Patent Publication Number: US-7900850-B2

Title: Microdosing apparatus and method for dosed dispensing of liquids

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This is a continuation, under 35 U.S.C. §120, of copending international application PCT/EP2004/009063, filed Aug. 12, 2004, which designated the United States; this application also claims the priority, under 35 U.S.C. §119, of German patent application DE 103 37 484.1, filed Aug. 14, 2003; the prior applications are herewith incorporated by reference in their entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to a microdosing apparatus, to methods for dosed dispensing of liquids and to methods for adjusting a desired dosing volume range when using an inventive microdosing apparatus. 
     2. Description of the Related Art 
     According to the prior art, volumes in the nanoliter range (10 −12  m 3 ) are not dosed with conventional pipettes, but require specific methods to ensure the required precision. 
     Here, in addition to contact methods, conventional dispensing methods, pin printing methods, etc., contactless methods are of significant importance. 
     A class of known methods is based on fast-switching valves. Therefore, a suitable valve, mostly based on magnetic or piezoelectrical drives, is connected to a media reservoir via a conduit and pressure is built up in the same. By the fast switching of the valve with a switching time of less than 1 ms, a very large flow is generated for a short term, so that the fluid, even with high surface tensions, can separate from the dispensing position and can impinge on the substrate as free jet. The dosing amount can be controlled by the pressure and/or the switching time of the valve. 
     Different approaches exist for generating the pressure, there are in the above-described concept with switched valves. 
     A schematic representation showing a first known approach, which can be referred to as syringe solenoid method, is shown in  FIG. 7 . Here, a fluid conduit  10  is fluidically connected to a syringe  14 , which can be removable, via a fast-switching microsolenoid valve  12 . At the lower end of the syringe  14 , there is a nozzle opening  16 . The opposite end of the fluid conduit  10  is connected to a syringe pump  20  via a switching valve  18 . Further, a fluid reservoir  22  is also connected to the switching valve  18  via a further fluid conduit  24 . 
     The switching valve  18  has two switching states. In a first switching state, a pump chamber  26  of the syringe pump  20  is fluidically connected to the fluid reservoir  22  via the fluid conduit  24 , so that liquid  28  can be drawn from the fluid reservoir into the pump chamber  26 , by increasing the volume of the pump chamber  26  by a corresponding movement of the piston  30  of the syringe pump. This process serves to fill the syringe pump  20 . In a subsequent dosing process, the switching valve  18  is switched to effect a fluidic connection of the pump chamber  26  to the microsolenoid valve  12  via the fluid conduit  10 . By using the piston  30 , pressure is applied to the liquid inside the pump chamber  26 , so that by fast switching the microsolenoid valve  12  (switching time &lt;1 ms), liquid can be dispensed from the dosing opening  18  of the syringe  14 . Dosing apparatuses of the type shown in  FIG. 7  are, for example, sold by the company Cartesian. 
     An alternative principle, as is practiced, for example, by the companies Delo and Vermes, is shown in  FIG. 8 . In this alternative method, a pressure container  40  is provided, containing liquid  42  under pressure. An outlet of the pressure container  40  is connected to a quickly switchable valve  46  via a fluid conduit  44 , which is again connected to a nozzle opening, shown merely schematically as arrow in  FIG. 8 , via a fluid conduit  48 . In this arrangement, liquid can also be dispensed in a free jet from the nozzle opening by fast switching of the valve  46 . 
     Alternative known microdosing apparatuses are, for example, described in DE-A-19802367, DE-A-19802368 and EP-A-0725267. The microdosing apparatuses described there comprise a pump chamber abutting to a flexible membrane and connected to a reservoir via a supply line and to a nozzle opening via a drain. An example for such a microdosing apparatus will be discussed below with reference to  FIGS. 9   a - 9   c.    
     In  FIG. 9   a , a schematic cross section through such a microdosing apparatus in the resting position is shown. The dosing apparatus comprises a dosing head  50  and an actuating device  52 . In the shown example, the dosing head  50  is formed by two interconnected substrates  54 ,  56 , in which respective recesses are formed. The first substrate  54  is structured such that a reservoir connection  58 , an inlet channel  60  and a dosing chamber  62  are formed in the same. The lower substrate  56  is structured such that a nozzle connection  64 , a nozzle  66  having a nozzle channel and an outlet opening, and an outlet area  68  having a significantly larger cross section than the outlet opening of the nozzle  66  are formed in the same. 
     Further, a membrane  70  is formed the upper substrate  54  by the structuring of the same. 
     The actuating device  52  has a displacer  72 , by which the membrane  70  can be deflected downwards to reduce the volume of the dosing chamber  62 , as shown in  FIG. 9   b . By this reduction of the volume of the dosing chamber  72 , on the one hand, a backflow  74  results through the inlet channel  60  and the reservoir connection  58 . On the other hand, a forward flow results through the nozzle connection  64  and the nozzle  66 , so that dispensing liquid  76  takes place at the outlet end of the nozzle  66 . The ratio between backflow  74  and dosed liquid  76  depends on the ratio of flow resistance of fluid connection between reservoir and dosing chamber to the flow resistance between dosing chamber and outlet opening of the nozzle  66 . 
     After the dosing process, the displacer  72  is moved upwards by using the actuating device  52 , see  FIG. 9   c , so that the same finally resumes its original position by elasticity, as shown in  FIG. 9   a . By this resetting of the membrane  70 , an increase of the volume of the dosing chamber  62  results, so that a refill flow  78  from the reservoir through the reservoir connection  58  and the inlet channel  60  occurs. In order to avoid an intake of air through the nozzle  66  during this phase, resetting the membrane  70  has to be performed slowly enough, so that capillary forces keeping the liquid in nozzle  66  are not overcome thereby. 
     Microdosing apparatuses as described above with reference to  FIGS. 9   a - 9   c  have originally been developed for enzyme dosage in biochemistry. By using these apparatuses, liquids with viscosities up to 100 mPas in a volume range of 1 nL to 1000 nL can be dosed very media independent and precisely. The liquid to be dosed is thereby dosed by displacing a dosing chip, preferably made of silicon, in free jet from the dosing chamber, which is. However, this method requires a comparatively complex micro device. 
     Finally, a droplet ejection system is known from U.S. Pat. No. 3,683,212, wherein a tube shaped piezoconverter connects a fluid conduit to a nozzle plate wherein a nozzle opening is formed. A voltage pulse with short rise time is applied to the converter to effect contraction of the converter. The resulting sudden decrease of the enclosed volume causes a small amount of fluid to be ejected from the opening in the opening plate. Thereby, the liquid is kept under no or no low pressure. The surface tension at the opening prevents that liquid flows out when the converter is not operated. 
     The ejected liquid is replaced by a capillary forward flow of liquid in the conduit. 
     It has been found out that according to U.S. Pat. No. 3,683,212, the drop is generated with the help of an acoustic principle similar to the piezoelectric inkjet methods. Here, an acoustic pressure wave is generated in a rigid fluid conduit, for example a rigid glass capillary, which results in a high pressure gradient locally at an output position, which leads to drop separation. The actuating time of the actuator is here in the range of the sound propagation in the system, which is normally several microseconds. Thus, in this context, the acoustic impedance of the fluid conduits below and above the actuator is of significance for the design. Thus, this is an impulse method where a high acoustic impulse is generated with a low volume displacement. In other words, a sound wave with pressure maxima and pressure minima is generated between the actuation position and the disposing position, wherein ejection of liquid is effected at the dispensing position by a corresponding pressure. According to U.S. Pat. No. 3,683,212, the fluid conduit is only negligibly deformed, the actuator mainly only transmits sound and the elasticity of the fluid conduit has no significant importance. 
     From DE 4314343 C2, an apparatus for dosing liquids is known, having a liquid supply tube connected at one end to a liquid reservoir and open at the other end. The tube is applied to an abutment socket and a hammer is provided on the side opposing the abutment socket of the tube. The hammer can vibrated periodically in a direction transversal to the tube axis, so that the whole tube cross section is crimped by the hammer, i.e. the flow area is substantially brought to zero. Thereby, impulsive force impacts are exerted on the tube and individual liquid drops are driven out of the open end. 
     SUMMARY OF THE INVENTION 
     It is an object of the present invention to provide a microdosing apparatus with a simple structure, which further preferably allows an easy change of a dosing volume to be dispensed. It is a further object of the present invention to provide a method for dosed dispensing of liquids. 
     In accordance with a first aspect, the present invention provides a microdosing apparatus having: a fluid conduit having a flexible tube, preferably a polymer tube, with a first end for connecting to a liquid reservoir and a second end where an output opening is located; and an actuating device having a displacer with adjustable stroke, by which the volume of a portion of the flexible tube can be changed, to thereby dispense liquid as free flying droplets or as free flying jet at the outlet opening by moving the displacer between the first end position and the second end position, wherein the tube is partly compressed at least in the first end position or the second end position. 
     In accordance with a second aspect, the present invention provides a microdosing apparatus, having: a fluid conduit with a first end for connecting to a fluid reservoir and a second end where an outlet opening is located, the fluid conduit having a portion along which a cross section of the fluid conduit can be varied to effect a change of the volume of the fluid conduit; an actuating device disposed at a position along the portion of the fluid conduit for effecting a change of the volume of the fluid conduit to thereby dispense liquid as free flying droplets or free flying jet from the outlet opening; wherein a ratio of the fluidic impedance between the position of the actuating device and the outlet opening to a fluidic impedance between the fluid reservoir and the position of the actuating device is variable by changing the position of the actuating device, so that a dosing volume dispensed at the outlet opening is variable by at least 10%. 
     Here, fluidic impedance means the combination of fluidic resistance and fluidic inductance determined by the length and the flow cross section of a line. 
     Thus, the present application allows adjusting of the dosing volume either by adjusting the stroke of the actuating device and/or adjusting the position of the actuating device along a fluid conduit whose volume can be changed. 
     Such a variability of the ratio of the mentioned flow resistances can be preferably achieved by designing the fluid conduit between fluid reservoir and ejection opening with a substantially linear structure, i.e. the same has a cross section without erratic cross section changes between fluid reservoir and ejection opening. In the simplest case, this can be achieved by a fluid conduit having a substantially constant cross section between fluid reservoir and ejection opening in the resting position. 
     The present invention requires no fine-mechanical or microstructured members as required in other drop generators, whereby production costs can be significantly reduced and the operation security is increased. Further, the fluid carrying part can be produced as disposable members, simply of plastics, for example polyimide, whereby an expensive cleaning when changing media is omitted. 
     Further, according to the invention, no limited pressure chamber is used for generating pressure, but a variable “active area”. Thereby, optimization possibilities result for different fluids by varying the displacer position, i.e. the position of the actuating device along the portion of the fluid conduit along which the cross section of the fluid conduit can be varied to effect a change of the volume of the fluid conduit. By an axially asymmetric volume change, a preferred direction of a fluid flow can be generated in the fluid conduit in the direction of the outlet opening. Further, a simple change of the maximum dosing volume can be caused by increasing the “active area”, for example by using a larger displacer, wherein such change of the maximum dosing volume does not require construction changes at the fluid carrying parts. Finally, a potential pressure difference between input opening and output opening can be explicitly provided to ensure a preferred direction during refill or to avoid leaking of the liquid from the outlet opening. Thus, media that cannot be moved by capillary forces in the fluid conduit can also be dosed. 
     In accordance with a third aspect, the present invention provides a method for dosed dispensing of liquids, having the steps of: filling a fluid conduit having a flexible tube, preferably a polymer tube, with a liquid to be dosed; effecting a volume change of a portion of the flexible tube by a displacer with adjustable stroke, to thereby dispense liquid as free flying droplets or as free flying jet at an outlet opening of the fluid conduit by moving the displacer between a first end position and a second end position, wherein the tube is partly compressed at least in the first end position or the second end position. 
     In accordance with a fourth aspect, the present invention provides a method for adjusting a desired dosing volume in a dosing process by using an inventive microdosing apparatus, having the step of: disposing the actuating device at a predetermined position along the portion of the fluid conduit, so that due to the resulting ratio of fluidic impedances in the step of effecting a change of the volume of the fluid conduit, a desired dosing volume can be dispensed at the outlet opening. 
     In accordance with a fifth aspect, the present invention provides a method for adjusting a desired dosing volume in a dosing process by using an inventive microdosing apparatus, having the step of: selecting a displacer with an axial length with regard to the portion of the fluid conduit, which is adapted to allow dispensing of a desired dosing volume in a step of effecting a change of the volume of the fluid conduit. 
     Thus, the present invention allows additional degrees of freedom when adjusting a desired dosing volume. On the one hand, with a predetermined stroke and thus a predetermined displacement of the actuating device, a desired dosing volume can be adjusted by the above-described steps. If the stroke and thus the displacement of the actuating device are adjustable, a desired dosing volume range can be adjusted by the above-mentioned steps, wherein then the dosing volume lying within the desired dosing volume range can be adjusted by adjusting the stroke or the displacement of the actuating device, respectively. 
     A characteristic property and a significant advantage of volume displacer systems, as they are realized by the present invention, is that in the same the dosing volume is largely independent of the viscosity of the liquid to be dosed. 
     Above that, according to the present invention, the actuating device can be designed together with the fluid conduit to allow a full crimping of the fluid conduit by the displacer as an extreme case of volume displacement. In that case, additionally, a valve function can be implemented. The possibility of fully interrupting the fluid conduit between reservoir and dispensing position can thus represent a further advantage compared to known methods. 
     In contrast to the teachings of U.S. Pat. No. 3,683,212, in the inventive microdosing apparatuses, a continuous pressure gradient is built up across the whole fluid conduit, wherein the fluid is actually pushed out of the conduit starting from the displacer. The whole fluid between displacer and outlet opening is moved in direction of the outlet opening. Acoustic phenomena play no part, since the volume displacement is performed on a time scale of a few milliseconds (significantly slower than with impulse methods). 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       These and other objects and features of the present invention will become clear from the following description taken in conjunction with the accompanying drawings, in which: 
         FIGS. 1   a - 1   c  are schematic cross section views for explaining an embodiment of an inventive dosing process; 
         FIGS. 2   a - 2   d  are schematic views of an embodiment of an inventive microdosing apparatus; 
         FIG. 3  is a schematic image sequence of the drop formation; 
         FIG. 4  is a diagram showing drop volumes generated via a prototype; 
         FIGS. 5   a - 5   b  are schematic representations for illustrating how a dosing volume range can be adjusted in an inventive microdosing apparatus; 
         FIGS. 6   a - 6   b  are schematic views for illustrating how a dosing volume range can alternatively be adjusted according to the invention; 
         FIGS. 7 ,  8 ,  9   a - 9   c  are schematic representations of known microdosing systems; and 
         FIGS. 10   a - 10   b  are schematic representations of alternative embodiments of inventive microdosing apparatuses. 
     
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     With regard to the schematic representations in  FIGS. 1   a  to  1   c , the essential features of the present invention as well as the concept underlying the same will be discussed below. 
     The present invention relates to an apparatus or a method, respectively, for generating microdrops or microjets, respectively, mainly in the nanoliter to picoliter range. A fluid carrying conduit is a central element of an inventive microdosing apparatus, whose inlet opening is connected to a liquid reservoir, in which the media to be dosed is located. On the other end of the conduit is an outlet opening through which the liquid to be dosed can be dispensed. The fluid carrying conduit is preferably mainly made of an elastic material, so that the volume of the conduit between inlet opening and outlet opening can be varied by deforming the conduit, for example compressing the same. 
     The essential elements of an inventive dosing apparatus during different phases of a dosing process are shown in  FIGS. 1   a  to  1   c.    
     As shown in  FIG. 1   a , a fluid conduit  100 , which is an elastic polymer tube in preferred embodiments of the present invention, comprises an inlet-side end  102 , which serves for connecting to a fluid reservoir, and an outlet-side end  104  where microdrops or microjets, respectively, can be dispensed. The outlet-side end  104  can thus also be referred to as nozzle. Respective walls  106  of the elastic polymer tube  100  are illustrated in  FIGS. 1   a  to  1   c  by dotted lines. 
     An actuator  108  in form of a displacer is provided, which has a connection part  110  where the displacer  108  can be attached to an actuating member for driving the displacer  108 . 
     In the shown embodiment, the elastic polymer tube has a substantially constant cross section, which will normally be circular, from its input end  102  to its output end  104 . 
     In such a microdosing apparatus, an area  112  disposed below the displacer  108  can be referred to as dosing chamber area, which is defined by the position of the displacer  108  with regard to the elastic polymer tube  100 . An area  114  beginning substantially at the right end of the displacer  108  represents an outlet channel fluidically connecting the displacer area  112  to the outlet end  104 . An area  116 , which is illustrated in the figures in a reduced form and extends from the left end of the displacer  108  towards the left, represents an input channel fluidically connecting the displacer area  112  to the input end  102 . 
     As further shown in  FIG. 1   a , the displacer  108  can comprise a displacer surface  120  running diagonally to the wall  106  of the polymer tube  100 , which allows generation of a preferred direction of a fluid flow in direction towards the outlet opening  104  by an axially asymmetric volume change during operation of the microdosing apparatus. 
     In the following, the mode of operation of the inventive microdosing apparatus will be discussed. 
     When switching on the dosing system, the fluid conduit  100  will be filled automatically either by an externally generated pressure difference or by capillary forces. 
     An externally generated pressure difference can, for example, be applied by using a fluid reservoir wherein the fluid is put under pressure. 
     When applying a static pressure positive with regard to the outlet end (overpressure), it has to be considered that the pressure by which the liquid in the conduit  100  is provided, is not higher than the capillary forces by which the liquid is kept in the conduit, since otherwise leaking of liquid would occur from the output end  104  in the non-operated state of the microdosing apparatus. 
     Alternatively, pressure negative with regard to the output end (underpressure) can be applied to avoid leaking of liquid from the output end in the non-operated state if the capillary forces are too weak. This opposing pressure has to be overcome by the capillary forces during refill. 
     At the beginning of a dosing process, in a first phase, which can be referred to as dosing phase, liquid is displaced from the conduit by reducing the conduit volume between inlet opening and outlet opening. This is achieved by moving the displacer  108  downwards, i.e. in direction towards the polymer tube  100 , so that a compression of the polymer tube occurs in the displacer area  112 . This downward movement is illustrated in  FIG. 1   b  by arrows  122 . Thus, the displacer area  112  represents the active area of the inventive microdosing apparatus. 
     The liquid displaced from the conduit due to this volume change of the fluid conduit  100  is pressed out of the ends of the conduit or stored at another position by changing the conduit cross section when the conduit has a fluidic capacity. 
     By the volume change of the fluid conduction  100  caused by a fast movement  122  of the displacer  108 , on the one hand, a fluid flow towards the outlet opening  104  takes place, as indicated by an arrow  124 . On the other hand, a backflow into the fluid reservoir through the input channel  116  takes place, as indicated by an arrow  126 . By the forward flow  124 , a fluid ejection in the form of a microdrop or a microjet, respectively, takes place at the outlet opening  104 . 
     Which portion of the fluid will be dispensed through the outlet opening  104  as jet or drop, respectively, depends on the position, type and dynamic of the volume change. As has already been mentioned above, a preferred direction of the current in the direction towards the outlet opening  104  can be affected by an axially asymmetrical volume change as caused by the displacer  108  and particularly the displacer surface  120 . For generating a jet or a drop dispensed in the dosing phase at the outlet end  104 , the volume change occurs sufficiently fast to transfer the required impulse to the fluid drop or fluid jet, respectively, so that the same can separate from the outlet opening  104 . Thereby, both the fluid properties, such as density, viscosity, surface tension and the same, as well as a pressure difference that can exist between inlet opening and outlet opening play an important part. Further, the fluidic resistances between outlet opening  104  and the active area  112 , wherein the volume change is performed (i.e. the fluidic impedance of the outlet channel  114 ) as well as the fluidic impedance of the conduit part between active area  14  and inlet opening  112  (i.e. the fluidic impedance of the inlet channel  116 ) are determining for the ratio between dispensed dosing amount (forward flow  124 ) and the fluid amount fed back into the reservoir (backflow  126 ). A good dosing quality can, for example, be achieved when the volume change is performed close to the outlet opening ( 104 ) with high dynamic (for example 50 nL within one millisecond). 
     By positioning the displacer close to the outlet opening ( 104 ), it can be effected that the fluidic impedance of the outlet channel  114  is low compared to the fluidic impedance of the inlet channel  116 , so that a large part of the displaced fluid is ejected from the outlet opening  104 . Thereby, it can be said that the displacer is disposed close to the outlet opening  104  when the length of the inlet channel  116  is at least twice the size of the length of the outlet channel  114 , preferably at least five times as large and more preferred at least ten times as large. 
     After ejecting the fluid drop or fluid jet, respectively, in a second phase, which can be referred to as refill phase, the volume between inlet opening  102  and outlet opening  104  is increased again. This is achieved by moving the displacer  108  away from the fluid conduit  100  in the direction of an arrow  132 , as shown in  FIG. 1   c . Due to this volume change, liquid flows from the reservoir through the inlet opening  102  and the inlet channel  116  into the conduit and particularly into the active area  112  of the same, as indicated in  FIG. 1   c  by arrow  134 . The drawing in of air through the outlet opening  104  is prevented through capillary forces, with correspondingly small conduit cross sections. Alternatively, a preferred direction for filling from the reservoir can be determined by a hydrostatic pressure difference between inlet opening and outlet opening. For this purpose, the fluid reservoir could, for example, again be provided with pressure. 
     At the end of the refill phase, again, the situation shown in  FIG. 1   a  is present, wherein then a dosing process can be preformed again. 
       FIGS. 2   a  to  2   d  show a drop generator using an inventive microdosing apparatus with respective mounts for the fluid conduit or the actuator, respectively.  FIG. 2   a  shows a side view of the drop generator, while  2   b  shows a bottom view of the same.  FIG. 2   c  shows a sectional view along line A-A of  FIG. 2   b , while  FIG. 2   d  illustrates an enlargement of portion B in the scale 5:1. 
     The drop generator shown in  FIGS. 2   a  to  2   d  comprises a polyimide tube  150 , which can have, for example, an inner diameter of 200 μm. For storing the polyimide tube  150 , a storage block  152  and an abutment block  154  are provided. A guide groove is provided in the storage block  152  and/or the abutment block  154 , wherein the polyimide tube is inserted, so that the polyimide tube is securely stored between storage block and abutment block in a stabilized way. The storage block  152  and the abutment block  154  are, for example, attached to a mounting portion  160  of a mount  162  by using mounting screws  156 . Further, the mount  162  is formed to hold a displacer  164  on the side of the polyimide tube  150  opposing the abutment  154 , with the help of which the tube can be compressed in the active area of the same, whereby the inventive volume change between inlet opening and outlet opening is obtained. Thereby, the displacer is driven by a piezostack actuator (not shown), whose displacement can be electronically controlled, and which is connected to the displacer  164  via an adapter  166 . In order to effect a preferred direction of a drop ejection  168  by the outlet opening of the polyimide tube  150 , the displacer  164  again has a displacing surface, which is diagonal in relation to the polyimide tube, i.e. running in an angle to the same. 
     Further, the mount  162  comprises a receiver  170  for the driving unit in the form of the piezostack actuator. Further, the mount  162  can have a recess  172  penetrating the same to allow attaching the same at a device, which also includes the drive unit, for example by using a screw joint. 
     With regard to the structure shown in  FIGS. 2   a  to  2   d , a prototype has been built and successfully experimentally tested.  FIG. 3  shows different phases of a dosing process performed with the prototype, wherein the polyimide tube  150  is shown with its outlet end  180  in each case. 
       FIG. 4  shows the dispensed mass in microgram with a number of 1800 dosing processes by using the prototype, wherein water has been used as liquid to be dosed. The medium drop mass was 22.57 μg, with a standard deviation σ of 0.35 μg. The polyimide tube had a diameter of 200 μm. The gravimetric measurement of the reproducibility illustrated in  FIG. 4  proves that a precision at least corresponding to the one of conventional dosing apparatuses and even superior to the same can be obtained with the inventive concept. 
     With regard to  FIGS. 5   a ,  5   b ,  6   a  and  6   b , it will be discussed below how a desired dosing volume or a desired dosing volume range, respectively, can be adjusted in an inventive microdosing apparatus. 
     In  FIGS. 5   a  and  5   b , the polymer tube  100  is shown schematically, whose inlet opening  102  is fluidically connected to a liquid reservoir  200  and whose outlet end  104  represents an ejection opening. The active area  112  as well as the outlet channel  114  and the inlet channel  116  are defined by the position of the displacer  108 . In the arrangement shown in  FIG. 5   a , the input channel  116  and the outlet channel  114  have substantially the same lengths x 1  and x 2 , so that the fluidic impedance of the same is substantially identical, when a constant cross section of the tube  100  is assumed. Thus, in the shown form of the displacer  108 ′, which effects no preferred flow direction, a volume displacement effected by the displacer  108 ′ would cause that flows of the same size would flow in the direction of the outlet opening  104  and the inlet opening  102 . Thus, when neglecting the fluid capacity of the tube conduit  100 , the volume ejected by the outlet opening  104  would be half as much as the volume displacement caused by the displacer  108 ′. 
     According to  FIG. 5   b , the displacer  108 ′ is disposed close to the outlet opening  104 . In other words, the length x 1  of the inlet channel  116  is about five times as large as the length of the outlet channel x 2 . Thus, with a constant cross section of the tube  100 , the fluidic impedance of the inlet channel  116  is five times as high as the one of the outlet channel  114 , so that a much higher portion of the volume change effected by the displacer  108 ′ effects a flow in the direction of the outlet opening  104  and thus an ejection through the same. 
     In the above-mentioned way, a desired dosing volume can be adjusted by changing the position of the displacer relative to the fluid conduit  100 . Further, if the drive means of the displacer allows a selective adjusting of the stroke of the same, i.e. a selective adjustment of the movement of the same by different distances vertically to the fluid conduit, so that the displacer can effect different volume changes in the dependence on its control, the above adjustment of the position can represent an adjustment of a desired dosing volume range, while the final adjusting of the desired dosing volume in the adjusted dosing volume range is performed by a corresponding control of the displacer. 
     According to the invention, the dosing volume dispensed at the outlet opening is adjustable by changing the position of the displacer, as long as the ratio of the flow resistances from inlet channel and outlet channel can be significantly changed by changing the position of the displacer. Here, significantly should mean a change which causes a change of a dosing volume dispensed at the outlet opening by at least 10%, whereby the actual adjustment range will depend on across which range the position of the displacer can be adjusted. Thereby, by using the inventive microdosing apparatuses, changes of the dispensed dosing volume by 50% and above can be realized by changing the position of the displacer. This inventive adjustability of the ratio of the flow resistances of inlet channel and outlet channel is preferably enabled according to the invention in that no erratic cross section changes occur between dosing chamber, i.e. active area, and inlet channel or outlet channel, respectively. In even more preferred embodiments of the present invention, the cross section of the fluid conduit is constant from the segment of displacement, i.e. the active area, to the outlet opening in the resting position. Further, in preferred embodiments, the whole fluid conduit between fluid reservoir and outlet opening has a substantially constant cross section. 
     A second possibility, how a desired dosing volume or a desired dosing volume range, respectively, can be adjusted according to the invention, can be taken from  FIGS. 6   a  and  6   b . According to  FIG. 6   a , the displacer  108 ′ has a length l 1  along the tube  100 , while according to  FIG. 6   b , a displacer  208  has a length l 2  along the tube  100 . The length l 2  is longer than the length l 1 , so that the displacer  208  allows a larger volume change of the fluid conduit  100  with the same stroke. Thus, according to the invention, by changing the length of the displacer along the fluid conduit with constant stroke, a desired dosing volume, or similar to the above discussions, a desired dosing volume range can be adjusted. 
     Thus, the present invention provides a microdosing apparatus having a fluid conduit filled with a medium to be dosed, whose one end can be connected to a fluid reservoir and at whose other end an outlet opening is located, as well as an actuator by which the volume of a certain segment of the fluid conduit can be temporally changed, so that through the volume change, fluid is dispensed as free flying droplets or as free flying jet at the outlet opening. According to the invention, the whole fluid conduit can be formed by a flexible polymer tube. Alternatively, only the mentioned determined segment can be formed by a flexible polymer tube, while feed and drain from this segment are formed by a rigid fluid conduit. 
     As explained above, according to the invention, the displacement occurs at an elastic segment of the fluid conduit. Preferably, the elastic segment can resume the starting position in the fluid conduit, for example the flexible polymer tube or the membrane, respectively, after operation automatically, so that the displacer does not have to be connected to the fluid conduit in a fixed way, so that the fluid conduit can be designed as a simple disposable member. 
     The present invention also comprises drop generators, wherein several inventive microdosing apparatuses are disposed in parallel. Such microdosing apparatuses disposed in parallel can be controlled separately, to dose different liquids or the same liquids. Alternatively, the drop generator can have several fluid conduits, which can be controlled simultaneously by a displacer, so that the same or different liquids can be dosed by the same. For that purpose, the inlet ends of the different fluid conduits can be connected to the same or different liquid reservoirs. 
     Thus, an inventive microdosing apparatus can consist of one or several microdrop generators, each having a (elastic) fluidic conduit filled with a medium to be dosed, whose one end has an inlet opening connected to a fluid reservoir and whose other end has an outlet opening, wherein a pressure difference can exist between inlet opening and outlet opening, and an actuating device by which the volume of the conduit between fluid reservoir and outlet opening can be temporally changed, wherein during a first phase the fluidic volume between inlet opening and outlet opening is reduced with sufficient speed from its initial volume to a smaller volume, whereby a microdrop or a microjet, respectively, is ejected through the outlet opening and part of the displaced volume can leak out to the inlet opening, wherein the volume of the microdrop or microjet, respectively, plus the volume receding into the reservoir through the inlet opening substantially corresponds to the volume change caused by the actuating device, and in a second phase, wherein the volume between inlet opening and outlet opening is increased again, the fluid conduit is again filled from the reservoir driven by pressure or capillary forces. 
     Apart from the mount described with reference to  FIGS. 2   a  to  2   d , an automatic mount can be provided, which allows automatic adjustment of the position of the displacer to the fluid conduit, for example in response to a signal indicating a desired dosing volume range or a desired dosing volume, respectively. 
     By using the inventive microdosing apparatuses, thus, individual free flying microdroplets are generated preferably at an outlet opening in contact with the surrounding atmosphere, to dispense fluid as free flying droplets or free flying jet at the outlet opening. Thereby, the present invention allows ejecting of a droplet already with a single operating cycle of the actuating device, during which the displacer effects once a reduction of the volume of the fluid conduit to thereby eject the droplet. 
     The present invention allows adjusting the dosing volume by adjusting the stroke of the actuating device and/or disposing the actuating device at a predetermined position along the portion of a fluid conduit. Additionally, a displacer with adapted axial length can be chosen. 
     When using an adjustable stroke for adjusting the dosing volume, the stroke h of the actuating device or the displacer, respectively, is variable and smaller than the diameter of the tube, i.e. the cross section dimension of the same in the direction of the movement of the displacer of the actuating device. 
     In the case where the whole tube cross section is crimped, i.e. the flow area is substantially brought to zero, as required in DE 4314343 C2, the drop volume is determined by the extension of the hammer along the tube axis and by the tube diameter. By crimping the tube, the whole volume within the relevant tube portion is displaced. Approximately, for the displaced volume which then significantly determines the drop volume—with otherwise equal arrangement—the following applies: 
     
       
         
           
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     Here, V represents the displaced volume, a the length of the displacer and d the diameter of the tube. 
     Compared with this, in a displacer with adjustable stroke, the stroke h around which the displacer is moved, plays a decisive role. Here, the displaced volume depends on the stroke h and can be approximately be described by the volume of a laterally trimmed cylinder: 
     
       
         
           
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     Here, h is the distance by which the tube is compressed. 
     By this dependence of the displaced volume V on stroke h and its described effect on the drop volume, the present invention allows a variable adjustment of the dosing volume without having to connect a tube with different diameter or a displacer with different dimensions, respectively. 
     According to the invention, there is a connection between volume displacement and drop generation or drop volume, respectively, in a single dosing process, so that the present invention allows dosing with a non-periodic excitation. This is advantageous, for example, when specific non-periodic patterns are to be printed on a substrate. 
     In the above-described embodiments, the actuating device is designed to effect an actuation of the tube starting from an uncrimped state of the same. Alternatively, embodiments are possible where the tube is partly or fully crimped, i.e. compressed, in standby mode. A schematic cross section representation of such an embodiment is shown in  FIG. 10   a . The tube  100  is applied to a counter mount  300  at its backside. On the opposing side of the tube  100 , a piezoactuator  302  is mounted to a mount  302  of an actuating device. A displacer  306  is disposed at the front end of the piezoactuator  302 . 
     In the arrangement shown in  FIG. 10   a , the tube  100  is fully crimped in the standby mode. The dosing cycle starts with slowly pulling back the piezoactuator  302 , so that the cross section of the tube  100  is partly freed. During this phase, fluid flows from the reservoir, to which the tube  100  is connected at the end  102  opposing the outlet opening  104 , in the previously crimped area, in order to compensate the increasing tube volume. The actual dosing process with the drop formation at the outlet end  104  is then performed by quickly extending the piezoactuator  302  to decrease the tube volume again. As in the above-described embodiments, the dosed volume is defined by the adjustment travel of the piezoactuator  302  and can thus be controlled by varying the operating voltage or by the variation of the charging current or discharge current at the piezoactuator  302 , respectively. It is an advantage of the configuration shown in  FIG. 10   a  that the crimped tube has a significantly lower evaporation rate of dosed material compared to the normally open tube. 
     Thus, this embodiment contains an integrated closing mechanism. However, it is a disadvantage that in commercially available conventional piezostack actuators the extended state of the piezoactuator is that state where the electric voltage is applied. When taking away the electric voltage, the piezostack actuator becomes shorter, the reduced state. Accordingly, this means that the embodiment of an integrated closing mechanism shown in  FIG. 10   a  effects a continuous but slight energy consumption. In order to fully use the advantages of the integrated closing mechanism, it is advantageous in the embodiment shown in  FIG. 10   a  to apply an electrical voltage continuously or to charge the piezoactuator, respectively, even when the dosing system is not used. 
     An integrated closing mechanism with reduced energy consumption can be implemented by providing the actuating device with a biasing means, for example a spring, pressing the displacer against the polymer tube in order to achieve partial or full crimping of the tube in the standby mode. Then, the actuating device preferably has an actuator, which is disposed to move the displacer against the force of the biasing means and to release the tube cross section partly or fully. 
     An embodiment for such an integrated closing mechanism is shown in  FIG. 10   b . Again, the tube  100  is applied against a counter mount  310 . In this embodiment, an actuating device comprises a combination of a spring  312  and a piezostack actuator  314 . Further, the actuating device comprises a displacer  316 , which is rigidly coupled to an actuating plate  318 . In  FIG. 10   b , two couplings rods  320  and  322  are shown as exemplary coupling means. The spring  312  is applied to a counter mount  324  at its right side end and presses the displacer  316  against tube  100  to crimp the same in the non-operated state of the actuator  314 . This embodiment allows the realization of a dosing apparatus whose tube is crimped with switched off electrical supply voltage, so that the same has an integrated closing mechanism without continuous energy consumption. 
     In the switched off state, the displacer  316  is pressed on to the tube  100  by the spring such that the same is pressed onto the counter mount  310  and crimped. If a dosing process is to be performed, the piezoactuator  314  is extended by applying an electrical voltage, and thus the displacer  316  is reset against the spring force. The tube relaxes and the liquid to be dosed flows in from the reservoir connected to the side  102  of the tube opposed to the outlet opening  104 . By quickly driving back the piezostack actuator  318 , the tube  100  is again crimped via the spring  312 , which is dimensioned in a sufficiently strong way. The spring is dimensioned rigidly enough so that liquid is dispensed from the outlet opening  104  as free flying jet. The dosed volume is again defined by the adjustment travel of the piezoactuator and can thus be controlled by varying the operating voltage or by varying the charging or discharge current in the piezostack actuator, respectively. 
     Here, it should be noted that embodiments discussed with regard to  FIGS. 10   a  and  10   b  also function when the tube is not fully crimped. 
     In the embodiments of the present invention, where the dosing volume is adjusted via the adjustable stroke of the displacer or the actuating device, respectively, the displacer is moved between a first end position and the second end position, wherein the polymer tube is partly compressed in the first end position and the second end position. Thereby, the first end position defines a larger tube volume than the second end position, so that by moving the displacer from the first end position, into the second end position liquid is dosed out of the ejection end. Thereby, the first end position can define a fully relaxed state of the tube or a partly compressed state of the same. The second end position can comprise a partly compressed state or a fully compressed state of the polymer tube. In other words, in the inventive embodiments, where the dosing volume is adjustable by an adjustable stroke of the actuating device, the tube wall is moved by the actuating device or by the displacer, respectively, via a part of the light cross section of the flexible polymer tube. In contrary, when fully crimping the tube from a non-crimped state to a fully crimped state, the tube wall is moved across the whole light cross section of the tube. 
     The embodiments shown in  FIGS. 10   a  and  10   b  can also be implemented such that the position of the actuating device can be varied to thereby be able to vary the dosing volume dispensed from the outlet opening. 
     While this invention has been described in terms of several preferred embodiments, there are alterations, permutations, and equivalents, which fall within the scope of this invention. It should also be noted that there are many alternative ways of implementing the methods and compositions of the present invention. It is therefore intended that the following appended claims be interpreted as including all such alterations, permutations, and equivalents as fall within the true spirit and scope of the present invention.