COATED TIP CUP

Abstract

A pipette tip extension attachable to a pipette tip is disclosed. The pipette tip extension has a proximal end, a distal end, and an exterior wall extending between the proximal end and the distal end. The exterior wall has an outer side and an inner side and forms at the proximal end a reception aperture for inserting a pipette tip. The pipette tip extension further has a bottom at the distal end, an inner cavity enclosed by the inner side of the exterior wall and the bottom, one or more distance elements arranged at the inner side of the exterior wall and protruding into the inner cavity, and a coating for interacting with a fluid present in a fluid uptake area.

Claims

1. A pipette tip extension attachable to a pipette tip, the pipette tip extension comprising: a proximal end, a distal end, and an exterior wall extending between the proximal end and the distal end, the exterior wall having an outer side and an inner side and forming at the proximal end a reception aperture for inserting a pipette tip, a bottom at the distal end, an inner cavity enclosed by the inner side of the exterior wall and the bottom, one or more distance elements arranged at the inner side of the exterior wall and protruding into the inner cavity, the distance elements being dimensioned to establish a fluid uptake area adjacent to the inner side of the exterior wall and the bottom, the fluid uptake area extending from the bottom up to the reception aperture and being in fluid connection with the surrounding atmosphere at the reception aperture, and a coating facing towards said fluid uptake area.

2. The pipette tip extension according to claim 1, wherein the coating is applied on the inner side of the exterior wall and/or on a side of the bottom facing towards the inner cavity, and/or on the one or more distance elements.

3. The pipette tip extension according to claim 1, wherein the coating is selected from: a sorption layer for an extraction of a target molecule, a coating for a binding assay, or a lyophilized or a dehydrated reagent.

4. The pipette tip extension according to claim 3, wherein the coating is a sorption layer for an extraction of a target molecule, and the coating is configured as: a sorption layer for a liquid liquid extraction, a sorption layer for a solid phase extraction, or a functionalized sorption layer.

5. The pipette tip extension according to claim 4, wherein the sorption layer is configured for the extraction of a target molecule from a sample, the target molecule being selected from a group comprising a protein, a peptide, a DNA molecule, an RNA molecule, a vitamin, a hormone, a drug, a medication substance, a metabolite, an allergene, a pesticide, a pollutant, an organic compound, an inorganic compound or molecule, a salt, a metal, and a metal ion.

6. The pipette tip extension according to claim 3, wherein the coating is configured as a coating for a binding assay, the coating preferably comprising a biologically active substance, selected from a group comprising an antibody or an antigen.

7. (canceled)

8. The pipette tip extension according to claim 3, wherein the coating is a lyophilized reagent which is selected from a group comprising a nucleic acid, a protein, a peptide, a biological cell, a buffer or assay reagent, or a biological sample, or a combination thereof.

9-12. (canceled)

13. The pipette tip extension according to claim 1, wherein at least one of the distance elements comprises a stop surface which is directed towards a medial axis of the pipette tip extension, and which can be abutted by a pipette tip when the pipette tip extension is attached to the pipette tip.

14-15. (canceled)

16. The pipette tip extension according to claim 1, wherein at least one, preferably each distance element is configured as elongated bar which extends along a direction from the proximal end towards the distal end of the pipette tip extension.

17. The pipette tip extension according to claim 1, wherein the exterior wall has a shape which is adapted to an outer shape of a pipette tip to which the pipette tip extension shall be attached, the exterior wall preferably being a circumferential wall which tapers towards the lower end of the pipette tip extension.

18-19. (canceled)

20. The pipette tip extension according to claim 1, comprising a constriction element for controlling an insertion depth of a pipette tip within the pipette tip extension, the constriction element defining a gap height between a distal end of an inserted pipette tip and the distal end of the pipette tip extension.

21. The pipette tip extension according to claim 20, wherein the constriction element is formed by: a stop surface or a part thereof of the one or more distance elements which is directed towards a medial axis of the pipette tip extension, and/or one or more spacing blocks arranged at the bottom in the inner cavity of the pipette tip extension.

22. (canceled)

23. An assembly comprising: a pipette tip for aspirating and/or dispensing a liquid, a pipette tip extension attached to the pipette tip, the pipette tip extension comprising: a proximal end, a distal end, and an exterior wall extending between the proximal end and the distal end, the exterior wall having an outer side and an inner side and forming at the proximal end a reception aperture for inserting the pipette tip, a bottom at the distal end, an inner cavity enclosed by the inner side of the exterior wall and the bottom, one or more distance elements for spacing apart the pipette tip from the attached pipette tip extension, the one or more distance elements being dimensioned to establish a fluid uptake area adjacent to the inner side of the exterior wall, the bottom and the inserted pipette tip, the fluid uptake area extending from the bottom up to the reception aperture and being in fluid connection with the surrounding atmosphere at the reception aperture, and a coating for interacting with a fluid present in the fluid uptake area.

24. A method of treating a sample in a liquid, the method comprising the following steps: providing a pipette tip extension according to claim 1, comprising a coating for interacting with a liquid present in the fluid uptake area, aspirating a liquid into a pipette tip, inserting the pipette tip filled with the liquid into the pipette tip extension, dispensing the liquid into the fluid uptake area of the pipette tip extension, thereby contacting the liquid with the coating and allow the liquid to interact with the coating, wherein the liquid is selected from a group comprising a liquid with or without an analyte or a biological sample.

25. The method of claim 24, comprising the step of moving the liquid one or multiple times between the pipette tip extension and the fluid uptake area of the pipette tip extension, thereby increasing the interaction between the liquid and the coating.

26. The method of claim 24, wherein the coating is a lyophilized reagent, and wherein the liquid is a solvent solution for the lyophilized reagent.

27. The method of claim 24, wherein the coating is a coating for a binding assay, preferably an immobilized antibody or antigen, and wherein the liquid comprises a biological sample comprising a protein or peptide.

28. The method of claim 24, wherein the coating is a sorption layer for an extraction of a target molecule, and the liquid comprises the target molecule.

29. The method of claim 28, further comprising the steps of: aspirating the liquid back into a pipette tip and discarding the liquid, inserting a pipette tip comprising a wash solution into the pipette tip extension, and dispensing the wash solution into the fluid uptake area by using a pipette tip, and optionally moving the liquid one or multiple times between the pipette tip extension and the fluid uptake area of the pipette tip extension.

30. The method of claim 28, further comprising the steps of: aspirating the liquid back into a pipette tip and discarding the liquid, inserting a pipette tip comprising an elution solution into the pipette tip extension, and dispensing the elution solution into the fluid uptake area by using a pipette tip, and optionally moving the liquid one or multiple times between the pipette tip and the fluid uptake area of the pipette tip extension.

31. The method of claim 24, wherein the pipette tip extension is moved by moving the pipette tip inserted into the pipette tip, using a handheld pipette or a pipette of a liquid handling workstation.

32. The method of claim 24, wherein each step of aspirating, dispensing or moving the liquid is controlled by a liquid handling workstation, the liquid handling workstation comprising a pipette to which the pipette tip is attached.

33. The method of claim 24, further comprising the step of removing the pipette tip extension from the pipette tip by using an ejection mechanism of a handheld pipette or of a liquid handling workstation.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0134] Embodiments of the current invention are described in more detail in the following with reference to the figures. These are for illustrative purposes only and are not to be construed as limiting. It shows

[0135] FIG. 1A a schematic side view of a pipette tip extension in a first embodiment,

[0136] FIG. 1B a schematic view onto the proximal end of the pipette tip extension of FIG. 1A,

[0137] FIG. 1C a schematic sectional drawing of the pipette tip extension of FIG. 1A according to the intersection plane C-C as indicated in FIG. 1B,

[0138] FIG. 1D a schematic sectional drawing of the pipette tip extension of FIG. 1A according to the intersection plane D-D indicated in FIG. 1B,

[0139] FIG. 2A a schematic side view of an assembly comprising the pipette tip extension of FIG. 1A and an inserted pipette tip,

[0140] FIG. 2B a schematic sectional drawing of the assembly of FIG. 2A,

[0141] FIG. 3 a schematic overview drawing of a pipette tip extension in a further embodiment functionally integrated into a liquid handling workstation,

[0142] FIG. 4A a schematic view of a selected embodiment of a distance element at the inner side of the exterior wall,

[0143] FIG. 4B schematic views of various embodiments of distance elements at the inner side of the exterior wall,

[0144] FIG. 5A a schematic perspective side view onto a pipette tip extension in a second embodiment,

[0145] FIG. 5B a schematic and perspective longitudinal section of the pipette tip extension of FIG. 5A,

[0146] FIG. 5C a schematic and perspective view of a cutaway-cross-section of the bottom region of the pipette tip extension of FIG. 5A,

[0147] FIG. 6A a schematic perspective side view onto a pipette tip extension in a third embodiment,

[0148] FIG. 6B a schematic and perspective longitudinal section of the pipette tip extension of FIG. 6A,

[0149] FIG. 6C a schematic and perspective view of a cutaway-cross-section of the bottom region of the pipette tip extension of FIG. 6A,

[0150] FIG. 7 a simplified schematic cross sectional view of the bottom of the pipette tip extension in the third embodiment with an inserted pipette tip,

[0151] FIG. 8 a schematic overview of possible method steps which can be carried out with a pipette tip extension, and

[0152] FIG. 9 a schematic overview of method steps involved in step VII-1 of FIG. 8 for recovering a target molecule from the coating.

DETAILED DESCRIPTION OF THE INVENTION

[0153] FIG. 1A shows an exemplary embodiment of a pipette tip extension 1 in a schematic side view. The pipette tip extension 1 here is an elongated, tube-like body with a proximal end 2 and a distal end 3. An exterior wall 4 extends between the proximal end 2 and the distal end 3, and forms said reception aperture 7 of the pipette tip extension 1. A bottom 8, which is connected to the exterior wall 4, closes the pipette tip extension 1 at the distal end 3. The exterior wall 4 and the bottom 8 enclose an inner cavity 9, more precisely the inner side 6 of the exterior wall 4 and the inner side of the bottom 8. The pipette tip extension 1 shown here is a rotationally symmetric body and further comprises three distance elements 10, which are configured as elongated bars and which are mounted flush with the proximal end 2, so that the proximal end of the exterior wall 4 and each proximal end of the distance elements form a common surface. The medial axis 13 is indicated, and corresponds here to the longitudinal axis of the pipette tip extension 1.

[0154] Along the longitudinal axis, the pipette tip extension 1 comprises three different sections: a more proximal section is formed as an essentially cylindrical tube, followed by a more distal section which tapers conically towards the bottom 8; the third section being the bottom 8. This embodiment shows one possibility to adapt the shape of the pipette tip extension 1 to the shape of a pipette tip 14 which is to be inserted into the pipette tip extension 1. In the present context, the term “a pipette tip extension 1 attachable/attached to a pipette tip 14” describes essentially the same situation as the term “a pipette tip 14 insertable/inserted into a pipette tip extension 1”. Other adaptations of the shape and dimension of the pipette tip extension 1 are possible, as shown exemplarily in the FIGS. 5A-C and 6A-C. Such adaptations are not restricted to the choice of the shape of the exterior wall 4. For example, the number shape and/or dimensions of one or more of the distance elements 10 may be used to configure the pipette tip extension 1 as being attachable to a pipette tip 14.

[0155] FIG. 1B shows a schematic view onto the proximal end of the pipette tip extension 1. The proximal surface is formed here commonly by the proximal end of the exterior wall 4 and the proximal end of the distance elements 10. The three distance elements are formed by the exterior wall 4 and protrude into the inner cavity 9. A pipette tip 14 which is inserted into the inner cavity 9 abuts the distance elements 10 so that the pipette tip 14 does not touch the inner side of the exterior wall 4 (see also FIGS. 2A and 2B). The distance element 10 or distance elements 10 therefore establish a fluid uptake area 12 which is essentially adjacent to the inner side of the exterior wall and within the inner cavity 9. The dimensions of the distance elements 10 may influence the volume of the fluid uptake area 12, though the coating 27 which naturally comprises a certain volume also influences the final volume of the fluid uptake area 12.

[0156] In FIG. 1B, the course of two intersection planes C-C and D-D are indicated, on which the FIGS. 1C and 1D are based on:

[0157] In FIG. 1C, a schematic sectional view of the pipette tip extension 1 according to the intersection plane C-C is shown. The pipette tip extension 1 of FIG. 1A can be seen here in a longitudinal section, which particularly allows a view onto one of the distance elements 10 which is configured as an elongated distance bar, a sectional view onto the bottom 8 of the pipette tip extension 1, and a sectional view onto the coating 27. As can be seen, the bottom 8 restricts the inner cavity 9 at the distal end 3 of the pipette tip extension 1. The bottom 8 and the exterior wall 4 lead seamlessly into one another and commonly form the inner side of the pipette tip extension 1. The distance bar reaches not up to the bottom 8 but leaves a gap g towards the bottom 8 in this case. In the embodiment shown, the distance bar(s) ensures that a pipette tip 14 which is inserted into the pipette tip extension 1 does not abut the bottom 8 but that a gap g of a gap height h is generated. In this way, which a continuous fluid flow between the inserted pipette tip 14 and the inner cavity 9 of the pipette tip extension 1 may be established.

[0158] The distance bar shown has a stop surface 11, which can be seen frontally. In this longitudinal section, the distance bar and its stop surface 11 extends essentially parallel to the exterior wall. This may allow an easy handling during the manufacturing process such as an injection molding process. A pipette tip 14 which is inserted abuts the stop surface of the distance bar, so that the insertion depth is controlled.

[0159] In this longitudinal section, the coating 27 can now also be seen. This coating 27 was not visible in the FIGS. 1A and 1B.

[0160] The coating 27 in this embodiment extends by a height 32 in a longitudinal direction along the tapering section of the pipette tip extension 1. In this embodiment, the proximal section and the bottom section do not comprise a coating 27, though it might be possible to cover also in these areas by a coating 27. The fluid uptake area 12 is in tapering area of the inner side 6 which is covered by a coating 27 adjacent to the coating 27, while in the proximal region and the bottom region, the fluid uptake area 12 is adjacent to the inner side 6 of the exterior wall 4 and the inner side of the bottom 8.

[0161] In FIG. 1D, a schematic sectional section of the pipette tip extension according to the intersection plane D-D indicated in FIG. 1B is shown. This section allows a view of the pipette tip extension of FIG. 1A in a longitudinal section, with a frontal view of one of the bars being cut (left side) and one of the bars shown in a side view. The gap g formed between the distal end of the cut distance bar on the left side and the inner side of the bottom 8 can be seen.

[0162] It can further be seen that the two visible distance bars extend continuously from the proximal end 2 towards the distal end 3, ending with an offset towards the distal end 3. The surface of each elongated bar which faces towards the medial axis 13 function as a stop surface 11 for the inserted pipette tip 14; all stop surfaces together form a “common” stop surface in this case which define the position of the pipette tip 14 within the pipette tip extension 1. The distance elements 10 are not covered by the coating 27 here.

[0163] The pipette tip extension 1 in this embodiment is a single-piece body with respect to the exterior wall 4, the bottom 8, and the distance elements 10. The pipette tip extension further comprises a cover 28 which closes the reception aperture 7 and which in this case configured to be peelable of the pipette tip extension 1 for making the reception aperture 7 being accessible for a pipette tip 14. A cover 28 is particularly suitable to protect the coating 27 for example during storage.

[0164] In FIG. 2A an assembly comprising a pipette tip extension 1 with an inserted pipette tip 14 can be seen in a schematic side view. The pipette tip 14 shown is in a typical disposable pipette tip for handling liquids e.g. with a handheld pipette or a with a pipette 23 of an automated liquid handling workstation 20. Such a pipette tip 14 is an elongated tube having different cylindrical or conically tapering wall sections of a circumferential wall 15, which may be adapted to particular technical requirements of a pipette 23 and/or a pipetting head 21 to which the pipette tip 14 shall be attached for pipetting. The pipette tip 14 shown here comprises at a proximal a collar 16 with strengthening struts and at the distal end an outlet opening 17 for dispensing or aspirating a liquid (see also FIG. 7). The pipette tip 14 is attached to a pipette 23 with the proximal end, and the collar 16 prevents a deformation of the pipette tip 14 during the attachment, and provides a stabilizing effect.

[0165] In FIG. 2A, the pipette tip 14 is inserted with the outlet opening 17 ahead into a pipette tip extension 1 which essentially corresponds to the pipette tip extension shown in FIG. 1A. The distance elements 10 are configured here as elongated bars which form the fluid uptake area 12 adjacent to the inner side 6 of the exterior wall 4, and which additionally control the insertion depth of the pipette tip 14 in a way to ensure the formation of a gap g between the distal end of the pipette tip 14 and the bottom 8 of the pipette tip extension 1. The coating 27 is not visible in this view.

[0166] The gap g which is formed after the insertion of the pipette tip 14 can be seen in the sectional view of FIG. 2B. FIG. 2B is a schematic sectional drawing of the assembly of FIG. 2A along the intersection plane A-A, and in this Figure it becomes also apparent that the gap g at the bottom 8 of the pipette tip extension 1 in this embodiment provides a fluid connection between the interior of the disposable pipette tip 14 and the fluid uptake area 12 in the inner cavity 9 of the pipette tip extension 1. An analogous situation can also be seen in FIG. 7. As the fluid uptake area 12 is additionally in fluid connection with the surrounding atmosphere at the proximal end 2 of the pipette tip extension 1, it is ensured that a liquid 20 may be moved between the interior 18 of the pipette tip 14 and the fluid uptake area 12 of the pipette tip extension 1 when they are assembled to a functional unit. It is an advantage of the formation of the gap g that for example when a mixing step is carried out in the pipette tip extension 1, relatively high flow velocities may be achieved, thereby increasing the efficiency of the mixing. The configuration of the pipette tip extension 1 further ensures that the fluid flow is guided over the coating 27, so that the contact of a sample fluid with the coating 27 is ensured when the sample fluid is dispensed out of an inserted pipette tip 14.

[0167] In FIG. 3, a pipette tip extension 1 is shown in a schematic overview during a liquid handling process of a liquid handling workstation 20. The liquid handling workstation 20 is configured to handle liquids 19 in an automated manner under the control of a controller 22. In particular, the controller 22 controls the activity for example of a pipetting head 21 for aspirating and dispensing liquids and moving liquids. In FIG. 3, the pipette tip extension 1 is shown in a schematic longitudinal section as being attached to disposable pipette tip 14 which in turn is attached to a pipette 23 of a pipetting head 21. A partial volume of a liquid 19 is present in the pipette tip 14, and another partial volume of the liquid 19 is present in the fluid uptake area 11 of the pipette tip extension 1, where it contacts the coating 27 for interaction. After insertion of a pipette tip 14, the pipette tip extension 1 is movable under the control of the liquid handling workstation 20. The possible movement directions are indicated by the arrows. The functional connection between the liquid handling workstation 20, the controller 22, and the pipetting head 12 are indicated by connection lines.

[0168] The liquid handling workstation 20 may additionally be configured to provide a mechanism of removing a pipette tip extension 1 from a pipette tip 14 to which it is attached. Such a mechanism may be for example an existing ejection mechanism 31 of a liquid handling workstation 20 used for removing a disposable tip 14 from a pipetting head 21, or may be a separate mechanism like a rake as discussed above.

[0169] FIG. 4A shows in a schematic view onto the inner side 6 of the exterior wall 4 an exemplary embodiment of a distance element 10 which is configured as an elongated bar, and which is arranged flush with the proximal end of the exterior wall 4 of a pipette tip extension 1. A coating 27 is not indicated here for a better overview. The elongated bar extends from the proximal end 2 towards the distal end 3, and has a width “a” which corresponds to its dimension along the perimeter of the inner side 6 of the exterior wall 4, it has a length “b” which corresponds to its longitudinal dimension, and it has a depth “c” which corresponds to its dimension by which it protrudes into the inner cavity 7 and towards a medial axis 13. The description of depth a, length b, and width c may be applied to the distance elements 10 also in general.

[0170] FIG. 4B shows schematically different configurations of a distance element 10. Also here, for reasons of clarity, a coating 27 is not shown. All distance elements 10 shown are arranged with an offset to the proximal end 2 of the peripheral wall 4. Shown are distance elements 10 which are configured as more or less elongated bars, or as cylindrical protrusions. It is possible to combine differently configured distance elements 10 to achieve a desired seat of a specific pipette tip 14 within the pipette tip extension 1. For example, a multitude of elongated bars may be arranged along the same line from the proximal end 2 towards the distal end 3. Such a distribution may particularly be advantageous for achieving a mixing effect within the pipette tip extension 1. Apart from simple elongated dimensions, also deviating forms such as snake- or nose-like extensions or other may be possible.

[0171] At the more distal section, additional constriction elements 24 for controlling the insertion depth of a pipette tip 14 are shown. On the left side, a distance bar is shown which comprises an additional protrusion towards the inner cavity 7 at its distal end. This additional protrusion sits on the side of the bottom 8 which faces towards the inner cavity 9. On the right side, a single constriction element 24 is shown, which is a simple protrusion directly from the inner side 6 of the exterior wall 4, and which may equally provide a stopper or stop surface that can be abutted from the distal end of a pipette tip 14.

[0172] The geometry of the inner gap which corresponds the fluid uptake area 31 may be adjusted by a respective adjustment of the number and geometry of the distance element(s) 10 used and also the geometry of the shape of the exterior wall 4, and, if desired, by the use of additional constriction elements 24. It might for example particularly desirable to minimize the width 29 of the fluid uptake area 12 when only smaller volumes of liquid 19 shall be used; in this case, special emphasis is needed for the geometry of the distance element(s) to minimize potential fluid trapping effects.

[0173] In FIG. 5A a schematic side view of a pipette tip extension 1 in a second embodiment concerning the configuration of the exterior wall 4, distance elements 10, and constriction elements 24 is shown. The coating 27 is not shown here due to clarity reasons. The pipette tip extension 1 comprises along the medial axis 13 two different sections, an upper section towards the proximal end 2, and a lower section towards the distal end 3. The upper section is longer than the lower section in this embodiment and is configured as an essentially cylindrical tube or as a tube only slightly tapering towards the lower section. The lower section is configured as a hollow tube with a higher degree of tapering towards the bottom 8. The lower section mouths into the bottom 8 at the distal end 3 of the pipette tip extension 1, which is more clearly visible in the FIGS. 5B and 5C. The upper section has a larger diameter than the lower section, so that a shoulder is formed at the transition from the upper section to the lower section. In this embodiment, the shoulder is formed both, on the outer side 5 and on the inner side 6 of the exterior wall 4.

[0174] The pipette tip extension 1 comprises at the upper section and on the inner side 6 of the exterior wall 4 three distance elements 10 which are configured as elongated bars. These elongated bars are flush with the proximal end 2 and extend continuously on the inner side 6 of the exterior wall 4 up to the shoulder at the transition to the lower section. The elongated bars protrude to a lesser extends into the inner cavity 9 at the immediate proximal end 2 of the pipette tip extension that close to the transition to the lower section. By this, the elongated bars, and specifically their surface which faces towards the medial axis 13, in the present context also referred to as stop surface 11, form in the inner cavity 9 a reception for a pipette tip 14, the reception tapering from the proximal end 2 of the pipette tip extension 1 towards the distal end 3. In this configuration, the pipette tip extension 1 is particularly useful for being attached to a pipette tip 14 which tapers in a complimentary way.

[0175] The configuration of the distance elements 10 as described for this second embodiment can be seen in more detail in FIG. 5B, which is a schematic and perspective longitudinal section of the pipette tip extension of FIG. 5A, thereby allowing a view into the inner cavity 9. By this it can be seen that at the transition from the upper section to the lower section, the elongated bars merge with the exterior wall 4 at the lower section. In any case, the inner side 6 of the pipette tip extension 1 is configured in such a way that if a pipette tip 14 is inserted into the pipette tip extension 1 of the FIGS. 5A to 5C, said pipette tip 14 essentially only abuts the elongated distance bars but not the inner surface 6 of the exterior wall 4 at the lower section. This is essential as it ensures that a fluid uptake area is formed at the inner side of the exterior wall 4 continuously from the bottom 8 up to the proximal end 2 of the pipette tip extension 1. Indeed, the configuration of the distance elements 10 define the positioning of a pipette tip 14 within the inner cavity 9 of the pipette tip extension 1, and ensure the formation of the fluid uptake area 12. The coating 27 may be applied on both, the inner side 6 of the lower section and the inner side of the upper section, and/or on the side surface of the elongated distance bars and/or the inner side at the bottom 8.

[0176] The pipette tip extension 1 shown comprises in addition to the distance elements 10 three constriction elements 24 which arranged at the bottom 8. These additional constriction elements 24 are configured here as separate spacing blocks which restrict at the bottom the insertion depth of a pipette tip 14 within the pipette tip extension 1. A pipette tip 14 inserted into the pipette tip extension 1 abuts the upper side of each of the spacing blocks. A direct contact of the distal end of the pipette tip 14 with the bottom 8 of the pipette tip extension 1 is prevented, and at the same time it is ensured that a fluid connection is established between the inner cavity of the inserted pipette tip 14 and the fluid uptake area 12 of the pipette tip extension 1 by the formation of the gap g.

[0177] These additional spacing blocks are shown in more detail in FIG. 5C. It may be seen that in this embodiment the spacing blocks are positioned on the bottom 8 at the side which faces the inner cavity 9 and are connected with the inner side of the exterior wall 4. The connection with the exterior wall 4 is established by a beveled section of the spacing block. The degree of inclination of this beveled section may be used as a tool to precisely position a pipette tip 14 within the inner cavity 9, to ensure the establishment of a fluid uptake area 12 and the fluid connection between the fluid uptake area 12 and the inner cavity of the inserted pipette tip 14.

[0178] In FIG. 6A a schematic side view of a pipette tip extension 1 in a third embodiment concerning the configuration of the exterior wall 4, distance elements 10 and constriction elements 24 is shown. Also in this embodiment, the pipette tip extension 1 comprises along the medial axis 13 two different sections, an upper section towards the proximal end 2, and a lower section towards the distal end 3. The upper section has a larger diameter than the lower section, so that a shoulder is formed at the transition from the upper section to the lower section. Also in this embodiment, the shoulder is formed both, on the outer side 5 and on the inner side 6 of the exterior wall 4. Also similar is that the upper section is an essentially cylindrical tube or as a tube only slightly tapering towards the lower section, and the lower section being also configured as a hollow tube with a higher degree of tapering towards the bottom 8. The lower section mouths into the bottom 8 at the distal end 3 of the pipette tip extension 1.

[0179] However, in this third embodiment, the upper section is shorter than the lower section, and the distance elements 10 are arranged at the inner side 6 of the lower section. The inner cavity 9 surrounded by the upper section here rather serves to provide space for the fluid uptake area at the height of the upper section, and to provide the fluid connection with the surrounding atmosphere.

[0180] The configuration of the distance elements 10 in this third embodiment and the configuration of the constriction elements 24 for further restricting the insertion depth of a pipette tip 14 can be taken from the FIG. 6B and FIG. 6C. Also in this embodiment, three distance elements 10, configured as elongated bars, are used for establishing the fluid uptake area 12. Each of the three bars are formed by protrusions of the exterior wall 4, beginning flush with the shoulder formed between the upper and the lower section, and extending towards the bottom 8. The elongated bars are wedge-shaped and taper towards the distal end 3 of the pipette tip extension 1. The angle of inclination of the elongated bars may be adapted to the outer shape of the pipette tip 14 which shall be inserted, with the provision that the distance elements 10 space the pipette tip 14 apart from the inner side 6 of the exterior wall 4 to establish the fluid uptake area 12, even when a coating 27 is provided at the inner side 6 of the exterior wall 4, for example.

[0181] As may be seen in particular in FIG. 6C, the position of a pipette tip 14 within the inner cavity 9 is further controlled also in this embodiment by the use of additional constriction elements 24 at the bottom 8 of the pipette tip extension 1. In total, three constriction elements 24 are used, each being configured as a spacing block. In contrast to the embodiment shown in the FIGS. 5A to 5C, the spacing blocks are here not further connected to the exterior wall 4. In this configuration, the spacing blocks do not separate the fluid uptake area 12 at the bottom area, as it is for example the case in the embodiment shown in FIGS. 5A to 5C. This configuration may have the advantage to further increase a mixing effect due to the introduction of additional flow turbulences, but may additionally introduce a risk of an increased dead volume. A can be taken from the FIGS. 5A-5D and 6A-6D, the choice of numbers and configuration of a constriction element 24 may additionally have an effect onto the fluid flow in an assembly of a pipette tip extension 1 and a pipette tip 14.

[0182] In FIG. 7, the configuration of the spacing blocks used on the bottom 8 of the third embodiment shown in FIG. 6C is shown in a more simplified schematic sectional view in higher magnification. Here, a pipette tip 14 is shown to be already inserted, abutting the upper surface of the one spacing block shown. The spacing block shown restricts the insertion depth of the pipette tip 14, and establishes a gap g between the distal end of the pipette tip 14 and the bottom 8 of the pipette tip extension 1. The gap g has a gap height h which in this case corresponds to the height of the spacing block along the longitudinal extension of the pipette tip extension 1 where the pipette tip 14 abuts the spacing block. The gap g formed at the bottom 8 of the pipette tip extension 1 allows a fluid being moved between the inner cavity of the inserted pipette tip 14 and the fluid uptake area 12 in the pipette tip extension 1. As the fluid uptake area 12 is not restricted towards the surrounding atmosphere at the proximal end 2 of the pipette tip extension 1, the fluid may be moved between pipette tip 14 and pipette tip extension 1 under the same conditions as for example for other standard aspiration or dispensing steps, while ensuring the contacting of the coating 27 with the fluid. By adapting the configuration of the one or more distance elements 10, the influence of the volume of the coating 27 onto the volume of the fluid uptake area 12 may additionally be controlled.

[0183] A particular advantage of a pipette tip extension 1 in one of the embodiments described herein or in an embodiment of a different combination of the single elements described or their equivalents is the possibility to simply put on the pipette tip extension 1 onto a pipette tip 14 and to move the pipette tip extension 1 with or without a liquid 19 by means of the pipette which holds the pipette tip 14. This is a particular advantage for example in the context of a liquid handling workstation 20, which is configured to move a pipette 23 in an automated manner. The pipette tip extension 1 here serves as a liquid handling vessel which may in a very simple way be transported on the liquid handling workstation 20 to the place where it is required, without the need of a user. For transporting the liquid handling vessel, only the existing robotic for moving the pipette is required; no further robotic is needed in this case.

[0184] FIG. 8 is a schematic overview of a series of method steps in a particularly useful application of a pipette tip extension 1 comprising a coating 27 according to the invention. A pipette tip extension 1 comprising such a coating 27 is provided in step I. A coating 27 is in the present context a fully or at least partly immobilized layer or phase of material which is applied in this example on the inner side 6 of the exterior wall 4.

[0185] The coating 27 may however be in addition or alternatively be applied on the inner side of the bottom 8, and/or on the distance element(s) 10 on such surfaces which do not function as a stop surface 11. It may be desired to apply the coating on all reasonably available surfaces if for example the amount of material of the coating 27 shall be increased without substantially increasing the thickness of the coating 27.

[0186] Additionally provided in step I is a pipette tip 14 to which the pipette tip extension 1 is adapted, and a sample liquid. The liquid 19 may or may not comprise a target molecule.

[0187] In a next step II, the sample liquid 19 is aspirated into the pipette tip 14. Aspiration occurs by use of a pipette 23, which may be under the control of a controller 22 of a liquid handling workstation 20. The pipette tip extension 1 according to the invention is particularly suitable for being used in an automated liquid handling workstation 20, though it is also usable using a handheld pipette as described above.

[0188] The pipette tip 14 comprising the aspirated liquid 19 is then moved to the pipette tip extension 1 and in a further step III inserted therein. In case the pipette tip extension 1 is closed by a cover 28 for example to protect the coating 27 therein, the cover 28 may for example be removed manually peeling off, or the cover 28 may be pierced open upon insertion of the pipette tip 14.

[0189] As discussed before, the pipette tip extension 1 may be configured for example to have a pipette tip 14 inserted in a friction fit manner. In this embodiment, the pipette tip extension 1 can for example be moved by use of the inserted pipette tip 14 and the associated robotics of a liquid handling workstation 20. This is of an advantage, as the liquid handling workstation 20 does not require a separate robotic for transport the pipette tip extension 1. The pipette tip extension may however alternatively be configured to have a pipette tip 14 merely guided into a desired position without establishing a friction fit connection. In this case, the pipette tip extension 1 needs to be moved by a separate robotic of manually.

[0190] Upon insertion of the pipette tip 14, the fluid uptake area 12 is restricted in the inner cavity 9 of the pipette tip extension 1 in addition by the outer wall of the pipette tip 14. As the pipette tip extension 1 remains open at the proximal end 2, the sample liquid, which is in a next step IV dispensed into the fluid uptake area 12, is distributed in the inner cavity and brought in to direct contact with the coating 27. The liquid 19 may spread in a guided manner from the bottom 8 towards the proximal end, thereby contacting the coating 27, without the requirement of applying an additional driving force by the pipette 23 or the liquid handling workstation 20, as the fluid uptake area 12 is in fluid connection with the surrounding atmosphere at the proximal end 2. Settings however for example of the liquid handling workstation 20 may eventually require an adaptation in the case when the gap g and the width 29 of the fluid uptake area 12 are chosen so small that the liquid 19 must be forced through the gap g and fluid uptake area 12 by additional forces. Such a small width and gap may be desired if for example a high flow velocity shall be achieved.

[0191] Upon contacting the coating 27 by the sample liquid, the interaction reaction is allowed to take place, as indicated in step V. This may require an incubation step. As mentioned before, the interaction which takes place depends on the liquid 19 and on type of coating 27. In case the coating 27 is for example a lyophilized reagent, the interaction reaction is the solving of the reagent in the solvent solution. In case the pipette tip extension 1 is configured for example for carrying out an immunological detection of a target molecule, the interaction is for example an antibody-antigen-binding reaction, and in case the pipette tip extension 1 is configured to carry out an extraction step, the interaction is the binding between the sorbents and the target molecule. In the last two cases, the target molecule contacts the components of the coating 27 and is thereby also immobilized by the coating 27 in the pipette tip extension 1.

[0192] For improving the interaction reaction, one or more mixing steps V-1 may optionally be carried out. Mixing steps may advantageously be carried out by moving the liquid 19 between the pipette tip extension 1 and the inserted pipette tip 14 under the control of a liquid handling workstation 20 or a handheld pipette. Mixing may however also be achieved for example by repositioning the pipette tip extension with the liquid in the fluid uptake area 12 to a mixing device. Eventually, a heating step may be desired. In these cases, it may be desired to withdraw the pipette tip 14 from the pipette tip extension 1, and to re-insert the pipette tip 14 or insert a new pipette tip 14 after the mixing step, for example for moving the pipette tip extension 1 for later pipetting steps.

[0193] After a certain incubation time, the liquid 19 is aspirated in step VI from the pipette tip extension 1 into the pipette tip 14. The subsequent steps VII depend mainly on the configuration of the coating 27. The liquid 19 may be used immediately for follow-up reactions, for example if the coating 27 is a lyophilized reagent, which is resolved in the solvent solution in step V. In case the coating 27 is configured to bind an analyte or target molecule which is present in the liquid 19 and remains immobilized in the pipette tip extension 1, additional steps to recover the target molecule from the coating 27 are necessary.

[0194] These additional steps may optionally include a washing step VII-1. by using a washing solution. The washing solution is dispensed into the fluid uptake area 12 by a pipette tip 14 which is has been inserted into the pipette tip extension 1. The washing step VII-1 may include one or more additional mixing steps as described above to improve the contacting of the washing solution with the coating 27. The washing step VII-1. may be repeated one or more times. The number of repetition may depend on the nature of the liquid 19, of the analyte and/or of the respective coating 27.

[0195] Typically, after the washing, the analyte is resolved into a suitable solvent liquid by an elution step VII-2. For this, the washing solution is removed from the pipette tip extension 1 by aspirating the washing solution into the inserted pipette tip 14, and the washing solution is discarded with or without the pipette tip 14. An elution solution is then dispensed into the pipette tip extension 1 by means of a newly inserted pipette tip 14 which comprises said elution solution. Also the elution step VII-2 may optionally include one or more mixing steps as described above, to improve the separation from the analyte from the coating 27 and the uptake of the analyte into the elution solution. The elution solution with the analyte is then aspirated and may be further processed in follow-up reactions.

[0196] In FIG. 9, a schematic overview with more details of the washing step VII-1 for recovering a target molecule from the coating as described for step VII is shown. The supernatant which has been aspirated from the pipette tip extension 1 in step VI is discarded. A wash buffer may be aspirated into a new pipette tip 14, the tip is inserted into the pipette tip extension 1, and the wash buffer is dispensed from the pipette tip 14 into the pipette tip extension 1 and contacting the coating with the bound target molecule there. A mixing step may be carried out by consecutively moving the wash buffer between the pipette tip 14 and the pipette tip extension 1 by aspiration and dispense steps. The wash buffer is then aspirated from the pipette tip extension 1 into the pipette tip 14 and the supernatant is discarded in that the pipette tip 14 is removed from the pipette tip extension 1 and the wash buffer is dispensed for example into a waste container. The washing step may be repeated a number n of times, for example 3 to 5 times. Afterwards, the elution step according to step VII-2 is carried out.

TABLE-US-00001 REFERENCE SIGNS LIST 1 pipette tip extension 2 proximal end 3 distal end 4 exterior wall 5 outer side of 4 6 inner side of 4 7 reception aperture 8 bottom 9 inner cavity 10 distance element 11 stop surface 12 fluid uptake area 13 medial axis 14 pipette tip 15 wall of 14 16 collar of 14 17 outlet opening of 14 18 interior wall of 14 19 liquid 20 liquid handling workstation 21 pipetting head 22 controller 23 pipette 24 constriction element of 1 27 coating 28 cover 29 width of fluid uptake area 30 pipette tip hosting area 31 ejection mechanism 32 height of coating g gap h gap height