Chemical apparatus and process disinfecting – deodorizing – preser – Control element responsive to a sensed operating condition
Reexamination Certificate
2001-03-26
2003-12-30
Warden, Jill (Department: 1743)
Chemical apparatus and process disinfecting, deodorizing, preser
Control element responsive to a sensed operating condition
C422S105000, C436S180000, C073S863320, C073S863710, C073S864000, C073S864010, C073S864020, C073S864110, C073S864130, C073S864340, C251S129080, C251S129180, C137S487500
Reexamination Certificate
active
06669909
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a dispensing assembly for liquid droplets of the order of 30 &mgr;l in volume and as low as 10 nl or even smaller. Further, the invention is directed towards providing a method for dispensing such liquids and measurement of their properties.
The present invention relates to an assembly for dispensing and aspirating small volumes of liquid as used extensively for drug development in pharmaceutical, medical diagnostics, biotechnology and indeed small droplets of liquid as used extensively for many techniques in industry. Particular examples of this are High Throughput Screening (HTS), Polymerase Chain Reaction (PCR), combinatorial chemistry, microarraying, and proteomics, although obviously not limited to those. In the area of high throughput screening, PCR, proteomics and combinatorial chemistry, the typical application for such a liquid handling system is in dispensing of small volumes of liquids, for example, 1 ml and smaller and in particular volumes around 1 &mgr;l and smaller. The invention is also directed to the aspiration of liquids from sample wells so that the liquids can be transferred between wells. The invention relates also to microarray technology, a recent advance in the field of high throughput screening and genomics. Microarray technology is being used for applications such as DNA and protein 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 liquids of submicroliter volume. The present invention is also directed to medical diagnostics, for example, for applications such as single nucleotide polymorphism or others.
Development of instrumentation for dispensing of minute volumes of liquids has been an important area of technological activity for some time. Numerous devices for the controlled dispensing of small volumes of liquids (in the range of 1 &mgr;l and smaller) for ink jet printing application have been developed over the past twenty five years. More recently, a wide range of new areas of applications has emerged for devices handling liquids in the low microliter range.
The requirements of a dispensing system vary significantly depending on the application. For example, the main requirement of 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. On the other hand in this application 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.
For biomedical applications such as High Throughput Screening (HTS), the requirements imposed on a dispensing system are completely different. 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 liquids 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.
DETAILED DESCRIPTION OF PRIOR ART
The most common method of liquid handling for the HTS applications is based on a positive displacement pump such as described in U.S. Pat. No. 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 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 sample liquid and therefore cross-contamination, an air bubble or bubble of another gas is usually left between them. This method does not allow reliable dispensing of droplets in the volume range below some 1 to 5 microliters. Somewhat smaller volumes can be dispensed if the tip of the dispenser touches the substrate to release the drop. The compressibility of the gas bubble between the reagent and the system liquid is a significant source of error. Examples of such positive displacement pumps are shown in U.S. Pat. No. 5,744,099 (Chase et al). Similarly the problems of dispensing drops of small volume are also described and discussed in U.S. Pat. No. 4,574,850 (Davis) and U.S. Pat. No. 5,035,150 (Tomkins).
Dispensing of drops of liquids using a conventional solenoid valve is well known. It has been used in ink printing applications for more than a decade. As explained below, there are still major problems associated with the use of a conventional solenoid valve for dispensing of minute droplets of reagents for biomedical and pharmaceutical applications.
U.S. Pat. No. 5,741,554 (Tisone) describes another method of dispensing submicroliter 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 tubing at the other end which there is a solenoid valve located close to the ejection nozzle. The tubing is also filled with the fluid to be dispensed. In this method 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 &mgr;l per second and the repetition rate is 100 open-close cycles per second, then the size of each drop in theory is 10 nl. This method is suitable for dispensing of large number of identical droplets. However, for dispensing of liquids for HTS applications, this method is often inappropriate since it is commonly required to aspire a liquid through the nozzle in small quantities (say 1 &mgr;l) and then dispense it in fractions of this quantity, say in a series of only five drops or even a single drop on demand. To avoid mixing of the liquid aspired with the one in the syringe pump, it is probably necessary to place a bubble of gas in the tube with the attendant problems described above. Without such a bubble, if the solenoid valve open time and/or operating frequency are too small for a given pump flow rate, the pressure in the dispenser will become too great, causing possible rupture or malfunctioning of the system. Another disadvantage of this solution is that the heat from the coil actuating the plunger of the valve may cause a heating of the liquid in the valve that can be a serious problem for some applications. Besides, for some regimes of operation the drops may amalgamate, e.g. one drop will be released for every two or three actuations of the 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
Makarov Sergei
Osing Juergen
Shvets Alexander
Shvets Igor
Allegro Technologies Limited
Gordon Brian R.
Warden Jill
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