WO2001068258A1

WO2001068258A1 - Pipette tip

Info

Publication number: WO2001068258A1
Application number: PCT/US2000/006623
Authority: WO
Inventors: Bart Joseph Zoltan; Marc Papi; Kevin Kjell Olsen
Original assignee: American Cyanamid Company
Priority date: 2000-03-15
Filing date: 2000-03-15
Publication date: 2001-09-20
Also published as: AU2000238821A1

Abstract

The present invention comprises pipettes and pipette tips designed to eliminate or decrease the probability that solid materials in a medium being drawn into or expelled from the pipette may occlude, clog, block or be held against the open distal end of the pipette tip. In general, the present invention provides a pipette or pipette tip of the type having conventional designs and configurations, the improvement for which being that the open distal end of the pipette or pipette tip is conformed such that a plane passing across the distal opening is not perpendicular to the longitudinal axis of the pipette's body.

Description

PIPETTE TIP

This invention concerns a new design for pipette tips. More particularly, the present invention provides a new pipette tip design which inhibits clogging of the pipette when used with a medium containing particulate matter and reduces errors in collection and transfer of the medium.

Background of the Invention

U.S. Patent No. 5,336,468 (Tezuka et al.) teaches a pipette tip molded from plastic material treated with a water repellant material to allow transfer of a predetermined amount of an aqueous solution, particularly for applying a body fluid during clinical assays.

U.S. Patent No. 4,981,315 (Poli et al.) discloses and claims vacuum pipette tips modified for gripping silicon wafers by means of suction.

U.S. Patents Nos. 4,072,330 (Brysch) and 4,961,350 (Tennstedt) teach conventional pipette tips, particularly showing means and dimensions through which pipette tips may be mated to pipetting devices.

U.S. Design Patent No. 387,426 (Husar et al.) discloses a pipette body having a large, syringe-like proximal volume, terminated by. a more restricted pipette-like distal portion.

Conventional pipettes and pipette tips generally comprise a tube open at both proximal and distal ends. For the purposes of this disclosure, the proximal end refers to the end of the pipette from which suction or pressure is applied to the pipette and the distal end refers to the end of the pipette through which materials are normally brought into and expelled from the pipette's central chamber. Also for the purposes of this disclosure, reference to the present invention in relation to either a pipette or a pipette tip is understood to equally relate to the other, unless specifically stated otherwise. In conventional pipettes and. pipette tips, the distal opening is formed substantially as a lateral cross-cut through the body of the tube. Therefore, the plane of the pipette's distal opening is substantially perpendicular to the longitudinal or central axis of the pipette's central chamber. When the pipette or tip is inserted upright into a flat bottomed container, the plane of the distal opening is substantially parallel to the bottom of the container. Unless the pipette tip is brought into contact with the bottom of a container, a sample fluid may be readily drawn into or expelled from the pipette. However, solid matter in a fluid sample medium may block or clog the pipette's distal opening and interfere with fluid passage into or out of the pipette. Solids held against the distal end of the pipette by suction may also serve as a substrate onto which droplets of fluid may carried. After withdrawal of the pipette from the sample container, such droplets may fall unexpectedly as a contaminate. The solid and additional liquid may also be dispensed in normal sample delivery, along with the prescribed volume of collected material.

Pipette tip occlusion and dripping problems diminish the efficiency, accuracy and sterility of pipette transfers of materials, particularly when the transferred material contains particulate matter. These problems are magnified when robotics and automation processes are used to transfer large numbers of unknown dissolved or suspended chemicals.

In manually pipetting operations these problems can be lessened, as an operator may visually assess the situation and orient a pipette tip away from particulates in the transfer medium, avoiding tip occlusion or pipette uptake of solids. Robotic or automated operations, on the other hand, maintain the transferable material containers and pipettes in prescribed positions, usually with the pipette tip maintained upright in the middle of the sample container, and extend the pipette's tip as far into the container as mechanical tolerances of the various components allow. Such regimented pipette collections of material do not account for particulates in the sample materials, which may be drawn to the open pipette during collection.

If solids occlude or clog the tip, incomplete collection of sample material into the pipette may occur. Without the intended sample volume, robotic or automated processes may transfer no sample or less than needed sample to subsequent containers. In addition, particulate material trapped by suction to the pipette's tip provide a surface onto which liquids may adhere as the pipette is withdrawn from the initial sample. As the pipette is moved to another position, the material may then drop and contaminate other samples or the process area. In rrucropipetting or other operations where transfer of a limited volume of material is desired, such solids and collected droplets may also add unwanted volume to the final site of deposition.

Another problem arises when conventional pipettes draw in aggregate solids as they fill properly, only to have the pipette's opening blocked by the aggregates during a dispensing step. In some cases, this leads to no material being deposited during scheduled dispensing steps. In other instances pressure can build up behind the blocked opening and cause a sudden release and spillage of the liquid contents. This can present significant problems for the transfer of potentially toxic substances and instances where cross-contamination and safety concerns are paramount.

Thus there is a need for a device which can transfer liquids without these shortcomings of the prior art.

Summary of the Invention

The present invention comprises pipettes and pipette tips designed to eliminate or decrease the probability that solid materials in a medium being drawn into or expelled from the pipette may occlude, clog, block or be held against the open distal end of the pipette tip. In general, the present invention provides a pipette or pipette tip of the type having conventional designs and configurations, the improvement for which being that the open distal end of the pipette or pipette tip is conformed such that a plane passing across the distal opening is not perpendicular to the longitudinal axis of the pipette's body. These pipettes and pipette tips may also be described as comprising a conventional pipette or^' pipette tip, preferably disposable, in which the distal, open end of the tip has been angled, slanted or contoured such that the distal opening of the tip is not perpendicular to a line or axis passing through the central or longitudinal axis of the length of the pipette tip. A pipette or pipette tip of this invention may generically be described as comprising a tube with a proximal end having a proximal opening, a distal end having a distal opening and an open central channel or chamber passing between the distal and proximal ends to allow passage of fluids into and out of the tube through the distal opening, the dimensions of the tube and open distal end being sufficient to allow fluids to be retained in and expelled from the tube, the distal end of the tube and distal opening been angled, slanted, conformed or contoured such that the distal opening of the tip is not perpendicular to a line or axis passing through the central or longitudinal axis of the length of the pipette tip. This distal end may also be described as being conformed such that a plane passing across the distal opening is not perpendicular to the central axis of the tubular body.

In a preferred embodiment of this invention, pipette tips may comprise:

a) a pipette tip body having an open proximal end and an open distal end; b) an internal channel, chamber or bore passing between and creating a passage for materials between the open proximal end and the open distal end, the channel having a central axis passing therethrough between the open proximal and distal ends; c) means associated with the open proximal end for securing the pipette tip to a pipetting device; and d) means associated with the open distal end which cause the pipette tip to terminate distally in one or more planes which are not perpendicular to the channel's central axis.

Among the preferred pipette tips of this invention are those which comprise: a) a substantially tubular pipette tip body having a proximal end and a distal end; b) a proximal opening at the proximal end, the proximal opening having internal and external dimensions which allow the pipette tip to be releasably secured to a conventional pipetting device; c) a distal opening at the distal end, the distal opening having internal and external dimensions allowing liquid materials to be drawn into, retained in and expelled from the pipette tip, the distal end also being terminated at an angle which is not perpendicular to the central axis of the tubular body; and d) an internal channel, chamber or bore in the tubular pipette body passing between and connecting in fluid communication the proximal opening and distal opening.

Li the preferred tips, above, it is further preferred that the tubular body and internal channel have an initial cross-sectional area, the area being diminished toward the open distal end of the tip. In one embodiment of this invention, it is preferred that the proximal portion of the internal chamber be substantially columnar in shape and that the volume- be diminished in a conical fashion as the internal chamber approaches and reaches the open distal end of the pipette tip. In other embodiments, the pipette tip is molded in the form of conventional in Pasteur, graduated or Eppendorf^® pipette forms, modified on their distal ends as described herein.

Another embodiment of the present invention may be understood as an improvement over conventional pipette tips which have a conical distal region terminating in an open distal end, the distal end of which is conventionally opened such that a plane passing across the opening is perpendicular or substantially perpendicular to an axis or line passing through the center of the pipette tip between its proximal and distal ends. In such conventional designs the improvement of the present invention comprises forming one or more slanted or angled openings in the distal, open end of the pipette tip such that one or more planes passing across the one or more openings is not perpendicular to an axis or line passing through the center of the pipette tip between its proximal and distal ends.

In another embodiment, a pipette of this invention comprises a substantially columnar tubular pipette body open at its proximal and distal end, having a central fluid conducting channel passing therethrough, the dimensions of the pipette body being sufficient to retain and expel fluids in a pipetting manner, the improvement being that the distal end of the columnar tubular pipette body is conformed as described herein.

Pipette tips of this invention, preferably being disposable and molded of polymeric material, may also be described as having a tabular body, a proximal end having a proximal opening and internal and external dimensions for releasably coupling or mating with a conventional hand-held or automated pipetting device, a distal end having a distal opening, an open central chamber passing through the tubular body in fluid communication between the proximal opening and the distal opening, and a central axis passing longitudinally through the center of the open central chamber, the improvement comprising the distal end being conformed such that a plane passing across the distal opening is not perpendicular to the central axis of the tubular body.

Brief Description of the Drawings

Figure 1 provides a 3-dimensional, partial side view of a prior art pipette tip, exposing proximal opening (3).

Figure 2 provides a 3-dimensional, partial side view of the prior art pipette tip of Figure 1, exposing distal opening (5).

Figure 3 provides a cross-sectional side view of the prior art pipette tip shown in Figures 1 and 2.

Figure 4 provides a slightly elevated, 3-dimensional side view of a pipette tip of this invention, exposing proximal opening (3) and distal opening (9).

Figure 5 provides a cross-sectional side view of the pipette tip of Figure 4, the tip having been rotated 90° to demonstrate angle A' of beveled distal end 8.

Figure 6 provides a cross-sectional side view of the distal portion of a prior art pipette tip, the tip's distal opening being occluded by a solid particle (11).

Figure 7 provides a 3-dimensional side view of the distal portion of a pipette tip of this invention, the tip's distal opening (9) being partially obstructed by a solid particle (11).

Figures 8, 9 and 10 provide 3-dimensional side views outlining the distal portion of pipette tips of this invention. Detailed Description of the Invention

The present invention may be readily exemplified by the views of Figures 1-9. Figures 1 and 2 demonstrate the general elements of a prior art pipette or pipette tip. Figure 1 shows a slightly elevated, 3-dimensional side view of a pipette having a tapered, tubular body (1) with an open proximal end (2) and a hollow central chamber (3) passing through the length of the body (1) to open distal end (5). The pipette body (1) is substantially columnar in its proximal portion and slopes toward open distal end (5) through a tapered portion (4). Figure 2 3-dimensionally illustrates the pipette tip of Figure 1 from a lower point of view, demonstrating the restricted and open distal end (5). Regardless of the volume or taper of the pipette tip in question, in lateral cross- section, each section of the pipette tube (1) and central chamber (3) is substantially circular in shape, as is the open distal end (5).

The pipette tip of Figures 1 and 2 is shown in the side view cross-section of Figure 3. In conventional practice, particularly in automated operations, a pipette tip is introduced into a container of liquid such that the central, longitudinal axis (6) of the pipette tube (1) is held at a substantially right angle (A) from the plane of the container's bottom (7). In this manner, the flattened bottom of the container (7) is substantially parallel to the plane of the pipette's open distal end (5).

Figures 4 and 5 illustrate the novel pipette distal ends and openings of the present invention. Figure 4 is a slightly elevated, 3-dimensional side view, comparable to Figure 1, and Figure 5 is a side, cross-sectional view of the same embodiment, comparable to Figure 3. The embodiment of Figures 4 and 5 comprises the original tabular body (1), open proximal end (2), central chamber (3), and tapered portion (4), seen in Figures 1-3. This embodiment differs from the prior art by the slanted or angled conformation of its distal end (8) to form an elongate opening (9) to central chamber (3).

Figure 4 shows the pipette tube (1) held upright with its central longitudinal axis (6) forming substantially a right angle (A) with the plane of a container's bottom, comparable to that seen in Figure 3. The slanted or angled distal end (8) of this embodiment is not substantially parallel to the plane of the container's bottom, as seen in the prior art. Rather, the plane of distal end (8) creates a positive angle (A¹) relative to the bottom of the container, represented by line (7) in Figure 5. The benefit of this angle can be readily understood in view of Figures 6 and 7.

Figure 6 provides a side, cross-sectional view of the lower, tapered portion (4) of the prior art pipette tip of Figures 1-3. Because of its smaller, uniformly circular dimensions, the prior art distal opening (5) is more readily blocked or occluded by particulate matter, exemplified by sphere (10). Such blockages can encompass most or all of the opening of distal end (5) to inhibit passage of fluids therethrough. Particularly under automated pipetting operations, the configuration of distal end (5) may also be less desirable in the absence of particulate matter. If incorrectly mounted or inserted, the pipette tip may contact the bottom of a sample container. In the alignment suggested by Figure 3, the substantially parallel distal end (5) and container bottom (7) may come into contact, inhibiting passage of fluid into the pipette tip.

Figure 7 provides a comparable 3-dimensional side view of a similar spherical particle (10) drawn by suction against an angled distal pipette opening (8) of the present invention. The angled distal end (8) creates an elongate opening (9) to the pipette's central chamber which is less amenable to complete blockage by an individual particulate. In the case of partial blockage, some amount of material may still be passed through opening (9). In addition, the angled distal end (8) is less likely to make sufficient contact with the bottom or wall of a sample container to block passage of fluid through opening (9).

It will be understood that this angle (8) at the distal end of the pipette may be any positive angle above base line (7) which inhibits the solids-related problems described herein and which allows the normal operation of the pipette regarding drawing in, retaining and dispensing of fluid materials. This angle is generally preferred to be between about 10° and about 60° relative to baseline (7), which represents a plane perpendicular to central axis (6), more preferably between about 20° and about 55°, most preferably between about 25° and about 50°. In some functions an angle of about 45° may be preferred. It will be understood that the angle or angles involved may be adapted according to the body style of the pipette involved and nature of the material being transferred, including concentration of solids therein, viscosity, etc.

Figures 8 through 10 provide side views of the distal most portion of pipettes or pipette tips of this invention. In each case, central axis (6) is aligned at right angles with a baseline (7) for comparison of the angle provided by one or more of the planes of each tips' distal termination. Figure 8 illustrates an end having two planes passing across the tips' distal opening. A substantially parallel portion (13) of the distal end is comparable to that of prior art tips. An angled portion (12) however opens an additional side portion of the tube to create a more opened distal opening. Partial blockage of either section of the opening would not inhibit fluid passage through the other.

Figures 9 and 10 demonstrate that the distal end of the pipettes and tips of this invention need not be formed from a single angle or plane. Figure 9 illustrates two angled portions, (12) and (14) , forming the distal opening, neither of which is parallel to baseline (7). Upon upright insertion into a sample container, neither of these angles

(12) or (14) will flushly encounter a flattened bottom demonstrated by baseline (7).

Similarly, solids blocking the planar opening of one will not fully inhibit flow through that of the other. Figure 10 demonstrates distal portion (15) similar to that of the embodiments of Figures 4, 5 and 7, except that a plane (16) passing comparably through the distal opening does not contact each portion of distal end (15). The scope of this invention includes distal openings created by one or more planar arrangements or curved or multi-dimensional openings which create a distal opening with a comparable combined angle. It will be understood that the distal angle(s) and distal opening size of the distal end of the pipettes and tips may be altered depending upon the medium and types of solids to be transferred or avoided.

The tube or channel of the pipettes of this invention may comprise any tabular arrangement useful in the pipetting art. For instance, the tube may be comprised substantially as a columnar tabe having a distal end as described herein. The pipette tips may also be formed in Pasteur pipette, graduated pipette or Eppendorf^® (Eppendorf-Netheler-Hinz Gmbh) pipette forms. In a preferred embodiment, the pipettes of this invention have an open proximal end having internal and external αimehsions^'tor mating with conventional pipetting devices. The pipetting instruments of this invention also include pipetting tools having a larger volume fluid storage compartment terminated on their distal end by pipette arrangements. Examples of these may include the transfer pipetters designed as a larger volume syringe terminated by a narrowed pipette-style distal tip or larger volume dispenser tips having a larger tabular chamber terminated by a pipette-style tip. An example of such a pipette is seen in the syringe-like design taught in U.S. Design Patent No. 387,426 (Husar et al.).

The pipettes of the present invention may be made of any material suitable for the pipetting function in question. If reusable pipettes are desired, they may be molded or drawn from metal or various conventional glasses, such as soda lime glass, borosilicate glass, flint glass, or the autoclavable glasses sold under the Pyrex^® (Corning) and Kimax^® (Kimble Glass) tradenames. In a preferred embodiment, the pipettes of this invention are molded from disposable polymeric materials, such as polypropylene, polystyrene or polyethylene.

It is also understood that the pipettes and pipette tips of this invention may be configured to mate with any conventional or comparable suction methods. These include proximally-opened pipettes and tips which may be operated by mouth or coupled to manual or automated pipetting instruments. They may also include pipette bodies onto which a suction-producing bulb is mounted or molded.

Comparative Testing

To demonstrate the utility of the present invention, comparative pipette transfer tests were run using conventional pipette tips and identical tips modified according to the present invention. The task tested was the transfer of 96 different solid or powdered chemical compounds in a solution/suspension of dimethyl sulfoxide into specified wells in each of six 96- well plates. The compounds were random and unknown, but the two sets of 96 compounds were identical for this comparison.

Approximately 10 mg of each compound were added to each tabe of two sets of ninety six (96) 17 mm by 100 mm polypropylene round bottom plastic test tubes (Becton Dickinson Labware, Franklin Lakes, New Jersey, Part No. 2018). Transfer of the compounds from test tabes to 96-well plates was conducted two compounds at a time, with both compounds being deposited in the same plate. After one plate was completed, the process was repeated for the second plate. Using an automated robotic system, 1.2 ± 0.02 ml of dimethyl sulfoxide (JT Baker, Phillipsburg, New Jersey) was added to each tube, followed by vortex blending of the resulting volume for approximately 10 seconds to yield a final sample volume.

Using an automated robotic system, utilizing new pipettes for each test tube, two pipettes were lowered into two of the sample tubes and sufficient suction was applied to each pipette to collect the substantially the entire Uquid volume of its corresponding test tube. The dual pipette array was then robotically moved into position sequentially over the two designated wells in a series of six 96-well deposition plates. The first five plates in the series were microtiter plates with a volume capacity of 330 μl per well (Corning No. 3794 (Acton, MA)). The sixth 96-well plate was a "deepwell" plate with a capacity of 1,000 μl per well (1 ml Titer-block, deep-well microplate, No. 755-9600 from USA Scientific Plastics, Ocala, Florida).

During each of the test runs the automated system applied appropriate force into each pipette at each appropriate station to deposit 50 μl per well in each of specified wells of the first five 96-well plates and a remaining volume of 1,000 μl per well in the final "deepwell" plate wells. The automated system was operated identically in each test run.

In the first test series (48 operations with 2 pipette tips/operation), 96 Matrix 1250 μl pipette tips (available from Matrix Technologies Corp., Lowell, Massachusetts, Part No. 8051) were used. In the second series (48 operations with 2 pipette tips/operation), 96 identical Matrix 1250 μl pipette tips were used, except that the distal end of each pipette tip was cut into an approximately 45° angle relative to its central axis, as described herein.

Each of the two test runs were monitored regarding the number of pipette tips presenting unwanted drips and clogs, or both. In Table 1, reference to "clogged" pipette means an occlusion occurred during aspirating or dispensing from the pipette tip. "Clogged with Much Dripping" indicates a condition wherein a clog allowed a large volume of Uquid to pass from the pipette tip when the system was not in a dispensing mode. "Clogged with Much Residual Matter" refers to sitaations in which a mass of material occluded substantiaUy the complete pipette distal orifice and prevented all or almost aU Uquid from being dispensed as prescribed. This final designation may prove the most detrimental in operation. As described previously, pressure building behind such a clog may lead to an undesirable explosive or spraying discharge which can contaminate the deposition plates and the robotic instrumentation. The term "essentiaUy empty" in Table 1 refers to those sample test tabes in which the initial automated suction into the pipette tip removed essentiaUy aU the Uquid any soUds from the sample test tube.

The following Table 1 Usts the observations of these two tests.

Table 1

First Test Run Second Test Run (96 Standard Pipette Tips) (96 Pipette Tips of Present Invention)

Samples Run 96 96

Source Volume 1250 μl 1250 μl

Average Weight of 10.93 mg 10.41 mg Sample in Test Tube

Standard Deviation 2.21 mg 2.09 mg in Test Tube

Pipettes Dripping 3 0 Table 1 Cont'd

First Test Run Second Test Run

(96 Standard Pipette Tips) (96 Pipette Tips of Present Invention)

Pipettes Clogged 1 0

Pipettes Clogged w/ 1 0 Much Dripping

Pipettes Clogged w/ 5 0 Much Residual Matter

No. of Sample Test Tubes 75 72 Left Essentially Empty

Residual Material Left 21 24 In Test Tube

Statistics for Samples Containing Residual Matter

Average Residuals 215 μl 104 μl per weU

Standard Deviation 212 42 of Residual Matter

Average Residual 17.20% 8.32% in Percent

Standard Deviation of 16.96% 3.36% Residual Matter

No. of Pipettes Rendering No Delivery to Any Plate

No. of Pipettes Rendering 2 0

No Delivery to Plates 5 and 6

In each of the final deepweU plates, 11 wells had less volume than intended, referenced below as a shortfall. However, the shortfaUs were considerably reduced using the pipette tips of the present invention, as demonstrated by the observations in Table 2. A "usable" plate is one which receives the intended volume of each of the 96 compound samples in the intended wells, only.

Table 2

First Test Run Second Test Run

(96 Standard Pipette Tips) (96 Pipette Tips of Present

Invention)

Average DeepweU 446 μl 75 μl

ShortfaU (below 1000 μl)

Standard Deviation 197 46 of ShortfaU

Average ShortfaU 19.70% 4.60%

Usable Set of Plates 0 of 6 6 of 6 w/ 96 WeUs Each

From this disclosure, it wUl be understood from this disclosure that this invention provides novel improvement to a wide range of pipettes and pipette tips.

Claims

What is Claimed:

1. A pipette or having a tabular body, a proximal end having a proximal opening, a distal end having a distal opening, an open central chamber passing through the tubular body in fluid communication between the proximal opening and the distal opening, and a central axis passing longitadinaUy through the center of the open central chamber, the improvement comprising the distal end being conformed such that a plane passing across the distal opening is not perpendicular to the central axis of the tubular body.

2. A pipette or pipette tip of Claim 1 in which the plane passing across the distal opening forms an angle between about 10" and about 60° relative to a plane perpendicular to the central axis of the tabular body.

3. A pipette or pipette tip of Claim 1 in which the plane passing across the distal opening forms an angle between about 20° and about 55° relative to a plane perpendicular to the central axis of the tubular body.

4. A pipette or pipette tip of Claim 1 in which the plane passing across the distal opening forms an angle between about 25° and about 50° relative to a plane perpendicular to the central axis of the tubular body.

5. - A pipette tip of Claim 1 which has a Pasteur pipette, graduated pipette or Eppendorf^® pipette form.

6. A pipette tip of Claim 1 which is molded from a polymeric material selected from the group of polypropylene, polystyrene or polyethylene.

7. A pipette tip having a tubular body, a proximal end having a proximal opening and internal and external dimensions for releasably mating with a pipetting device, a distal end having a distal opening, an open central chamber passing through the tubular body in fluid communication between the proximal opening and the distal opening, and a central axis passing longitudinally through the center of the open central chamber, the improvement comprising the distal end being conformed such that a plane passing across the distal opening is not perpendicular to the central axis of the tubular body.

8. A pipette tip of Claim 7 in which the plane passing across the distal opening forms an angle between about 10° and about 60° relative to a plane perpendicular to the central axis of the tabular body.

9. A pipette tip of Claim 7 in which the plane passing across the distal opening forms an angle between about 20° and about 55° relative to a plane perpendicular the central axis of the tabular body.

10. A pipette tip of Claim 7 in which the plane passing across the distal opening forms an angle between about 25° and about 50° relative to a plane perpendicular the central axis of the tubular body.

11. A pipette tip of Claim 7 which has a Pasteur pipette, graduated pipette or Eppendorf^® pipette form.

12. A pipette tip of Claim 7 which is molded from a polymeric material selected from the group of polypropylene, polystyrene or polyethylene.