Patent Description:
The present invention relates to a biological fluid sample collection device and to a method of using such a device.

Blood used for diagnostic testing is most often extracted from a patient with a hypodermic needle and collected in a test tube. The collected blood is then packaged for shipment to a remote lab where various diagnostic tests are performed. However, many diagnostic tests require significantly less volume than the actual collected sample. Separation of cellular components from the sample is also needed for some tests.

Many tests only require small blood samples, where a finger stick rather than a hypodermic needle can produce enough blood. But this small amount of blood cannot be easily transported to a remote lab. If the testing method cannot be immediately used at the same time the blood is extracted, convenient and reliable methods of collecting, prepping, and preserving small amounts of blood are still needed.

US Patent Publication <CIT>, describes several ways to implement a portable, user-friendly device for collecting a biological fluid sample and stabilizing it for transport to a remote lab. The devices include a small, handheld housing that provides a chamber for collecting a fluid sample. Movement of the housing itself, and/or mechanisms located within the housing, initiate collection of a predetermined, metered volume of a fluid sample. The devices may also stabilize the collected sample and/or seal the sample in the chamber. Other mechanisms in the device may mix the collected sample with a reagent.

<CIT>describes a biological fluid sample collection device comprising: a housing comprising a first housing section and a second housing section, the housing configurable from a first position to a second position by moving the first housing section and the second housing section together, the housing enclosing: a sample collection well; a capillary in fluid communication with the sample collection well, wherein the capillary is configured to hold a predetermined volume of the biological fluid sample, wherein the biological fluid sample comprises one or more analytes; a medium in fluid communication with the capillary, wherein the medium is configured to retain at least a portion of the biological sample or a derivative thereof, wherein the medium comprises a conjugate configured to bind the one or more analytes to perform a test, wherein the medium comprises an immunoassay strip comprising the conjugate configured to bind the one or more analytes a mechanically actuated fluid controller, configured to dispense a predetermined volume of the biological sample or a derivative thereof from the capillary onto the medium , wherein, when the housing is in the first position, the sample collection well is positioned to receive the sample from a user, and when the housing is in the second position the sample collection well is fully enclosed within the housing and is inaccessible to the user.

According to the present invention there is provided a biological fluid sample collection device comprising the features of claim <NUM> and a method comprising the features of claim <NUM>.

A sample collection device can be used to collect, meter, analyze and/or store a body fluid sample such as a blood sample. Fluid collected from a patient is first introduced into the device via a sample port, such as by directing blood droplets from a fingertip into a well, or in other ways. In some configurations, capillaries or other microfluidic channels then extract a metered amount of blood from the sample port and deposit it onto a media via capillary action. One or more plungers may further provide mechanical force to encourage dispensing fluid from the metering capillaries and onto the media.

In a preferred arrangement, the media includes two or more membranes, immunoassay strips, or other substrates. For example, the media may include both a collection membrane and an immunoassay strip. The collection membrane(s) and immunoassay strip(s) may be disposed parallel to one another, adjacent an outlet of the capillaries. The collection membrane(s) may receive and store a blood sample from some capillaries, and the immunoassay (or other test) strip(s) may receive and process a blood sample provided from other capillaries. Types of membranes such as those based on plastic or glass, or microfluidic detectors may be used.

In some configurations, the sample is delivered to an assay region within the housing where captured blood molecules are exposed to a surface that binds to analytes. These analytes can then be bound by a conjugate to make them detectable. For example, the bound analytes may also modify the optical or electrical properties of the surface they are bound to, making them directly detectable via visual inspection, or electronic circuits.

Having the ability to perform different processes in parallel on the same blood sample provides several advantages. For example, one membrane may have an analyte that provides immediate results for a critical condition (such as HIV or hepatitus C), and another membrane may be a collection media, such as LF-<NUM> paper, designed store the blood sample for testing of less critical conditions, at a later time in a lab (such as testing for glucose).

In some configurations, the plungers may be attached to one or more movable housing pieces, such that when the housing is moved from an open to a closed position, the capillaries are exposed to the blood in the sample port.

Some embodiments of the device include a stabilization or anticoagulation agent arranged to engage the fluid as it is dispensed onto the media. The agent may be heparin and/or EDTA. The stabilization agent may be coated or deposited onto an interior of at least one of the capillaries, or the plungers, or the media. This configuration may also include a desiccant located adjacent or on the media.

In other arrangements, an assay region may also be located between the capillaries and the media, such that a stored reagent is mixed with the fluid when the fluid is dispensed, e.g., as the housing is moved from the open position to the closed position.

The housing may also include one or more windows positioned in a location such that at least a portion of the capillaries and / or media are visible through the window. It may be desirable to have a window to view each of the two or more media. However, in other configurations, at least some of the media may be hidden from view when the housing is closed. One practical use for this may be when the device collects blood for use in clinical trials, such as a United States' Food and Drug Administration (FDA) <NUM>(k) substantial equivalency test.

The media may take different forms. For example, it may include a mylar substrate having a pair of engagement tabs spaced apart from one another. The media is then disposed on the substrate and held in place between the engagement tabs.

A backbone may be included within the housing to support the two or more media and hold then in place adjacent the capillary exit ports.

<FIG> is an isometric view of an example fluid collection device <NUM>. The device <NUM> includes a two-piece housing <NUM> that supports and encloses a fluid sample port <NUM>. The housing <NUM> includes a first housing piece <NUM>-A and second housing piece <NUM>-B. In this view, the housing is in the open position with the two housing pieces <NUM>-A, <NUM>-B spaced apart from one another, to provide access to the sample port <NUM>. A sample collection well <NUM> and one or more capillaries <NUM> located adjacent the sample port <NUM> are partially visible in this figure. A window <NUM> in the housing permits a user to confirm the status of one or more portions of a fluid sample in the process of being collected and/or stored within the device <NUM>.

<FIG> is a similar isometric view of the device <NUM>. In this view, a blood sample has been taken via the sample port <NUM>, and the two housing pieces <NUM>-A and <NUM>-B have been pushed together to place the device <NUM> in a closed position. In this closed position, the window <NUM> still provides access to the blood collection status.

The device <NUM> is typically used to collect a blood sample as follows. The device <NUM> is initially presented in its open position, as per <FIG>, to provide access to the well <NUM>. A user, such as a patient herself or a health care professional, then uses a lancet to produce a blood sample such as from a finger tip. Drops of whole blood are then taken with the finger positioned near to, above, adjacent to, or even in contact with the well <NUM> or other parts of the sample port <NUM> to minimize blood spillage.

Blood is then eventually drawn into the rest of the device <NUM> in one or more different ways. As will be explained in more detail below for one embodiment, blood flows and/or is first drawn from the well <NUM> by one or more collection capillaries <NUM> adjacent the sample port via capillary action. The capillaries may be visibly transparent so that the user can confirm that blood is being properly drawn into the device <NUM>. The capillaries <NUM> can optionally be pre-coated with reagents such as heparin and/or EDTA for subsequent stabilization and preservation of the sample. The capillaries <NUM> can also have a known and predetermined volume, in which case the incoming sample is precisely metered. The collection capillaries <NUM> then direct the metered sample to a media inside the device housing <NUM>.

The user, who can be the patient himself/herself or a healthcare professional, then manually closes the device <NUM> by pushing the two housing pieces <NUM>-A, <NUM>-B together, resulting in the housing position shown in <FIG>. As more fully explained below, the motion associated with closing the housing may then optionally enact one or more mechanisms that further process the sample, and to securely store it inside the device <NUM>.

The window <NUM> may include a transparent piece of material that enables the user to view the state of the sample port <NUM>, the well <NUM>, and/or collection capillaries <NUM>. In that way, an indication of whether a sufficient sample of blood is being drawn into the device <NUM> (when the housing <NUM> is in the open position of <FIG>) or was drawn into the device (when the housing <NUM> is in the closed position as in <FIG>).

<FIG> is a more detailed, exploded view of the components of an example device <NUM>. The first housing piece <NUM>-A consists of a top case <NUM>-A-<NUM> and bottom case <NUM>-A-<NUM>, and second housing piece <NUM>-B consists of a top case <NUM>-B-<NUM> and bottom case <NUM>-B-<NUM>.

A backbone structure <NUM> provides a support for the two housing pieces <NUM>-A, <NUM>-B. The inside vertical walls of the housing pieces <NUM>-A, <NUM>-B may engage elongated slots or other structures formed in the backbone <NUM>, thus enabling at least second housing piece <NUM>-B to slide back and forth along the backbone, and to thus move the housing into the open or closed position. In one arrangement, first housing piece <NUM>-A remains fixed in position on backbone <NUM>. However other embodiments are possible where first housing piece <NUM>-A slides on backbone <NUM> and second housing piece <NUM>-B remains fixed, or where both housing pieces <NUM>-A, <NUM>-B can slide with respect to one another.

The backbone <NUM> also supports other components of the device <NUM>. For example, the backbone <NUM> provides a location for the sample collection port <NUM>, as formed from an inlay part (also referred to as a capillary support element) <NUM>. A plunger rack <NUM> is also supported by the backbone <NUM>. The backbone <NUM> may further include a ribbed section <NUM> to support a desiccant tablet (not shown in <FIG>) to further dry the collected sample. The backbone <NUM> may also have tines at an end that provide a ratcheting closure <NUM>, which is activated when the two housing pieces <NUM>-A, <NUM>-B are pushed together.

Capillaries <NUM> (also referred to with reference number <NUM> in other figures) are inserted into and held in place by longitudinal holes (not shown in <FIG>) formed in the inlay <NUM>. The capillaries and may be formed as a rigid tube of precisely defined volume, in which case they also serve a metering function. The capillaries <NUM> extract a defined quantity of blood by engagement with the blood in the sample collection port <NUM> through capillary action. The inlay <NUM> may fit into a hole <NUM> in backbone <NUM>. As explained in further detail below, the inlay <NUM> defines the location of a well <NUM> into which the patient's blood is introduced.

The capillaries <NUM> can optionally be pre-coated with reagents, heparin, EDTA, or other substances.

One or more capillaries <NUM> may also store a predetermined amount of a liquid reagent. Such a reagent may then be dispensed together or in parallel with the blood sample when the housing is moved from the open to the closed position. However, reagents of other types may also be located in a storage region within the housing. The storage region (not designated in the figures), may hold a first type of reagent such as a solid surface or substrate, and a second type being a liquid storage chamber, each of which are placed in the path of the blood sample collected by the device <NUM>.

In one arrangement, the one or more plungers <NUM> firmly engage with the inner diameter of the capillaries <NUM>, creating a shutoff that blocks off any excess blood sample while also pushing the metered sample volume to the subsequent downstream processing steps.

A base <NUM> may also fit into the backbone <NUM> to provide additional mechanical support for a blood collection element <NUM>. The collection element <NUM> may consist of a sample media (also called a membrane herein) <NUM> that is supported and/or held in place by other components that assist with handling the sample media <NUM> when it is removed from the device <NUM> for processing by a laboratory. These other parts of the collection element <NUM> may include the base <NUM>, a top frame <NUM>, media support <NUM>, and bottom frame <NUM>. The top <NUM> and bottom <NUM> frame may have extensions 222A-, <NUM>-B on an outboard end. The extensions <NUM> further assist with handling the collection element <NUM> during and after its removal from the housing <NUM>.

<FIG> is an exploded view of another example device <NUM>, similar to the device in <FIG>. However, this device <NUM> presents the blood sample to two types of media, including both a collection membrane <NUM> and an immunoassay strip <NUM>. The membrane <NUM> and strip <NUM> may be arranged in parallel. The collection membrane <NUM> receives and stores a blood sample from some capillaries, and the immunoassay (or other test) strip <NUM> may receive and process a blood sample from other capillaries.

Other arrangements for two or more types of media are possible. For example, a collection membrane <NUM> and immunoassay strip <NUM> may be stacked on top of one another (instead of located in parallel with one another). It may be desirable for the test strip to be visible but the collection strip to not be visible, or vice versa. In some arrangements, a flow thorough test in addition to a lateral flow test may be housed in the same device. In addition to testing, a multiple layer (flow path) configuration could be used for sample separation (e.g., red blood cells on one layer, plasma on another) or for isolating competing analytes.

Samples from a first set of the capillaries may be exposed to an anti-coagulant such as heparin and directed to a sample storage media such as the membranes described herein. Samples from a second set of the capillaries may be mixed with reagent and directed for an on-the-spot test (e.g., via chemical media or electronic sensors) that provide an immediate test indication (such as via a color change in a chemical media or via a display of an electronic sensor output).

In one example use case, a single device provides and on-the-spot test for an immediate indication of a serious condition such as HIV or hepatitis C. The same device collects and stores a blood sample at the same time, which can then be used for less critical tests at a remote lab, such as blood glucose.

Other test strips may include colored bands that indicate a result of a test performed within the device itself. For example, test strips may be configured to indicate an HIV or hepatitus C condition. In the case of testing for HIV, the strip may be a nitrocellulose film that includes a detection area coated with HIV recombinant antigens and a control area.

Qualitative test strips for the presence of the hepatitus C virus in whole blood and plasma can also be applied.

The media <NUM> may be a plasma separation membrane or filter of various types located at or near an exit port of the capillaries <NUM>. For example, the membrane may be a mixed-cellulose ester membrane such as the Pall Vivid Plasma Separation membrane available from Pall™ Corporation. The membrane <NUM> may also be an LF1 glass fiber membrane (sold by General Electric™ Company) or some other media designed to receive serum or whole blood which it then separates into a blood portion and a plasma portion. A media such as LF1 paper has a fibrous structure that causes differential migration of the sample, with a slower rate for red cells, resulting in a gradual separation of plasma sample as it migrates down the paper. The membrane <NUM> can optionally be previously impregnated with heparin, EDTA, sugars, or other stabilization agents. LF1 paper, which separates plasma from red blood cells through a fiber matrix, is preferred in some embodiments, because it causes a slower migration rate for the blood cells. However other types of separation membranes for blood either liquid or dried may be used.

Plasma separation may also be achieved through non-membrane microstructures that exclude red cells by size. For example, plasma separation can be achieved or enhanced by selectively binding red cells as well. Binding agents are typically coated on a membrane or micro structure but could also be deposited in a channel.

The sample media can also be coated with various chemicals to perform a test, such as an assay, on the collected sample. Thus, an immunoassay strip <NUM> can be substituted for all, or for part of, or together with the sample media <NUM>. When device <NUM> is closed, the sample is delivered to a sample pad area on the immunoassay strip.

The media itself may be the aforementioned cellulose or glass fiber media, or other porous or non-porous media such as a plastic or glass. The media may include microfluidics chip(s).

The window <NUM> permits visual confirmation that the blood sample has been stored on the membrane <NUM> after the housing is closed. However, the same or other windows <NUM> may also allow for visual inspection of color change results of the immunoassay <NUM> or other test strip. In other configurations, the window(s) <NUM>, if present may only permit visual inspection of some of the media, and not others. That may be useful where the device is used to collect blood samples for compliance with a test such as an FDA <NUM>(k) equivalency test.

Alternatively, the sample could be delivered to an assay region within the housing <NUM> where capture molecules are exposed to the sample and bind analytes. These analytes could then be bound by a conjugate, making them detectable. The bound analytes may also modify the optical or electrical properties of the surface they are bound to, making them detectable directly.

It can now be appreciated that the action of closing the housing pieces together causes the blood sample to be drawn from the well <NUM>, to be drawn into the capillaries <NUM> via both capillary action and mechanical force, exiting the capillaries to be deposited onto the sample membrane <NUM>, the immunoassay strip <NUM>, or other media. In particular, the plungers <NUM> are engaged by housing piece <NUM>-A, and the capillary tubes <NUM> are in turn held in place within the inlay <NUM>. Thus, as the housing sections are closed together, the plungers <NUM> are forced into the capillaries <NUM>, which in turn force blood to exit onto the membrane <NUM>.

In some implementations, the material used to fabricate one or more sections or parts of the inlay piece <NUM> may have an elasticity that is sufficient to hold the capillary tubes <NUM> in place while the plungers <NUM> are forced into them. The elasticity of inlay <NUM> may also be chosen to seal and/or prevent at least some blood from flowing around, rather than flowing through, the capillary tubes <NUM>.

The closed housing <NUM> also creates a small and isolated internal air space above the sample media. The sample can be further encouraged to dry with the aid of one or more desiccant tablets (not shown) located in this air space. For example, a desiccant may be supported by the backbone <NUM> adjacent where the sample media <NUM> sits when the housing is in the closed position.

During or after the housing is closed, a ratcheting mechanism provided by the far end of the backbone <NUM> encourage the housing to remain shut. For example, the tines <NUM> may act as a ratcheting pall and engage small holes <NUM> or other features in the end of housing piece <NUM>-A (See <FIG>) when the housing is pushed shut. The tines <NUM> may be shaped to permit opening of the housing only with a pinching tool that accesses small holes <NUM> in the side of the housing piece <NUM>-B to release the ratchet pawl, e.g. by pinching the tines <NUM>. Thus, once the device <NUM> is closed by pushing the housing pieces <NUM>-A, <NUM>-B together, the blood sample remains enclosed within, and ready for transport to a remote lab.

<FIG> are respective top and side views of one way to implement the sample media, in this case a membrane <NUM> and media support <NUM>. <FIG> is a top view of the media <NUM> and <FIG> a top view of the support <NUM>.

The media <NUM> may be a generally rectangular, thin, paper or fibrous, membrane that slips under or fits into tabs <NUM>, <NUM>. Tabs <NUM>, <NUM> may be cut into or formed as port of support <NUM> to hold media <NUM> in place. The support <NUM> may also have a handle portion <NUM>. The handle <NUM> may conform to extensions <NUM> in the frame pieces <NUM>, <NUM>. The handle <NUM> and makes it easier to handle the collection media <NUM> when it is removed from the housing <NUM>. The handle <NUM> may also have other features such as shaped peripheral edges <NUM> to provide a more secure fit of the support <NUM> (and/or frame pieces <NUM>, <NUM>) within the housing.

<FIG> is a plan view of a collection media <NUM> sometime after a blood sample has been taken and after it has been removed from the housing <NUM>. Note a blood loading location <NUM> that was located adjacent the sample port <NUM> when the sample was taken. A first region <NUM> of the sample media <NUM> contains filtered red blood cells (RBCs). However other portions of the blood sample have diffused through the media <NUM>, to provide a sample separation region <NUM> and a purified plasma region <NUM>.

In use, the device <NUM> is a very convenient way to collect blood expressed by a patient after using a lancet on one of his/her fingers. Commercially-available lancets may be used, and it generally is the choice of the user to select the type of lancet. Once a drop of blood has been expressed on the finger, the patient skims the drop into a well <NUM> in the sample collection port <NUM> by gliding the finger across the protruding resilient edge <NUM>. The blood drop, through gravitational force and surface forces, proceeds to the bottom of the well <NUM> where it encounters openings in the collection (metering) capillaries <NUM>. From there, blood is further drawn into the collection element <NUM> including the sample storage media <NUM>, further encouraged by plungers that force blood out of the capillaries as the two housing pieces are closed together.

The closed device <NUM> then creates a small and isolated internal air space which can be quickly dried with the aid of desiccant tablets contained in an internal pocket. In its current form, use of LF1 paper as a collection media creates spots of red-cell free plasma as well as plasma-depleted whole blood. The LF1 paper's structure causes differential migration, with a slower rate for red cells, resulting in a gradual separation of plasma sample the further down the paper the sample migrates. Plasma is far better for any quantitative blood test, eliminating red cells, which tend to interfere with many analyte assays.

The device <NUM> therefore offers substantially better opportunity for high-quality quantitative assays as compared to standard dried blood spots. Furthermore, infectious disease tests can still be done on the red cell portion of the dried sample-though plasma-depleted, it is still adequate for accurate detection of infectious agents.

Claim 1:
A biological fluid sample collection device (<NUM>) comprising:
a housing (<NUM>) comprising a first housing section (<NUM>-A) and a second housing section (<NUM>-B), the housing configurable from a first position to a second position by moving the first housing section and the second housing section together, the housing enclosing:
a sample collection well (<NUM>);
a capillary (<NUM>) in fluid communication with the sample collection well, wherein the capillary is configured to hold a predetermined volume of the biological fluid sample, wherein the biological fluid sample comprises one or more analytes;
a medium (<NUM>) in fluid communication with the capillary, wherein the medium is configured to retain at least a portion of the biological fluid sample or a derivative thereof, wherein the medium comprises a conjugate configured to bind the one or more analytes to perform a test, wherein the medium comprises an immunoassay strip (<NUM>) comprising the conjugate configured to bind the one or more analytes;
a reagent configured to be dispensed onto the medium when the housing is moved from the first position to the second position;
a mechanically actuated fluid controller (<NUM>), configured to dispense a predetermined volume of the biological sample or a derivative thereof from the capillary onto the medium when the housing is moved from the first position to the second position,
wherein the reagent and the sample are mixed when dispensed onto the medium when the housing is moved from the first position to the second position to initiate performance of the test, and
wherein, when the housing is in the first position, the sample collection well is positioned to receive the sample from a user, and when the housing is in the second position the sample collection well is fully enclosed within the housing and is inaccessible to the user.