WO2000021664A9 - Collection device for biological samples and methods of use - Google Patents
Collection device for biological samples and methods of useInfo
- Publication number
- WO2000021664A9 WO2000021664A9 PCT/US1999/023680 US9923680W WO0021664A9 WO 2000021664 A9 WO2000021664 A9 WO 2000021664A9 US 9923680 W US9923680 W US 9923680W WO 0021664 A9 WO0021664 A9 WO 0021664A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- analyte
- ofthe
- blood sample
- separation member
- separation
- Prior art date
Links
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/487—Physical analysis of biological material of liquid biological material
- G01N33/49—Blood
- G01N33/491—Blood by separating the blood components
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5023—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures with a sample being transported to, and subsequently stored in an absorbent for analysis
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/02—Adapting objects or devices to another
- B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0681—Filter
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0825—Test strips
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
- B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0887—Laminated structure
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
- B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
Definitions
- the subject invention relates to a device and method for collection, transport, storage, processing (e.g., separation of cells from serum), and compatibility with laboratory analysis of a biological sample obtained from a living organism.
- the subject invention relates to a device and method used in the analysis of a biological component in a dried blood or urine sample obtained from an animal.
- Liquid sample collection, handling, transport, and storage which is the conventional approach, has many problems associated with it including: (1) the risk of container breakage or leakage which causes loss of sample and the danger of infection; (2) sample instability during shipment and storage; (3) refusal of transport carriers to accept liquid biohazardous shipments; and (4) collection of more sample than is necessary for testing, to ensure quantities compatible with common laboratory methods of serum or plasma preparation and subsequent analysis.
- a biological sample e.g.. a drop or two of whole blood
- filter paper e.g. a paper
- These dried blood spot samples are mailable and are accepted by all common carriers.
- analysis of certain dissolved blood components is not currently possible from a whole blood sample unless the red blood cells are first separated from the blood plasma or serum.
- the most conventional manner of separating serum or plasma from blood cells is by centrifugation.
- the handling ofthe blood samples can also be a critical part ofthe ultimate accuracy of measurement in the sample. Therefore, even when a blood sample is removed from the body, the concentration ofthe component within a liquid blood sample can change over time. Dried blood spots have the advantage of helping to preserve certain components for later analysis.
- the subject invention concerns a device for use in collection, separation, stabilization, preservation, transport, storage, and elution of a biological sample for laboratory analysis of particular components in the sample, methods of use for the device, and kits comprising the device.
- the subject invention concerns a device which is useful for collection of a whole blood sample, allowing separation ofthe blood cells from the blood serum or plasma, drying the blood serum or plasma sample on the device, transporting the collected and dried blood serum or plasma sample to a laboratory or other facility for analysis, and extracting an analyte of interest from the sample for determining presence or absence ofthe analyte or, if present, the concentration thereof.
- one embodiment ofthe subject device comprises a plurality of separate components, including a quantitation member for facilitating delivery of a particular volume or amount of sample to a collection member.
- the sample can also be passed through another component, e.g., a separation member which can separate certain undesirable components from the components of interest in the sample.
- a separation member which can separate certain undesirable components from the components of interest in the sample.
- blood cells e.g., red blood cells
- the collection member which can be an absorbent or non-absorbent filter or membrane material, can serve to collect the component of interest in the sample, e.g.. serum or plasma, provide a surface for drying ofthe component of interest, and a means for storage of that component for subsequent transport to, and analysis in, a laboratory.
- the device can have a plurality of any one ofthe quantitation, separation, or collection members.
- One preferred embodiment has a plurality of separation members, including one which also can be useful as a quantitation member.
- the quantitation member serves to collect overflow of sample so that a defined volume of sample component of interest is delivered to the collection member, over which the other described members are superimposed.
- the separation/ overflow member can be a track etched membrane, as is well-known in the art, or can be a screen material which can spread the liquid sample such that a particular volume of the sample is provided in each cell ofthe screen. This embodiment is termed the "multilaminate configuration.”
- the trilaminate configuration comprises a substantially three-layered collection device, having a separation member, a quantitation member, and a collection member.
- the quantitation member can be a material having a wicking property, e.g., standard capillary tube such as is used in routine laboratory work (typical volumes are 5-50 microliters), or can be an absorbent or non-absorbent material which has quantitative liquid volume properties for liquids, or an encased fiber bundle or other like configuration which accepts a quantitative liquid uptake and can deliver a predetermined volume of sample to another component ofthe device.
- a material having a wicking property e.g., standard capillary tube such as is used in routine laboratory work (typical volumes are 5-50 microliters)
- an absorbent or non-absorbent material which has quantitative liquid volume properties for liquids
- an encased fiber bundle or other like configuration which accepts a quantitative liquid uptake and can deliver a predetermined volume of sample to another component ofthe device.
- the separation member can be an absorbent, adsorbent, non-absorbent, or non- adsorbent material, for delivering the sample to the serum/plasma collection member via capillary action.
- the separation member can also provide a separation function for selectively separating different components within the sample, or can provide a quantitative volumetric measurement function.
- the separation member useful for separating a component of interest from an undesired component in the biological sample prior to introduction ofthe component of interest to the collection member, according to one embodiment, can be a substantially circular section of absorbent filter paper having a predetermined standard size.
- a device according to the subject invention comprises a first wicking or quantitation member and a second "separation member," as described.
- a third "collection member” component is substantially circular and disposed in contact with the separation member for collecting sample therefrom.
- a device of this embodiment is configured to include a substantially circular collection member contacting a substantially circular separation member which is contactingly disposed between the quantitation or wicking member and the circular collection member. This configuration is referred to herein as a "dual pad" configuration.
- the members namely, the quantitation member, the separation member, and the collection member, must contact one another for transferring the sample from one member to the other. These members can be abutted to one another, can overlap, or can be superimposed over one another.
- the separation member and collection member are typically substantially similar in diameter; the separation member which also serves as an overflow quantitation member can be substantially the same size or larger in diameter than the collection member.
- the separation and collection members can have thicknesses, absorbencies, or migration or other physical properties different from one another in order to produce a particular desired effect or result.
- the quantitation member is typically a capillary tube
- the separation member is typically a substantially circular section of absorbent filter or chromatography paper having cell separating properties and a predetermined, standard size
- the collection member is an elongate strip of absorbent material, e.g.. filter chromatography paper.
- This embodiment is used by obtaining a small amount of a biological sample to be tested, e.g., a drop of blood from a sterile lancet fmgerstick, and bringing the sample in contact with the wicking or quantitation member.
- the sample then wicks into the separation member and separates into particular components whereby the components of interest migrate to and are retained on the elongate collection member.
- the quantitation or wicking member can be eliminated.
- the sample e.g., whole blood, is applied directly to the separation member, and the collection member achieves quantitation by uniformly distributing the serum or plasma in the collection member so that a fixed area of collection member contains a quantitative amount of serum or plasma.
- a collector of absorbent material e.g., HemaSep L (Gelman), or a non-adsorbent screen, such as Nitex 3- 8/1 (Tetko), can function in such a manner.
- a cover for at least the collection member and, more preferably, a cover which substantially envelopes the separation member and collection members, except for an aperture or perforation through which the separation member communicates with the outside environment.
- This aperture further provides a means for applying a liquid sample directly to the separation member if desired.
- the cover comprises a pair of plastic sheets which are superimposed over one another to form a laminated device. At least one of the sheets can have adhesive disposed on one of its facing surfaces so that the sheets can be adhered together around substantially the entire perimeter ofthe separation and/or collection members.
- the quantitation or wicking member can extend from the laminated sheets, forming an uncovered
- one ofthe sheets covering the dual pad configuration is perforated to allow air to reach the separation member to facilitate drying ofthe sample- saturated separation member prior to transport ofthe collected sample to a facility for analysis. This advantageously can prevent spill-over or undesired migration of separated components, e.g., red blood cells, retained in the separation member to the collection member
- At least one additional layer of plastic sheet can be disposed between two members ofthe device.
- a layer of plastic sheet is disposed between opposing faces of a screen member and a separation member
- the plastic layer so disposed must provide a means for allowing fluid communication between the screen and separation member
- an aperture or pore can be provided to allow sample to migrate from one member to another member, including the collection member
- a centered aperture or pore in this additional plastic layer can facilitate directly the sample to that juxtaposed member and can control volume of sample ultimately received by the collection member
- a "bridge-strip" type device or apparatus for isolating an analyte from a blood sample In general, this apparatus features a separation member for receiving a portion ofthe blood sample, the separation member havmg a filter that selectively retains cellular components contained withm the portion of the blood sample and delivers non-cellular components ofthe portion ofthe blood sample containing the analyte, a wicking b ⁇ dge fluidly connected to the separation member such that the wicking b ⁇ dge can receive the non-cellular components ofthe portion ofthe blood sample containing the analyte from the separation member, the wickmg b ⁇ dge including a st ⁇ p of porous mate ⁇ al for transporting the non-
- the separation member has a layer of glass fiber filter material and a layer of track-etched membrane.
- the layer of track-etched membrane can be composed of polyester and/or polycarbonate and have a plurality of pores having a mean diameter of about 0.2 to 5.0 micron (e.g. one micron).
- the separation member can be impregnated with a surfactant such as polyoxyethylene sorbitan ester (e.g., Tween-20).
- the separation member can also be impregnated with a protein that reduces adsorption of components ofthe blood sample to the separation member.
- the protein can be bovine serum albumin.
- the apparatus can also include a separation member that is impregnated with an erythrocyte agglutinin such as a lectin or an antibody that specifically binds to erythrocytes.
- a separation member that is impregnated with an erythrocyte agglutinin such as a lectin or an antibody that specifically binds to erythrocytes.
- the wicking bridge ofthe apparatus can take the form of a fibrous polyester matrix.
- the quantitative collection member can include a layer of glass fiber filter material, a layer of nylon, and/or a layer of cellulose.
- the apparatus can also include a second and/or a third quantitative collection member, the second and third quantitative collection members being fluidly connected to the wicking bridge such that the second and third quantitative collection member can receive the non-cellular components ofthe portion of the blood sample containing the analyte from the wicking bridge, substantially free of any reactants for analyzing the analyte, and comprised of a swatch of material that is adapted for absorbing and retaining a specific quantity ofthe non- cellular components ofthe portion ofthe blood sample containing the analyte.
- the apparatus further features an application member fluidly connected to the separation member, the application member including a swatch of material having a plurality of pores for absorbing the blood sample and delivering a portion ofthe blood sample to the separation member.
- the application member can be composed of polyester and can be impregnated with a protein (e.g., bovine serum albumin) that reduces adsorption of components ofthe blood sample to the application member.
- the application member can also be impregnated with a surfactant such as a polyoxyethylene sorbitan ester, and/or an erythrocyte agglutinin such as a lectin and/or an antibody that specifically binds to erythrocytes.
- Some embodiments ofthe apparatus further include a casing which houses the application member, the separation member, the wicking bridge, and the quantitative collection member.
- the casing can have an opening for applying the blood sample to the application member.
- the casing can, for example, have two pieces of a fluid impermeable plastic material sealed together in an airtight manner such that gas exchange between the ambient atmosphere, the application member, the separation member, the wicking bridge, and the quantitative collection member occurs almost entirely through the opening ofthe casing.
- the apparatus can further feature an impermeable spacer interposed between the wicking bridge and the application member, the impermeable spacer can have a thickness of about 0.5 mm (0.020 inches), a first perforation through the thickness for accommodating the separation member, and a second perforation through the thickness for accommodating the quantitative collection member(s).
- the first perforation and the second perforation each have a diameter of about 4.75 mm (0.1875 inches)
- the separation member and the quantitative collection member each have a diameter of about 4.65 mm (0.1825 inches).
- the application member can include polyester impregnated with at least one protein that reduces adsorption of components of blood sample to the application member and at least one agglutinin;
- the separation member can include a layer of glass fiber filter material and a layer of polyester track-etched membrane;
- the wicking bridge can include a fibrous polyester matrix;
- the quantitative collection member can include a layer of nylon and a layer of glass fiber filter material.
- the various versions ofthe apparatus ofthe invention can also have an identification label attached to the casing, the identification label for displaying information indicating the source of blood sample.
- the identification label can include a bar code.
- the invention additionally features another apparatus for isolating an analyte from a blood sample.
- This apparatus includes a capillary tube for quantitatively aspirating a specific volume ofthe blood sample and delivering a specific volume of a portion ofthe blood sample to the separation member; a separation member fluidly connected to the capillary tube such that the separation member can receive the specific volume of the portion ofthe blood sample from the capillary tube, the separation member comprising a filter that selectively retains cellular components ofthe portion ofthe blood sample and delivers non-cellular components ofthe portion ofthe blood sample containing the analyte; a wicking bridge fluidly connected to the separation member such that the wicking bridge can receive the non- cellular components ofthe portion ofthe blood sample containing the analyte from the separation member, the wicking bridge comprising a strip of porous material for transporting the non-cellular components ofthe portion ofthe blood sample containing the analyte away from the separation member; and a quantitative collection member fluidly connected to the wick
- the subject method begins with the application of a sample, e.g., a drop of whole blood (or "blood spot"), typically procured by a fingerstick using a lancet, to the device by bringing the sample into contact with a quantitation member, an application member, or a separation member, allowing certain components ofthe sample to selectively migrate to the collection member, and drying the collection member containing the collected sample or allowing it to dry by exposure to air over a period of time, e.g., overnight.
- the dried sample then can be mailed to the analytical laboratory for determination of presence, absence, or quantity of analyte present in the sample.
- the analytes contained by the collection member can be physically separated or extracted from the collection member and used for quantitative or qualitative analysis of one or more of those analytes.
- the subject device can perform at least two functions: (1) as a blood collection means and (2) as a blood transport medium for subsequent clinical analysis.
- One objective of this invention is to eliminate problems encountered with currently used devices or methods, including providing a device and method wherein variation of sample size is minimized when absorbed onto a filter paper.
- kits for enabling an individual to collect a sample and transport it to a facility for analysis can further include components selected from the following: lancet, antiseptic swab, transport packaging, or an information card for providing information, e.g., medical history or health status, ofthe individual being tested.
- the invention features a kit for isolating an analyte from a sample of blood, the kit including an apparatus having a separation member for receiving a predetermined volume ofthe blood sample, the separation member including a filter that selectively retains cellular components ofthe portion ofthe blood sample and delivers non-cellular components ofthe portion ofthe blood sample containing the analyte; a wicking bridge fluidly connected to the separation member such that the wicking bridge can receive the non-cellular components of the portion ofthe blood sample containing the analyte from the separation member, the wicking bridge comprising a strip of porous material for transporting the non-cellular components ofthe portion ofthe blood sample containing the analyte away from the separation member; and a quantitative collection member fluidly connected to the wicking bridge such that the quantitative collection member can receive the non-cellular components ofthe portion ofthe blood sample containing the analyte from the wicking bridge, the quantitative collection member being substantially free of any reactants for analyzing the analyte and comprising
- the quantitative fluid dispenser can , for example, take the form of a micropipet or a capillary tube.
- all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing ofthe present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are inco ⁇ orated by reference in their entirety. In the case of conflict, the present specification, including definitions will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
- FIG. 1 shows a perspective view of one embodiment ("lateral flow" configuration) of a device according to the subject invention.
- Fig. 2 shows a perspective view of an embodiment ofthe device according to the subject invention, termed the "single pad" configuration.
- Fig. 3 shows a perspective view of a second embodiment (dual pad configuration) of a device according to the subject invention.
- Fig. 4A shows a side view of a third embodiment (trilaminate variation of a multilaminate configuration) of a device according to the subject invention.
- Fig. 4B shows a variation ofthe trilaminate configuration wherein the screen quantitation member is superimposed over the separation and collection members.
- Fig. 4C shows an enlarged elevated view of a quantitation member formed from a screen material.
- Fig. 4D shows a top plan view of a third embodiment (trilaminate variation of a multilaminate configuration) of a device according to the subject invention.
- Fig. 4E shows a side view of a third embodiment (trilaminate variation of a multilaminate configuration) of a device according to the subject invention, illustrating the quantitative function achieved by the screen/collection member interface.
- Fig. 4F shows an exploded perspective view of a multilaminate configuration of an embodiment ofthe subject invention comprising separation members, including an overflow member and a collection member adhered between cover members.
- Fig. 4G shows an exploded perspective view of a multilaminate configuration of an embodiment ofthe subject invention comprising a screen member and an aperture liner member.
- Fig. 4H shows an elevated view of a back face of a multilaminate configuration ofthe subject invention, illustrating a cut-out area for drying and removal of the collection member.
- Fig. 41 shows an exploded perspective view of a bridge strip configuration of an embodiment ofthe subject invention.
- Fig. 4J shows an exploded perspective view of a bridge strip configuration of an embodiment of the subject invention having two quantitative collection members.
- Fig. 4K shows an exploded perspective view of a bridge strip configuration of an embodiment ofthe subject invention having three quantitative collection members and three wicking bridges.
- Fig. 5A shows a perspective view of a lateral flow configuration ofthe subject device having a cover laminated over top and bottom faces of the separation member.
- Fig. 5B shows a perspective view of a lateral flow configuration ofthe subject device having a cover laminated over top and bottom faces ofthe separation and collection members.
- Fig. 5C shows a perspective view of a dual pad configuration ofthe subject device having a cover laminated over top and bottom faces ofthe separation member and collection member, having the wicking member extending therefrom.
- Fig. 6A shows an elevational view of a device according to the subject invention, illustrating a separable flap formed in one cover sheet for facilitating removal of a collection member.
- Fig. 6B shows an elevational view of a device according to the subject invention illustrating a separable flap formed by pattemly disposed adhesive on the cover sheets which adheres the sheets together around the separation member, but allows separation ofthe sheets around the collection member.
- Fig. 7 shows an elevational view of an embodiment ofthe subject invention illustrating a perforation formed in the cover laminate.
- Figs. 8A-8D show alternative configurations of a device according to the subject invention having a plurality of collection or separation members.
- Fig. 9 shows regression analysis results for blood sample eluates vs. neat blood samples analyzed for cholesterol concentration using a single pad configuration of a device according to the subject invention.
- Fig. 10 shows regression analysis results for blood sample eluates (adjusted) vs. neat blood samples analyzed for cholesterol concentration using a single pad configuration of a device according to the subject invention.
- Fig. 11 shows regression analysis results for blood sample eluates vs. neat blood samples analyzed for triglyceride concentration using a single pad configuration of a device according to the subject invention.
- Fig. 12 shows regression analysis results for blood sample eluates (adjusted) vs. neat blood samples analyzed for triglyceride concentration using a single pad configuration of a device according to the subject invention.
- Fig. 13 shows regression analysis results for blood sample eluates vs. neat blood samples analyzed for HDL concentration using a single pad configuration of a device according to the subject invention.
- Fig. 14 shows regression analysis results for blood sample eluates (adjusted) vs. neat blood samples analyzed for HDL concentration using a single pad configuration of a device according to the subject invention.
- Fig. 15 shows regression analysis results for blood sample eluates vs. neat blood samples analyzed for fhictosamine concentration using a single pad configuration of a device according to the subject invention.
- Fig. 16 shows regression analysis results for blood sample eluates (adjusted) vs. neat blood samples analyzed for fhictosamine concentration using a single pad configuration of a device according to the subject invention.
- Fig. 17 shows regression analysis results for blood sample eluates vs. neat blood samples analyzed for direct LDL concentration using a single pad configuration of a device according to the subject invention.
- Fig. 18 shows regression analysis results for blood sample eluates (adjusted) vs. neat blood samples analyzed for direct LDL concentration using a single pad configuration of a device according to the subject invention.
- Fig. 19 shows regression analysis results for blood sample eluates vs. neat blood samples analyzed for cholesterol concentration using a dual pad configuration of a device according to the subject invention.
- Fig. 20 shows regression analysis results for blood sample eluates (adjusted) vs. neat blood samples analyzed for cholesterol concentration using a dual pad configuration of a device according to the subject invention.
- Fig. 21 shows regression analysis results for blood sample eluates vs. neat blood samples analyzed for triglyceride concentration using a dual pad configuration of a device according to the subject invention.
- Fig. 22 shows regression analysis results for blood sample eluates (adjusted) vs. neat blood samples analyzed for triglyceride concentration using a dual pad configuration of a device according to the subject invention.
- Fig. 23 shows regression analysis results for blood sample eluates vs. neat blood samples analyzed for ALT concentration using a dual pad configuration of a device according to the subject invention.
- Fig. 24 shows regression analysis results for blood sample eluates (adjusted) vs. neat blood samples analyzed for ALT concentration using a dual pad configuration of a device according to the subject invention.
- the subject invention concerns a device which can be useful for collection, separation, stabilization or preservation, transport, storage or elution, of components of interest in a biological sample for laboratory analysis of an analyte contained in that sample component.
- the subject device comprises a separation member for separating and retaining, without leaching from the separation member, an undesired component (e.g., cells), from a component of interest (e.g., serum or plasma) that constitute the sample.
- an analyte which is typically contained within, and is collected with, the component of interest, namely, serum or plasma in a sample of whole blood.
- serum or plasma can be used interchangeably and would be understood by those of ordinary skill in the art to refer to a blood sample having certain cellular components removed or separated therefrom.
- the serum or plasma containing the analyte selectively migrates through the separation member and becomes retained or "collected” in a second component of the subject device, namely, an absorbent or non-absorbent collection member.
- the collection member comprises a membrane on which the sample can be collected, stored, or transported, and further can be eluted or analyzed therefrom.
- the collection member is a material which allows the analyte to be extracted or eluted from the membrane using standard chemistry procedures for subsequent quantitative or qualitative analysis.
- FIG. 1 A first embodiment for the subject invention is shown in Fig. 1 wherein the device 10 comprises a collection member 11 having a first free end 13 and a second end 14 contacting a separation member 12.
- the collection member 11 and separation member 12 preferably contact one another in an overlapping manner so that a sample placed onto the separation member 12 can migrate, e.g., via capillary action, toward the collection member 11 so that analyte in the sample, selectively separated from an undesired component, is delivered to, and absorbed into, the collection member.
- the collection member is positioned to overlap with the separation member wherein the second end ofthe collection member contacting the separation member is disposed approximately in the center ofthe separation member.
- the opposite or free end ofthe collection member is allowed to extend away from the separation member to form a "tail".
- the separation member can be pre-saturated or pre-treated with a reagent which facilitates separation of an undesired component in the sample from the component of interest which can contain analyte.
- a reagent which facilitates separation of an undesired component in the sample from the component of interest which can contain analyte.
- the separation member in a device ofthe subject invention useful for collection, storage, transport, or analysis of a blood plasma or serum analyte, the separation member can be pre-treated with a reagent which retards migration of red blood cells or a reagent such as a surfactant (e.g., a polyoxyethelene sorbitan ester such as Tween-20) which facilitates flow of sample through the separation member.
- a surfactant e.g., a polyoxyethelene sorbitan ester such as Tween-20
- a reagent which agglutinates red blood cells can be used to pre-treat the separation member in the sample, so that a clotting cascade is initiated in a whole blood sample placed on the separation member, retarding movement of the red blood cells to the collection member so that blood serum containing an analyte of interest first reaches and substantially saturates the collection member.
- the separation member can be pre-treated with a red blood cell agglutinating reagent (i.e., agglutinin) to facilitate separation ofthe red blood cells from the blood serum.
- agglutinin can be, e.g., a lectin such as concanavalin A or the like, or an antibody that specifically binds erythrocytes such as a polyclonal rabbit anti-human erythrocyte antibody preparation.
- Agglutinins are typically added to the separation member in an amount sufficient to agglutinate most ofthe erythrocytes in the applied sample, e.g., usually less than 1% concentration by weight (agglutinin: applied sample).
- agglutinin applied sample.
- serum which can contain an analyte of interest can continue to migrate through the separation member 12 and onto collection member 11 whereby the collection member can become at least partially or, preferably, substantially saturated with serum for subsequent analysis.
- the separation member can be pre-treated with a reagent which separates unclotted red blood cells from plasma so that plasma proteins, e.g., clotting factors, can be measured or analyzed.
- a material can be used for the separation member which can selectively separate biological sample components by their biological, chemical, or physical properties.
- Other reagents that non- specifically reduce adso ⁇ tion of components of the blood sample to the separation member can be used to pretreat the separation member.
- the separator member can be treated with a protein such as albumin (e.g., bovine serum albumin).
- albumin e.g., bovine serum albumin
- the single pad configuration ofthe subject invention as shown in Fig. 2, comprises a separation member 12 and collection member 13 as described for the lateral flow configuration.
- this configuration further comprises a quantitation or wicking member 20 which can quantitatively load the sample onto the separation member.
- the wicking member is preferably a capillary tube which can advantageously provide a means for delivering a specific volume of sample to the collection member.
- the inner wall ofthe capillary tube quantitation or wicking member can be coated with an anti-coagulant for facilitating migration of a whole blood sample through the separation member to the collection member.
- the "dual pad" configuration ofthe subject device 30 comprises separation member 31 , which is preferably abutting the second end 32 of capillary tube quantitation or wicking member 33, and is overlappingly in contact with the collection member 34.
- the sample is collected at the free end 35 of wicking member 33 and migrates by capillary action to separation member 31.
- the capillary tube volume is matched to the abso ⁇ tion capacity ofthe collection member. For example, we have identified that a capillary volume of about 30 ⁇ l is preferred to saturate, but not over-saturate, a collection member of certain materials.
- a 20 ⁇ l capacity capillary tube will adequately saturate a 0.48 cm (3/16 inch) diameter collection member with sample, but does not sufficiently saturate a 0.635 cm (1/4 inch) diameter collection member; optimal saturation of a collection member was obtained using a
- the separation member 31 can separate sample constituents in a lateral direction (in a direction from the quantitation or wicking member, as shown by arrow a in Fig. 3) such that migration of undesired constituents, e.g., red blood cells, is retarded, allowing lateral passage of components of interest, e.g., analytes, to migrate onto collection member 34, which is at least partially overlapped by the separation member 31.
- a variety of materials can be used for the separation member. These materials are preferably selected from glass fiber, glass fiber/cellulose mixtures, cellulose, or other proprietary materials, including synthetic materials, e.g., nylon.
- Useful glass fiber materials include GF-24, GF-25, and #33, available from Schleicher & Schuell (Keene, NH, USA); G143, G144, and G167, available from Ahlstrom (Mount Holly Springs, PA, USA); GFQA30VA, GF/P 30, GF/DE 30, GF/SE 30, GF/CM30VA,
- GF/CM 30, F 075-14, GF DVA, GFVA 20, and GD-2 available from Whatman (Fairfield, NJ, USA); G 40, available from Micron Separation, Inc. (Westborough, MA, USA); AP 25 and APFD, available from Millipore (Bedford, MA, USA): and GC-90 and GA-200, available from Osmotics.
- Useful glass fiber/cellulose mixture materials include F255-07 90 glass/10 cellulose, F255-09 70 glass/30 cellulose, F255-11 50 glass/50 cellulose, and F255-12 50 glass/50 cellulose, available from Whatman.
- Useful cellulose materials include 598, available from Schleicher & Schuell. Miscellaneous or other materials falling outside the above categories can also be used, including HemaSep V and Leukosorb; which article of manufacture according to the subject invention available from Pall BioSupport (Port Washington, NY, USA).
- Nylon 6.6 Transfer Membrane which is commercially available under the tradename Biodyne B (Pall Specialty Materials, Port Washington, NY).
- Another useful separation member is a track-etched membrane having pores of mean diameter between 0.2 and 5.0 ⁇ m.
- One such track-etched membrane is available from Whatman and commercialized under the tradename Cyclopore (e.g., Cyclopore PET 1.0 ⁇ m pore size).
- the separation member ofthe dual pad configuration can be selected from a variety of materials, including those described for the separation member used in the single pad configuration.
- the material known as "PlasmaSep”, available from Whatman, can be used.
- the separation member comprises an absorbent chromatography membrane or filter paper, e.g., HemaSep V (Pall BioSupport), which can separate constituents of a biological sample by size or binding characteristics which are well known in the art.
- the separation member is typically a substantially circular membrane, but is not limited by shape. HemaSep V is well-documented for its vertical separation characteristics (in the direction shown by arrow a in Fig. 1 ) and can be useful in the lateral flow configuration to separate serum or plasma from undesired sample constituents (cells) in
- a preferred separation member selectively separates serum or plasma from undesired sample components (cells) in a lateral direction, i.e., in the direction of flow from quantitation or wicking member to collection member.
- HemaSep L Pall BioSupport
- constituents which are not desired to be analyzed are substantially bound or retained in the separation member, whereas an analyte in serum or plasma, is allowed to freely or selectively move with the separated plasma or serum through the membrane to the collection member.
- the collection member used in the lateral flow configuration can be made from a variety of materials, including cellulose, polypropylene, nylon (including single or multi filament screens), polyester, modified polyester, polyethersulfone, nitrocellulose, high density polyethylene (HDPE), composites of natural and synthetic fibers.
- these materials can include DE81 and C/CM30, available from
- Ahlstrom 319 available from Ahlstrom; X-4588. available from Porex; Nitex 3-8/1, Nitex 3- 10/1, Nitex 3-15/5, Nitex 3-20/14, and 7-1 IF/826, available from SEFAR (Charlotte, NC; formerly Tetko).
- the absorbent collection member is formed as an elongate or rectangular strip of material at least approximately 2 mm in width by at least about 10 mm in length. These dimensions are optimized to be capable of absorbing the total volume of separated sample. More preferably, the absorbent collection member is between about 3-5 mm in width and between about 25-45 mm in length. Most preferably, the absorbent collection member is about 4 mm in width by about 35 mm in length.
- the most preferred embodiment (4 mm x 35 mm) ofthe collection member provides for an appropriate amount of liquid sample, e.g., a single drop of blood, to saturate but not over-saturate the collection member. Over-saturation occurs when the liquid front ofthe separated sample reaches the end ofthe strip, which can result in the analyte bunching up at the tip ofthe strip, making elution or analysis more difficult or inconsistent.
- the collection member can also be pre-treated with a preservative or stabilizer to enhance stability or "shelf-life" ofthe separated sample or can be treated with a reagent to facilitate the release ofthe analytes from the member during the elution process.
- devices intended for use in a protein assay can include a collection pad that is pre- treated with a reagent formulated to improve the stability of a protein in the sample.
- Other preservatives or stabilizers that can be used in the subject device include antioxidants, carbohydrates, buffers, other proteins, or the like, which are known in the art to provide a preservative or stabilizing effect on a biological sample.
- the release ofthe analytes from the collection pad can be enhanced with a pre-treatment ofthe collection member of a variety of surfactants.
- the flow of sample applied to the device can be reversed, i.e., by applying sample to an elongate separation member.
- the elongate separation member can comprise an absorbent material capable of selectively retaining undesired sample component, e.g., red blood cells, and allowing fluid (serum or plasma) containing a component of interest to migrate to, and absorb into, a circular collection member.
- a known lateral flow membrane for the separation member.
- GF-24 Schottamper & Schuell
- the separation member can be pretreated with other reagents, e.g., surfactants to facilitate flow of sample through the member.
- useful materials for the dual pad configuration include those described for use in the single pad configuration.
- certain highly absorbent materials were identified as providing advantageous results in the dual pad configuration. For example, Gelman Accuwick 14, Whatman BSM (also termed "PlasmaSep”), S&S 903, and
- Ahlstrom 319 can provide advantageous results.
- a still further embodiment ofthe subject invention concerns a multilaminate configuration which includes a separation member and quantitation member disposed directly over a collection member.
- a trilaminate device shown in Figs. 4A-4E.
- Fig. 4A a side view ofthe subject device in a trilaminate configuration 90 is shown.
- This configuration comprises a separation member 91 which is preferably a substantially flat, substantially circular disc made from material as described herein for a separation member.
- the separation member 91 has an upper face 92 for disposing a drop of biological sample, e.g., blood, thereon.
- the separation member 91 has a second face 93 which contacts the quantitation member 94 on its top face 95.
- a bottom face 96 ofthe quantitation member 94 is disposed so that it contacts the collection member 97.
- the collection member 97 can be an absorbent material as previously described.
- This particular configuration can include a track-etched membrane or a screen material as the quantitation member 94.
- a track-etched membrane used in the trilaminate configuration ofthe subject device can be useful as an overflow member, i.e., to absorb excess volume of plasma transferred to the collection member.
- the track-etched membrane e.g., Cyclopore (Whatman)
- the track-etched membrane is disposed between the separation member and the collection member, as it is preferred to employ the properties ofthe track-etched membrane following separation of cellular components from a blood sample.
- An additional advantage ofthe track-etched membrane is that it can serve as a filter to further separate any remaining cellular components which may not be removed from plasma or serum by the separation member or members.
- Use of a screen material for the quantitation member 94 can advantageously provide a means for applying consistent and accurate volumes of sample to the collection member 97.
- This consistent volumetric application can be achieved as a result ofthe structure of non- absorbent screen material used for the quantitation member 94.
- materials useful for a screen quantitation member include synthetic polymeric materials, e.g., nylon, polyester, or the like, which are commonly available having different pore sizes.
- SEFAR manufactures a plurality of polyester screens under the numerical designation 7-16/8; 7-5/2;
- Nylon screens available from SEFAR include those designated 3-10/2; 3-5/1 ; and 3-20/14.
- a variation of this trilaminate configuration as shown in Fig. 4B includes a device having a screen quantitation member 94 preferably disposed to overlay both the separation member 91 and collection member 97.
- Use of a screen material can also have the advantage of serving as an indicator of minimum volume.
- a minimum volume of liquid sample can be indicated and applied to the device by calibrating relative distance or area of saturation on the overflow member. Accordingly, if a saturation spot does not reach a particular sized area on the overflow member, more sample may be necessary to provide a minimum volume of serum to the collection member for accurate measurement or determination of analyte.
- Fig. 4C which is a magnified view ofthe pore structure forming the screen material of the quantitation member 94
- liquid applied to the screen 94 spreads to cover the surface ofthe screen material and thereby distributes evenly into the pores 99 ofthe screen, formed by the cross-hatching structure ofthe screen material.
- Each of the pores can contain a fixed volume of liquid which is then absorbed onto the separation member 92 and collection member 97 disposed below the quantitation member 94.
- the separation member 91 has an upper face 92 which has a surface area smaller than the bottom face 96 ofthe quantitation member 94 and is smaller than the surface area ofthe spread liquid which is disposed onto the screen.
- the liquid sample when liquid sample is applied to the upper surface 95 ofthe quantitation member 94, the liquid spreads to cover an area larger than the surface area of upper face 92 of separation member 91. Therefore, only liquid sample contained in the pores ofthe screen material of quantitation member 94, which directly overlay the top surface ofthe separation member 91, is delivered to the collection member 97.
- the liquid sample 100 spreading onto the quantitation member 94 has a surface area larger than the separation member 91 and the collection member 97 (shown in phantom). This is further illustrated in Fig. 4E, showing the liquid sample 100 covering an area having a diameter d which is larger than the width d' ofthe separation member 91 or collection member 97.
- Figs. 4F and 4G show variations of the multilaminate configuration having more than three members constituting the subject device. These are shown in exploded perspective view to illustrate each layer.
- a multilaminate device 70 is shown comprising a top cover sheet 71 which can be made from a non-porous material, e.g., a polymer or plastic which is typically non-absorbent and non-permeable (e.g., Adhesive Research 7843 plastic; Adhesive Research, Inc., Glen Rock, Pennsylvania).
- the cover sheet 71 is shown as a sectional view.
- Sample 72 e.g., a drop of blood, is applied to the top face ofthe device so that it crosses cover sheet 71 through an aperture, perforation, or pore 73 formed thereon prior to construction ofthe laminated device.
- the multilaminate configuration ofthe device as shown in Fig. 4F further comprises a separation member 74 which serves to separate and retain an undesired component, e.g., red blood cells, yet allow passage therethrough of a desired component, e.g., serum or plasma.
- Fig. 4F shows a device comprising two superimposed separation members 74.
- the separation members 74 can be the same or different materials, and are preferably independently selected from commercially available filter material described herein, e.g., GF 24, HemaSep V, Biodyne B, or the like.
- the multilaminate device 70 comprises an overflow member 75 which can serve to absorb excess volume of liquid sample.
- the excess can be absorbed from liquid flowing from the separation member disposed in contact with the overflow member, or can absorb excess serum which oversaturates a collection member 76, contactingly disposed below the overflow member.
- the overflow member 75 can be made from filter material as described herein for a separation member. However, it is preferable to provide an overflow member which is equal to or greater in size than the separation member in order to function as an absorber of excess volume.
- the overflow member is preferably Cyclopore (Whatman).
- the collection member 76 can also be made from material as described herein for a collection member used in other configurations ofthe subject device. Particular examples of materials that can be used as a collection member are Biodyne B or Ahlstrom 319.
- the overflow member 75 can also be a screen material, having structure and properties as described herein.
- a non-permeable plastic or polymer can also be used to form the bottom layer or coversheet 77 ofthe subject device.
- a coating of adhesive 78 can be applied to an inner face of coversheet 71 or 77 so that the cover sheets adhere together around the periphery of the other members.
- adhesive can be omitted from one edge area so that the coversheets 71 and 78 do not permanently adhere at a particular location to facilitate removal ofthe collection member 75 from the unitary device.
- a variation ofthe multilaminate configuration is illustrated, showing a device 80 according to the subject invention having a separation member 74, and overflow member 75, collection member 76, and top and bottom coversheets 71 and 77, respectively, as in Fig. 4F.
- this variation ofthe multilaminate configuration comprises an application or screen member 81 for evenly spreading the liquid sample, and an additional impermeable layer 82 which can serve as a liner for the screen member 81.
- Aperture or perforation 83 provided in layer 82 provides for fluid communication between screen member 81 and separation member 74.
- Further variations can include an additional screen member 81 or additional separation members 74.
- Figs. 4F and 4G show a solid bottom coversheet 77.
- the bottom coversheet can be notched or apertured to provide communication between the collection member and the ambient air.
- the aperture or notch in the bottom coversheet can be various designs, but should provide the stated communication with ambient air while being capable of retaining the collection member in its position.
- a notch design which achieves this, and further allows access to the collection member for its removal from the device for conducting analysis on the collected serum is shown in Fig. 4H.
- Fig. 4H A notch design which achieves this, and further allows access to the collection member for its removal from the device for conducting analysis on the collected serum is shown in Fig. 4H.
- bottom coversheet 87 has a plurality of cut-out areas 88 which provide ambient air communication to the collection member 76 and overflow member 75, shown partially in phantom. It would be understood that other notch designs can also be useful to obtain said results of facilitating drying and accessing for removal ofthe collection member.
- a "bridge strip" configuration ofthe subject invention is shown as device
- a perforation 113 is present on the top cover sheet 111 such that sample 72 (e.g., a drop of blood) can be applied to application member 114.
- Application member 114 is used as a target for placing, evenly spreading, and absorbing sample 72.
- Application member 114 is fluidly connected to separation member 1 18 via separation member perforation 115, an aperture through impermeable spacer 117.
- Separation member 118 can be any device that selectively retains cellular components from sample 72 and delivers non-cellular components of sample 72 to wicking bridge 120, shown in Fig.
- Wicking bridge 120 can take the form of any device that fluidly connects separation member 118 to collection member 119 such that a portion of applied sample 72 can flow from separation member 118 to collection member
- the bottom of device 110 is formed by bottom cover sheet 121.
- Sheet 121 can include an adhesive 122 at the edges of its top face such that sheet 121 can adhere to top cover sheet 1 11 and form a casing around the other components of device 110.
- the bottom face of top cover sheet 111 can have an adhesive such that sheet 111 can adhere to bottom cover sheet 121.
- cover sheets 111 and 121 can be any type of material that can form a substantially impermeable barrier around application member 114, separation member 1 18, collection bridge 119, and wicking bridge 120.
- sheets 111 and 121 are comprised of plastic.
- sheets 11 1 and 121 are comprised of a clear, flexible plastic having adhesive on one side (face) such as adhesive plastic 7843 (Adhesive Research, Inc.).
- Perforation 113 can be any opening through which a sample can be applied to application member 114. Typically, it takes the form of a round hole punched through top cover sheet 111 having a diameter slightly smaller than member 114.
- Application member 114 can be any device that can receive, absorb, and deliver a sample (e.g., a blood drop). It is preferably sized and shaped for facilitating application of a blood drop. For example, it can be round with a diameter of about between 9.5 and 12.7 cm (3/8-1/2 inch). In preferred embodiments, it is a polyester screen material such as 7-2F777
- Impermeable spacer 117 can be device that can engage application member 114, separation member 118, and collection member 119. It is preferably composed of a fairly rigid impermeable material such as plastic (e.g., 0.5 mm thick polystyrene plastic), so that it can securely engage the aforesaid components in a manner where unintended leaching ofthe liquid sample does not occur (i.e., it defines the fluid connection among members 114, 118, 119, and bridge 120). In preferred embodiments, spacer 1 17 has two perforations 115 and 116 through its thickness (see Fig. 41).
- separation member perforation 115 is preferably positioned within spacer 117 such that it forms an aperture into which separation member 118 can be inserted such that the top face of member 118 contacts application member 114 and the bottom face of member 118 contacts one end of wicking bridge 120.
- collection member perforation 116 is positioned on spacer 117 such that collection member 119 can be inserted in to perforation 116 in a manner in which an end of wickmg bridge 120 is contacting member 119.
- Separation member 118 can be any device that can receive a portion ofthe sample applied to the device and act as a filter that selectively retains one portion ofthe sample (e.g., the cellular components) and delivers another portion ofthe sample (e.g., the non-cellular components containing an analyte of interest).
- separation member 118 is shaped and sized so that it can be placed within device 110 (e.g., within perforation 115).
- a preferred form for member 118 is a flattened circular piece of material having a diameter just slightly smaller than the diameter of perforation 115 (e.g., about 0.075 - 0.150 mm smaller).
- separation member 118 can comprise a glass fiber filter material, a cellulose filter material, a mixed glass fiber/cellulose filter material, track-etched membranes, or other materials such as filter material for separating blood components (e.g., Hemasep V,
- separation member 1 18 can comprise multiple layers of one, two or more ofthe foregoing materials.
- separation member 118 is comprised of a sandwich of GF-24 glass fiber filter material (Schleicher and Schuell) and Cyclopore PET (1.0 micron pore size) polyester track- etched membrane. This sandwich can be cut into circles having a diameter of about 4.65 mm to fit within a perforation 1 15 having a diameter of about 4.75 mm.
- Wicking bridge 120 can take the form of any device that can receive a portion of a liquid from one component of device 110 (e.g., separation member 118) and transfer the portion to another component of device 110 (e.g., collection member 119).
- wicking bridge 120 can take the form of a rectangular strip of absorbent material sized (e.g., 4 X 10 mm for some embodiments of device 110) and positioned on device 110 such that it fluidly connects separation member 1 18 and collection member 119.
- Bridge 120 can, for example, be comprised of filter type material.
- bridge 120 can be formed of a rectangular strip of polyester fiber (e.g, AW14-20 from Pall) or Hemasep L (also from Pall). Materials that selectively retain cellular components of a sample applied to device 110 while allowing non- cellular components to flow through are preferred to prevent any cellular components that have passed through separation member 118 from being delivered onto collection member 119.
- Collection member 119 can be any device that can receive, absorb, and retain a quantitative portion of the sample applied to device 1 10 after the sample has passed through separation member 118 and wicking bridge 120.
- collection member 1 19 is shaped and sized so that it can be placed within device 110 (e.g., within perforation 116).
- a preferred form for collection member 119 is a flattened circular piece of material having a diameter just slightly smaller than the diameter of perforation 116 (e.g.. about 0.075 to 0.150 mm smaller).
- collection member 1 19 can comprise glass fiber, cellulose, polypropylene, nylon, polyester, polyethersulfone, composites of natural and synthetic materials, nitrocellulose, polyethylene, and/or other suitable materials.
- collection member 119 can comprise multiple layers of one, two or more ofthe foregoing materials.
- collection member 119 is comprised of a sandwich of two or more of APFF glass fiber filter material (Millipore), Biodyne B (0.45 micron) modified nylon material and BFC-180 cellulose material (Whatman).
- collection member 119 is substantially free of any chemical or biological reactants used for analyzing an analyte in the sample applied to device 110. Such analytical reagents are preferably not applied to collection member 119 so that analytes on collection member 119 can later be eluted and analyzed (e.g., at a clinical laboratory) without interference caused by contaminating chemicals or biologies.
- Collection member 119 can, however, be pre-treated with a preservative or stabilizer to enhance stability or "shelf-life" ofthe collected portion ofthe sample or can be treated with a reagent to facilitate the release ofthe analytes from the member during the elution process.
- devices intended for use in a protein assay can include a collection member that is pre-treated with a reagent formulated to improve the stability of a protein in the sample.
- preservatives or stabilizers that can be used in the subject device include antioxidants, carbohydrates, buffers, other proteins, or the like, which are known in the art to provide a preservative or stabilizing effect on a biological sample.
- the release ofthe analytes from the collection pad can be enhanced with a pre-treatment ofthe collection member of a variety of surfactants.
- collection member 1 19 is quantitative in that it absorbs and retains a relatively invariant quantity of a sample, independent ofthe quantity of sample applied to device 110 (i.e., as long as a minimum threshold volume of sample is applied). For example, if device 1 10 has a minimum threshold volume of 25 microliters, whether 25, 40, or 60 microliters of a blood sample is applied to application member 114 of device 110, collection member 119 will absorb and retain a specific volume (8 microliters for example) ofthe non-cellular portion ofthe sample. In other words, in this example, the quantity of sample absorbed and retained by collection member 119 will be roughly the same (i.e., 8 microliters) if more than 25 microliters of a blood sample is applied.
- collection member 119 being quantitative is that accidental overloading of a sample will not deleteriously affect a later determination of analyte concentration. Therefore, materials that become saturated at a useful minimum threshold volume (e.g., between 2 ⁇ l and 25 ⁇ l) are preferred for use as a quantitative collection member. For example, materials such as nylon (e.g., Biodyne B 0.45 micron from Pall) and glass fiber filter material (e.g.,
- APFF from Millipore are preferred for use in quantitative collection members.
- a particularly preferred quantitative collection member is comprised of a circular 2 layer sandwich of Biodyne B (0.45 micron) nylon membrane and APFF glass fiber filter material. This particular construction is preferred because it offers superior sample collection and retention properties over a wide variety of parameters. For example, the volume of sample collected and retained is fairly consistent over a range of different applied sample volumes and loading times (i.e., time between application ofthe sample to the device and recovery of the collection member for analysis). For example, in bridge strip devices having a collection member made of the Biodyne B/APFF sandwich having a diameter of about 4.65 mm, the collection and retention volume is consistently about 7-8 microliters.
- devices ofthe invention can have more than one of application member 114, impermeable spacer 117, separation member 118, collection member 119, wicking bridge 120, and/or other components of device 119.
- device 110 can feature multiple collection members
- device 110 has two collection members 1 19 arranged in a line such that one wicking bridge 120 can deliver fluid from separation member 118 tow each of the two collection members 1 19.
- device 110 can have three collection members 119 and three wicking bridges 120, each wicking bridge 120 dedicated to delivering fluid from separation member 118 to a particular collection member 119.
- Still other variations ofthe foregoing with multiple application members 114, impermeable spacers 117, separation members 118, collection members 119, wicking bridges 120, etc. can be fashioned by one of skill in the art based on the foregoing description.
- Devices 110 having multiple collection members 119 are preferred for applications where more than one analyte is to be measured from the same sample (e.g. HDL and LDL cholesterol) or to provide a control for error (e.g., standard deviation and like calculations among the different values obtained from analyzing multiple collection members 119 from the same device 110).
- a control for error e.g., standard deviation and like calculations among the different values obtained from analyzing multiple collection members 119 from the same device 110.
- a device having application member in fluid communication with separation member 118 which is in fluid communication with collection device 119 via wicking bridge 120, but not having the aforesaid other components is within the invention.
- Such a device could simply have separation member 118, collection device 119, and wicking bridge 120 fastened together.
- a preferred device for any ofthe configurations described herein can include a cover sheet or casing for protecting the absorbent collection or separation members (e.g., 4F-4K). See additionally, for example, Figs. 5A-5C, which illustrate cover sheets included with the lateral flow and the dual pad configurations.
- the covered subject device 41 includes a cover sheet 40 layered over the top and bottom faces of separation member 12 (Fig. 5 A) or, more preferably, a cover sheet 40 layered over separation member 12 and collection member 1 1 (Fig. 5B). These are shown as having an aperture or perforation 60 in at least one cover sheet.
- a cover sheet or casing for protecting the absorbent collection or separation members (e.g., 4F-4K). See additionally, for example, Figs. 5A-5C, which illustrate cover sheets included with the lateral flow and the dual pad configurations.
- the covered subject device 41 includes a cover sheet 40 layered over the top and bottom faces of separation member 12 (Fig. 5 A) or, more preferably, a cover sheet 40
- the subject device includes cover sheet 40 layered over the top and bottom faces of separation member 31 and collection member 34.
- cover sheet 40 comprises two separate sheets superimposed over and adhered to one another to completely encase the collection member or separation member (or both) ofthe subject device. It would be understood that the cover sheet can be formed by folding over a single sheet onto itself to form a double layer. While a maximum size for the cover sheet can be determined as a matter of convenience of handling, at a minimum, the preferred cover sheet provides complete enclosure of these members in order to provide for proper migration of liquid sample and saturation ofthe collection member. Thus, for a lateral flow or single pad configuration, using a 6 mm diameter collection member, two 2.54 cm (1 inch) square sheets can be used.
- a rectangular sheet approximately 2.54 cm (1 inch) wide by approximately 3.8 - 5.1 cm (1.5 - 2 inches) long can be used to completely cover the separation member and elongate collection member.
- cover sheets approximately 2.54 x 3.8 cm (1 x 1.5 inches) is preferred. This allows for substantially complete closure of the sheets around the separation and collection members, while allowing the wicking member to extend from the cover sheet to facilitate collection of sample.
- Any non-porous material, e.g., a polymeric or plastic material, can be used to form the cover sheets.
- an adhesive-backed plastic sheeting which does not affect test results, can be used and cut to appropriate size for use.
- plastic sheeting material and adhesive material are well-known in the art.
- the cover sheet advantageously functions to hold together the separate components ofthe subject device as a single unit.
- an adhesive which can be released for removal of a collection member from therebetween can be used.
- adhesive plastic 7843 Adhesive Research, Glen Rock, PA, USA
- the sheets 40 are formed so as to provide a flap 50 on one side of the device 30 to facilitate release ofthe adhesive.
- adhesive is caused to be disposed on only a portion ofthe cover sheets such that a flap is formed at one end of said cover sheets, leaving one end unadhered and easily opened for removal of the collection member from between the cover sheets.
- the pattemly disposed adhesive can be selectively applied at the end ofthe cover sheets which cover the separation member and the wicking member so that adherence is only made at the end covering these members.
- cover sheets having adhesive coated on their entire inner surface can be provided, and removal of adhesive from the collection member end can be carried out prior to adhering the cover sheets together. Also on one side ofthe cover sheets, shown in Fig.
- a perforation or aperture 60 formed in the cover 40.
- This perforation 60 which is preferably formed in the portion ofthe plastic cover sheet to overlay the separation member, permits exposure to the air ofthe separation member in the dual pad configuration to facilitate or expedite drying ofthe sample which can be advantageous for preventing spill-over of undesired sample components (cells) onto the collection member, as well as application, transport, and analysis ofthe sample.
- the diameter ofthe perforation is approximately 60-75% ofthe diameter of the collection member.
- the perforation or aperture can be a plurality of holes formed within substantially the same diameter ofthe aperture shown in the Figures. It would be readily understood by those of ordinary skill m the art that other dimensions could be used for any ofthe components forming the subject device, as long as those other dimensions are used routinely and consistently
- Va ⁇ ations ofthe subject device include embodiments having more than one collection member or more than one separation member Certain of these va ⁇ ations contemplated for the subject invention are shown in Figs. 8A-8D
- Fig 8A shows a device 170 having a wickmg member 171, separation member 172, and a pair of collection members 173 and 174 overlappingly disposed m contact with the separation member, but are positioned separate from each other at acute angles around the pe ⁇ phery ofthe separation member
- Fig 8B shows an alternative embodiment 270 to the configuration m Fig 8A wherein three (3) collection members 271, 272, and 273 are overlappingly disposed in contact with the separation member 274
- Fig. 8C shows an embodiment 370 wherein two collection members 371 and 372 are disposed sequentially relative to the separation member 373 The first collection member 371 is overlappingly m contact with separation member 373, and the second collection member
- a further va ⁇ ation 470 shown in Fig 8D shows a pair of collection members 471 and 472 overlappingly disposed m contact with opposing faces of the separation member 473
- the single pad configuration can be assembled in an identical manner except that it includes, prior to application ofthe second cover sheet, providing a wicking member which is disposed to abut the separation member, diametrically opposite to the collection member.
- similar steps are taken except that the device is assembled in a "right-side-up" manner, i.e.. building the layers forming the device from the bottom face to the top face.
- the collection member is first placed toward the center of an adhesive backed cover sheet forming the back face ofthe device, ensuring that the sheet will encase the collection member.
- a separation member is then overlapped onto the collection member and a quantitation or wicking member abutted thereagainst.
- top cover sheet is then super-imposed over the first cover sheet and adhered thereto, ensuring that the entire separation member is covered by the cover sheets and that the aperture in the top cover sheet is positioned over the separation member.
- the top and bottom cover sheets are adhered together over the two faces ofthe device and are adhered together at least at the quantitation or wicking member end.
- the adherence is from the end covering the quantitation or wicking member, extending about half the length ofthe cover sheet so as to provide a non-adhered section at the end of the cover sheets covering the collection member.
- the multilaminate configuration and bridge strip configuration can be assembled by using a cover sheet as a base and layering the component members over one another in a desired configuration.
- the multilaminate configuration can be assembled from top to bottom or from bottom to top. Apertures or other cut-out areas or shapes ofthe component members are preferably pre-formed prior to assembly. Preferred layering sequences are illustrated in
- the subject method for using a device according to the subject invention as described herein comprises applying, either directly or indirectly, a liquid sample to the separation member, allowing the liquid sample to separate thereon and substantially saturate the collection member, allowing the separation member and collection members to dry, for at least two hours, preferably overnight, at room temperature after collection of the sample, and then shipping, typically by mail, the dried separation and collection members to a facility for analysis.
- Clinical analysis using the device ofthe subject invention is achieved through a series of steps that allow for the specific quantification of sample components as captured by the collection member.
- the dried collection member is removed from the device assembly, components of interest are extracted from the collection member.
- Extraction ofthe analyte is typically achieved by eluting the analyte of interest into a liquid eluent, e.g., water, aqueous buffer, reactive reagent, inorganic or organic solvent, or the like.
- Analysis ofthe extract is usually performed by established clinical methodologies, with values adjusted according to the dilutions made.
- Analyses of blood components (analytes) from a sample of whole blood using the subject device can include, but are not limited to, determining presence or absence (and if present, quantification of) total cholesterol, triglyceride, bone alkaline phosphatase, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, ALT, glucose and fhictosamine.
- Analyses can be performed with the use of a commercially available blood chemistry analyzer, e.g., Roche Cobas Mira Plus Chemistry Analyzer, using readily recognized modifications of established assay parameters. Results of analyses of samples assayed for certain typically assayed blood components are shown in Figs. 9-24, demonstrating comparable results using a device ofthe subject invention versus standard liquid blood sample analysis.
- Various materials for use as a component ofthe subject device were shown to successfully absorb separated sample, e.g., serum or plasma, from the wicking or separation member.
- Optimal plasma migration is obtained when the collection member is positioned to overlap the separation member by approximately 1 mm.
- Plasma migration was only about 50% as successful when the separation member and collection member abutted to one another rather than over-lapped.
- the device performed superiorly when encased in a minimum of about 3.8 cm (1.5 ") of plastic cover sheet material. Substantially complete enclosure ofthe device is required for the migration ofthe serum using a GF24 separation member contacting the collection member.
- Spill-over is defined here as the migration of red blood cells onto the collection pad immediately following blood application.
- Hemolysis was observed after more than 24 hours of drying time when the cover sheets were not perforated. Hemolysis is defined as an overall redness that appears on the collection member over time, distinguishing it from "spill-over" which is evident at the point of contact at the time of blood application. All devices were free of hemolysis on the day of spotting. Overall, the degree of hemolysis is much less with the dual pad configuration than was observed with the single pad configuration.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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MXPA01003536A MXPA01003536A (en) | 1998-10-09 | 1999-10-08 | Collection device for biological samples and methods of use. |
DE69935440T DE69935440D1 (en) | 1998-10-09 | 1999-10-08 | DEVICE FOR COLLECTING BIOLOGICAL SAMPLES AND USE PROCEDURES |
EP99951927A EP1119414B1 (en) | 1998-10-09 | 1999-10-08 | Collection device for biological samples and methods of use |
AU64260/99A AU6426099A (en) | 1998-10-09 | 1999-10-08 | Collection device for biological samples and methods of use |
JP2000575623A JP2002527726A (en) | 1998-10-09 | 1999-10-08 | Biological sample collection device and collection method |
CA002346380A CA2346380A1 (en) | 1998-10-09 | 1999-10-08 | Collection device for biological samples and methods of use |
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US09/169,843 | 1998-10-09 | ||
US09/169,843 US6036659A (en) | 1998-10-09 | 1998-10-09 | Collection device for biological samples and methods of use |
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WO2000021664A1 WO2000021664A1 (en) | 2000-04-20 |
WO2000021664A8 WO2000021664A8 (en) | 2000-07-13 |
WO2000021664A9 true WO2000021664A9 (en) | 2001-07-05 |
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PCT/US1999/023680 WO2000021664A1 (en) | 1998-10-09 | 1999-10-08 | Collection device for biological samples and methods of use |
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US (2) | US6036659A (en) |
EP (1) | EP1119414B1 (en) |
JP (1) | JP2002527726A (en) |
AT (1) | ATE355905T1 (en) |
AU (1) | AU6426099A (en) |
CA (1) | CA2346380A1 (en) |
DE (1) | DE69935440D1 (en) |
MX (1) | MXPA01003536A (en) |
WO (1) | WO2000021664A1 (en) |
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DE19523061A1 (en) * | 1995-06-24 | 1997-01-02 | Boehringer Mannheim Gmbh | Element and system for collecting, transporting and storing sample material to be analyzed |
US5981294A (en) * | 1995-11-29 | 1999-11-09 | Metrika, Inc. | Device for blood separation in a diagnostic device |
DE19629657A1 (en) | 1996-07-23 | 1998-01-29 | Boehringer Mannheim Gmbh | Volume-independent diagnostic test carrier and method for determining analyte with its aid |
DE19629656A1 (en) * | 1996-07-23 | 1998-01-29 | Boehringer Mannheim Gmbh | Diagnostic test carrier with multilayer test field and method for the determination of analyte with its aid |
JPH10132800A (en) * | 1996-09-05 | 1998-05-22 | S R L:Kk | Specimen-protecting container integral with humor-separating sheet |
US6001658A (en) * | 1996-09-13 | 1999-12-14 | Diagnostic Chemicals Limited | Test strip apparatus and method for determining presence of analyte in a fluid sample |
JP3640278B2 (en) * | 1996-12-20 | 2005-04-20 | 日本化薬株式会社 | Assay apparatus and assay method using the same |
US5922288A (en) | 1997-05-29 | 1999-07-13 | Herst; C. V. Taylor | Device for isolating a component of a physiological sample |
US5948695A (en) | 1997-06-17 | 1999-09-07 | Mercury Diagnostics, Inc. | Device for determination of an analyte in a body fluid |
US6009632A (en) * | 1997-12-12 | 2000-01-04 | Mercury Diagnostics, Inc. | Alignment system for optical analyte testing meter components |
-
1998
- 1998-10-09 US US09/169,843 patent/US6036659A/en not_active Expired - Lifetime
-
1999
- 1999-10-08 CA CA002346380A patent/CA2346380A1/en not_active Abandoned
- 1999-10-08 EP EP99951927A patent/EP1119414B1/en not_active Expired - Lifetime
- 1999-10-08 US US09/415,304 patent/US6258045B1/en not_active Expired - Fee Related
- 1999-10-08 AU AU64260/99A patent/AU6426099A/en not_active Abandoned
- 1999-10-08 AT AT99951927T patent/ATE355905T1/en not_active IP Right Cessation
- 1999-10-08 WO PCT/US1999/023680 patent/WO2000021664A1/en active IP Right Grant
- 1999-10-08 MX MXPA01003536A patent/MXPA01003536A/en unknown
- 1999-10-08 DE DE69935440T patent/DE69935440D1/en not_active Expired - Lifetime
- 1999-10-08 JP JP2000575623A patent/JP2002527726A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
US6258045B1 (en) | 2001-07-10 |
JP2002527726A (en) | 2002-08-27 |
DE69935440D1 (en) | 2007-04-19 |
EP1119414A1 (en) | 2001-08-01 |
AU6426099A (en) | 2000-05-01 |
MXPA01003536A (en) | 2003-06-09 |
WO2000021664A8 (en) | 2000-07-13 |
US6036659A (en) | 2000-03-14 |
ATE355905T1 (en) | 2007-03-15 |
CA2346380A1 (en) | 2000-04-20 |
WO2000021664A1 (en) | 2000-04-20 |
EP1119414B1 (en) | 2007-03-07 |
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