MXPA99000806A - Dispensing apparatus having improved dynamic range - Google Patents

Abstract

A method and apparatus (10) for dispensing precise quantities of liquid reagent (14) is disclosed including a positive displacement syringe pump (22) in series with a dispenser (12), such as an aerosol dispenser (12a) or solenoid valve dispenser (12b). The pump (22) is controlled by a stepper motor (26) or the like to provide an incremental quantity or continuous flow of reagent (14) to the dispenser (12). The pump (22) and dispenser (12) are operated in cooperation with one another such that the quantity and/or flow rate of liquid reagent (14) dispensed by the dispenser (12) can be precisely metered substantially independently of the particular operating parameters of the dispenser (12) to attain a desired flow rate, droplet size or mist quality, droplet frequency and/or droplet velocity.

Description

DISTRIBUTOR APPARATUS. THAT HAS AN IMPROVED DYNAMIC INTERVAL BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates, generally, to an improved method and apparatus for distributing chemical reagents and other liquids on a substrate and, in particular, to various methods and apparatus particularly adapted to distribute precise amounts of chemical reagents on a membrane. receiving, for example, to form a diagnostic test strip, having an improved dynamic operating range. 2. Description of the Prior Art The clinical tests of various bodily fluids, performed by medical personnel, are well-established tools for the diagnosis and medical treatment of various diseases and medical conditions. Such tests have become increasingly sophisticated, as medical advances have led to many new ways of diagnosing and treating diseases. The routine use of clinical tests for the classification and early diagnosis of diseases or medical conditions has led to an increased interest in simplified procedures for such clinical tests, which do not require a high degree of experience or that people can perform for themselves, with the purpose of acquiring information in the relevant physiological condition. Such tests can be carried out with or without consulting a health care professional. Contemporary procedures of this type include blood glucose tests, ovulation tests, blood cholesterol tests and tests for the presence of human chorionic gonadotropin in urine, the basis of modern household pregnancy tests. One of the most frequently used devices in clinical chemistry is the test strip or dipstick.These devices are characterized by their low cost and simplicity of use.In essence, the test strip is placed in contact with a sample of the fluid of the body to be tested Several reagents incorporated in the test strip react with one or more of the analytes present in the sample to provide a detectable signal. Many test strips are chromogenic, whereby a predetermined soluble constituent of the sample interacts with a particular reagent, or to form a single colored compound, as a qualitative indication of the presence or absence of the constituent, or to form a compound. of color with a variable intensity in the color, as a quantitative indication of the quantity of the present constituent. These signals can be measured or detected either visually or by means of a machine - specially calibrated. For example, test strips for determining the presence or concentration of leukocyte cells, esterase or protease in a urine sample, use chromogenic esters that produce an alcohol product, as a result of hydrolysis by esterase or protease. The intact chromogenic ester has a different color of the alcohol hydrolysis product. The color change, generated by the hydrolysis of the chromogenic ester, therefore provides a method to detect the presence or concentration of the esterase or protease, which, in turn, correlates with the presence or concentration of the cells - leukocytes. The degree and intensity of the color transition is proportional to the amount of leukocyte esterase or HLE detected in the urine. See the patent of E. U. A., No. 5,464,739. The emergence and acceptance of such diagnostic test strips ~~ as a component of clinical testing and health care, in general, has led to the development of a number of quality diagnostic test strip products. Also, the range and availability of such products will likely increase substantially in the future. Because the test strips ~ are used to provide both quantitative and qualitative measurementsIt is extremely important to provide uniformity in the distribution of the reagents in the substrate of the test strip. Chemicals are often very sensitive and medical practice requires that the test system be extremely accurate. When using automatic systems, it is particularly important to ensure that the test strips are reliable and that the measurements taken are quantitatively accurate. The application of one or more reagents to a test strip substrate is a highly difficult task. The viscosities and other flow properties of the reagents, their reactivity with the substrate or other reagents vary from one reagent to another, and often from one batch to another of the same reagent. It is also sometimes necessary or convenient to provide precise patterns of the reagent on the test strip, which have predetermined reagent concentrations. For example, some test strips supply multiple test areas that are arranged in series, so that multiple tests can be performed using a single test strip. The U.A. Patent No. 5,183,742, for example, discloses a test strip having multiple regions or detection zones, side by side, to simultaneously perform several tests on a sample of bodily fluid. Such a test strip can be used to determine, for example, levels of glucose, protein and the pH of a single blood sample. However, it is often difficult to form sharp lines or other geometric configurations that have uniform reagent concentrations. For several years, the industry has been developing distribution methods based on the use of air gun distributors or solenoid valve distributors. The air guns use pressurized air that flows through a needle valve that opens to atomize the reagent into a mist, which is then deposited on the test strip substrate. The quality of the mist, the pattern of dispersion of the reagent and the amount of the flow of the reagent on the substrate, are controlled by adjusting the opening of the needle valve and / or the pressure of the atomizing air flow. The solenoid valve manifolds comprise a small, solenoid-operated valve, which can be opened and closed electronically at high speeds. This solenoid valve is connected to a pressurized container or reservoir containing the fluid to be dispensed. In operation, the solenoid is energized by a pulse of electrical current, which opens the valve for a predetermined duty cycle or opening time. This allows a small volume of liquid to be forced through the nozzle, which forms a droplet, which is then expelled from the valve onto the target substrate. The size and frequency of the droplets and the amount of reagent flow on the substrate are typically controlled by adjusting the frequency and pulse width of the energy stream, provided for the solenoid valve and / or adjusting the reservoir pressure. However, the distribution methods, currently available, are limited in the flexibility they have to independently adjust and regulate the outlet of the distributor in terms of droplet size and mist quality, droplet velocity and flow rates of the reagent distributed. These flow rates can often vary due to changes in the temperature or viscosity of the reagent. This can cause unwanted variations from one batch to another of the coating concentrations of the reagent or coating patterns. Many reagents that are used for the diagnostic test are so reactive with the receptor membrane or substrate that large droplets can form impressions on the membrane surface at the point of initial contact, before the droplets flow together to form the desired pattern . As a result, it is sometimes convenient to distribute a fine mist or very small droplets of the reagent onto the substrate. Nevertheless, often a desired droplet size or fog quality simply can not be obtained for a desired flow rate of production. It is sometimes necessary, therefore, to carry out production operations of the test strips at slower speeds than the optimal ones, in order to ensure adequate results. This can significantly increase the cost of production. Certain distributors, such as solenoid valves, are also susceptible to changing by small air or gas bubbles, which are formed in the valve itself, or in the lines or conduits that supply the reagent or other liquids to the distributor. This is a major reliability problem with many conventional solenoid valve distributors. While some of these problems can be controlled or mitigated by the addition of surfactants or various other chemical additives to modify the surface tension or other flow characteristics of the droplets, compatible chemicals are not available for all reagents. Likewise, the use of surfactants and other chemical products can often lead to other problems, either in the test strip itself or in the distributor apparatus or production processes.

SUMMARY OF THE INVENTION The reagent dispensing method and apparatus, according to the present invention, can distribute desired quantities of chemical reagents or other liquids onto a substrate, such as a receptor membrane, while advantageously providing the ability to adjust, independently and precisely , droplet size or mist quality, droplet velocity and reagent flow regimes, in terms of either unit of time or unit of distance. Thus, the present invention provides new devices and methods for distributing precise quantities of liquids having an improved performance and dynamic range of operation. According to a preferred embodiment, the present invention comprises an improved apparatus for distributing precise quantities of liquid on a substrate. The apparatus comprises a distributor, having an inlet and an outlet, and adapted to form droplets of liquid having a predetermined size and / or quality. The droplets are emitted by the distributor in order to be deposited on a receptive substrate. A positive displacement pump is supplied in series with the inlet of the distributor, to dose predetermined quantities of liquid supplied to the distributor. In this way, the quantity and / or the rate of flow of the liquid distributed by the dispenser can be dosed accurately, independently, substantially, of the particular operating parameters of the dispenser. According to another preferred embodiment, the present invention comprises a method and apparatus for distributing a reagent onto a substrate. A positive displacement syringe pump is supplied in series with a reagent dispenser. The pump is controlled by means of a stepping motor or the like, to accurately deliver the incremental or continuous flow of reagent to the distributor. This distributor is selectively operated to form droplets or a mist of droplets of predetermined size and / or quality, which are then deposited on the target substrate. Advantageously, the size of the reagent droplets, fog quality, speed and / or flow rate can be controlled precisely, independently of the operating parameters of the particular system of the dispenser. According to another preferred embodiment, the present invention comprises an apparatus for distributing a liquid on a substrate, comprising a distributor having an inlet and outlet and a valve adapted to be opened and closed at a predetermined frequency and duty cycle, to form droplets that are deposited on the substrate. A positive displacement pump, such as a syringe pump operated by a stepping motor, is hydraulically disposed in series with the inlet of the manifold, to dose predetermined amounts of liquid to the manifold. The pump and the distributor are operated in mutual cooperation, so that the quantity and / or rate of flow of the liquid distributed by the distributor, can be dosed accurately, substantially independently of the particular operation parameters of the distributor. In this way, the size, frequency and speed of the droplets distributed by the distributor can each be adjusted substantially independently of the amount and / or flow regime of the liquid that is distributed.

According to another preferred embodiment, the present invention comprises an apparatus, as described above, in combination with a carriage adapted for movement X, X-Y or X-Y-Z, relative to the distributor. This dispenser and cart are arranged and controlled in a coordinated manner to form droplets of reagent, ink, liquid toner (toner) or other liquids, according to a predetermined desired pattern or matrix. If desired, an array of distributors and associated positive displacement pumps can be supplied and the outputs of the distributors arranged in a desired pattern., to obtain a desired print pattern or dot pattern. These and other embodiments and modes of carrying out the present invention will be readily apparent from the following detailed description of the preferred modes, with reference to the accompanying drawings, however, the invention is not limited to any particular preferred mode. BRIEF DESCRIPTION OF THE DRAWINGS Figure IA is a schematic drawing of a dispensing apparatus, accurately dosed, having the characteristics according to the present invention; Figure IB is a schematic drawing of an alternative embodiment of a dispensing apparatus, accurately dosed, particularly adapted for the operation "of continuous web production and having the characteristics according to the present invention, - Figures 2A and 2B are cross-sectional and detailed views, respectively, of an air gun dispenser, having the characteristics according to the present invention, - Figure 2C is a graphic representation of the substrate of the test strip of Figure 2B, illustrating the surface concentration of the distributed reagent and the concentration gradients resulting from the absorbed reagent; - Figure 3 is a cross-sectional view of a solenoid valve distributor, having the characteristics according to the present invention; a cross-sectional view of an optional piezoelectric distributor, which has the characteristics d In accordance with the present invention, - Figure 5 is a detailed cross-sectional view of the syringe pump of Figure 1; Figure 6 is a graph illustrating comparatively the range of flow rates that can be obtained with the accurately dosed aerosol dispenser apparatus constructed and operated in accordance with the present invention; Figure 7 is a schematic drawing illustrating two possible modes of operation of a solenoid valve manifold, constructed and operated in accordance with the present invention; Figure 8 is a schematic view of an electrostatic printer, for use in accordance with an embodiment of the present invention; and Figure 9 is a front elevational view of an optional manifold platform and a manifold manifold for use in accordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS FIG. IA is a schematic drawing of a dispensing device 10 accurately metered, having the characteristics according to the present invention. The dispensing apparatus 10 generally comprises a distributor 12 for distributing the reagent 14 from a reservoir 16 and a positive displacement syringe pump 22, intermediate the reservoir 16 and the dispenser 12 for accurately dosing the volume and / or flow rate of the reagent distributed. The distributor 12 is selectively operated to deliver individual droplets or a spray pattern of the reagent, as desired, to the predetermined incremental amount or dosed flow rate. Figure IB is a schematic drawing of an alternative embodiment of a precision metered dispensing apparatus, 10 ', particularly adapted for the web production operation,. and having the characteristics according to the present invention. For convenience of description and ease of understanding, similar reference numbers are used to refer to similar components, previously identified and described in Figure IA. The dispensing apparatus 10 'generally comprises a distributor 12' for distributing reagent 14 'from a reservoir 16'. As described above, the distributor 12 'can be operated "selectively to deliver individual droplets or a spray pattern of the reagent, as desired, in a predetermined incremental amount or dosed flow rate. syringe pumps, 22a, 22b, of positive displacement, in tandem, are arranged intermediate the reservoir 16 'and the distributor 12', to dose, accurately and continuously, the volume and / or flow rate of the distributed reagent. The pumps 22a, 22b are preferably connected in parallel, as shown, and are isolated from each other by appropriate check valves 24 ', so that each syringe pump 22a, 22b is capable of independently dosing a volume and / or rate of flow of the reagent to be distributed. This particular configuration of the distributor apparatus has significant advantages for web production applications, since the syringe pumps 22a, 22b can be operated in alternate succession while allowing the non-dispensing syringe pump to suck additional reagent 14 'from the reservoir 16'. In this way, the production of continuous band is facilitated without interruption. Of course, one or more additional syringe pumps may also be used in a similar manner, if desired, such as to distribute a wash fluid or other suitable reagents or fluids. Alternatively, if desired, one or more positive displacement continuous pumps, such as a peristaltic pump, can be used for continuous band production. The distributors, 12 and 12 ', described above, may comprise any of a number of suitable distributors, well known in the art, for dispensing a liquid, such as an air gun distributor, a solenoid valve distributor or a distributor piezoelectric. Several particularly preferred examples are described below for illustrative purposes. Those skilled in the art will readily appreciate that a wide variety of other suitable distributors can also be used to achieve the benefits and ventures taught herein.

Air Gun Distributor Figures 2A and 2B are cross-sectional and detailed views, respectively, of an air gun manifold 12a, for use in accordance with an embodiment of the present invention. a nozzle portion 32 and a manifold portion 34. This manifold 34 allows the compressed air to enter a first annular chamber 36 and allows the reagent to enter a second annular chamber 38, formed between a needle valve 40 and a corresponding orifice 42. Needle valve 40 is mounted within and extends through port 42, as shown.It is preferably axially adjustable, in accordance with well-known needle valve adjusting techniques. of needle 40 relative to the orifice 42, determines the effective size of the opening 43 resulting from the needle valve and thus the amount of reagent flow for a pre-differential The air under pressure flows over the opening 43 of the needle valve, creating a venturi effect, which sucks the reagent through the orifice 42 on the tip of the needle valve 40. The pressurized air is accelerated by passing the orifice 42 and the opening 43 of the needle valve over the tip of the needle 40. The resulting air at high velocity atomizes the reagent 14 flowing down the needle 40. This creates a aerosol mist 45, which is ejected from the nozzle 32 together with the excess air flow. In a conventional air gun dispenser, the volume of the reagent distributed by the nozzle 32 is determined by the pressure differential of the compressed air source relative to the atmospheric pressure, the size of the opening 43 of the needle valve and the viscosity and other flow characteristics of the reagent 14. However, according to one embodiment of the present invention, a positive displacement pump 22 is provided in series between the reservoir 16 and the air gun 12a, as shown in FIG. Figure 1. The orifice 42 now admits a reagent flow, as determined solely by the positive displacement pump 22. The reagent is ejected out of the orifice opening 42 and mixed with the pressurized air flowing out of the nozzle 32. Advantageously, according to the present invention, the absolute volume or flow rate is an input parameter controlled by the Dosing pump, rather than an output parameter, which must be calibrated by a trial and error setting. Thus, the air gun can be used to deliver precise quantities and flow rates of the reagent onto a test strip substrate. This substrate is preferably a receptor membrane, adapted to bind with the reagent to thereby form a diagnostic test strip. However, the substrate 30 may also be paper, cellulose, plastic or any surface, wet or dry, capable of receiving a distributed reagent or other liquid. As discussed in more detail below. a reagent distributor apparatus and a method using the combination of an air gun distributor and a metering pump, provides a new dimension of control that provides additional production capabilities that could not be achieved with conventional air gun dispensers . Unlike conventional methods of operation, an air gun manifold, which typically supplies only a single stable operating point for a given inlet opening of air pressure and needle valve, the method and apparatus of the present invention. Provides a wide range of dosed flow rates to achieve a stable dispersion pattern. The limits of this interval can be determined experimentally. An even wider range of production flow rates can be achieved using a single pressure setting and a series of adjustable orifice openings, as illustrated in Figure 6, discussed later. Figure 2C is a graphic representation of the test strip membrane 30 of Figure 2B, illustrating the surface concentration 46 of the absorbed reagent distributed and the resulting concentration gradients 48, in the membrane 30. For stable dispersion patterns, the concentration 46 of the surface reagent assumes a standard Gaussian distribution, as shown. The width or standard deviation of the distribution pattern will depend on the configuration of the dispersion pattern created by the nozzle 32 (Figure 2B). This is primarily dependent on the configuration of the outlet nozzle 32, the needle valve 40 and the inlet air pressure. Higher entry pressures will generally result in wider dispersion patterns.

Solenoid Valve Distributor Figure 3 is a cross-sectional view of a solenoid valve manifold 12b, for use in accordance with another embodiment of the present invention. Solenoid valve manifolds of this type are commonly used for inkjet printing and are commercially available from sources, such as The Lee Company, of Estbroo, Connecticut. The distributor 12b generally comprises a portion 32 of solenoid and a valve portion 34. This portion 32 of solenoid comprises an electromagnetic coil or winding 36, a static core 38 and a movable plunger 40. The static core 38 and the movable plunger 40 are disposed within a hollow cylindrical sleeve 41 and are preferably spaced apart, at least slightly apart , from the inner walls of the sleeve 41, so as to form an annular passage 42, through which the reagent and another liquid to be distributed, can flow. The static core 38 and the movable plunger 40 are preferably formed of a ferrous or magnetic magnetic material, such as iron, and are separated by a small gap 44. Those skilled in the art will appreciate that when the solenoid coil 36 is energized, a magnetic field is created which drives the plunger 40 towards the static core 38, closing the gap 44 and opening the valve 34. The valve portion 34 comprises a valve seat 52, having a hole opening 54 and "a shutter" 56, having a valve face 58 adapted to seal against the valve seat 52. This plug 56 is in mechanical communication with the plunger 40 and is spring-oriented towards the valve seat 52 by means of the coil spring 60. Again , those skilled in the art will readily appreciate that as the plunger 40 moves up and down, the valve 34 will open and close correspondingly.Also, each time the valve 34 is opened and closes, a volume of liquid is forced through the valve orifice 54 to form a pressure wave pulse, which ejects a droplet of liquid from the exit orifice 61 of the nozzle tip 59. Conventionally, a pressurized reservoir (not shown), having a predetermined constant pressure, is used to force the liquid reagent or other liquid through the valve orifice 54, during the time interval in which the valve 34 opens. Under controlled conditions, these distributors can have a repeatability of + 2% with a minimum fall size of around 30-35 nanoliters. The size of the droplet will be determined by the operating parameters of the system, such as the reservoir pressure, valve opening time or duty cycle, and the viscosity and other flow characteristics of the particular reagent or liquid that is distribute. Of course, certain fixed parameters, such as the size and configuration of the nozzle 59, will also play an important role in the operational characteristics of the valve, in terms of droplet size and reproducibility. However, in In general, the size of the droplets will increase with the pressure of the increasing deposit and the opening time of the valve. However, according to the present invention, a positive displacement pump 22 is provided in series between the supply reservoir 16 and the solenoid valve distributor 12, as shown in Figure 1. For a given range of regimes of flow, the orifice 54 of the valve (Figure 3) now admits a quantity and / or rate of flow of the reagent, as determined solely by the positive displacement pump 22. For example, the flow rate can be adjusted to deliver 1 microlitxo per second of reagent. The pump 22 will then deliver a constant flow of reagent to the distributor 12b of the solenoid valve at a programmed rate. As the solenoid valve is opened or closed, a series of droplets will be formed at a desired volume flow rate and ejected onto the target substrate 30. This substrate is preferably a receiving membrane, adapted to join with the reagent, in order to form a diagnostic test strip. Alternatively, the substrate 30 can be paper, cellulose, plastic or any other surface, wet or dry, capable of receiving a distributed reagent or other liquid. Advantageously, within a certain range of operation, the size of the droplets can be adjusted without affecting the flow rate of the reagent, by simply changing the frequency of the energy pulses 13, provided to the distributor 12b of the solenoid valve. Of course, there are physical limitations of the opening time of the valve or the work cycle, necessary to achieve stable formation of droplets. If the opening time is too short in relation to the flow rate provided by the metering pump 22, the pressure will increase and possibly prevent the valve from opening or operating properly. If the opening time "" is too long relative to the flow rate, then the droplet formation may not be uniform for each opening / closing cycle. However, for a given flow rate of the reagent, provided by the pump 22, there will be a range of compatible frequencies and / or valve opening times or work cycles in which stable distribution operations can be achieved at the regime of desired flow and the size of droplets. This interval can be determined experimentally for an adjustment of a given production. Another significant advantage of the present invention is that the velocity of the individual droplets can be adjusted independently without affecting the reagent flow rate or droplet size. This can be achieved, for example, by varying the duty cycle of the energy pulses 13 provided to the solenoid valve distributor 12b. For example, at a drop volume of 83.3 ni, the drop can be formed using 20 syringe passages with a valve opening using a 100 μl syringe and with a resolution of 24,000 steps. Using an opening time of 5% will result in a higher speed of drops than using an opening time of 7%. This is due to the fact that with the shortest opening time, the accumulated pressure in the hydraulic line is greater than 7%.

Again, there are physical limitations possessed by the length of the work cycle necessary to achieve stable formation of droplets, as mentioned above. However, for a given flow rate and droplet size there will be a range of compatible duty cycles, in which stable distribution operations can be achieved at the desired flow rate, droplet size and velocity. Again, this interval can be determined experimentally for a given production adjustment. As discussed in more detail below, the distribution of a reagent using a combination of a solenoid valve manifold and a metering pump provides a new control dimension that provides additional production capabilities, which can not be achieved with conventional dispensers. Solenoid valve. Unlike conventional solenoid valve manifolds, which typically have only a single flow rate or operating point for a given set of system operating parameters (eg, reservoir pressure, valve frequency and duty cycle) , the present invention provides a broad dynamic range of dosed flow rates, droplet size, droplet frequency and droplet velocity, to achieve the stable distribution operation. Also, because the solenoid valve distributor 12d is forced to deliver precise quantities and / or flow rates of the reagent, the solenoid valve manifold is not as susceptible to clogging due to air or gas bubbles. . Rather, any air or gas bubble tends to be condensed or ejected out of the solenoid valve manifold 12b by the operation of the positive displacement pump 22.

Piezoelectric Distributor Figure 4 shows a cross-sectional view of an optional piezoelectric distributor 12c, which may also have an advantageous use in accordance with the present invention. This piezoelectric distributor generally comprises a capillary tube 84 made of glass or other suitable material and a piezoelectric constrictor 86, disposed about the capillary tube 84, as shown. The capillary tube 84 has a nozzle portion 88 of reduced diameter. When the capillary tube 84 is constricted by the piezoelectric constrictor 86, droplets are formed in the outlet orifice 89 of the nozzle portion 88. Advantageously, the dynamics of the piezoelectric distributor 12c are such that it is capable of operating at higher frequencies and cycles. Work shorter than typical solenoid valve dispensers, resulting in even smaller droplets. The operation of the piezoelectric distributor, in terms of adjustment of the droplet size, frequency, velocity and flow rates, is substantially the same as that described above in relation to the distributor 12b of the solenoid valve of Figure 3 and, therefore, Therefore, it will not be repeated here.

Syringe Pump A positive displacement pump, for use in accordance with a particular embodiment of the present invention, may be any of the various varieties of pumping devices, commercially available, for dispensing precise quantities of liquid. A syringe-type pump 22, as shown in Figures IA and IB, is preferred because of its convenience and commercial availability. A wide variety of other pumps can be used, however, to achieve the benefits and advantages described herein. They may include, without limitation, rotary pumps, peristaltic pumps, flexible plate pumps, and the like. As discussed in greater detail in Figure 5, the syringe pump 22 generally comprises a syringe housing 62 of a predetermined volume and a plunger. 44, which is sealed against the syringe housing by O-rings, or the like. The plunger 64 is mechanically coupled to a plunger shaft 66, having a portion of guide screw 68, adapted for screwing and unscrewing a base support (not shown). Those skilled in the art will readily appreciate that as the screw portion 68 of the plunger shaft 66 is rotated, this plunger 64 will move axially, forcing the reagent from the syringe housing 62 into the outlet tube 70. Any number of suitable motors or mechanical drives can be used to drive the guide screw 68. Preferably, a stepping motor 26 (Figure 1) or other incremental or continuous device is used, so that the amount and / or flow rate of the reagent can be precisely regulated. Suitable syringe pumps are commercially available, such as the Bio-Dot CV1000 Syringe Pump Distributor, available from Bio-Dot, Inc., of Irvine, California. This particular syringe pump incorporates an electronically controlled stepping motor, to deliver the precise handling of a liquid, which uses a variety of syringe sizes. The CV1000 is energized by a single 24 volt DC power supply and is controlled by an industry standard RS232 or RS485 collector interface. The syringe pump can have any of 3,000 to 24,000 steps, although higher resolution pumps, having 48,000 steps or more, can also be used to enjoy the benefits of the invention disclosed herein. Higher resolution pumps, such as piezoelectric pumps, can also be used to deliver even finer resolutions, as desired. The guide screw 68 can optionally be equipped with an optical encoder or similar device to detect any lost stage. Alternatively, the guide screw of the dosing pump can be replaced with a piezoelectric cursor to provide both smaller volume increases as well as faster acceleration / deceleration characteristics. Multiple syringe pumps may also be used in parallel, for example, to deliver various concentrations of reagent and / or other liquids to the distributor or to alternate distribution operations between two or more reagents. This may have application, for example, for inkjet printing, using one or more colored liquid inks or toners (toner). The travel of the plunger 64 is preferably about 60 mm. Piston speeds can vary from 0.8 seconds per stroke, with a minimum of 10 steps for low resolution pumping, or 1.5 seconds per stroke with a minimum of 20 steps for high speed resolution pumping. The stroke speed may vary, depending on the size of the syringe and the tubing used. Syringes can vary from less than 50-microliters to 25 milliliters, or more as needed. For most reagent distribution applications, it should be suitable to supply a syringe having a volume of approximately 500 microliters to approximately 25 milliliters. The minimum incremental displacement volume of the pump will depend on the - resolution of the pump and the volume of the syringe. For example, for a housing volume of the 500 ml syringe and a resolution pump of 12,000 steps, the minimum incremental displacement volume will be around 42 nanoliters. Minimum incremental displacement volumes of approximately 2.1 nanoliters to 2.1 milliliters are preferred, although larger or smaller incremental displacement volumes may be used while still benefiting from the benefits of the present invention. The syringe housing 62 can be fabricated from any of a number of suitable biocompatible materials, such as glass, Teflon ™ or Kel-F. The plunger 64 is preferably formed from virgin Teflon ™. Referring to Figure 1, the syringe is connected to the reservoir 16 and the dispenser 12 using a Teflon tubing 23, such as a tubing with an external diameter of 6.35 mm, provided with Luer-type fittings for connection to the syringe and distributor. Several check valves 24 or shut-off valves 25 may also be used, as desired or necessary, to direct the flow of the reagent to and from the reservoir 16, the syringe pump 22 and the dispenser 12c.

Reagent Tank Reagent reservoir 16 may be any of a number of suitable receptacles, capable of allowing a liquid reagent 14 to be siphoned to pump 22. The reservoir may be pressurized, as appropriate, but it is preferable that it be open to the atmosphere, as shown, by means of a vent opening 15. The particular size and configuration of the reservoir 16 are not relatively important. A siphon tube 17 extends downwardly within the reservoir 16 to a desired depth sufficient to allow siphon action of the reagent 14. Preferably, the siphon tube 17 extends as deep as possible into the reservoir 16, without causing the blocking the lower inlet portion of the tube 17. Optionally, the lower inlet portion of the tube 17 can be cut at an angle or have other characteristics, as necessary or convenient, to provide a consistent and reliable siphon action of the reactive 14.

Operation As indicated above, a key operating advantage "reported by the present invention is that over a certain dynamic range of reagent flow, droplet size or mist quality, droplet frequency and / or droplet velocity, which they can be controlled substantially independently of each other and of the characteristics of the particular flow of the reagent and the operation parameters of the distributor 12. For example, the size of the droplets formed by the distributor can be adjusted without affecting the flow regime of the reagent dosed by the pump, changing the operating frequency (for the solenoid valve or the piezoelectric distributor) or adjusting the size of the outlet orifice (for an air gun distributor) The quantity or flow rate of the distributed reagent is not affected substantially, because it is precisely controlled by the positive displacement pump 22. This has the particular advantage, for example, in applications that require the distribution of very small droplets or to distribute reagents of higher viscosity, since the flow of the reagent can be controlled accurately without substantially affecting the operating parameters of the system, otherwise required for achieve stable distribution operations. Figure 6 illustrates comparatively the range of flow rates and operating conditions for openings with a given orifice, which can be obtained according to the present invention, with the use of an air gun distributor, versus conventional methods of distribution, they use this air gun distributor. Similarly, with a conventional solenoid valve manifold, in order to obtain very small droplets, one should try to shorten the opening time or duty cycle of the valve. However, as the opening time of the valve is shortened, the flow rate of the reagent decreases, so that the cycle frequency of the valve must be increased for compensation. At a certain point, the reagent flow characteristics will limit the ability to achieve uniform formation of the droplets, when the valve opening time is very small. Also, even if the stable distribution operation can be achieved by increasing the reservoir pressure, such increased pressure will tend to increase the size of the drops and the flow rate of the reagent., still needing further adjustments to achieve the stable distribution operation in the desired flow regime and droplet size. However, the present invention overcomes these and other problems of the prior art by accurately dosing the amount and / or flow rate of the reagent. Advantageously, the amount of the reagent can be precisely regulated over a wide dynamic range, without being substantially affected by the particular operating parameters of the dispenser. This feature makes it possible to drastically vary droplet size, droplet frequency, droplet velocity and other system parameters, from one interval to another with a given flow rate. Thus, the present invention not only provides a method for accurately dosing the reagent, but also adds a new operation dimension to the dispenser, not being possible previously. Another important operational advantage is that the range of droplet sizes, which can be obtained with the present invention, is much wider than that achieved with conventional solenoid valve dispensers. The method and apparatus of the present invention, using the solenoid valve manifold, for example, is capable of achieving minimum stable droplet sizes in the range of 1 to 4 nanoliters, compared to 30 to 35-nanoliters for most of conventional solenoid valve manifolds. In principle, even smaller droplet sizes (of the order of 0.54 nanoliters or less) can be obtained according to the present invention, with the use of syringe pumps having a resolution of 48,000 steps and a syringe volume of 25 microliters. Droplet experiments have demonstrated the ability to distribute 4.16 nanoliter droplets with very good repeatability, using a nozzle 59 (Figure 3) having an exit orifice 61 of about 175 microns in diameter. A smaller exit orifice 61 having a diameter in the range of 75 to 125 microns, should provide the stable formation and even smaller droplet distribution, according to the present invention. On the other hand, with the same setting, one can program drop sizes or volume delivered up to the size of 1 μl, by pressing the syringe many times per valve opening and increasing the valve opening time to allow a larger volume to flow through the open valve. For example, for a drop size of 4.16 ni, the preferred setting will be 1 syringe step, 1 valve opening and the opening time will be 2% or about 0.2 millisecond. For a droplet size of 1,000 ni or 1.0 μl, the preferred setting will be 24-0 syringe steps, 1 valve opening and the opening time will be in the range of 25% -30% or 2.5 to 3.5 milliseconds. One can also deliver larger volumes in high frequency inflows of smaller drops. For example, one can deliver 4.16 μl as 100 drops of 41.67 ni, each using a frequency of 100 Hz and an opening time of -6% or 0.6 milliseconds. Thus, the range of droplet sizes that can be obtained for a stable distribution operation can vary by a factor of about 250 or more. This feature of the present invention has particular advantage for the manufacture of high production and process of diagnostic test strips. In certain production applications, for example, it may be convenient to distribute very small droplets or fine mists of the reagent, to provide optimum coating characteristics. At the same time, it may be convenient to provide high reagent flow rates for increased production levels. With a conventional solenoid valve distributor, for example, to increase the output flow rate, the valve frequency or the valve opening time length, must be increased. But the longer the valve opening time, the greater the droplets. There is also an operating limit for a given valve and the outlet orifice of how short the valve opening time can be and how high the operating frequency can be within stable operation is still obtained. However, the present invention allows the use of much shorter valve opening times, to obtain a stable operation at high flow rates, positively displacing the reagent through the valve opening. In other words, the flow of the reagent is not substantially affected by the particular operating frequency of the valve or the length of the opening time. It is dependent only on the displacement of the syringe pump, which acts as the forced function for the whole system. Of course, as mentioned above, there will be a maximum range of operation for a solenoid valve manifold, which operates at a given operating frequency and valve opening time. The upper limit will be the maximum amount of reagent that can be forced through the valve at a design maximum pressure for a given operating frequency and valve opening time. The lower limit will be determined by the stability of the droplet formation. If the opening time of the valve and / or the operating frequency are too small for a given flow rate, the pressures in the distributor will become too large, causing possible breakdown or malfunction of the system. valve opening and / or operating frequency are too large for a given flow rate, the droplet formation may not be uniform for each opening / closing cycle, however, for a given luxury regime of the reagent provided by the pump 22, there will be a range of compatible frequencies and / or valve opening times for which stable operation can be achieved.This interval can be determined experimentally, adjusting the operating frequency and the opening time of the valve to achieve stable formation of droplets Similar advantages can be achieved with air pistol distributors or other types of distributors.

XYZ Distribution Platform In a particularly preferred mode of operation, a distributor can be integrated into an X, XY or XYZ platform, in which the programmed motion control can be coordinated with the dosing pump to deliver a desired volume per unit length, with the ability to also independently control the frequency and size of droplets of the reagent that is distributed. For example, it is possible to deliver a reagent at a rate of 1 microliter per centimeter at a constant rate, with a droplet size ranging from 4 to 100 nanoliters. The droplet size for a given flow rate of a distributor can be controlled by adjusting the operating frequency of the solenoid valve. In this 'context, there are several particularly convenient modes of operation: (1) online or continuous distribution; (2) distribution of zone or "points"; (3) aspiration and (4) 1-dot matrix printing. Each of these preferred modes of operation are directed below: Continuous distribution In the "continuous distribution mode," the dosing pump is set to a prescribed flow rate, to deliver a volume of reactant volume per unit time. For example, the flow rate can be programmed to deliver 1 microliter per second. The syringe then pumps the reagent to the solenoid valve 12 at a predetermined rate. By opening and closing the valve during this flow, the droplets will be formed according to the opening time and the operating frequency of the valve. Thus, in continuous distribution mode, the system is only able to deliver accurately metered flow rates, but this can be done with independent control of table speed, reagent concentration per unit length, and droplet size . If the solenoid valve manifold is placed very close to the substrate, as shown in Figure 7 (left), then the reagent will flow directly onto the substrate, supplying a continuous line. This continuous mode of operation can provide a particular advantage when reagent patterns, which have very sharp lines are necessary or convenient. "If desired, a continuous pulse reagent pump can also be used to ensure a constant flow of reagent to the solenoid valve distributor Most commonly, however, the solenoid valve manifold will be spaced at least slightly away from the substrate, as shown in Figure 7 (right) In this mode, discrete droplets will form , which are ejected on the substrate to form the desired pattern The size of each droplet will determine the effective resolution of the resulting pattern formed on the substrate.It is convenient to express this resolution in terms of dots per inch (2.54 cm) or "dpi" The present invention must be capable of delivering resolutions in the range of 300 to 600 dpi or more.

Point Distribution In the point distribution mode, individual droplets can be distributed in previously programmed positions. This can be achieved by synchronizing the solenoid valve and the displacement pump with the X, X-Y or X-Y-Z platform. The dosing pump is increased to create a hydraulic pressure wave. The solenoid valve is coordinated to open - and close at predetermined times, in relation to the pump increment. The valve may be open initially, or before or after the pump is increased. While the valve is open, the pressure wave pushes a volume of fluid down to the nozzle that forms a droplet in the outlet orifice at the time of the peak pressure amplitude. The droplet will have a size determined by the incremental volume supplied by the dosing pump. For example, a 50 microliter syringe pump, with a resolution of 12,000 steps, will provide an incremental displacement volume of 4.16 nanoliters. The time and duration of each valve cycle relative to the hydraulic pressure wave, created by the pump, can be determined experimentally to achieve the stable distribution operation, which has the desired droplet size. If the wavelength of the hydraulic pressure wave is too large in relation to the opening time of the valve, the pressure wave can actually force the closing of the valve. If the wavelength is approximately equal to or shorter than the valve opening time, then a pulse of fluid will be displaced, forming a droplet. Again, the size or volume of the droplet will be determined primarily by the incremental displacement volume of the syringe pump. If the valve opening time is large in relation to the pressure wavelength, then several pulses or displacements may travel through the valve during the time it is opened. This may be acceptable, or even convenient, for some applications, such as where droplet gusts are convenient at a programmed valve frequency. For example, the dispensing apparatus can be programmed to produce 10 drops at 100 Hz to provide a droplet size composed of about 41-5 nanoliters. This mode of operation can provide the ability to distribute descending droplet sizes to less than 1 nanoliter, with the appropriate nozzle design. It will depend on the resolution of the dosing pump and the minimum opening / closing time of the valve and the size of the outlet orifice. If the valve is left open for too long a time, however, then the system may not maintain enough pressure to eject the droplets. To achieve the most stable distribution operation, the valve opening time must be almost consistent with the volume of droplets or the volume of droplets distributed. The time, frequency and duty cycle of the solenoid valve in relation to the syringe pump and the carriage / moving platform, can be coordinated or synchronized by any of a number of controllers, well known in the art. Typical controllers are microprocessors based and provided by either a number of output control pulses or electrical signals of predetermined phase, pulse width and / or frequency. These signals can be used, for example, to control and coordinate the syringe pump, carriage / mobile platform and distributor of the solenpide valve, in accordance with the present invention. There may also be some optimum timing of the pressure pulse relative to the -opening / closing times of the solenoid valve. Stable operation has been observed, for example, when the valve opening time is adjusted to be a multiple multiple of the pulse width of the pump increment, with the opening / closing time of the valve being synchronized to be in phase with the resulting pressure wave. For example, with a 50 microliter syringe pump, which operates at a resolution of 12,000 steps, the incremental displacement volume will be about 4.16 nanoliters. Therefore, stable operation should be possible with droplet sizes of some multiple of 4.16 nanoliters. The minimum droplet size for stable operation can be increased or decreased correspondingly by adjusting the resolution of the pump or increasing the size of the syringe. For a large drop, for example of 9 x 4.16 nanoliters = 33.28 nanoliters, it may be preferred to open the valve more than for the smaller droplets, in order to obtain more uniform lines and a stable operation. Again, the range of the stable operation can easily be determined experimentally for each desired mode of operation.

Aspiration Another preferred mode of operation is the aspiration ("suction") of precise quantities of reagents or other liquids, from a sample or reservoir. This mode can be used, for example, in a "suction and division" operation, by which a precise amount of fluid is drawn from a scratch that contains a sample fluid and then distributed in another vial or on a test strip. Diagnostic for the test or further process. The distributor / aspirate can be a simple nozzle or needle ("suction pipe") or, more preferably, it may be a solenoid valve distributor. The dosing pump and the distributor / vacuum cleaner are preferably synchronized or coordinated with a mobile platform X, X-Y or X-Y-Z. In operation, the dosing pump is filled with a washing fluid, such as distilled water. The tip of the distributor or suction tube is placed inside the fluid to be sucked and the metering pump is decremented to suck a precise amount of fluid into the tip of the distributor or suction tube. It is generally convenient to suck only a small volume of reagent into the tip of the solenoid valve manifold that does not pass inside the valve. The metering pump is then increased to distribute a precise portion of the fluid within a receptacle or receiving substrate. The remaining fluid is distributed in a waste / wash receptacle, along with a predetermined amount of the wash. This ensures that the fluid sample is not diluted with the wash fluid and the sample is cleaned after each cycle of aspiration and distribution. This mode of operation has the particular advantage of distributing reagents with high viscosity. Conventional solenoid valve manifolds typically do not work very well with solutions that have a viscosity above about 5 centipoise. However, there are many applications where it is desirable to distribute reagents that have high viscosities. Advantageously, the present invention, when used in the suction / distribution mode, provides a solution to this problem. Again, in the suction / distribution mode, the system will be filled with a wash fluid, such as water, or a water-based solution, which has a low viscosity. The reagent is first aspirated and then distributed, followed by the washing of the valve distributing the excess washing fluid. In the case of a viscous reagent, the present invention can suck and distribute such reagents very effectively, decreasing the aspiration rate. This allows more time for the more viscous fluid to flow into the distributor tip of the solenoid valve or suction tube. Because the viscous liquid will then be hydraulically coupled to the wash fluid, it can now be dispensed from the nozzle effectively, since the system is driven by the positive displacement and the fluids are incompressible.Using this mode, the present invention can distribute reagents of a viscosity that typically could not be directly distributed.

Printing Another possibly advantageous mode of operation may be to use the droplet dispensing capability of the present invention in connection with electrostatic, dot matrix, or other printing techniques to create printed patterns, lines, and other geometric configurations on a substrate. In this case, the metering pump can be used as an internal force function to quantitatively control the droplet size of each point in a matrix pattern. By overlaying the programmed distribution frequency function and selective loading and deviation of the droplets, the present invention can provide drop demand printing, which has extended capabilities for finer point sizes and print resolution. For example, a distributor 10", which has the features of the present invention, can be used in conjunction with an electrostatic print head 200, as shown in Figure 8, to create a dot matrix pattern on a substrate. The dispensing apparatus can be programmed to distribute droplets of a predetermined size and frequency pattern. These droplets can be charged electrically so that they can be deflected by an electric field, generated between a pair of deflection plates 210. The amount of charge placed in a droplet is variable, and thus, the amount of deviation is also variable. The electronic elements can be arranged and adjusted so that the droplets can be placed in any number of predetermined positions. The loading and selective deviation of individual droplets can be used to form a desired pattern of dot matrix, as shown. Alternatively, multiple distributors and pumps can be arranged to form an array of distributors with droplet demand, for simple dot matrix printing operations.

Distribution Platforms As mentioned above, the dispensing apparatus, according to the present invention, can also be mounted in any of a number of membrane placement and handling modules. For example, a single platform 100 can be used to mount multiple distributors to handle one or more reagents, as shown in Figure 9. Such distribution platforms can be microprocessor-based and are preferably controlled through the input / output controller. industry standard (not shown), such as an RS232 interface. A remote programmable controller 110 may also be used, as desired, to control the various distribution equipment and platforms or to program a central input / output controller. The invention is also very suitable for use with modules for handling individual membrane strips and continuous handling modules from one reel to another. An individual membrane strip module can incorporate a X-Y table movement for distribution. The reel to reel platform can incorporate a constant velocity membrane transport, with assemblies attached to the movement of one or more distributors. A drying oven (not shown) can also be used to increase the total production, as desired. It will be appreciated by those skilled in the art that the methods and apparatuses described, according to the present invention, can be used to distribute a wide variety of liquids, reagents and other substances and a variety of substrates. Although the invention has been described in the context of certain preferred embodiments, those skilled in the art will readily appreciate that the present invention extends beyond the modalities specifically described to other alternative embodiments of the invention. Thus, it is intended that the scope of the invention is not limited by the particular embodiments disclosed, described above, but will be determined only by a reasonable reading of the claims that follow.

Claims (27)

1. An apparatus for distributing predetermined amounts of liquid on a substrate, this apparatus comprises: a dispenser, having an inlet and an outlet, and adapted to form droplets of the liquid, having a predetermined size and / or quality, which deposit on the substrate; and a positive displacement pump, hydraulically arranged in series with the inlet of the distributor, for dispensing predetermined quantities of the liquid to the distributor; whereby the quantity and / or flow regime of the liquid distributed by this distributor, can be accurately dosed, in a manner substantially independent of the parameters of the particular operations of the distributor.

2. The apparatus of claim 1, wherein the dispenser comprises an aerosol dispenser, having an outlet comprising an air passage terminating in a nozzle, and an inlet comprising a passage of liquid ending in a venturi orifice, mixing the liquid with an air flow, to form an aerosol mist close to the substrate.

3. The apparatus of claim 1, wherein the dispenser comprises a valve adapted to be opened and closed at a predetermined frequency and duty cycle, to form liquid droplets, which are ejected on the substrate.

4. The apparatus of claim 3, wherein the valve is actuated by an electric solenoid.

5. The apparatus of claim 3, wherein the valve is actuated by a piezoelectric constrictor device.

6. The apparatus of claim 3, wherein the frequency and duty cycle of the valve can each be adjusted substantially independently for a given amount or flow rate of the liquid, to produce droplets of one size, frequency and / or Desired speed of departure.

7. The apparatus of claim 1, in combination with a carriage, adapted for movement X, X-Y or X-Y-Z, relative to the dispenser, for movably transporting the substrate and where this dispenser is mounted in juxtaposition with the carriage.

8. The combination of claim 7, further comprising a controller in communication with the positive displacement pump and the carriage, to coordinate the output of the pump with the movement of the carriage, so that the liquid can be distributed in precise quantities of the flow per unit length, and such flow can be accurately dosed substantially, without being affected by the particular parameters of the distributor's operation.

9. The combination of claim 8, further comprising an array of distributors and positive displacement pumps, the outputs of the distributors are arranged in a desired pattern, suitable for obtaining a desired print pattern or dot pattern.

10. The apparatus of claim 1, wherein the positive displacement pump comprises a jigging pump.

11. The apparatus of claim 10, wherein the syringe pump comprises a syringe housing, a plunger, which can be moved axially within the syringe housing, and a stem of the plunger, having a guide screw formed therein.

12. The apparatus of claim 11, wherein the guide screw is sized and positioned so that when this guide screw is rotated, the plunger moves axially, causing a predetermined amount of the liquid to be delivered to the inlet of the distributor.

13. The apparatus of claim 12, wherein the positive displacement pump further comprises a stepping motor, adapted to cause "the pump to distribute incremental quantities or predetermined flow rates of the liquid to the distributor.

14. The apparatus of claim 1, further comprising a second positive displacement pump, hydraulically coupled to the first positive displacement pump, to "supply the production capacity in the form of a continuous band.

15. The apparatus of claim 1, wherein the distributor and the positive displacement pump are configured and adjusted to thereby provide a range of selectable droplet sizes, which can be obtained for stable operation and varying by a factor greater than about 250.

16. The apparatus of claim 15, wherein the distributor and the positive displacement pump are configured and adjusted to provide "selectable droplet sizes, ranging from less than about 4.2 nanoliters to greater than about 1 microliter.

17. An apparatus for distributing a liquid on a substrate, this apparatus comprises: a manifold, having an inlet and a seal and a valve adapted to be opened and closed at a predetermined frequency and duty cycle, to form liquid droplets, which they are deposited on the substrate; and a positive displacement pump, hydraulically arranged in series with the inlet of the distributor, to dose predetermined quantities of the liquid-to the distributed; whereby the quantity and / or the flow rate of the liquid distributed by the distributor, can be dosed substantially independently of the particular operation parameters of the distributor.

18. The apparatus of claim 17, wherein the size, frequency and speed of the droplets distributed by the dispenser can each be adjusted substantially independently of the amount and / or flow rate of the liquid to be dispensed.

19. The apparatus of claim 17, wherein the valve is actuated by an electric solenoid.

20. The apparatus of claim 17, wherein the valve is actuated by a piezoelectric constrictor device.

21. The apparatus of claim 17, wherein the frequency and duty cycle of the valve can each be adjusted substantially independently for a given amount or flow rate of the liquid, to produce droplets of one size, frequency and / or Desired speed of departure.

22. The apparatus of claim 17, wherein the positive displacement pump comprises a syringe pump.

23. The apparatus of claim 22, wherein the positive displacement pump further comprises a stepping motor, adapted to cause the syringe pump to distribute predetermined incremental amounts or flow rates of the liquid to the dispenser.

24. The apparatus of claim 23, wherein the distributor and the positive displacement pump are configured and adjusted to thereby provide a range of selectable droplet sizes, which can be obtained for stable operation and varying by a factor greater than about 250.

25. A method for distributing a liquid on a substrate, this method comprises the steps of: mobile transporting the substrate; metering a predetermined amount or flow rate of the liquid, using a positive displacement element; supplying the dosed flow rate or quantity to a distributor, to form droplets of a predetermined size and / or quality, which are deposited on the substrate; and regulating the dosage of the predetermined amount or flow rate of the liquid and the transport of the substrate, so that the density of the liquid deposited on the substrate is controlled independently in terms of volume per unit length of the "substrate.

26. The method described in claim 25, wherein the droplets are in the approximate range of 4 nanoliters to about 1 microliter. "

27. The method described in claim 25, wherein the sizes of the droplets, which can be obtained, vary by a factor greater than about 250.