or potentially contaminated chamber of the valve needs to be washed frequently to avoid cross contamination. This is a major issue for HTS applications and microarraying as the dispenser typically switches from one liquid to another up to several times a minute.
  • the fluid path in the valve is torturous, the valve contains a number of parts and pockets where the contamination can build up complicating the cleaning routine.
  • Patent Specification No. WO 98/52640 (Shalom) describes a flow control device for medical infusion systems. These systems are used for the slow injection of relatively large volumes, namely millilitres up to a litre, into a patient over a relatively long period of minutes, if not hours. Essentially, there is described a system for the slow injection of fluids into a patient with real time control of the process. The system uses valves to mix or select fluids coming from a number of inlets and to route their flow via selected outlets. Nothing in the description would lead one to believe that such a valve would be suitable for the dispensing of droplets of liquid with volumes of the order of 5 nl at a high frequency. In this patent specification, there is illustrated an actuation coil embedded in the body of the valve and the use of spherical magnetic bosses or a multiple of bosses, as described, is to increase the resistance of fluid flow through the valve.
  • US Patent No 5,758,666 (Carl O. Larson, Jr. et al) describes a surgically implantable reciprocating pump having a floating piston made of a permanent magnetic material and incorporating a check valve.
  • the piston can be moved by means of energising the coils in a suitable timing sequence.
  • the piston allows the flow of liquid through it when it moves in one direction as the check valve is open, and when it moves in the opposite direction, the check valve is closed and the liquid is pumped by the piston.
  • US Patent No 4,541,787 (Sanford D. DeLong) describes an electromagnetic reciprocating pump with a "magnetically responsive" piston so called as it contains some ferromagnetic material.
  • the piston is actuated by at least two coils located outside the cylinder containing the piston. The coils are energised by a current with a required timing.
  • Drops of microlitre volume and smaller can be also generated by the method of electrospray which is mainly used for injection of a fluid into a chemical analysis system such as a mass spectrometer.
  • the desired output of an electrospray system is not a stream of small drops but rather of ionised molecules.
  • the method is based on supplying a liquid under pressure through a capillary tube towards its end or tip and then a strong electrostatic field is generated at the tip by applying a high voltage, typically over 400V, between the tip of the capillary and a conductor placed close to it.
  • a charged volume of fluid at the tip of the capillary is repelled from the rest of the capillary by Coulomb interaction as they are charged with the like charge.
  • the electric field is applied in a similar way to keep the particles away from each other until the sheath of the particles has solidified.
  • the particles are formed from a jet by applying a periodic disturbance to the jet.
  • US Pat. No 4,956,128 (Martin Hommel et al) teaches how to dispense uniform droplets and convert these into microcapsules.
  • a syringe pump supplies the fluid into a capillary.
  • a series of high voltage pulses is applied to the capillary.
  • the size of the droplets is determined by the supply of fluid through the capillary and the repetition rate of the high voltage pulses. The specification does not discuss generation of a single drop on demand.
  • No 5,639,467 (Dorian et al) teaches a method of coating of substrates with a uniform layer of biological material.
  • a droplet generator is employed which consists of a pressurised container connected to a capillary.
  • a high constant voltage is applied between the capillary and a receiving gelling solution.
  • the most common method of handling reagents used in HTS applications is based on a positive displacement pump and a gas bubble.
  • the problem is that when dispensing volumes of reagents around 1 microlitre or smaller the variation in the volume of the bubble during the dispensation compromises the accuracy. It has been found difficult to eject small droplets of precisely required volume using this method.
  • a solenoid valve has two main disadvantages when used for HTS applications.
  • the first one is the relatively high cost of a solenoid valve such that it cannot be a disposable element and thus cross contamination can be a major problem. Further difficulties have been experienced in achieving dead volumes smaller than 1 to 2 microlitres in a conventional solenoid valve.
  • Piezo dispensers while used are often not well suited for dispensing reagents for medical applications. The reason is that the piezo dispenser commonly requires that fluid to be dispensed has well-defined and consistent properties.
  • reagents and bodily fluids used in medical and biomedical applications have broadly varying properties and often contain particles and inhomogenities which can block the nozzle of the piezo dispenser.
  • solenoid valves could be used, they would have enormous commercial and technical advantages. They would have considerable advantages over positive displacement pumps, piezo dispensers and various contact mode techniques.
  • US Patent No. 5,559,339 (Domanik) teaches a method for verifying a dispensing of a fluid from a dispenser nozzle.
  • the method is based on coupling of electromagnetic radiation which is usually light from a source to a receiver.
  • the mechanism of such an obstruction is absorption of electromagnetic radiation by the droplet.
  • the disadvantage of this method is that the smaller the size of the droplet, the smaller is the absorption in it. Almost certainly the method will not work for fluids which do not absorb the radiation.
  • the methods disclosed in this specification are inappropriate. Further the specification acknowledges that it will only operate satisfactorily with major droplets.
  • Another objective is to provide a method where the quantity of the fluid dispensed can be freely selected by the operator and accurately controlled by the dispensing system.
  • the system should be capable of dispensing a drop of one size followed by a drop of a widely differing size, for example, a 10 nl drop followed by a 500 nl one. This is in contrast to for example ink jet printing where the volume of one dispensation is fixed, and dispensations are only possible in multiples of this quantity.
  • the invention is also directed towards providing a method where the fluid can be dispensed on demand, i.e. one quantity can be dispensed at a required time as opposed to a series of dispensations with set periodic time intervals between them. Yet, the method should also allow for dispensation of doses with regular intervals between subsequent dispensations, for example, printing with reagents.
  • Another objective of the present invention is to provide a method and a device suitable for dispensing a fluid from a supply line to a sample well and also for aspiring a fluid from the sample well into the supply line.
  • the device should be able to control accurately the amount of the fluid aspired into the nozzle of the dispenser from a supply well.
  • Another objective is to provide a low cost front end of the dispensing device called herein the dispenser which could be disposed of when it becomes contaminated namely the part which comes in direct contact with the reagents dispensed. It is an important objective of the invention to provide a dispenser such that the disconnection and replacement is achieved simply such as by an arm of a robot.
  • Another objective is to provide a method for handling fluids in a robotic system for high throughput screening or microarraying which would be suitable for accurate dispensing and aspiring volumes smaller than the ones obtainable with current positive displacement pumps.
  • Yet another objective is to provide means of more accurate delivery of a drop of liquid reagent to a correct target well on a substrate and also to improve the accuracy of delivery of the drop to a correct location in a well forming part of a receiving substrate.
  • Yet another objective is to provide means for directing the doses of fluids into different wells of a sample well plate and means of controlling the delivery address of the dose on the sample well plate to speed up the liquid handling procedure.
  • Yet another objective of the invention is to reduce “splashing" as the drop arrives at the well.
  • An additional objective is to improve the operation of the conventional solenoid valve for the dispensing and aspiring of liquids and in particular the invention is directed towards providing specific constructions of such solenoid valve type dispensers.
  • Another objective of the invention is to provide information if the drop was dispensed or not. It is additionally an objective to measure the volume of the drop which was dispensed. Similarly, the measurement of other properties such as the viscosity of the droplet is desirable
  • a dispensing assembly for liquid droplets of the type comprising a dispenser having a main bore communicating with a nozzle having a nozzle bore terminating in a dispensing tip, and delivery means for moving liquid to the dispenser and from there through the bore to form a droplet on the exterior of the tip and then to cause the droplet to fall off therefrom, characterised in that:
  • valve seat is in the form of a capillary tube projecting proud of the base.
  • valve boss is covered with a layer of soft polymer.
  • valve boss is a floating valve boss of a magnetic material and the means for altering the relative position of the valve boss and valve seat comprises a separate valve boss actuating assembly adjacent the body member which may be of a hard magnetic material or manufactured from a flexible polymer bonding magnetic material.
  • valve boss actuating assembly is an electrical coil surrounding the body member and may be biased into a closed position into engagement with the valve seat by an external magnetic field generated by the actuating coil assembly.
  • the actuator coil assembly may comprise two separate sets of coils for moving the valve boss in opposite directions within the body member and may comprise a source of electrical power and a controller for varying the current over time as each droplet is being dispensed.
  • a valve boss actuating assembly may comprise a permanent magnet and means for moving the magnet along the elongate body member towards and away from the valve seat which magnet may be substantially U-shaped to embrace the body member.
  • the valve actuating assembly comprises a pair of spaced apart magnetizing assemblies each comprising a coil wrapped around a core of soft magnetic material which core may be substantially U-shaped to embrace the body member.
  • valve boss the body member and nozzle form the one separate sub assembly releasably detachable from the remainder of the dispenser.
  • valve boss is constructed for limited movement out of line with the main bore longitudinal axis.
  • the valve boss may be a cylindrical plug which in some instances may have a convex valve seat engaging surface and in some instances may have both upper and lower convex surfaces.
  • annular rim is formed on the exterior wall of the plug intermediate its ends.
  • the invention comprises means for measuring the velocity of the valve boss and in which when the valve boss actuating assembly comprises an electrical actuating coil surrounding the body member, the means for measuring the velocity of the valve boss comprises a secondary coil adjacent the valve boss and means for measuring the induced voltage in the secondary coil.
  • valve boss actuating assembly when the valve boss actuating assembly is an electrical actuating coil surrounding the body member, means are provided to measure the total voltage induced in the actuating coil to provide a measure of the velocity of the valve boss.
  • the body member is a two part body member having an upper portion and a lower portion interconnected in liquid tight manner, the upper portion housing the valve boss which is rigidly mounted therein and the lower portion housing the base and valve seat and in which actuation means are provided for moving the upper and lower portions relative to each other to cause the valve boss to move between the open and closed positions.
  • the upper and lower portions are connected by a flexible concertina type wall.
  • the dispenser when the dispenser is a two part body member having an upper portion and a lower portion, they are telescopically connected in liquid tight manner, the upper portion housing the valve boss which is rigidly mounted therein and the lower portion housing the base and the valve seat and in which means are provided for causing the movement between the open and closed positions.
  • the dispenser comprises a solenoid valve.
  • the solenoid valve comprises a solenoid and core external of the body member, the core mounting the valve boss on a lower valve boss carrying rod forming an extension of the core.
  • the rod is a two part rod releasably connected together external of the body member. It has been found preferably that the cross sectional area of the main bore is between 50 to 1500 times greater than that of the nozzle bore, but generally is of the order of 100 times that of the nozzle bore.
  • the nozzle bore diameter is usually between 300 and 75 ⁇ m and preferably between 200 and 100 ⁇ m.
  • the body member and the nozzle ideally form the one integral moulding of plastics material or are made from stainless steel.
  • the dispensing assembly comprises:
  • the receiving assembly may be below the dispensing tip and a droplet receiving substrate is mounted between the receiving electrode and the dispensing tip.
  • the receiving electrode when a droplet receiving substrate is mounted below the receiving electrode, the receiving electrode having at least one hole for the droplet to pass through to the receiving substrate
  • synchronous indexing means are provided for the dispenser and the receiving electrode for accurate deployment of droplets on the substrate.
  • a detector for sensing the separation of the droplet from the dispening tip which detector may comprise:
  • the source of radiation is mounted within the dispenser nozzle.
  • the invention provides means for measuring the charge of the droplet which may comprise a standard Faraday Pail or a bottomless Faraday Pail.
  • the invention provides a method of dispensing a droplet having a volume less than ten micro litres (10 ⁇ l) from a pressurised liquid delivery source through a metering valve dispenser comprising an elongate body member having a base including a valve seat forming an entrance to the nozzle which valve seat projects proud of the base, a valve boss in the bore, the cross-sectional area of which is sufficiently less than that of the main bore to permit the free passage of liquid therebetween by passing the valve boss and means for altering the relative positions of the valve boss and the valve seat between an open position with the valve boss spaced-apart from the valve seat and to a closed contact position sealing the valve seat and spaced-apart from the base comprising the steps of:
  • valve boss when the valve boss is a floating valve boss of a magnetic material and there is means for moving the valve boss comprising a separate valve boss actuating assembly including an actuating coil adjacent the body member and in which the method includes actuating the assembly by energising the actuating coil.
  • the speed of the floating boss is obtained by doctorng the voltage induced in an actuating coil due to its velocity and magnetisation or may be obtained by measuring the voltage indicated in a coild adjacent the floating boss.
  • the speed of the valve boss may be used to determine the viscosity of the liquid.
  • the liquid is not as highly pressurised and may be pressurised at less than 4 bar or even as low as 2 bar or less.
  • the receiving electrode is mounted beneath a droplet receiving substrate or between a droplet receiving substrate and the nozzle.
  • spaced-apart deflection electrodes are placed between the dispensing tip and a droplet receiving substrate and the electrodes are differentially charged to cause the droplet to move laterally as it drops from the dispensing tip.
  • the invention provides a method comprising the steps of:
  • the drop off voltage may be measured by a Faraday Pail. To record the drop off of voltage, there is performed the steps of:
  • a light beam may be used as a source of electromagnetic radiation and the amount of light reflected and/or refracted by the droplet is monitored.
  • the invention provides a method of performing the steps of:
  • a motor 1 driving a piston 2 of a positive displacement pump 3 containing a system liquid, namely, water 4 connected by flexible tubing 5 to a robotic arm 6 carrying a nozzle 7 having a tip 8 into which the tubing 5 projects.
  • a reagent 9 is contained in the nozzle 7 adjacent to the tip 8 and separated from the water 4 by a gas bubble 10 see Fig. 1 (b).
  • the motor 1 which is usually a stepper or servo motor will each time move the piston 2 to dispense reagent.
  • the dispensing assembly 20 comprises a delivery means indicated generally by the reference numeral 21 which, in turn, comprises a pressure source 22 feeding a pressure regulator 23 and a pressure readout device 24 all connected to an electronic controller 25.
  • the pressure readout device 24 in turn feeds through a high pressure airline 26, a switch 27 which is also fed by a vacuum pump 28 and vacuum line 29.
  • the switch 27 is also connected to the electronic controller 25.
  • the switch 27 connects by a further airline 30 to a reagent reservoir 31 which in turn feeds by a liquid carrying pipe 32, a dispenser, indicated generally by the reference numeral 40.
  • a reagent reservoir 31 will normally only be used where there is a relatively large amount of reagent been used.
  • the dispenser 40 is illustrated in more detail in Fig. 3 and comprises of an elongated body member 41 having a main bore 42 connected at one end to the liquid carrying pipe 32. At the other end the main bore has a valve seat 43 in a base 49, connecting to a nozzle 44 having a nozzle bore 45 terminating in a dispensing tip 46.
  • the valve boss 47 of a ferromagnetic material covered with a soft polymer material 48 is mounted in the main bore 42 and has a cross sectional area less than that of the main bore 42.
  • the top or exposed portion of the valve seat 43 is essentially sharp to engage firmly in the soft polymer material 48.
  • the valve seat 43 projects proud of the base 49 such that when in the closed position with the valve boss 47 seated on the valve seat 43, there is a gap between the base 49 and the boss coating 48.
  • a separate valve boss actuating coil assembly comprising upper and lower coils 50 and 51 respectively are provided separate from the body member 41 and are also connected to the electronic controller 25. As can be seen in Fig. 2 the power source for the coils 50 and 51 is not illustrated.
  • a droplet receiving substrate 55 usually in the form of a series of wells is mounted below the dispensing tip 46 and above a conducting plate 56.
  • the conducting plate 56 is connected to the electronic controller 25 through a high voltage source 57.
  • Reagent when in the form of droplets is identified by the reference numeral 58 in Fig. 2.
  • the dispenser 40 is grounded to earth through an earthline 59, in effect making the dispensing tip 46 an electrode.
  • the tip may have to be made out of a conducting material such as metal or an electrically conducting polymer.
  • the reagent is stored in the main bore 42 of the body member 41 and the controller 25 is operated to cause the coils 50 and 51 to be activated to raise the valve boss 47 off the valve seat 43 and to allow the reagent to pass between the valve boss 47 and the walls of the main bore 42 down into the nozzle bore 45 until the coils are activated again to shut off the valve by lowering the valve boss 47.
  • the controller 25 is operated to cause the coils 50 and 51 to be activated to raise the valve boss 47 off the valve seat 43 and to allow the reagent to pass between the valve boss 47 and the walls of the main bore 42 down into the nozzle bore 45 until the coils are activated again to shut off the valve by lowering the valve boss 47.
  • the controller 25 is operated to cause the coils 50 and 51 to be activated to raise the valve boss 47 off the valve seat 43 and to allow the reagent to pass between the valve boss 47 and the walls of the main bore 42 down into the nozzle bore 45 until the coils are activated again to shut off the valve by lowering the valve boss 47
  • the vacuum pump 28 is operated and the switch 27 suitably arranged to ensure that the vacuum pump 28 and vacuum line 29 is connected to the dispensing assembly 20.
  • the valve is opened and the liquid sucked up into the dispenser 40.
  • a cylindrical valve boss 61 of a ferromagnetic material surround by a polymer coating 62.
  • a floating valve boss stop 63 which is mounted in the main bore 42 remote from the base 49.
  • the nozzle is formed from a capillary tube 64 again forming the valve seat 43 which, it will be noted, projects a distance I above the base 49.
  • Figs 5 and 6 there is illustrated an alternative construction of dispensing assembly.
  • the dispenser is indicated generally by the reference numeral 70 and parts similar to those described in the previous Fig. 3 are identified by the same reference numerals.
  • the delivery means indicated generally by the reference numeral 72 comprises a positive displacement liquid handling system.
  • a stepper motor 73 incorporating suitable controls operating a piston 74 of a pump 75 containing water 76 delivered by flexible tubing 77 to the dispenser, air 78 separates the water 76 from reagent 80.
  • the tubing 77 is connected by a suitable seal 79 to the dispenser 70.
  • a pressure sensor 81 is connected to the tubing 77 and to a pump controller 82.
  • a dispenser indicated generally by the reference numeral 90 in which parts similar to those described in the previous drawings are identified by the same reference numerals.
  • the dispenser 90 includes a cylindrical valve boss 91 of permanent magnetic material surrounded by a polymer coating 92.
  • the polymer coating 92 is thicker adjacent the lower portion to form a convex valve seat engaging surface 93.
  • the valve seat 43 does not project above the base 49.
  • the cross sectional area of the valve boss 91 with the coating is less than that of the main bore 42. It is advantageous to have the cylinder 91 magnetised along its axis as indicated by the arrow.
  • Fig. 8 illustrates a dispenser indicated generally by the reference numeral 94 substantially similar to the dispenser 90 of Fig. 7, except that the nozzle is provided by the capillary tube 64 and the valve seat 43 projects above the base 49. There is an upper convex surface 95 as well as the lower convex surface 93 on the valve boss 90 for improved hydrodynamic performance and faster movement.
  • Fig. 9 illustrates the bottom portion 94 of Fig. 8 and shows the contour of the convex valve seat engaging surface 93 by the subscript (a) when it is still open, by the subscript (b) when it is just about to open and by the subscript (c) when it is fully closed.
  • the contour of the convex valve seat engaging surface changes as it closes but it still remains spaced-apart from the base 49. Similarly the shape will change as it opens. On opening there is some movement of the valve boss 90 before the seal on the valve seat 43 is broken. The significance of this is discussed later.
  • Fig 10 shows another construction of dispenser, identified generally by reference numeral 100, again parts similar to those described in the previous drawings are identified by the same reference numerals.
  • a valve seat 101 with a sharpened peripheral tip 102 which will engage the polymer coating of 92 of the cylindrical valve boss 91.
  • bosses described above have been either spherical or cylindrical and thus circular in cross-section and similarly all the bores have been circular in cross-section, this is not necessarily essential.
  • a boss could be made of any suitable shape. It could be square, rectangular or polygonal in cross-section.
  • the bore does not have to be circular in cross-section. Nor indeed do both the bore and the boss have to be of the same shape in cross-section.
  • the boss can form an elongate plug-like member which effectively is constructed for limited movement at a line with the main bore.
  • Fig. 11 illustrates portion of an alternative construction of dispenser, indicated generally by the reference numeral 105, in which parts similar to those described with reference to the previous drawings are identified by the same reference numerals.
  • the body member 41 and nozzle 44 are manufactured from the one piece, for example, of a plastics material.
  • Fig. 12 illustrates a still further construction of dispenser, indicated generally by the reference numeral 107, in which the body member 41 and the nozzle, which in this case is formed from a capillary tube 64, are again of the one piece moulding.
  • the base 49 forms a conical inner surface rising towards the valve seat 43 from the sides of the body member 41.
  • FIGs 13(a) and 13(b) there is illustrated another dispenser indicated generally by the reference numeral 110 in which parts similar to those described with reference to Fig. 7 are identified by the same reference numerals. This shows clearly the opening and closing of the dispenser 110 together with the direction of the liquid flow around the cylindrical valve boss 91. Two sets of coils 50 and 51 are used though the valve boss 91 is of a permanent magnetic material.
  • the cross sectional area of the nozzle bore A N is significantly smaller than that of the main bore A M . Accordingly 50 ⁇ A M /A N ⁇ 1500. Indeed, it could be greater than 1500.
  • the valve seat should project above the base of the body member of the dispenser such that as, for example, illustrated in Fig. 9 where even with the floating valve boss fully home and pressed against the valve seat 43, there is still a gap between the bottom of the floating boss and the base of the body member.
  • the length I has to be carefully chosen and depends on various parameters such as the thickness of the coating and its elastic properties.
  • the thickness of the coating is determined by the requirement of forming a reliable seal on the valve seat which in turn will depend on the geometry of the valve seat and also the axial alignment of the floating boss on the valve seat which will obviously vary depending on the gap between the valve boss and the inner surface of the main bore and also on the actual construction of the valve boss, namely, where there is a cylindrical valve boss or a spherical valve boss.
  • the actuator area of the valve is separated from the plunger area by a seal.
  • the seal, the shaft and the spring pressing against the plunger are the areas where contamination can build up.
  • the situation with the cross contamination in the solenoid valve gets worse with the reduction in the overall size of the valve.
  • the ratio of the two, S/V is the essential indicator of the cross-contamination.
  • a further advantage of the use of a floating boss solenoid valve is that the dead volume inside the dispenser is reduced as is the wastage of reagents. It is important to consider the constraints which are imposed on the diameter of the outlet of the dispenser for it to dispense nanolitre range volumes. Suppose there are two different dispensers having outlets of inner diameters of 2r and 4r respectively. Further presume a straight length of tube with a constant bore is connected to each outlet. Suppose both dispensers are designed for the same flow rate meaning that they can dispense comparable volumes of liquids.
  • This volume indicates the amount of liquid stored in the nozzle bore which effectively forms an outlet tube. This volume will stay in the outlet tube during the last dispensation to maintain the accuracy of the dispensation and is effectively wasted. Therefore, as the diameter of the second dispenser's outlet is twice that of the first one, and the length is 16 times as large, the dead volume of the second dispenser is 64 times greater. The important conclusion here is that the diameter of the outlet should be as small possible to reduce the dead volume and wastage of the liquids. Diameters considerably smaller than 100 micron are unpractical as the capillaries begin to be blocked by the inhomogenities in the liquids which can often be of the size of some 20-50 microns for some applications. In certain circumstances, this may not be a problem.
  • the critical pressure needed to separate the droplet from the tip of capillary is: ⁇ P crit ⁇ Const* ⁇ *(L/r 5/2 )*( ⁇ / ⁇ )1 ⁇ 2,
  • valve seat outlet Another important reason making it necessary to reduce the diameter of the valve seat outlet into the nozzle bore or capillary is that when particulate reagents are being dispensed, the particles suspended in the liquid can get attached to the inner walls of the dispenser thus blocking the flow path.
  • the problem of blockage can be particularly severe for microvalves, i.e. when dispensing small volumes and also for dispensing of biological liquids and bodily fluids which can normally contain cells, particles etc.
  • a valve seat of smaller diameter in the region of some 100-200 ⁇ m
  • a particle with diameter d is about to be attached to the wall of the tube or the valve seat.
  • Fig. 14 illustrates a dispenser indicated generally by the reference numeral 115 substantially similar to the dispenser 90 disclosed in Fig. 7 where the valve seat 43 does not project above the base 49 of the main body member 41.
  • the cylindrical boss is illustrated with a polymer coating 92 having a valve seat engaging portion 116 having a dished configuration identified by the reference numeral 117 with subscript (a) and interrupted lines showing the shape of the surface of the bottom of the floating valve boss 91 when the surface 117 first contacts the base 49 and then by a full line and the subscript (b) when it finally is at rest sealing the valve seat 43.
  • the valve boss 91 first contacts the base 49, liquid is trapped between it and the valve seat 43.
  • the contour of the valve seat engaging portion 116 changes with the surface changing from the configuration identified by the reference numeral 117(a) to the configuration identified by the reference numeral 117(b).
  • the dispensing assembly can operate at a higher pressure than in conventional assemblies. It is suggested that this is due to the fact that the force acting on the boss due to the pressure difference is proportional to area of the outlet, i.e. of the valve seat. As the area of the outlet is reduced to some 10 4 -10 5 ⁇ m 2 , the pressure range at which the boss can still be reliably actuated, increases to over 10 Bar.
  • a typical state-of-the art miniature solenoid valve from the Lee company used for the ink jet printing applications can be used up to the pressure of only approximately 0.7 Bar (Technical Handbook, The Lee Company, 6 th edition, 2 Pettipaug Road, P.O.
  • a further advantage in the reduction in the cross sectional area of the valve seat and hence the nozzle bore is that it reduces the flow rate of the liquid.
  • valve boss As the valve boss is energised to open, the seal remains closed for certain time after the coil is being actuated and the boss starts moving. Only after a certain duration of time, when the boss passes through the length by which the elastomeric coating on the boss is compressed, the valve seat becomes open. As the boss moves with a constant acceleration during this time, its velocity at the moment of the opening of the seal is a lot higher than the velocity at the moment of the actuation of the coil. The same applies for the closure of the boss.
  • the dispenser typically aspirates a few microlitres of a reagent, dispenses it in other locations and then moves to a new reagent.
  • the contaminated part of the dispenser needs to be disposed of after a few cycles of aspiration and dispensation, and in some cases after each cycle.
  • the conventional solenoid valve is a rather complex device designed for hundreds of thousand of open-close cycles. Solenoid valves are not used as disposable elements due to the complexity of design and cost considerations. The simplicity of the present invention addresses and solves this problem making the contaminated part of the dispenser essentially a disposable component.
  • conventional solenoid valves with nozzles and valve seats according to the invention are advantageous.
  • valve boss with the soft polymer material coating. All the mass of the valve boss can be effected and actuated by the electromagnetic action of the actuating coil assembly. This minimises very much the inertia of the dispenser. This minimisation of inertia leads to a reduction in the open-close cycle thus minimizing the amount of liquid that can be dispensed. This also reduces the heating of the liquid as the boss can be operated at a lower current to achieve the same open-close cycle.
  • the present dispenser can also operate at a significantly higher pressure than a conventional solenoid microvalve, by a factor of over two or three (the typical specifications for the solenoid microvalves used in ink printing can be seen e.g. in the Technical Handbook, The Lee Company, 6 th edition, 2 Pettipaug Road, P.O. Box 424, Westbrook, Connecticut, 06498-0424, 1994 pages 22-23).
  • This increase in the pressure range is also due to the fact that almost the entire boss can be affected by the electromagnet.
  • Operating at a higher pressure may be beneficial for the dispensation of high viscosity liquids and also volumes in the low nanolitre range.
  • a dispensing assembly indicated generally by the reference numeral 120 incorporating a dispenser 40 as described above with reference to Figs. 2 and 3.
  • the droplets are identified by the numeral 58 and successive subscripts thus 58(a) to 58 (c).
  • the dispensing tip 46 effectively forms or incorporates an electrode by virtue of being grounded by the earth line 59.
  • a receiving substrate 121 incorporating reagent wells 122.
  • a receiving electrode 123 Positioned below the receiving substrate 121 is a receiving electrode 123 in turn mounted on an indexing table 124.
  • the receiving electrode 123 is connected to a high voltage source 125.
  • the indexing table 124 is used to position the receiving electrode 123 below the appropriate reagent well 122 as shown by the interrupted lines in the drawing.
  • Fig. 16 there is illustrated an alternative construction of dispensing assembly, indicated generally by the reference numeral 130 in which parts similar to those described in Fig. 15 are identified by the same reference numerals.
  • this embodiment there is provided a plurality of receiving electrodes 131 on the indexing table 124, which are individually connected to the high voltage source 125.
  • Fig. 17 there is illustrated still further construction of dispensing assembly indicated generally by the reference numeral 140 in which parts similar to those described with reference to Fig. 15 are identified by the same reference numerals.
  • additional deflecting electrodes 141 and 142 are provided in this embodiment. It will be appreciated that depending on the voltage on the deflecting electrodes 141 and 142, the droplets 58 will in conjunction with the receiving electrodes 123 navigate into the appropriate reagent well 122. This is illustrated clearly in Fig. 17 by the interrupted lines. In Fig. 17 there is also shown a receiving electrode 123 but it will be appreciated that such a receiving electrode 123 will not always be necessary. It is also possible to use a conducting plate such as illustrated in Fig.
  • the receiving electrode could be in the form of a plate having at least one hole to allow a droplet pass therethrough.
  • Fig. 18 shows the dependence of the volume of the droplet grown at the dispensing tip as a function of the duration of phase 2.
  • the conditions of the dispensing assembly were identical as for Tests No. 1 and No. 2 with the addition of a conducting plate. This was spaced from the dispensing tip by 10mm and had dimensions 100mm X 100mm.
  • a high voltage was applied to the conducting plate which was arranged in substantially the same manner as the dispensing assembly of Fig. 2.
  • the test was carried out by growing a droplet on the dispensing tip of the nozzle by opening the valve. Then the valve was closed and the voltage was gradually increased until drop off occurred, when it was recorded. The volume of the droplet was measured by repeating this with the electromagnetic balance, details of which are described later.
  • Fig. 20 shows clearly the dependence of the drop off voltage as a function of the volume of the drop grown at the end of the dispensing tip.
  • a volume of droplet 40 nanolitre was chosen with the remainder of the conditions the same as Test No. 3.
  • the dependence of the drop off voltage as a function of the distance between the end of the nozzle and a conducting plate was tested and the results are given in Fig. 21.
  • test assembly indicated generally by the reference numeral 150 incorporating a dispensing assembly as illustrated in Fig. 5 and 13.
  • a substrate 151 below which is mounted a pair of receiving electrodes in the form of plates 152 and 153 which in turn are connected to an electrical circuit indicated generally by the reference numeral 154 incorporating a high voltage supply 155 of approximately 5 KV.
  • the separation between the dispensing tip and the substrate 151 was 15 mm. Tests were carried out, the results of which are shown in Fig. 23.
  • Fig. 23 shows the deviation of a droplet as a function of the potential difference applied to the plates 152 and 153.
  • the potential difference between the plates 153 and 152 is measured in percentage of the potential difference between the average of the potentials of 152 and 153 and the nozzle 46.
  • Figs. 24 and 25 there is illustrated an electromagnetic balance for the measurement of the mass of droplets dispensed in accordance with the invention.
  • the electromagnetic balance 160 comprises a receiving coil 161 across which a magnetic field may be applied suspended on a fine spring provided by a twisted spring coil 162 and powered by a controlled current source 163. Lines of the magnetic field are schematically indicated with the numeral 169.
  • the receiving coil 161 supports a balance arm 164 carrying a droplet receiving plate 165.
  • a position sensor 166 is provided adjacent the balance arm 164 and is connected to a feed back controller 167 which in turn is connected to the controlled current source 163.
  • the position sensor 166 in one embodiment is a light emitting diode and a photo diode coupled optically. It will be appreciated that the torque acting on the receiving coil 161 is proportional to the current carried by the receiving coil 161.
  • the feedback controller 167 signals the controlled current source 163 to change the current into the receiving coil 161 until the previous unloaded position is attained.
  • the gravity force exerted by the droplet 168 is proportional to the change in current in the coil 161, then using simple calibration the mass of droplets can be measured directly and accurately.
  • Fig. 25 shows in some more detail the electronic circuit of the electromagnetic balance 160.
  • D1 is the light-emitting diode
  • Q1 is the photodiode.
  • Output J1 supplies the voltage which is dependent on the position of the arm.
  • This output is connected to the analogue-to-digital converter and processor controlled feedback circuit for continuous comparison of the actual position of the arm with the preset value.
  • the feedback circuit produces signal proportional to the current needed to be supplied to the coil to control the position of the arm.
  • This signal in the form of a voltage is applied to the input J2 and the current is taken from the output as marked "Moving Coil" normally the coil 161.
  • the drop off voltage depends on the volume of the droplet on the dispensing tip. It becomes important to ascertain exactly when the droplet is released from the dispensing tip. Accordingly the invention provides various methods of detection of the separation of a droplet from the dispensing tip. Once the electrostatic field causing the drop off to be achieved is known, then the volume of the droplet can be calculated within relatively fine limits.
  • a detector indicated generally by the reference numeral 170, for sensing the separation of a droplet from the dispensing tip.
  • the detector 170 comprises source 171 of electromagnetic radiation, an electromagnetic collector 172 and a controller 173 connected to the electromagnetic radiation source 171 and collector 172.
  • the electromagnetic radiation source 171 is a laser. There is illustrated a laser beam 174 emanating from the electromagnetic radiation source 171 and then either being reflected as a further laser beam 175 to the electromagnetic collector 172 or as a beam 176 passing straight beyond the dispensing tip 46 when a droplet 58 is not in position.
  • Fig. 27 there is illustrated another construction of detector arrangement indicated generally by the reference numeral 180 in which parts similar to those described with reference to Fig. 26 are identified by the same reference numerals.
  • the laser beam 174 is either refracted by the droplet 58 if it is in position as shown by the numeral 181 or simply bypasses undeflected when the droplet 58 is not in position as shown by the numeral 176.
  • Fig. 28 there is illustrated a slightly different arrangement of the detector illustrated in Fig. 27 and thus parts similar to those described with reference to the previous drawings are identified by the same reference numerals.
  • additional scattered light beams 185 are illustrated as is a modulator 186 and a lock-in amplifier 187.
  • a signal input to the lock-in amplifier 187 is identified by the reference numeral 188 and a reference input signal is identified by the reference numeral 189.
  • Fig. 29 there is illustrated a further construction of detector indicated generally by the reference numeral 190 again used with the dispenser of Fig. 2 and in which parts similar to those described with reference to Figs. 26 and 27 are identified by the same reference numerals.
  • the electromagnetic radiation source 171 delivers radiation through a fibre-optic cable 191 down the nozzle 44.
  • Reference numerals 192 and 193 show the meniscus of a droplet being formed on the dispensing tip 46, namely one forming a flat meniscus 192 and the other a curved meniscus 193.
  • the beam 174 when there is flat meniscus 192 on the dispensing tip 46 will be delivered through it as the beam 194 to the detector 172.
  • the beam 174 will be delivered as a beam 195 and a further beam 196 away from the detector 172.
  • Fig. 30 there is illustrated a further construction of detector indicated generally by the reference numeral 200 in which the parts similar to those described with reference to the previous drawings are identified by the same reference numerals.
  • the beam 174 will always form a reflected beam 201 once a droplet whether formed or not is present.
  • the reflected beam will vary in intensity.
  • an optical coupler will need to be installed between the electromagnetic radiation source 171 and the collector 172 on one side and the fibre-optic guide 191 on the other.
  • the dispenser should be calibrated.
  • the drop off voltage is a function of the volume of the droplet, and over a substantial range of volumes it is effectively a monotonous function. That is to say the smaller the volume of the drop, the greater it is the drop off voltage for a given diameter of the nozzle and a given fluid.
  • the Faraday Pail consists of an outer shield and an inner conductive box or chamber.
  • the shield and chamber are well insulated from each other and indeed it is advantageous to keep the outside shield and the chamber at the same potential.
  • a charged droplet arriving at the chamber induces the same charge with opposite sign at the surface of the chamber. This charge is created by the current flowing from inside to outside which can be easily measured by a charge measurement circuit.
  • the dispenser and hence the nozzle will be maintained at a relatively high voltage, and the shield and chamber connected to ground potential, as will be described hereinafter, the charge can be measured without catching the droplet in the pail.
  • charged droplets will progress through the induced charge detector which is effectively the function of the Faraday Pail.
  • Phase 1 0.2ms Phase 2 0.3ms Phase 3 0.3ms Phase 4 105ms
  • Fig. 31 illustrates that the charge is directly related to the volume of the droplet.
  • Fig. 32 shows the results obtained from this test again the charge is directly related to the volume of the droplet.
  • Figs. 33 and 34 there is shown typical signal detection traces from the Faraday Pail.
  • Fig. 33 there is shown a change in the output voltage of a charge amplified as a result of the charge of approximately 3*10 -11 C on a droplet and it is easy to calculate the volume of the drop from the calibration curves of Figs. 31 and 32.
  • Fig. 34 shows the zoom in to indicate the extent of the noise and sensitivity of the system.
  • Fig. 35 there is illustrated the electronic circuit of the amplifier measuring the charge in the Faraday Pail.
  • the two inputs of the amplifier are connected to the chamber and the shield of the Faraday Pail, respectively.
  • the relay is added to the circuit to prevent damage to the amplifier by electrostatic charge when the circuit is idle.
  • By deactivating relay the two inputs are connected together and they are also connected to the output voltage of OPA111 to bypass the storage capacitor C1. It is advantageous to have the storage capacitor C1 having a value of capacitance much greater than the capacitance between the chamber and the shield of the Faraday Pail.
  • a Faraday Pail indicated generally by the reference numeral 210 for use in a dispensing assembly similar to that described with reference to the Figure 10 above.
  • a high voltage source 211 is connected to the nozzle 44.
  • the Faraday Pail 210 comprises of an inner chamber 212 and an outer shield 213 connected to a controller 214 in the form of a charge amplifier. In use samples of droplets are taken and an average for droplet volume and mass is calculated.
  • a contactless method is implemented. This method is based on the Faraday Pail principle.
  • a droplet reaches the bottom of the inner chamber and sticks to it.
  • An output signal of the charge amplifier will be a step-like function. The height of the step indicates the value of the arrived charge.
  • the charge measured can be created by induction. Putting the charge inside the Faraday Pail induces charge on the inner chamber, and removing the charge from it cancels the induced charge.
  • the charge amplifier When the droplet passes the bottomless Faraday Pail, the charge amplifier will create only a short pulse at its output. The rising edge of this pulse will correspond to the arrival of the charge in the chamber while a falling edge corresponds to the charge leaving.
  • the width of this pulse is proportional to the time of the droplet flight through the pail and therefore inversely proportional to the speed of droplet.
  • the height of the pulse peak is proportional to the charge of droplet.
  • charge and speed of droplet provides an estimate of the charge-to-mass ratio for the flying droplet.
  • Droplets with different charge to mass ratios will have different acceleration and final speed in viscose air, which can be detected by the pail. This means that charge-to-mass ratio can be estimated if the applied voltage and the final speed of droplet are both known. Dividing the droplet charge by its charge-to-mass ratio gives mass of droplet. The speed of the droplet and the calculation of its mass from the calculated charge to mass ratio can be achieved.
  • FIG. 37 there is illustrated a further construction of Faraday Pail indicated generally by the reference numeral 220 having an inner chamber 221 an outer shield 222 and a charge amplifier circuit forming a controller 223.
  • the drop off voltage is determined by the potential difference between the shield 222 and the dispensing tip 46 of the nozzle 44.
  • 224 is the high voltage source connected to the tip.
  • FIG. 38 to 40 inclusive there is illustrated an alternative construction dispenser indicated generally by the reference numeral 240 substantially similar to the dispenser 70 illustrated in Fig. 5 and thus the same reference numerals are used to identify the same or similar parts.
  • a spherical valve boss 241 of a soft magnetic material there is provided a spherical valve boss 241 of a soft magnetic material.
  • the dispenser 41 is mounted between an upper coil 242 and a lower coil 243, each wrapped around a core of soft magnetic material 244 and 245 respectively.
  • This construction is particularly advantageous in that it allows removing the dispenser 41 while keeping the source of the gradient magnetic field in place. This is particularly advantageous for replacing contaminated dispensers.
  • Figs. 41 to 43 inclusive there is illustrated an alternative construction of dispenser indicated generally by the reference numeral 250 in which parts similar to those described with reference to Fig. 38 to 40 inclusive are identified by the same reference numerals.
  • valve boss actuating assembly indicated generally by the reference numeral 251.
  • the dispenser 250 incorporates a spherical valve boss 252 of a soft magnetic material.
  • the actuating assembly 251 comprises a permanent magnet 253 mounted in a nozzle embracing U shaped sleeve 254 movable up and down relative to the body member 41 by a pneumatic ram of which only a plunger 255 is shown connected to the sleeve 254.
  • a two-part elongated body member comprising an upper portion 261 and a lower portion 262 interconnected in liquid tight manner, in this case by a flexible type concertina type wall 263 of a suitable elastomeric material.
  • a cantilever arm 264 Mounted in the upper portion 261 by a cantilever arm 264 is a valve boss 265 including a lower valve seat engaging portion 266 of a suitable resilient polymeric material having a valve seat engaging surface 267.
  • the lower portion 262 forms the base 49 of the body member and carries the nozzle formed from the capillary tube 64 such as illustrated in Fig. 4 which projects above the base 49.
  • Actuation means 268 is provided to move the upper portion 261 towards and away from the lower portion 262 in the direction of the arrows A. It will be noted that there is a considerable gap between the valve boss 265 and the bore of the upper portion 261 and the lower portion 262.
  • the actuation means 268 is simply illustrated by two blocks as it could be of any suitable construction such as an electromagnetic coil arrangement, a mechanical or fluid power actuator and so on.
  • any suitable means can be used to push them towards and away from each other and indeed the upper portion 261 could form effectively the boss of a solenoid valve similar to the floating bosses previously described and actuating coils could be used to raise and lower the upper portion 261.
  • the actuator could be attached to the lower portion 262.
  • Fig. 45 there is illustrated an alternative construction of dispenser, indicated generally by the reference numeral 270 in which parts similar to those described with reference to the Fig. 44 are identified by the same reference numerals.
  • this embodiment there is provided an upper portion 271 telescopic and slidable within a lower portion 272. Again, actuating means 273 are provided for raising and lowering the lower portion 272 relative to the upper portion 271 in the direction of the arrows A.
  • a still further construction of dispenser indicated generally by the reference numeral 280 in which parts similar to those described with reference to the previous drawings are identified by the same reference numerals.
  • a conventional solenoid valve 281 carrying a rod 282 projecting into the bore 42 of the main body member 41 carrying on its extremity a piston forming a valve boss 283 mounting a polymeric valve seat engaging seal 284 having a convex surface 285.
  • the liquid carrying pipe 32 feeds the body member 41.
  • Portion of the rod 282 forms the core of the solenoid 281.
  • Fig. 47 there is illustrated an alternative construction of the dispenser identified by the reference numeral 290 which dispenser 290 is substantially similar to the dispenser 280 except that the rod 282 engages a further rod 291 which is connected thereto by a suitable quick release connector. A suitable membrane seal 292 is provided. Thus, the body member 41 and the piston 283 are totally disposable.
  • Fig. 48 there is illustrated an alternative construction of dispenser, indicated generally by the reference numeral 300 having a main body 301 in which is mounted a fixed valve boss 302 having a soft polymer coating 303.
  • the nozzle is again formed by the capillary tube 64, in this case, projecting through the main body 301 through a seal 304.
  • the capillary tube 64 is mounted in an actuator 305 which can move the capillary tube 64 up and down in the direction of the arrow A and thus now the valve seat 43 moves towards and away from contact with the fixed valve boss 302.
  • Fig. 49 illustrates a still further construction of dispenser, indicated generally by the reference numeral 310, in which parts similar to those described with reference to Fig. 48 are identified by the same reference numerals.
  • the capillary tube is mounted in a core 311 of a solenoid 312.
  • Fig. 50 illustrates an alternative construction of dispenser, indicated generally by the reference numeral 320 in which parts similar to those described with reference to the Fig. 48 are identified by the same reference numerals.
  • the polymer coating 62 incorporates an annular rim 321 in an exterior wall of the valve boss 61 which is in the form of a cylindrical plug 61.
  • This annular rim 321 in use, gives improved high dynamic performance.
  • the valve boss 61 can move faster and therefore accuracy of dispensation is improved.
  • the valve boss does not have to be circular in cross-section.
  • the velocity of the valve boss can be measured.
  • the voltage is measured in one of the coils 50 or 51, that voltage will have essentially three components. Firstly, there will be the voltage due to the inherent resistance R of the coil and the current i being iR; then self inductance Ldi/dt where L is the self-inductance of the coil, and finally the induced voltage which is proportional to the velocity of the valve boss and its magnetisation.
  • the first two components can be easily calculated and then eliminated and therefore relatively easily the voltage induced by the motion can be determined which will give the velocity of the valve boss.
  • the voltage induced in the secondary coil would comprise two components.
  • the first one is proportional to the mutual inductance of the two coils L 12 and the rate of current change in the coil actuating the valve boss, namely L 12 * di 1 /dt.
  • the second voltage would be proportionate to the velocity of the boss and its magnetic moment.
  • the first component can be independently measured as the rate of change of current di 1 /dt is known and therefore the velocity of the boss can be calculated. This could have considerable importance where you wish to measure the viscosity of a liquid. For example, if the viscosity of a liquid were to change during a test, this might indicate some form of malfunction. It will be possible to calibrate any dispenser according to the present invention to so measure the viscosity.
  • the dispenser in so far as it comprises the elongate body member the valve seat and nozzle can be manufactured from a suitable polymer material by micro machining or indeed any standard polymer mass production technique such as injection moulding. The purpose of this is to provide a disposable dispenser.
  • the body of the dispenser could be also manufactured of other materials such as steel.
  • valve boss as will be appreciated from the description above can be cylindrical, spherical or indeed a body of any geometric shape made from magnetic material for example iron, ferrite or NdFeB. It is preferably coated with a polymer or inert layer of another material to prevent chemical reaction between the boss and the liquid dispensed. In order to obtain a good seal with the valve seat, the valve boss may need to be coated with a specially selected soft polymer such as chemically inert rubber. The choice of the materials for the coating on the boss depends on the requirements of the liquids which must be handled by the dispenser.
  • the most likely materials include fluoroelastomers such as VITON, perfluoroelastomers such as KALREZ and ZALAK and for less demanding applications, materials with lower cost could be considered such as NITRILE.
  • TEFLON PTFE
  • VITON, KALREZ, TEFLON and ZALAK are Du Pont registered trademarks.
  • the valve boss may be made of magnetic material bonded in a flexible polymer. These materials can have either hard or soft magnetic properties as required. The specific choice of material will be determined by the cost-performance considerations. Materials of families FX, FXSC, FXND manufactured by Kane Magnetics are suitable for certain applications. Other materials such as magnetic rubbers can be also used for certain designs. Making the boss of a mechanically soft material can improve the performance of the seal.
  • the polymer coating on the boss can consist of two or more layers of different polymers.
  • the first layer could be deposited on the boss 61 to improve the adhesion of the second outer layer with the first one.
  • the dispenser may be operational in either active or passive mode.
  • active mode the valve is actuated to make an open-close circuit for each dispensation and aspiration.
  • passive mode the dispenser is connected to a syringe pump as illustrated in Fig. 5.
  • the valve boss is made of hard magnetic material, i.e. a material having a well-defined direction of magnetisation even in the absence of any external magnetic field.
  • the plunger is usually made of soft magnetic material such as iron or iron-nickel alloy. This material has no significant magnetisation in the absence of an external magnetic field.
  • the valve boss is a cylinder with the axisymmetrical magnetisation for instance in direction along its axis. The dispenser could also operate with a boss of soft magnetic material.
  • the dispenser can dispense volumes as small as 50 nl without any electrostatic field if the pressure in the line is as high as 10 Bar. It is often advantageous to decrease the pressure in the line connected to the dispenser.
  • the dispensing assembly operating at a low pressure has considerable advantages.
  • the connection requirements for the pneumatic components are less stringent. Normally it is desirable to use a basic push fit connector in robotic dispensers for these applications.
  • the invention when used at reduced pressures allows using a simple push-fit connection between the dispenser and the pressure line, which is a desirable feature of the dispenser.
  • the drops are ejected with a lower speed which reduces the chances of splashing as the drop touches the substrate or the well plate.
  • High pressure in the line may result in gases dissolved in the liquids dispensed. This is not acceptable for many biological applications.
  • the gas dissolved in the liquid dispensed can also result in small air bubbles at the nozzle, which make its operation unreliable.
  • the technique comprises firstly opening the valve of the dispenser to allow a droplet of the desired size to grow on the dispensing tip.
  • the valve is then closed and subsequently a strong electrostatic field is generated between the dispensing tip and the substrate on which the droplet is to be deposited.
  • a strong electrostatic field is generated between the dispensing tip and the substrate on which the droplet is to be deposited.
  • the dispenser can also be used with the valve continuously open.
  • the fluid from the dispensing tip is ejected as a jet.
  • the flow of the jet is determined by the pressure in the line connected to the dispenser and where present the value of the electrostatic field at the nozzle.
  • the jet may split into droplets partly due to the electrostatic repulsion between the charged parts of the jet.
  • the size between the subsequent drops covering the substrate herein called pitch, could be as small as 0.1 mm.
  • this invention there are two different means of controlling the destination of the drop, both are based on the electrostatic forces acting on the drop as it travels between the nozzle and the well.
  • the first way is to generate the electrostatic field with a small charged receiving electrode positioned underneath the well instead of a large conducting plate.
  • the size of the electrode is smaller than the size of the well for accurate navigation. It may be advantageous as described above to have the receiving electrode in the shape of a tip to produce the strongest electric field at the centre of a destination well.
  • the electrode produces a strong electric field underneath the well attracting the drop to the required destination position (usually the centre of the well).
  • the receiving electrode may be attached to an arm of a positioner capable of moving it underneath the well plate and pointing to the correct destination well. Alternatively, the sample well plate may be repositioned above the receiving electrode in order to target a different well. It may be necessary to move the dispensing tip and receiving electrode synchronously.
  • the distance between the electrodes could be the same as the distance between the centres of the wells in a well plate. In this case the drops could be navigated to different wells without actually moving the dispenser or the receiving electrode.
  • deflection electrodes are positioned along the path between the nozzle and the destination well.
  • the electrodes are charged by means of a high voltage applied to them. As the drops leaving the dispensing tip are charged by the voltage between the dispensing tip and the receiving electrode, they will be deflected by the deflection electrodes.
  • the electrostatic force acting on the drop could much greater than the gravity force.
  • the direction of the path is determined by the direction of the electrostatic field.
  • the present invention proposes a method for the direct measurements of volume of the droplet which is not based on the detection or the timing of the drop-off but on direct measurement of the charge on the droplet.
  • the first phase is accelerating the valve boss fast from the initial position when the valve is closed by sending a short pulse of a large current through the coil or coils.
  • the duration of the first phase is typically in the range of 0.2 to 0.5ms.
  • the second phase is maintaining the valve in the open position and during this phase, the current in the coil is considerably reduced. The duration of the second phase mainly determines the volume of the droplet dispensed as demonstrated above.
  • the duration of the second phase of some 0.1 to 5ms would result in the volume of the droplets dispensed being in the range of 100 nl to some few microlitres.
  • the third phase is closing the valve with a short pulse of a high current. In the case of a specific dispenser constructed the duration of the third phase was typically in the range of some 0.2 to 0.4ms.
  • the fourth phase is maintaining the valve in the closed position, i.e. holding the boss against the seal for the duration between cycles. The value of the current during the fourth phase was typically in the range of some 20% of the peak current supplied through the coil/coils during the first and third phases.
  • Such a separation is advantageous as it allows getting the highest value of the actuating force from the coil or coils.
  • Driving a large current through a coil or coils over an extended length of time may cause overheating with a detrimental effect.
  • a much higher current value is acceptable.
  • a much higher current resulting in much higher actuating force is particularly suitable for dispensing of droplets of submicrolitre volumes.
  • a similar separation into separate phases can be advantageous during the aspiration of the liquids.
  • the dispenser By having the dispenser separate from the actuating coils etc., it is possible to produce a very low cost dispenser which can be easily and rapidly removed thus avoiding cost and cross contamination problems. There is thus great disposability with the present invention. It is also advantageous that the present invention can work at both high and low pressures.

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  • Physics & Mathematics (AREA)
  • Fluid Mechanics (AREA)
  • Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
EP20000650123 1999-11-11 2000-09-04 Distribution de gouttelettes de liquide Expired - Lifetime EP1099483B1 (fr)

Priority Applications (1)

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Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP19990650106 EP1099484B1 (fr) 1999-11-11 1999-11-11 Procédé et appareil de distribution de gouttes
EP99650106 1999-11-11
EP20000650123 EP1099483B1 (fr) 1999-11-11 2000-09-04 Distribution de gouttelettes de liquide

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1334770A1 (fr) * 2002-01-24 2003-08-13 Packard Instrument Company, Inc. Systeme de distribution precise de liquides
DE102004020864A1 (de) * 2004-04-28 2005-11-24 Jan Harnisch Tropfenerzeuger mit elektromagnetischem Wirkprinzip
DE10350614B4 (de) * 2003-10-30 2007-11-29 Bruker Daltonik Gmbh Dispenser
WO2008055256A2 (fr) * 2006-11-02 2008-05-08 The Regents Of The University Of California Procédé et appareil de commande de rétroaction en temps réel d'une manipulation électrique de gouttelettes sur une puce
WO2011090396A1 (fr) 2010-01-24 2011-07-28 Instytut Chemii Fizycznej Polskiej Akademii Nauk Système et procédé de production et de manipulation automatisées de mélanges liquides
EP2662139A1 (fr) * 2012-05-08 2013-11-13 Roche Diagniostics GmbH Soupape de distribution d'un fluide
WO2015143812A1 (fr) * 2014-03-28 2015-10-01 京东方科技集团股份有限公司 Appareil permettant d'étaler de la colle, procédé permettant d'étaler de la colle, et gel d'encapsulation de dispositif
CN105486885A (zh) * 2015-12-23 2016-04-13 云南大学 一种高精度喀斯特洞穴滴水传感器及其收集装置
TWI565528B (zh) * 2012-01-27 2017-01-11 Musashi Engineering Inc Droplet forming apparatus and droplet forming method
CN108970661A (zh) * 2018-07-23 2018-12-11 中冶武汉冶金建筑研究院有限公司 一种手动移液器
CN110075936A (zh) * 2019-05-27 2019-08-02 中国计量大学 一种基于电润湿原理的粒径可控的粘弹性液滴发生装置
CN111700632A (zh) * 2019-03-18 2020-09-25 西门子医疗有限公司 用于局部减弱x射线辐射的过滤系统、x射线仪器和用于局部改变x射线辐射的强度的方法
CN114642796A (zh) * 2020-12-19 2022-06-21 深圳麦克韦尔科技有限公司 主机和医疗雾化装置

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Cited By (24)

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Publication number Priority date Publication date Assignee Title
US7410615B2 (en) 2002-01-24 2008-08-12 Perkinelmer Las, Inc. Precision liquid dispensing system
EP1334770A1 (fr) * 2002-01-24 2003-08-13 Packard Instrument Company, Inc. Systeme de distribution precise de liquides
DE10350614B4 (de) * 2003-10-30 2007-11-29 Bruker Daltonik Gmbh Dispenser
DE102004020864A1 (de) * 2004-04-28 2005-11-24 Jan Harnisch Tropfenerzeuger mit elektromagnetischem Wirkprinzip
DE102004020864B4 (de) * 2004-04-28 2012-05-16 Jan Harnisch Tropfenerzeuger mit elektromagnetischem Wirkprinzip
US9266076B2 (en) 2006-11-02 2016-02-23 The Regents Of The University Of California Method and apparatus for real-time feedback control of electrical manipulation of droplets on chip
WO2008055256A2 (fr) * 2006-11-02 2008-05-08 The Regents Of The University Of California Procédé et appareil de commande de rétroaction en temps réel d'une manipulation électrique de gouttelettes sur une puce
WO2008055256A3 (fr) * 2006-11-02 2008-08-07 Univ California Procédé et appareil de commande de rétroaction en temps réel d'une manipulation électrique de gouttelettes sur une puce
WO2011090396A1 (fr) 2010-01-24 2011-07-28 Instytut Chemii Fizycznej Polskiej Akademii Nauk Système et procédé de production et de manipulation automatisées de mélanges liquides
TWI565528B (zh) * 2012-01-27 2017-01-11 Musashi Engineering Inc Droplet forming apparatus and droplet forming method
JP2015516084A (ja) * 2012-05-08 2015-06-04 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 流体を分注するための弁
US10252273B2 (en) 2012-05-08 2019-04-09 Roche Diagnostics Operations, Inc. Valve for dispensing a fluid
EP2662139A1 (fr) * 2012-05-08 2013-11-13 Roche Diagniostics GmbH Soupape de distribution d'un fluide
WO2013167578A1 (fr) 2012-05-08 2013-11-14 Roche Diagnostics Gmbh Robinet pour distribuer un fluide
US10121580B2 (en) 2014-03-28 2018-11-06 Boe Technology Group Co., Ltd. Gluing device, gluing method and colloid for packaging devices
WO2015143812A1 (fr) * 2014-03-28 2015-10-01 京东方科技集团股份有限公司 Appareil permettant d'étaler de la colle, procédé permettant d'étaler de la colle, et gel d'encapsulation de dispositif
CN105486885A (zh) * 2015-12-23 2016-04-13 云南大学 一种高精度喀斯特洞穴滴水传感器及其收集装置
CN105486885B (zh) * 2015-12-23 2023-06-20 云南大学 一种高精度喀斯特洞穴滴水传感器及其收集装置
CN108970661A (zh) * 2018-07-23 2018-12-11 中冶武汉冶金建筑研究院有限公司 一种手动移液器
CN111700632A (zh) * 2019-03-18 2020-09-25 西门子医疗有限公司 用于局部减弱x射线辐射的过滤系统、x射线仪器和用于局部改变x射线辐射的强度的方法
CN111700632B (zh) * 2019-03-18 2023-08-29 西门子医疗有限公司 用于局部减弱x射线辐射的过滤系统、x射线仪器和用于局部改变x射线辐射的强度的方法
CN110075936A (zh) * 2019-05-27 2019-08-02 中国计量大学 一种基于电润湿原理的粒径可控的粘弹性液滴发生装置
CN114642796A (zh) * 2020-12-19 2022-06-21 深圳麦克韦尔科技有限公司 主机和医疗雾化装置
CN114642796B (zh) * 2020-12-19 2023-07-07 深圳麦克韦尔科技有限公司 主机和医疗雾化装置

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