Patent Publication Number: US-9415388-B2

Title: Pipette tip, pipette device, and combination of pipette tip and pipette device

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This application is a divisional application of U.S. Ser. No. 09/959,132, filed Oct. 16, 2001, currently pending. 
    
    
     TECHNICAL FIELD 
     The invention concerns the placement of a pipette tip on a pipette device. 
     BACKGROUND OF THE INVENTION 
     Pipette devices are used, for example, in the area of molecular biology or medicinal analysis for the transfer of liquids. Special pipette tips are thereby often used which are placed on the pipette device and are intended for one-time use. Such disposable tips are also known by the designation “tip.” The pipette device may be a manual pipette device which merely has one single pipette unit. In the course of progressive automation, which is making its entrance into modern analysis laboratories, automated pipettes or so-called pipette robots having a large number of pipette units arranged in a row or in a matrix are also often used. With such automated pipettes, it is possible to suction samples simultaneously from a large number of vessels and to release them elsewhere. 
     The pipette tips have been constructed, up to now, mostly with a jacket area, which expands conically with which they are mounted on a correspondingly conically shaped coupling stud of the pipette device or preferably of the individual pipette unit. The pipette tip is thereby pressed onto the coupling stud firmly to establish a frictionally engaged press fit between the pipette tip and the coupling stud. In order to achieve the desired tightness comparatively high pressing forces are required. The material of the pipette tip has a certain elasticity which leads to the pipette tip expanding upon pressing onto the coupling cone. In this way microfissures may be formed in the pipette tip which are a cause of leakage. Also dirt particles on the coupling cone may lead to leakage. Moreover the high pressing forces upon placement of the pipette tip have the disadvantage that for the release of the pipette tip correspondingly high forces have to be applied. 
     To avoid high pressing forces it has been proposed (see U.S. Pat. No. 5,063,790) that the coupling stud be constructed with an O-sealing ring. The pipette tip is thereby put more loosely over the coupling stud. The O-sealing can then be compressed by means of a squeezing device in such a manner that it expands in its radial direction and produces a frictionally engaged support for the pipette tip. In order to release the pipette tip it is sufficient to disengage the O-sealing ring so that it contracts again, and the frictional engagement between the pipette tip and the O-sealing ring is cancelled. This has the advantage that high forces do not have to be applied on the pipette tip neither during the placement of the pipette tip nor during its release. 
     If a pipette tip, which is designed in the form of a cone in its area intended for coupling with the coupling stud, is pressed on the coupling cone of the first-mentioned solution or is placed on the coupling stud of U.S. Pat. No. 5,063,790, whereby the O-sealing ring is squeezed, in both cases, the problem arises that the position of the pipette tip relative to the coupling stud cannot be adjusted in a defined manner. In the first case various pressing forces result in the pipette tip being shoved onto the coupling cone to various extents. This relates to the expansion of the pipette tip, which occurs in various degrees, depending on the amount of the pressing forces. In the second case, the O-sealing ring—if it is squeezed—presses against a cone surface of the pipette tip. If, in the beginning, there is still no frictional engagement between the O-sealing ring and the pipette tip, then the radial expansion of the O-sealing ring can lead to a slipping of the pipette tip. 
     A defined position of the pipette tip relative to the coupling stud is however, of essential importance, particularly for automated pipettes, which have a large number of pipette units. During the suctioning of the liquid, different positioning of the pipette tips of automated pipettes with tens or even several hundreds of pipette units can lead, for example, to some pipette tips being properly immersed in the vessels assigned to them or in depressions of a microtiter plate, whereas other pipette tips remain above the level of the liquid in the vessels or depressions. Likewise, it may happen that individual pipette tips hit the bottom of the vessels or depressions, and in this way their mouth opening is blocked, at least to some extent. The consequence can be an insufficient metering accuracy both in the liquid intake as well as in the liquid release. 
     Therefore the problem of the invention is to describe a way in which, particularly with automated pipette devices with a large number of pipette units, the metering accuracy can be improved during the transfer of liquids. 
     SUMMARY OF THE INVENTION 
     According to a first aspect in solving this problem, the invention is based on a pipette tip for placement on a pipette device, wherein the pipette tip has a jacket and a passage opening enclosed by the jacket, wherein the passage opening extends along a longitudinal axis between a first front end of the pipette tip, intended for immersion in a medium to be pipetted, and a second front end of the pipette tip, being opposite in an axial direction, and wherein the pipette tip, close to the second front end, has an area for the coupling with a coupling stud of the pipette device. 
     According to the invention it is provided that the jacket carries axial positioning means in the coupling area which are intended for interaction with complementary counter-axial positioning means of the coupling stud and which, together with the counter-axial positioning means, define an axial coupling position of the pipette tip on the pipette device. The axial positioning means allow to obtain a predetermined, defined axial position of the pipette tip, relative to the pipette device, in any placement of the pipette tip on the pipette device. This permits the equipping of all pipette units of an automated pipette with pipette tips at an accurate and equal position. In introducing into vessels or depressions of a microtiter plate different axial positions of the individual pipette tips do not occur, and for this reason the same liquid dosage can be suctioned or released by each pipette unit. This produces a metering accuracy of the pipette device which is, as a whole, increased. 
     Usually the pipette tip can be stuck with its second front end ahead, on the coupling stud; for this reason, the axial positioning means advantageously are placed at least in part on the inside circumference of the jacket, at an axial distance from the second front end of the pipette tip. At least in the coupling area the jacket inside circumference can have an envelope essentially formed by cylindrical sections. 
     The axial positioning means can comprise at least one axial stop placed on the jacket which is intended to interact with a complementary counter-stop of the coupling stud. When coupling the pipette tip to the coupling stud, the axial stop engages with the counter-stop of the coupling stud, so that a defined axial position of the pipette tip is established. If, moreover, the coupling stud carries an elastically shapeable O-sealing ring, that meshes by means of an axial squeezing and thus a related radial expansion in a frictional engagement with a sealing surface of the pipette tip, a particularly simple, but nevertheless highly accurate possibility is given for the placement of the pipette tip on the pipette device. 
     With simple manufacturing technology, the axial stop can be formed by an axially-stepped shoulder of the jacket inside circumference, which connects a first cylindrical jacket inside circumference section having a larger diameter and being closer to the second front end, with a second cylindrical jacket inside circumference section having a smaller diameter and being farther from the second front end. Thereby the following dimensions are recommended: The diameter diminution from the first to the second jacket inside circumference section, caused by the stepped section, can be between 0.8 and 1.2 mm, preferably between 0.9 and 1.1 mm, and most preferably approximately 1.0 mm. The diameter of the first jacket inside circumference section can be between 6.5 and 7.1 mm, preferably between 6.7 and 6.9 mm, and most preferably approximately 6.8 mm. With regard to the diameter of the second jacket inside circumference section, this can be between 5.5 and 6.1 mm, preferably between 5.7 and 5.9 mm, and most preferably approximately 5.8 mm. It is recommendable to define a standard coupling interface between the pipette tip and the pipette device, so that pipette tips with different intake volumes for the liquids to be pipetted, but with standard coupling areas, can be combined with one and the same pipette device. 
     The exact axial positioning of the pipette tip by its axial stop and the counter-stop of the coupling stud can be further improved in that the jacket has a working surface for a prestress member, which is supported on the pipette device and which is intended to prestress its axial stop, axially, against the counter-stop of the coupling stud in the coupling position of the pipette tip. A particularly simple construction solution can be found in that the working surface is designed, to simultaneously provide for the sealing placement of a sealing element made of elastically shapeable material forming the prestress member and serving to seal off the pipette tip with respect to the coupling stud. Accordingly the sealing element takes over not only the sealing function, but simultaneously the prestress function as well. For the sealing element one can have recourse to solutions that are in fact known. Thus, the sealing element can be formed from an O-ring and, in accordance with U.S. Pat. No. 5,063,790, can be compressible axially by a squeezing unit of the pipette device. In this case it may be provided that the working surface is shaped in such a way and located on the jacket so that in the coupling position of the pipette tip the sealing element is in an axially uncompressed state, essentially outside the prestress force-producing engagement with the working surface and, in the course of an axial compression enters into the prestress force-producing engagement with the working surface. 
     The axial supporting forces produced by an interaction of the working surface with the sealing element provide for a better support of the pipette tip at the coupling stud than is the case in the solution according to U.S. Pat. No. 5,063,790. Also a strong squeezing of the sealing element such as in U.S. Pat. No. 5,063,790 is not necessary, to attain a secure axial support of the pipette tip which increases the lifetime of the sealing element. 
     The working surface can, for example, be formed on a circumference groove, which is worked into the jacket inside circumference and in which the sealing element of the coupling stud can “engage.” In considering a cross section containing the longitudinal axis the circumference groove can be bent in the form of an arc wherein its radius of curvature can be between 0.3 and 0.9 mm, preferably between 0.4 and 0.8 mm, and most preferably between 0.5 and 0.7 mm. The working surface is preferably axially located between the axial stop and the second front end of the pipette tip. 
     According to a further aspect for the solution of the problem formulated in the beginning, the invention provides a pipette device with at least one pipette unit which has a pipette channel extending along a channel axis, and a coupling stud for the coupling of a pipette tip, in particular, of the type described in the preceding, wherein, in accordance with the invention, the coupling stud has complementary counter-axial positioning means intended for interaction with axial positioning means of the pipette tip, which, together with the axial positioning means, define an axial coupling position of the pipette tip on the pipette unit. 
     Again the coupling stud can be stuck with a plug end, ahead into the pipette tip, wherein it is advantageously recommendable to place the counter-axial positioning devices, at least in part, on the outside circumference of the coupling stud at an axial distance from the plug-end. 
     In accordance with the previously mentioned cylindrical design of the jacket inside circumference of the pipette tip, the outside circumference of the coupling stud can have an envelope essentially formed of cylindrical sections at least in the area of the coupling stud, which in the coupling position projects into the pipette tip. 
     The counter-axial positioning means may comprise at least one complementary counter-stop at the coupling stud which is intended for interaction with an axial stop of the pipette tip. This counter-stop may be formed by a stepped shoulder on the outside circumference of the coupling stud. 
     The coupling stud can carry a sealing element, in particular an O-sealing ring made of an elastically shapeable material which is used for sealing between the pipette tip and the coupling stud, wherein a squeezing device for the axial compressing of the sealing element can be allocated to the pipette unit. The sealing element can have not only a sealing function but, at the same time can have a prestress function as well, if the pipette tip has a correspondingly shaped and located working surface for the sealing element which has a radial surface component and can be loaded with an axial force component from the sealing element. 
     According to another aspect the invention finally also concerns the combination of a pipette tip of the type described above with a pipette device of the type described above. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The invention is explained in more detail below with the aid of the attached drawings. The figures represent the following: 
         FIG. 1 , in cross section, an embodiment of a pipette tip in accordance with the invention; and 
         FIGS. 2-5  situations during the coupling of a pipette tip to a pipette device and during the release of the pipette tip. 
     
    
    
     DETAILED DESCRIPTION OF THE DISCLOSED EMBODIMENTS 
     Reference is made to  FIG. 1  first. There one can see a pipette tip  1  which is also designated as a tip, with a jacket  5  which is rotationally symmetric around a longitudinal axis  3  and encloses a passage opening  7  which axially passes through the pipette tip  1 . As seen in  FIG. 1 , in the area of its upper, open front end  9 , the pipette tip  1  has a coupling area  11  used for coupling to a pipette device that is not depicted in  FIG. 1 . Opposite the front end  9 , the pipette tip  1  has a mouth end  13 , which is intended for immersion in the medium to be pipetted. 
     The jacket  5  of the pipette tip  1  has an outside circumference  15  and an inside circumference  17 . In the coupling area  11  the inside circumference  17  has a cylindrical inside circumference section  19 , which essentially extends from the front end  9  to an annular stepped shoulder  21 , followed by another cylindrical inside circumference section  23 . The stepped shoulder  21  forms an axially directed stop surface. An annular groove  25 , extending in the direction of the circumference is worked into the jacket  5  in the area of the inside circumference section  19 . This annular groove  25  axially located between the front end  9  and the stepped shoulder  21 , has a groove contour which follows an arc in the cross-sectional representation of  FIG. 1 . 
     Following the coupling area  11  the jacket  5  has a first conical wall section  27  and a second conical wall section  29 , the conicality of which is weaker than that of the wall section  27 . In the area of the wall sections  27  and  29  the jacket  5  is constructed with a smaller wall thickness than in the coupling area  11 . The larger wall thickness in the coupling area  11  increases there the stability and rigidity of the pipette tip  1 . This permits a secure and leakage-free coupling of the pipette tip  1  to a pipette device. 
     As a numerical example for the pipette tip shown in  FIG. 1  the inside diameter of the jacket  5  in the area of the inside circumference section  19  can be approximately 6.8 mm, and in the area of the inside circumference section  23  it can be approximately 5.8 mm. The stepped shoulder  21  can be located at an axial distance from the front end  9  of approximately 5 mm. The radius of curvature of the circular contour of the annular groove  25  can be approximately 0.6 mm. The maximum radial depth of the annular groove  25  can be approximately 0.2 mm. The axial distance between the stepped shoulder  21  and the axial center of the annular groove  25 —that is, its deepest point—can be approximately 2.1 mm. 
     In the other figures, the same reference symbols as in  FIG. 1  are used for the same or functionally equivalent components of the pipette tip, but they are increased by the number  100 . To avoid repetitions, reference is made to the preceding statements regarding  FIG. 1 . 
     In the upper part of  FIG. 2  one can see a section of a pipette unit  201  which is a part of a pipette device which can be operated manually or automatically, and which has a coupling stud  203  intended for coupling with the pipette tip  101 . The pipette device under consideration can carry a large number of such pipette units  201 , for example, up to several hundred, in the formation as a pipette robot. The pipette unit  201  has a pipette tube  205  that contains a pipette channel  207  extending along a channel axis  209 , and being continued in the coupling state of the pipette tip  101  on the pipette unit  201  by the passage opening  107  of the pipette tip  101 . The coupling stud  203  comprises a coupling sleeve  211 , which is placed firmly at the lower end of the pipette tube  205 , for example, pressed onto it or screwed on it. An O-sealing ring  213  made of an elastically shapeable and, if desired, electrically conductive material is shoved onto the pipette tube  205  and is adjacent to the front side of the coupling sleeve  211  turned away axially from the pipette tip  101 . Furthermore a squeezing sleeve  215  is shoved onto the pipette tube  205 . This squeezing sleeve  215  can be slid axially relative to the pipette tube  205  and is used for the axial squeezing of the O-sealing ring  213 . The squeezing sleeve  215  can be actuated by actuating means, which are not depicted. These actuating means can permit a manual or automatic actuation of the squeezing sleeve  215 . For example, the squeezing sleeve  215  can be actuated hydraulically. It is also conceivable to provide a threaded drive for the adjustment of the squeezing sleeve  215  which can be actuated manually but which can also be actuated by means of an electric motor. 
     To release the pipette tip  101  furthermore a release member  217  is provided that is axially movable relative to the pipette tube  205 , and which is designed as the squeezing sleeve  215  and the release tube enclosing the pipette tube  205  in the represented exemplified embodiment. The mode of actuation of the release mechanism  217  will be discussed in more detail further below. 
     An annular stepped shoulder  219  complementary to the stepped shoulder  121  of the pipette tip  101  is formed on the coupling sleeve  211 , which upon inserting the coupling stud  203  into the pipette tip  101  strikes the stepped shoulder  121  of the pipette tip  101 . By the interaction of these two stepped shoulder  121 ,  219  the axial position of the pipette tip  101 , relative to the pipette unit  201  is precisely defined in the final assembly state. Toward the end of the coupling stud  203  which moves forward during insertion the coupling sleeve  211  has a cylindrical outside circumference section  221 ; its diameter is coordinated with the diameter of the inside circumference section  123  of the pipette tip  101  in the sense of a smooth-running sticking of the pipette tip  101  onto the coupling stud  203 . Toward the axially seen other side, another cylindrical outside circumference section  223  of the coupling sleeve  211  follows the stepped shoulder  219 ; its diameter is coordinated in the same sense with the diameter of the inside circumference section  119  of the pipette tip  101 . 
       FIG. 3  shows the situation if the pipette tip  101  has been stuck on and the O-sealing ring  213  has not yet been squeezed. One can see that the axial distance of the stepped shoulder  219  of the coupling sleeve  211  from the axial front surface of the coupling sleeve  211 , on which the O-sealing ring  213  lies, is dimensioned in such a way that in the sticking position shown in  FIG. 3 , the O-sealing ring  213  is moved axially somewhat with respect to the annular groove  125 . Stated more precisely the axial center of the annular groove  125  with respect to the axial center of the uncompressed O-sealing ring  213  is moved somewhat toward the pipette tip  101 . Starting from this sticking position the squeezing sleeve  215  is moved axially downwards in the direction of the pipette tip  101 , so as to achieve an axial squeezing of the O-sealing ring  213 . In this regard, reference is made to  FIGS. 4 and 4   a , of which  FIG. 4  shows that state in which the squeezing of the O-sealing ring  213  has been finished and in which the final assembly position of the pipette tip  101  is reached on the pipette unit  201 , and of which  FIG. 4 a    shows an enlarged section in the area of the O-sealing ring  213 . When considering the last figure, one can see that the squeezing sleeve  215  has a forward tip  225  on its end facing the O-sealing ring, which penetrates between the O-sealing ring  213  and the pipette tube  205  upon approach of the squeezing sleeve  215  to the O-sealing ring  213 , so that the O-sealing ring  213  is compressed not just axially, but also radially by the tip  225 , somewhat toward the annular groove  125 . In the course of its squeezing the O-sealing ring  213  as a whole undergoes an enlargement of its outside diameter. Its radially pressed-out parts can escape into the space recessed by the annular groove  125  which is indicated by a dashed line in  FIG. 4 a   . The parts of the O-ring  213  escaping into the annular groove  125  attempt to relax and expand in the annular groove  125  wherein they arrive at the bottom of the annular groove  125  and press against it. The previously addressed axial displacement of the annular groove  125 , with respect to the O-sealing ring  123 , causes the O-sealing ring  213  to press primarily against the axially upper area of the bottom of the annular groove  125 , in  FIG. 4 a   . In this area the bottom of the annular groove  125  forms a working surface  127  for the O-sealing ring  213 . This working surface  127  has a radial component as a result of its curvature, so that in case the O-sealing ring  213  presses against the working surface  127 , a force is exerted on the pipette tip  101  with an axial component. This axial force prestresses the stepped shoulder  121  of the pipette tip  101  axially against the stepped shoulder  219  of the coupling sleeve  211 , whereby a secure axial support of the pipette tip  101  on the pipette unit  201  is achieved. As a result of the force with which the O-sealing ring  213  presses against the working surface a tight placement of the O-sealing ring  213  on the working surface  127  is established, so that a secure sealing is guaranteed between the pipette tip  101  and the pipette unit  201 . 
     One can see in  FIG. 4 a    that the O-sealing ring  213  does not necessarily completely fill the axially lower area of the annular groove  127  in its squeezed position (shown as a dashed line). Although this is possible, what is important, however, is that the engagement conditions between the squeezed O-sealing ring  213  and the annular groove  125  are established in such a way that such a resulting axial force is always exerted on the pipette tip  101  by the O-sealing ring  213  that the previously addressed pressing of the stepped shoulder  121  of the pipette tip  101  against the stepped shoulder  219  of the coupling sleeve  211  is achieved. The final coupling state of the pipette tip  101  on the pipette unit  201 , in which the secure and sealing support of the pipette tip  101  on the pipette unit  201  is achieved by the axial squeezing and radial expansion of the O-sealing ring  213 , is shown in  FIG. 4 . 
     For the release of the pipette tip  101 , the squeezing sleeve  215  is moved up axially from its squeezing position shown in  FIG. 4 , whereby the O-sealing ring  213  is relaxed again and drawn back from the annular groove  125 . The prestress force exerted on the stepped shoulders  121 ,  219  in the coupling state according to  FIG. 4 , is thereby cancelled. The state shown in  FIG. 3  is finally established once again. Advantageously, in this state in accordance with  FIG. 3 , the O-sealing ring  213  will not be completely out of contact with the inside circumference  117  of the pipette tip  101 , but rather will be in such engagement with the inside circumference  117  of the pipette tip  101  that the pipette tip  101  does not fall by itself from the pipette unit  201 . 
     Considering  FIG. 4 a    in this situation the O-sealing ring  213 , for example, can collide onto the transition edge designated as  129  between the annular groove  125  and the cylindrical inside circumference section  119  of the pipette tip  101 . To release the pipette tip  101  this transition edge  129  must be moved past the O-sealing ring  213  which is possible only with a simultaneous slight radial compressing of the O-sealing ring  213 . This radial compression of the O-sealing ring  213 , however, acts to increase friction which would run contrary to the requirement of a smooth sliding off of the pipette tip  101  from the pipette unit  201 . For this reason, the cylindrical inside circumference section  119  of the pipette tip  101  located above the annular groove  125  is preferably constructed with steps as can be seen in particular in  FIG. 4 a   . In a small axial distance from the transition edge  129  it has a step expansion formed by a step  131  which produces a corresponding diameter enlargement of this inside circumference section  119 . If the O-ring  213  has overcome the “constriction zone” formed between the transition edge  129  and step  131  it can relax completely and it loses contact with the inside circumference  117  of the pipette tip  101 , so that the pipette tip  101  can then be smoothly slipped off from the pipette unit  201 . 
     In order not to have to perform the slipping off of the pipette tip  101  from the pipette unit  201  manually the release member  217  is provided. This can be actuated in different ways. For example, a hydraulic actuation of the release member  217 , or one using an electric motor, is conceivable. Alternatively, a prestress spring, which is not depicted can act upon the release member  217 ; it is stressed when the pipette tip  101  is set on the pipette unit  201  when the pipette tip  101  presses the release tube forming the release member  217  upwards by its front end  109 . If the squeezing of the O-sealing ring  213  is then cancelled this release prestress spring is again relaxed. By its spring force it presses the release tube  217  downwards once again, which is accompanied by a release of the pipette tip  101 . It is clear that the release prestress spring is dimensioned in such a way that the force exerted by it on the release tube  217  in the stressed state does not exceed the axial support force of the O-sealing ring  213 . Simultaneously, it is dimensioned in such a way that the force exerted on the pipette tip  101  in the course of its relaxation is sufficient to move the edge  129  past the O-sealing ring  213 . 
       FIG. 5  shows the release state in which the release member  217  has moved downwards, and the pipette tip  101  has moved completely past the O-sealing ring  213 . 
     It is clear that suitable suction means are associated to the pipette tube  205  of the pipette unit  201 , which permit to produce a reduced pressure in the pipette channel  207  and thus in the pipette tip  101 , which leads to the suctioning in of the liquid to be pipetted. This suctioning means can comprise, for example, a piston placed axially movable in the pipette tube  205 , being axially displaceable by means of electrical, hydraulic, or pneumatic actuation means. 
     The pipette tip  101  is preferably made of a plastic material, for example, by injection molding. This plastic material may be electrically conductive, to be able to carry out conductivity measurements in the liquid to be pipetted in a manner that is, in fact, known. Accordingly the coupling sleeve  211  and the pipette tube  205  may also be made of conductive materials. For reasons having to do with strength and wear and tear, metals are preferably used here, although plastic materials are not ruled out for the coupling sleeve  211  and the pipette tube  205 . The capacity of the pipette tip  101  designed as a disposable article can be between 0.1 and 1300 μL, for example.