Patent Description:
In some liquid sample processing techniques, it is desirable to separate agglomerated, clotted or otherwise formed clumps of material from liquid and other small components in the sample. For example, clotting may occur in a blood sample after its removal from the body, and it may be desirable to separate fibrin or platelet clots from other portions of the blood sample (such as serum), whether the clotting occurs naturally or artificially such as in response to a reagent added to the sample.

Various devices are known to separate clumps of material from liquid portions of a sample. For example, one type of a device, known as a serum separator, is used to mechanically separate serum or plasma from other portions of a blood sample. One example of a serum separator is shown in <FIG> and includes a blood collection tube <NUM> with a cylindrical filter member <NUM> disposed within the tube. A weight <NUM> is attached to the filter member <NUM> so that the filter member moves down the tube and through the sample during centrifuging. The filter member is made from a material having pores which permit the passage of the liquid phase of a blood sample, but prevents the passage of the insoluble solid blood phase portion <NUM>. As the filter member <NUM> moves down the tube <NUM>, the serum or plasma <NUM> is forced through the pores of the filter element while particulates remain below the filter element in the solid phase portion <NUM>. <CIT>, <CIT>, <CIT> all disclose multiwell plates having wells suitable for filtering clotted blood.

Aspects of the invention provide a method and apparatus for separating portions of a sample including liquid. In one embodiment, the method and apparatus are configured to separate various types of clumps of material from the sample, e.g., blood clots, from other portions of a blood sample, such as blood serum. As discussed in greater detail below, in one embodiment, the method and apparatus are configured to be employed in high volume and/or automated liquid sample processing techniques.

According to one aspect of the invention, a tube for separating a liquid component from other portions of a sample includes a chamber having a closed bottom and a sidewall extending upwardly from the bottom. The sidewall defines a chamber opening for removing a separated liquid portion of the sample from the chamber. The tube also includes a sample inlet branch fluidly coupled to the chamber, and having a sidewall defining a sample inlet branch opening for dispensing an unseparated sample into the sample inlet branch. A slit may be positioned between the chamber and the sample inlet branch and arranged so that after the unseparated sample is dispensed into the sample inlet branch opening, a portion of the unseparated sample (e.g., serum having components with a size smaller than the slit) passes through the slit and into the chamber. Material in the unseparated sample having a size larger than the slit (e.g., blood clots of a blood sample) may remain in the sample inlet branch. As used herein, a "liquid portion" or "liquid component" of a sample may include only liquid, or liquid with solid particles that are suspended or otherwise carried by the liquid and are of a size small enough to pass through the slit between the sample inlet branch and the chamber.

According to another aspect of the invention, a method of separating a sample includes providing a tube having a chamber with a closed bottom and a sidewall extending upwardly from the bottom where the sidewall defines a chamber opening. The tube also has a sample inlet branch coupled to the chamber, with the sample inlet branch having a sidewall defining a sample inlet branch opening and a slit positioned between the chamber and the sample inlet branch. The method further includes placing an unseparated sample into the sample inlet branch opening, and passing a portion of the sample through the slit and into the chamber. Material in the unseparated sample having a size larger than the slit may remain in the sample inlet branch. The method also includes removing at least a portion of the separated sample from the chamber through the chamber opening.

These and other aspects of the invention are described below with reference to illustrative embodiments and in the claims. Various embodiments of the present invention provide certain advantages. Not all embodiments of the invention share the same advantages and those that do may not share them under all circumstances.

In the drawings, each identical or nearly identical component that is illustrated in various figures is represented by a like descriptor.

Various embodiments of the invention will now be described, by way of example, with reference to the accompanying drawings, in which:.

Aspects of the invention are directed to a device for separating portions of a sample, and methods for using the device to separate portions of a sample.

As discussed above, there are a variety of known devices to separate agglomerated material or clumps of material from a sample that includes a liquid component. Applicant recognized that some of these prior devices may lead to undesirable loss of the liquid portion of the sample in some cases. For example, as shown in <FIG>, as the filter element <NUM> moves down the tube <NUM>, the liquid portion of the sample <NUM> passes through the filter element, leaving the solid phase portion <NUM> at the bottom of the tube <NUM>. Although this device separates some of the liquid <NUM> from the solid phase <NUM>, some of the liquid <NUM> remains intermixed with the solid phase <NUM> below the filter element <NUM>. With this particular type of device, it may be difficult to separate and thus recover the remaining amount of the liquid <NUM>. It may not be possible to recover this liquid portion without removing the filter element from the tube <NUM> and employing further separation techniques to separate the solid phase <NUM> from the remaining liquid <NUM>. Aspects of the present invention are directed to a device for separating agglomerated material or clumps of material out from a sample where there is little and/or substantially no loss of the liquid portion of the sample during the separation process.

Aspects of the invention employ a tube for separating a liquid portion of a sample where the tube includes a first opening for dispensing an unseparated sample including liquid and solid material into the tube and a second opening for removing a separated liquid component from the tube after the agglomerated material or clumps of material have been separated out from the liquid component.

As set forth in greater detail below, aspects of the present invention involve a tube for separating a liquid portion of a sample where the tube includes a slit arranged so that after the sample is dispensed into the tube, a portion of the sample passes through the slit while material in the sample having a size larger than the slit does not pass through the slit.

It should be appreciated that it is contemplated that the tube may be used to separate a variety of types of samples, as the invention is not limited in this respect. For example, as discussed above, in one embodiment, the tube may be configured to separate a blood sample such that fibrin clots and/or platelet clots may be separated from serum portions of the sample. In another embodiment, the tube may be configured to separate other types of samples, such as, but not limited to other bodily fluids, as well as other fluids, such as but not limited to samples including reagents or other liquid as well as beads or other solid material to be separated from the liquid (e.g., as in the case of beads having attached DNA or other genomic components in a liquid), and so on. As discussed in greater detail below, the slit in the tube may be sized for a particular application based upon the type of sample and the size of the material that is desired to be separated in the sample.

Turning to the drawings, it should be appreciated that the drawings illustrate various components and features which may be incorporated into various embodiments that incorporate aspects of the invention. For simplification, some of the drawings may illustrate more than one optional feature or component. However, aspects of the invention are not limited to the specific embodiments disclosed. It should be recognized that aspects of the invention encompass embodiments which may include only a portion of the components illustrated in any one figure, and/or may also encompass embodiments combining components illustrated in multiple different drawings.

<FIG> illustrate a tube <NUM> for separating a sample according to one embodiment of the present invention. The tube <NUM> has a chamber <NUM> with a closed bottom <NUM> and a sidewall <NUM> extending upwardly from the bottom <NUM> and defining a chamber opening <NUM>. A sample inlet branch <NUM> is coupled to the chamber and has a sidewall <NUM> defining a sample inlet branch opening <NUM>. As discussed in greater detail below, the tube <NUM> has a slit <NUM> positioned between the chamber <NUM> and the sample inlet branch <NUM>.

A sample may be placed into the tube <NUM> through the sample inlet branch opening <NUM>, e.g., by a pipette or other suitable arrangement placing a blood sample in the sample inlet branch opening <NUM>. Once within the sample inlet branch <NUM>, a portion of the sample (such as blood serum or other liquid component containing solid material smaller than the slit <NUM>) passes through the slit <NUM> and into the chamber <NUM>. Material in the sample having a size larger than the slit, such as blood clots, may remain within the sample inlet branch <NUM>. Thus, the liquid portion of the sample having a size smaller than the slit <NUM> is separated from the larger material. This liquid portion collects in the chamber <NUM> and may be removed from the chamber <NUM> through the chamber opening <NUM>, e.g., by a pipette aspirating the liquid portion.

In one embodiment, it is desirable for the slit <NUM> to be constructed such that the liquid portion of the sample is still able to pass through the slit <NUM> even after material, such as blood clots, collects at the bottom of the sample inlet branch <NUM>. For example, in one embodiment, the slit <NUM> extends along a substantial length of the sample inlet branch <NUM> and in one embodiment, the slit extends along a majority of the length of the branch <NUM>. In this respect, material that has collected at the bottom <NUM> of the branch <NUM> may be less likely to obstruct the entire slit <NUM>. Thus, in some cases, liquid will still be able to pass through the upper portion of the slit <NUM> and pass into the chamber <NUM>. In other cases, relatively large size material that collects above the bottom <NUM> (e.g., material that is suspended in the sample or floats at the sample top surface) will not impede the passage of liquid material, which may pass through the slit <NUM> near the bottom <NUM>. In the illustrated embodiment, the slit <NUM> extends to the bottom <NUM> of the branch <NUM> and up to the sample inlet branch opening <NUM>. It may be desirable for the slit <NUM> to extend down close to the bottom <NUM> of the branch <NUM> to minimize the amount of liquid that is able to pool or otherwise collect at the bottom <NUM> of the branch <NUM>. In certain embodiments, it may be desirable for the slit <NUM> to extend close to the branch opening <NUM> so that the liquid portion of the sample is still able to pass through the slit <NUM> even after a substantial amount of material has collected at the bottom <NUM> of the branch <NUM>.

As shown in <FIG> and <FIG>, in one embodiment, the bottom <NUM> of the sample branch <NUM> is sloped for liquid to drain towards the slit <NUM>. As also illustrated in the embodiment shown in <FIG>, the bottom of the sample inlet branch and the bottom of the chamber are substantially rounded. It should be appreciated that in another embodiment, the bottom <NUM> of the sample branch <NUM> may be shaped differently, and may for example be substantially flat, curved or irregular shaped. Furthermore, it should also be recognized that the bottom <NUM> of the chamber may either be configured the same as or different than the bottom <NUM> of the sample inlet branch as the invention is not so limited.

The shape of the tube <NUM> for separating a sample may also vary, as the invention is not limited in this respect. In the embodiment illustrated in <FIG>, the chamber sidewall <NUM> is substantially cylindrical shaped and the sample inlet branch sidewall <NUM> is also substantially cylindrical shaped. It is also contemplated that the chamber sidewall <NUM> and/or the branch sidewall <NUM> may be rectangular shaped, square shaped, or irregular shaped. Furthermore, the shape of the chamber <NUM> may be configured as either the same shape or a different shape than the sample inlet branch <NUM>.

In the embodiment illustrated in <FIG>, the tube <NUM> is bifurcated such that the sample inlet branch <NUM> extends outwardly from the chamber sidewall <NUM>. Furthermore, in the embodiment illustrated in <FIG>, the chamber <NUM> and the sample inlet branch <NUM> both have a longitudinal axis <NUM>, <NUM>, and the longitudinal axis <NUM> of the sample inlet branch <NUM> is substantially parallel to the longitudinal axis <NUM> of the chamber <NUM>. As discussed in greater detail below, in another embodiment, the tube <NUM> may not be bifurcated, and/or the longitudinal axes <NUM>, <NUM> of the chamber <NUM> and branch <NUM> may not be parallel.

<FIG> illustrate one embodiment of a slit <NUM> in greater detail. In this particular embodiment, the slit <NUM> is tapered such that the width of the slit near the sample inlet branch opening <NUM> is greater than the width of the slit <NUM> near the bottom <NUM> of the sample inlet branch. In another embodiment, the slit may have a substantially constant width along its length, and in yet another embodiment, the slit <NUM> may taper in the opposite direction such that the width of the slit <NUM> is greater towards the bottom <NUM> of the sample inlet branch <NUM>.

As illustrated in the embodiment of <FIG>, the sample inlet branch opening <NUM> is connected to the chamber opening <NUM>. In this embodiment, the slit <NUM> extends up to the branch opening <NUM> and is positioned between the branch opening <NUM> and the chamber opening <NUM> such that it fluidly connects these two openings. In another embodiment, the sample inlet branch opening <NUM> may be spaced apart and distinct from the chamber opening <NUM>.

The size of the tube <NUM> may vary as the invention is not limited in this respect. The size of the chamber <NUM> and sample inlet branch <NUM> may vary based upon the volume of sample to be collected and separated within the tube. In one illustrative embodiment, the volume of the sample inlet branch <NUM> is less than the volume of the chamber <NUM>. This may be desirable where the sample being separated has a larger volume of liquid that passes through the slit in comparison to the volume of material that will remain in the branch <NUM>. In one embodiment, the volume of the chamber <NUM> is at least double the volume of the sample inlet branch <NUM>. In another embodiment, the volume of the branch <NUM> may be approximately the same as the volume of the sample inlet branch <NUM>, and in yet another embodiment, the volume of the branch <NUM> may be greater than the volume of the chamber <NUM>. In one embodiment, the volume of the chamber may be between approximately <NUM> microliters and <NUM> milliliters (ml). In one embodiment, the maximum volume of the chamber <NUM> is approximately <NUM>. In another embodiment, the volume of the chamber <NUM> is between approximately <NUM>-<NUM>. In yet another embodiment, the volume of the chamber may be approximately <NUM> - <NUM>.

The orientation of the slit <NUM> relative to other components of the tube <NUM> may vary according to different embodiments of the present invention. In the embodiment illustrated in <FIG>, the chamber <NUM> has a longitudinal axis <NUM> and at least a portion of the slit <NUM> is positioned vertically such that the slit is substantially parallel with the longitudinal axis <NUM> of the chamber <NUM>. In this particular illustrative embodiment, the slit <NUM> is also substantially parallel with the chamber sidewall <NUM>. As discussed in greater detail below, in another embodiment, the slit <NUM> may not be parallel with a longitudinal axis <NUM> of the chamber <NUM>.

<FIG> illustrates another embodiment that is similar to the above-described embodiment shown in <FIG> except that the tube <NUM> shown in <FIG> further includes a groove <NUM> in the bottom <NUM> of the sample inlet branch <NUM> that is configured to guide the liquid portion of the sample toward the slit <NUM>. In this particular embodiment, the groove <NUM> extends along a substantial portion of the bottom <NUM>.

<FIG> illustrates yet another embodiment of a tube <NUM> for separating a sample. The tube <NUM> has a chamber <NUM> and a sample inlet branch <NUM> which are similar to the embodiment illustrated in <FIG>. The tube <NUM> also has a slit <NUM> positioned between the chamber <NUM> and the sample inlet branch <NUM>. The slit <NUM> is formed into a plate component <NUM> and the slit <NUM> is arranged so that a liquid portion in the branch <NUM> passes through the slit <NUM> and into the chamber <NUM>. In this illustrative embodiment, the slit is not substantially parallel with the longitudinal axes <NUM>, <NUM> of either the chamber <NUM> or the branch <NUM>. As illustrated, at least a portion of the slit <NUM> is positioned at a diagonal such that the slit <NUM> is neither substantially parallel or substantially perpendicular with the longitudinal axis of the chamber <NUM>. In this embodiment, a dashed line extends up from the slit <NUM> up to the longitudinal axis <NUM> of the chamber <NUM> and illustrates the angle A between the slit <NUM> and the longitudinal axis <NUM>. In one particular embodiment, the angle A is between approximately <NUM> degrees - <NUM> degrees. In one embodiment, the angle A is approximately <NUM> degrees.

<FIG> illustrate yet another embodiment of a tube <NUM> for separating a sample. The tube <NUM> has a chamber <NUM> and a sample inlet branch <NUM> which together form a cylindrical shaped component with a slit <NUM> positioned between the chamber <NUM> and the sample inlet branch <NUM>. The slit is arranged so that liquid can pass through the slit from the sample inlet branch <NUM> into the chamber <NUM>. In this embodiment, the slit <NUM> is formed into to flat plate component <NUM> which is positioned within the cylindrical shaped component. It should be appreciated that in another embodiment the tube <NUM> may be shaped and configured differently.

As previously mentioned, a sample may be dispensed into the tube <NUM> through the sample inlet branch opening <NUM> (see arrow A). Once within the sample inlet branch <NUM>, a portion of the sample passes through the slit <NUM> (see arrow B) and into the chamber <NUM> (see arrow C). In the embodiment illustrated in <FIG>, the bottom <NUM> of the branch <NUM> is a substantially flat surface that is sloped towards the slit <NUM>. Material in the sample having a size larger than the slit remains within the sample inlet branch <NUM>. Thus, the liquid portion of the sample having a size smaller than the slit is separated from the larger material. This liquid portion collects in the chamber <NUM> and may be removed from the chamber <NUM> through the chamber opening <NUM> (see arrow D). It should be appreciated that material collected in the sample inlet branch <NUM> may be collected for further processing and/or discarded.

In one embodiment, the tube for separating a sample is configured to be employed in high volume and/or automated liquid sample processing techniques. For example, there may be an array of multiple tubes for separating samples. A plurality of automated pipetting instruments may be aligned with the tubes and the system may be configured to simultaneously dispense a sample into the sample inlet branches of the plurality of tubes. The sample is separated using the above-described slit positioned in each of the tubes, and thereafter, at least a portion of the sample is removed from one of the tube chambers. In one embodiment, a pipetting instrument is used to aspirate the sample portion out of the chamber.

The size of the tube may vary as the invention is not limited in this respect. In one embodiment, the chamber is between approximately <NUM> - <NUM> in length and the sample inlet branch is approximately <NUM> - <NUM> in length.

In one embodiment, the width of the slit is approximately <NUM> - <NUM>. In one embodiment, the width of the slit is less than <NUM>. In another embodiment, the width of the slit is less than <NUM>, and in yet another embodiment, the width of the slit is less than <NUM>. In one tapered slit embodiment, the width of the slit may double from the narrow end of the slit to the widest section of the slit. For example, in one embodiment, the tapered slit may have a width of approximately <NUM> at one end and a width of approximately <NUM> at the other end of the slit. It should be appreciated that in one embodiment, the tapered slit may be substantially v-shaped. The angle of the taper may vary, and in one embodiment, the angle of the taper may vary from approximately <NUM>-<NUM> degrees, although other angles are possible.

It should be appreciated that the slit may be configured based upon the size of the material that is desired to be separated or removed from the sample. The width of the slit may be configured to be smaller than the size of the agglomerated material, clumps of material or other components that will be separated out from smaller components of the sample.

The tube may be formed from a variety of different types of materials and manufacturing techniques. The tube may be made from a material such as, but not limited to, glass, metal or plastic, such as polystyrene. The tube may be formed of either transparent or opaque materials. In one embodiment, the chamber and sample inlet branch are integrally formed. In another embodiment, the chamber and branch may be separately formed and thereafter coupled. In one embodiment, the tube is molded.

It should also be recognized that in one embodiment, the tube for separating a sample may include no movable components. In particular, the tube may rely on gravity to move portions of the sample from the top of the tube, through the slit and to the bottom of the chamber.

It should be appreciated that various embodiments of the present invention may be formed with one or more of the above-described features. The above aspects and features of the invention may be employed in any suitable combination as the present invention is not limited in this respect. It should also be appreciated that the drawings illustrate various components and features which may be incorporated into various embodiments of the present invention. For simplification, some of the drawings may illustrate more than one optional feature or component. However, the present invention is not limited to the specific embodiments disclosed in the drawings. It should be recognized that the present invention encompasses embodiments which may include only a portion of the components illustrated in any one drawing figure, and/or may also encompass embodiments combining components illustrated in multiple different drawing figures.

Claim 1:
A tube (<NUM>, <NUM>) for separating a clot from serum of a blood sample, the tube comprising:
a chamber (<NUM>, <NUM>);
a sample inlet branch (<NUM>, <NUM>) coupled to the chamber (<NUM>, <NUM>), the sample inlet branch having a sidewall defining a sample inlet branch opening (<NUM>, <NUM>) for receiving the blood sample into the sample inlet branch (<NUM>, <NUM>);
wherein the tube has a slit (<NUM>, <NUM>) positioned between the chamber (<NUM>, <NUM>) and the sample inlet branch (<NUM>, <NUM>) and arranged so that serum of the blood sample in the sample inlet branch passes through the slit (<NUM>, <NUM>) and into the chamber (<NUM>, <NUM>) when dispensed in the sample inlet branch, wherein clot in the blood sample having a size larger than the slit (<NUM>, <NUM>) remains in the sample inlet branch (<NUM>, <NUM>), wherein the width of the slit (<NUM>) is less than <NUM>,
and wherein the sample inlet branch (<NUM>, <NUM>) has a bottom (<NUM>, <NUM>), the slit (<NUM>, <NUM>) extends from near the sample inlet branch opening (<NUM>, <NUM>) toward the sample inlet branch bottom (<NUM>, <NUM>), and the sample inlet branch has a groove (<NUM>) in the bottom configured to guide a portion of the blood sample toward the slit (<NUM>),
wherein the slit (<NUM>, <NUM>) is tapered such that a width of the slit near the sample inlet branch opening is greater than a width of the slit near the bottom of the sample inlet branch,
and characterized in that the chamber is between <NUM> - <NUM> in length and the sample inlet branch is <NUM> - <NUM> in length.