WO2012104812A2 - Dispositifs à format non de carte pour recueillir, stocker et analyser des taches de liquides organiques séchés et procédés associés - Google Patents

Dispositifs à format non de carte pour recueillir, stocker et analyser des taches de liquides organiques séchés et procédés associés Download PDF

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Publication number
WO2012104812A2
WO2012104812A2 PCT/IB2012/050498 IB2012050498W WO2012104812A2 WO 2012104812 A2 WO2012104812 A2 WO 2012104812A2 IB 2012050498 W IB2012050498 W IB 2012050498W WO 2012104812 A2 WO2012104812 A2 WO 2012104812A2
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WO
WIPO (PCT)
Prior art keywords
sample
body fluid
handling device
container
removable cover
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2012/050498
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English (en)
Other versions
WO2012104812A3 (fr
Inventor
Michel Wagner
Emmanuel Varesio
Gérard Hopfgartner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universite de Geneve
Original Assignee
Universite de Geneve
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universite de Geneve filed Critical Universite de Geneve
Publication of WO2012104812A2 publication Critical patent/WO2012104812A2/fr
Publication of WO2012104812A3 publication Critical patent/WO2012104812A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • B01L3/508—Rigid containers without fluid transport within
    • B01L3/5082—Test tubes per se
    • B01L3/50825—Closing or opening means, corks, bungs
    • 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
    • B01L3/508—Rigid containers without fluid transport within
    • B01L3/5085—Rigid containers without fluid transport within for multiple samples, e.g. microtitration plates
    • B01L3/50853—Rigid containers without fluid transport within for multiple samples, e.g. microtitration plates with covers or lids
    • 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
    • B01L2200/16—Reagents, handling or storing thereof
    • 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
    • B01L2300/04—Closures and closing means
    • B01L2300/041—Connecting closures to device or container
    • B01L2300/043—Hinged closures
    • 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
    • B01L2300/04—Closures and closing means
    • B01L2300/041—Connecting closures to device or container
    • B01L2300/044—Connecting closures to device or container pierceable, e.g. films, membranes
    • 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
    • B01L2300/04—Closures and closing means
    • B01L2300/046—Function or devices integrated in the closure
    • B01L2300/047—Additional chamber, reservoir
    • 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
    • B01L2300/0609—Holders integrated in container to position an object
    • 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
    • B01L2300/069—Absorbents; Gels to retain a fluid
    • 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
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • 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
    • B01L2300/0848—Specific forms of parts of containers
    • B01L2300/0851—Bottom walls

Definitions

  • the present invention relates to devices and methods for collecting, storing and analysing dried body fluid spots, in particular dried blood spots (DBS).
  • dried blood spots DBS
  • DBS Dried blood spots
  • DBS assays consist in applying a small amount of blood on filter paper which is then dried, and this has resulted early on in the development of a card format which has been maintained ever since.
  • DBS assays blood samples are deposited on the designated areas of a card made of filter paper of calibrated density and thickness such that a certain area of the spot which will be formed on its surface contains a certain concentration of blood, the card is then dried, stored and transported at room temperature.
  • small areas of typically 3-6 mm diameter are punched out from the dried spot on the card with a punching hammer (e.g. manual hand punching, semi- automated punching or fully automated punching) and inserted into a test tube, the sample is solubilized in an appropriate working solution, any paper debris are removed by filtration or centrifugation and the supernatant is used for analysis.
  • a punching hammer e.g. manual hand punching, semi- automated punching or fully automated punching
  • Dedicated instruments also exist for online analysis where the DBS card is hold in-between two clamps and where the dried spot is extracted by perfusing appropriate solvents (e.g. methanol/water mixture).
  • Dried blood has several advantages over liquid samples, in particular increased stability at room temperature for extended periods of time and less biohazard as most pathogens become non-infectious when the sample is dried. Therefore, handling, storage and transport of such samples is highly simplified over liquid samples.
  • the DBS assays are facing several problems and limitations.
  • these assays are suffering from the size of the sample volume (less than 10 ⁇ ), the risk of sample cross-contamination during punching of successive spots, the costs and risk of errors in sample tracing with manual punching, the need of expensive and complex robotics for automating the process in industrial settings (need of punch cleaning and dust extracting systems) and the difficulty in automating whole analysis process due to the need of transferring the sample from the card into a liquid solution for further analyses.
  • the card format for DBS assays is widely recognised as a standard and efforts have been made for automating various steps of the analysis card-format DBS samples but the card-format itself has not been really questioned so far.
  • sample handling device that does not need further processing of the dried body fluid spots outside the sample handling device, once collected. It is advantageous to provide a sample handling device that allows for cost-efficient collecting, storing and analysing of body fluid samples either manually or by automated sample processing with standard liquid handling robots (e.g. TecanTM).
  • standard liquid handling robots e.g. TecanTM
  • a sample handling device for preparing and storing dried body fluid spots and analysing body fluid samples from said dried body fluid spots
  • the sample handling device including a sample absorbing substrate having a major surface configured for receiving and allowing to dry a body fluid sample to form a dried body fluid spot retained by said sample absorbing substrate and a recipient.
  • the recipient comprises a container base comprising one or several container portions each defining an interior chamber configured for containing a liquid medium for processing the dried body fluid spot and an opening; and a removable cover comprising one or several removable cover portions configured for sealingly closing the openings of the said one or several container portions.
  • the sample absorbing substrate is permanently fixed in each of said one or several removable cover portions or, alternatively, in each one or several container portions, and disposed such that the major surface of the sample absorbing substrate is freely accessible for reception of a body fluid sample when the removable cover portion is positioned not closed on the opening of said container portion and fully contained within the interior chamber when the removable cover portion is positioned on the opening of said container portion.
  • the removable cover and the container base are optionally coupled together by a flexible or breakable or bendable bridging tie.
  • the sample handling device when in a configuration where the removable cover portion does not close the opening of the container portion ("opened” configuration), allows the preparation of a dried body fluid spot onto the major surface of the sample absorbing substrate patch by depositing a body fluid sample of a predetermined amount (e.g. a drop of a pre-determined amount) which then forms a dried body fluid spot, upon drying.
  • a body fluid sample of a predetermined amount e.g. a drop of a pre-determined amount
  • the sample handling device when in a configuration where the removable cover portion closes the opening of the container portion ("closed” configuration), allows to store and transport the formed dried body fluid spot.
  • the sample absorbing substrate patch is an essentially flat absorbing patch made of an absorbing material defined by a contour and a thickness, which thickness is rather negligible compared to its surface size (typically a ratio surface to thickness of about 1 to about 500). Typically, the thickness of a sample absorbing substrate patch is of about 0.5 to about 5 mm.
  • the major surface of the sample absorbing substrate patch is defined by the surface of said sample absorbing substrate for receiving a body fluid sample. Typically, the major surface of the sample absorbing substrate patch is comprises between about 7 to about 100 mm 2 .
  • the contour of said essentially flat absorbing patch can be of any shape. In a particular embodiment, the contour of the major surface of the sample absorbing substrate patch is of essentially circular, ovoid, rectangular or square shape. In a further particular embodiment, the contours of the major surface of the sample absorbing substrate patch are of essentially circular shape.
  • Suitable absorbing materials which can be used to form the sample absorbing substrate patch include any filter paper, optionally pre-coated (e.g. with cell lysing buffer or a preservative solution or an internal standard solution of a chemical or a biological substance in relation with the quantification of the analytes of interest), that allows absorbing a body fluid sample when spotted on its surface, especially a blood sample, and forming a dried body fluid spot after drying.
  • sample absorbing substrate includes cellulose filter paper for blood collection for new-born genetic screening programs (Clinical and Laboratory Standards Institute (CLST). Blood Collection on Filter Paper for Newborn Screening Programs; Approved Standards"" Edition.
  • CLSI document LA4-A5 ISBN 1-56238-644-1).
  • the sample absorbing substrate patch may be pre-coated with one or a mixture of several substances having similar physico-chemical properties to those of the analyte of interest and being used as internal calibrant in the case of quantitative assays.
  • deuterated or 13 C or 1 N analogues of the analytes of interest may pre-coated on the sample absorbing substrate patch as internal reference for further analysis.
  • the thickness/absorbing capacity of the sample absorbing substrate patch can be modulated to adapt to the desired volume size of the body fluid sample or the type of body fluid sample to be collected, e.g. saliva or plasma or serum or blood.
  • the dried body fluid spot formed on the sample absorbing substrate patch contains a predetermined amount of body fluid sample and therefore can be analysed in its integrity without punching.
  • the sample absorbing substrate patch is selected from a blood, plasma, serum and saliva absorbing substrate patch.
  • the sample absorbing substrate is a blood absorbing substrate.
  • the sample absorbing substrate patch is freely accessible for reception of a body fluid sample when the removable cover portion is positioned not closed on the opening where one or several body fluid sample drops are dropped onto the major surface of the sample absorbing substrate patch by a drop providing instrument such as a pipette or a syringe or a pre-calibrated capillary (e.g. Microcaps from Drummond Scientific, Broomall, PA, USA).
  • a drop providing instrument such as a pipette or a syringe or a pre-calibrated capillary (e.g. Microcaps from Drummond Scientific, Broomall, PA, USA).
  • the sample absorbing substrate patch is permanently maintained in each of said one or several removable cover portions through one or several fixation elements.
  • the said one or several fixation elements are advantageously located on the inner surface of the removable cover portion.
  • the said one or several fixation elements may further advantageously comprise a recess or a hollow or a protrusion to lodge the sample absorbing substrate patch and/or one or several fixing teeth to maintain the sample absorbing substrate patch on the inner surface of the removable cover portion.
  • the body fluid sample may be spotted on the sample absorbing substrate patch fixed on the inner surface of the removable cover portion and air dried before apposing the removable cover portion on the opening of the container portion to close the latter before storing and/or shipping the formed dried body fluid spot.
  • the removable cover portion comprises a perforable portion configured for insertion of a probe or a needle.
  • the sample absorbing substrate patch comprises a cutout facing said perforable portion.
  • the removable cover portion remains positioned closed on the opening of the container portion during sample analysis. This advantageously provides protection of the samples from external contaminants from sample collection through analysis by avoiding the need of opening the removable cover portion, after the sample has been extracted in liquid medium. This configuration further advantageously provides an easy and reliable sample tracking by avoiding the need of separating the sample absorbing substrate patch from the container portion during the analytical step.
  • the sample absorbing substrate patch is permanently maintained in each of said one or several container portions, through one or several fixation elements and the cover portion comprises a perforable portion configured for insertion of a probe or a needle.
  • the said one or several fixation elements are advantageously located on the inner surface of the containing walls of the one or several container portions.
  • the said one or several fixation elements may further advantageously comprise a recess or a hollow or a protrusion to lodge the sample absorbing substrate patch and/or one or several fixing teeth to maintain the sample absorbing substrate patch on the inner surface of the containing wall, for example at the bottom of the interior chamber of the container portion.
  • the body fluid sample may be spotted on the sample absorbing substrate patch located at the bottom of the interior chamber of the container portion and air dried before apposing the removable cover portion on the opening of the container portion to close the latter before storing and/or shipping the formed dried body fluid spot and the removable cover portion remains positioned closed on the opening of the container portion during sample analysis.
  • This advantageously provides protection of the samples from external contaminants from sample collection through analysis by avoiding need of opening the removable cover portion, after the sample has been extracted in liquid medium.
  • This configuration further advantageously provides an easy and reliable sample tracking by avoiding the need of separating the sample absorbing substrate patch from the container portion during the analytical step.
  • the fixation of the sample absorbing substrate patch by said one or several fixation elements may result from moulding or squeezing the sample absorbing substrate between on the said one or several fixation elements.
  • the container portion allows containing any liquid useful to process the dried body fluid spot, e.g. to re-solubilize or re-suspend in liquid medium (e.g. a solvent or a mixture of solvents used as an extracting solution) the analytes from the dried body fluid spot before analysis.
  • liquid medium e.g. a solvent or a mixture of solvents used as an extracting solution
  • Suitable materials which can be used to form the container base and/or the container portion include polypropylene, glass, glass-coated with plastic, coated plastic and the like.
  • the interior chamber of the container portion is made of materials suitable for handling body fluid samples, in particular their analysis such as gas chromatography or liquid chromatography with and without mass spectrometry detection, colorimetry, ion mobility mass spectrometry, matrix-assisted laser desorption/ionization-mass spectrometry or immunoassays.
  • the container portion may be of any suitable form such as a tube or a well.
  • the inner surface of the containing walls of the container portion may be glass coated such as for example with fused silica.
  • the recipient may further contain a desiccant for allowing the body fluid sample to dry on the sample absorbing substrate patch more quickly than spontaneous air drying or allowing the body fluid sample to dry on the sample absorbing substrate patch to dry when the removable cover portion is positioned on the opening of said container portion and to keep the formed dried body fluid spot in a dry state during storage or transportation.
  • the desiccant is fixed in the recipient the vicinity of the sample absorbing substrate patch, preferably in the vicinity of the surface of the sample absorbing substrate patch which is opposite to the major surface of the sample absorbing substrate freely accessible for reception of a body fluid sample when the removable cover portion is positioned not closed on the opening of said container portion.
  • the desiccant and the sample absorbing substrate patch are separated by a semi permeable membrane (such as a polytetraf uoroethylene membrane).
  • desiccants may be selected from water-absorbing material (e.g. molecular sieve or diatomaceous earth).
  • the removable cover portion of the recipient of a sample handling device may be made of the same material as the container portion or a different material such as polypropylene or aluminium.
  • the removable cover portion comprises a perforable portion configured for insertion of a probe or a needle.
  • the perforable portion may be configured to open when applying, preferably with low insertion forces, the tip of a probe or a needle by breaking, tearing, collapsing or puncture.
  • the perforable portion may be made of perforable material such as polypropylene.
  • the perforable portion may comprise a septum member through which a probe or a needle is easily inserted by low insertion forces and which reseals in a leaktight manner after removal of said probe or needled.
  • the septum member for example may comprise a soft thermoplastic elastomer portion which permits the septum to reseal after multiple punctures or insertions of a probe or a needle.
  • This configuration advantageously avoids the need of opening the removable cover portion during the whole analytical process as the extraction medium may be delivered into the container portion through the said perforable septum member and further handling of the sample handling device can be carried out in a leaktight manner before analysis where a probe or a needle can be inserted as well in said septum member to analyse the analytes in the liquid medium in the container portion.
  • the removable cover portion may be located essentially in the middle of the cover portion.
  • the one or several removable cover portions of the recipient of a sample handling device are configured to sealingly close the openings of said one or several container portions and thereby allow, when positioned closed on the openings of the said one or several container portions, to store and transport the formed dried body fluid spot in a fully controlled environment and to ensure fluid tightness when the recipient system is filled with a liquid medium for processing the body fluid spot within the sample handling device of the invention.
  • the removable cover portion comprise a closing arrangement for sealingly close the opening of the container portion. Examples of closing arrangement comprise snap cap system, or screw cap system.
  • the closing arrangement comprises a clamping portion and/or a sealing element.
  • the clamping portion of the closing arrangement is located on the inner surface of the removable cover portion.
  • the one or several removable cover portions of a sample handling device comprise on their inner surface a protrusion (for example a cylindrical protrusion when the contour of the major surface of the sample absorbing substrate patch is essentially circular), with one or several fixing teeth to permanently fix the said sample absorbing substrate patch, said protrusion fits into the opening of the container portion when the removable cover portion is positioned on the opening of said container portion such that the container portion is sealingly closed by the protrusion.
  • a protrusion for example a cylindrical protrusion when the contour of the major surface of the sample absorbing substrate patch is essentially circular
  • the removable cover portion and the container portion constitute two separate or non-coupled elements of the sample handling device in a configuration where the removable cover portion does not close the opening of the container portion.
  • the removable cover is fixed to the container base in an open position configured for receiving a sample such that the cover remains attached to the base or the removable cover portion is fixed to the container portion in an open position configured for receiving a sample such that the cover portion remains attached to the container portion throughout handling from sample collection to analysis
  • the removable cover portion and the container portion are coupled together by a bridging tie, preferably in a removable manner.
  • the removable cover portion and the container portion are coupled together by a flexible or bendable or hinged bridging tie.
  • the removable cover portion and the container portion are coupled together by a breakable or detachable bridging tie.
  • the bridging tie is in a form of a connecting tongue.
  • the bridging tie is able to form a hinge between the removable cover portion and the container portion.
  • the bridging tie is made of flexible or semi- flexible material such as polypropylene.
  • the removable cover portion, container portion and bridging tie may be integrally made as a single component, for instance of an injected plastic material suitable for handling body fluid samples and the processing liquid medium filled in the interior chamber of the container portion.
  • the sample handling device according to the invention is adapted to automatic handling of samples and therefore fits into a multiple sample handler.
  • the container base of the sample handling device according the invention fits into a multiple sample handler.
  • the sample handling device further comprises a handling support comprising a container base holding portion having an essentially flat seating surface for supporting the said container base of the sample collecting device and for maintaining it in an essentially vertical position during storage, shipping and/or analysis of the dried body fluid spot within the sample collecting device.
  • the sample handling device comprises a container base comprising several container portions in the form of wells and a handling support comprising a container base holding portion supporting the said container base having an essentially flat seating surface for maintaining it in an essentially vertical position during dried body fluid spot storage, shipping and/or analysis.
  • a kit comprising at least one sample handling device according to the invention together with instructions of using and optionally at least one further sample handling device according to the invention wherein the sample absorbing substrate is pre-coated with an internal reference.
  • a method for preparing non-card format dried body fluid spots that can be easily and safely stored or shipped on a traceable and easily robotable manner.
  • a method for analysing non-card format dried body fluid spots obtainable from a method according to the invention that allows analysis of the dried body fluid spots in situ, i.e. directly from their storage environment without further heavy handling on a traceable, cost-effective and easily robotable manner.
  • Figure la is a cross-sectional view of a sample handling device according to an embodiment of the invention.
  • Figure lb is a cross-sectional view of a variant of the sample handling device of figure la;
  • Figure 2a is a perspective view of a sample handling device according to another embodiment of the invention.
  • Figure 2b is a side view of a sample handling device of Figure 2a;
  • Figure 2c is a perspective view of a variant of sample handling device of figure 2a;
  • Figure 3a is a cross-sectional view of a sample handling device according to an embodiment of the invention.
  • Figure 3b is a cross-sectional view of a variant of the sample handling device of figure 3 a;
  • Figure 4a is a perspective view of a sample handling device according to another embodiment of the invention.
  • Figure 4b is a side view of the sample handling device of figure 4a;
  • Figure 4c is a perspective view of a sample handling device according to an embodiment of the invention.
  • Figure 4d is a side view of the sample handling device of figure 4c;
  • Figure 5 schematically illustrates the steps of an extraction of analytes from a dried body fluid sample formed in a sample collection device according to the invention by solid- liquid extraction ( Figures 5 A, optionally B 1 and C) or by paper supported micro liquid- liquid extraction ( Figures 5A, B2 and C), respectively;
  • Figure 6 represents the elution profile by LC-MS for analytes of interests and phospholipids from a sample extracted from a dried blood spot by solid- liquid extraction (Figure 6A) or by micro liquid-liquid extraction (Figure 6B), as described under Example 2.
  • Figure 7a is a cross-sectional view of a sample handling device according to an embodiment of the invention.
  • Figure 7b is a cross-sectional view of a variant of the sample handling device of figure 7a;
  • a sample handling device 1 comprises a sample absorbing substrate patch 2 having a major surface 23 configured for receiving and allowing to dry a body fluid sample to form a dried body fluid spot retained by said sample absorbing substrate patch and a recipient system 3 comprising a container base 4 comprising one container portion 41 comprising containing walls 9 defining an inner surface 22 and an interior chamber 11 configured for containing a liquid medium for processing the dried body fluid spot; and an opening 10, a removable cover 5 comprising a removable cover portion 51 configured for sealingly closing the opening of the container portion 41.
  • the removable cover portion comprises an inner surface 12 facing the interior chamber 11 of the container portion 41 when the removable cover portion 51 is positioned on the opening of the container portion 41 and an outer surface 13.
  • the sample absorbing substrate patch 2 is an essentially flat absorbing patch having a thickness 24 negligible compared to its surface.
  • the removable cover portion comprises a protruding wall portion 20 extending from or formed within its inner surface 12.
  • the protruding wall portion 20 surrounds, defines or forms a cavity 20a to lodge the sample absorbing substrate patch 2.
  • the sample absorbing substrate patch 2 is positioned within the cavity 20a such that the major surface 23 it is below an edge 20b of the protruding wall portion 20. This advantageously provides protection against interference with external objects and better holds the substrate within the open cover portion during sample collection and pre-wetting steps until the sample handling device is closed.
  • the sample absorbing substrate patch 2 is permanently fixed in the removable cover portion 51 ( Figures la, lb, 2a, 2b and 2c) and disposed such that the major surface 23 of the sample absorbing substrate patch 2 is freely accessible for reception of a body fluid sample when the removable cover portion 51 is positioned not closed on the opening 10 of the container portion 41 and fully contained within the interior chamber 11 when the removable cover portion 51 is positioned in the opening 10 of the container portion 41.
  • the sample absorbing substrate patch 2 is permanently fixed on the inner surface 12 of removable the removable cover portion 51 through one or several fixation elements 18.
  • the one or several fixation elements 18 are mounted on the protruding wall portion 20 to lodge the sample absorbing substrate patch 2 ( Figures la, lb, 2a, 2b, 2c) and comprise one or several fixing teeth 21 ( Figure la, lb) to maintain the sample absorbing substrate patch 2 within the cavity 20a of the protruding wall portion 20.
  • the removable cover portion 51 comprises a closing arrangement 6 for sealingly closing the openings 10 of the container portion 41 ( Figures la, lb, 2a, 2b, 7a, 7b).
  • the closing arrangement 6 comprises a clamping portion 12 and a sealing element 15 wherein the clamping portion 12 of the closing arrangement 6 is located on the inner surface 12 of the removable cover portion 51.
  • the sample absorbing substrate patch 2 is of circular shape.
  • the removable cover portion 51 comprises on its inner surface 12, a cylindrical protruding wall portion 20 with one or several fixing teeth to permanently fix the said sample absorbing substrate patch 2 within the cavity 20a, said protruding wall portion 20 fits into the opening 10 of the container portion 41 of the recipient 3 when the removable cover portion 51 is positioned on the opening 10 of said container portion 41 such that the said container portion 41 is sealingly closed by said protruding wall portion 20.
  • the protruding wall portion serves not only to define the cavity 20a that lodges and protects the sample absorbing substrate patch but also serves to guide and seal the cover 5 to the interior chamber 11.
  • the cover 5 is advantageously fixed to the container base 4 in an open position configured for receiving a sample, such that the cover remains attached to the base throughout handling from sample collection to analysis. This is particularly advantageous for identification and tracking of the sample during the complete process of collection through to analysis.
  • the sample absorbing substrate patch 2 can be of any other shape and the shape of the protruding wall portion 20 may be adapted to lodge and protect the sample absorbing substrate patch.
  • the removable cover portion 51 comprises a perforable portion 52 configured for insertion of a probe or a needle.
  • the sample absorbing substrate patch 2 comprises a cutout 53 facing said perforable portion.
  • a sample handling device 1 comprises a sample absorbing substrate patch 2 having a major surface 23 configured for receiving and allowing to dry a body fluid sample to form a dried body fluid spot retained by said sample absorbing substrate patch and a recipient system 3 comprising a container base 4 comprising one container portion 41 comprising containing walls 9 defining an inner surface 23 and an interior chamber 11 configured for containing a liquid medium for processing the dried body fluid spot; and an opening 10, a removable cover 5 comprising a removable cover portion 51 configured for sealingly closing the opening of the container portion 41.
  • the removable cover portion comprises an inner surface 12 facing the interior chamber 11 of the container portion 41 when the removable cover portion 51 is positioned on the opening of the container portion 41 and an outer surface 13.
  • the sample absorbing substrate patch 2 is an essentially flat absorbing patch having a thickness 24 negligible compared to its surface.
  • the removable cover portion comprises a perforable portion 52 configures for insertion of a probe or a needle.
  • the sample absorbing substrate patch 2 is permanently fixed at the bottom of the interior chamber 11 of the container portion 41 through one or several fixation elements 18.
  • the fixation elements 18 comprise one or several fixing teeth 21 to maintain the sample absorbing substrate patch 2 on the inner surface 22 of the containing wall 9 at the bottom of the interior chamber 11 of the container portion 41.
  • the removable cover portion 51 and the container portion 41 constitute two separate or non-coupled elements of the sample handling device in a configuration where the removable cover portion 51 does not close the opening of the container portion 41.
  • the removable cover portion 51 and the container portion 41 are coupled together by a detachable bridging tie 7.
  • the bridging tie 7 forms a hinge between the removable cover portion 51 and the container portion 41 when the removable cover portion 51 is positioned closed on the opening 10 of the container portion 4.
  • the removable cover portion 51, container portion 41 and bridging tie 7 are integrally made as a single component.
  • the recipient 3 further contains a desiccant 25 lodged in the cavity 20a and in the vicinity of the surface 26 of a sample absorbing substrate patch 2 opposite to the major surface 23 which is freely accessible for reception of a body fluid sample when the removable cover portion 5 is positioned not closed on the opening 10 of said container portion 41.
  • the desiccant 25 and the surface 26 of a sample absorbing substrate patch 2 opposite to the major surface 23 are separated by a semipermeable membrane 27.
  • the sample handling device comprises a recipient 3 container base 4' comprising several container portions 41 in the form of wells each defining an interior chamber 11 configured for containing a liquid medium for processing the dried body fluid spot and an opening 10; and a removable cover 5' comprising several cover portions 51 configured for sealingly closing the openings 10 of the said several container portions 41.
  • the sample absorbing substrate patch 2 is permanently fixed in each of said several removable cover portions 51 and disposed such that the major surface of the sample absorbing substrate patch 2 is freely accessible for reception of a body fluid sample when the removable cover portion 51 is positioned not closed on the openings 10 of said container portions 41 and fully contained within the interior chambers 11 when the removable cover portions 51 are positioned on the openings 10 of said container portions 41.
  • the removable cover portion 51 comprises a protruding wall portion 20 extending from or formed within its inner surface 12.
  • the protruding wall portion 20 surrounds, defines or forms a cavity 20a to lodge the sample absorbing substrate patch 2.
  • the sample absorbing substrate patch 2 is positioned within the cavity 20a such that the major surface 23 it is below an edge 20b of the protruding wall portion 20.
  • the sample absorbing substrate patch 2 is permanently fixed to the inner surface 12 of each the said several removable cover portions 51 through fixation elements 18.
  • the fixation elements 18 are mounted on the protruding wall portion 20 to lodge the sample absorbing substrate patch 2 and comprise one or several fixing teeth 21 ( Figure 7b) to maintain the sample absorbing substrate patch 2 within the cavity 20a of the protruding wall portion 20.
  • the sample handling device further comprises a handling support 8 comprising a container base holding portion 17 and an essentially flat sitting surface 19 for maintaining the container base in an essentially vertical position during dried body fluid spot preparation, storage, shipping and/or analysis.
  • the sample handling device comprises a recipient 3 container base 4' comprising several container portions 41 in the form of wells each defining an interior chamber 11 configured for containing a liquid medium for processing the dried body fluid spot and an opening 10; and a removable cover 5' comprising several cover portions 51 configured for sealingly closing the openings 10 of the said several container portions 41.
  • the sample absorbing substrate patch 2 is permanently fixed at the bottom of the interior chamber 1 1 of each of the said container portions 41 such that the major surface of the sample absorbing substrate patch 2 is freely accessible for reception of a body fluid sample when the removable cover portion 51 is positioned not closed on the openings 10 of said container portions 41.
  • the removable each cover portion 51 comprises a perforable portion 52 configured for insertion of a probe or a needle.
  • the sample handling device further comprises a handling support 8 comprising a container base holding portion 17 and an essentially flat sitting surface 19 for maintaining the container base in an essentially vertical position during dried body fluid spot preparation, storage, shipping and/or analysis.
  • the invention provides a sample handling device, a kit and methods according to the invention useful for the preparation and storing of dried body fluid spots, in particular dried blood spots, and the further analysis of body fluid samples from said stored dried body fluid spots for clinical motoring (e.g. therapeutic drug monitoring), pre-clinical investigations (e.g. pharmacokinetics), genetic screening (e.g. metabolic and genetic profiling) or quantitative or qualitative detection of illicit substances.
  • clinical motoring e.g. therapeutic drug monitoring
  • pre-clinical investigations e.g. pharmacokinetics
  • genetic screening e.g. metabolic and genetic profiling
  • quantitative or qualitative detection of illicit substances e.g., quantitative or qualitative detection of illicit substances.
  • a sample handling device allows re-suspending the analytes present on the in-situ prepared and stored dried body fluid spots within the container portion by addition of at least one solution (e.g. hydro-organic mixture such as water/methanol mixture) when the removable cover portion is open and optionally homogenizing the eluting solution for example by mechanical or wave stirring of the recipient system when the removable cover portion is closed by the closing arrangement.
  • Re-suspension of said analytes may be carried out by liquid-liquid extraction, thereby allowing more selectivity in the extraction of analytes, analysing larger sample volumes compared to DBS assays without the need of ultra-sensitive analytic methods, which is not possible with the standard DBS assay card formats.
  • the transfer of the analytes into liquid phase can be achieved within the sample handling device by various methods such as solid-liquid extraction (SLE), paper supported micro liquid-liquid extraction ( ⁇ ) or microwave- or thermally-assisted extraction.
  • a volume of an extraction solvent e.g. methanol, acetonitrile
  • an extraction solvent typically in the range of 5-1000 ⁇ for a 1.5 ml container
  • the removable cover portion is then closed and the liquid medium is homogenized, typically by shaking or sonication (e.g. for 15 minutes) such that the analytes of interest captured in dried state on the sample absorbing substrate patch are extracted in the solvent within the container portion of the recipient system of a sample handling device.
  • an intermediate step of pre-wetting the dried body fluid spot on the sample absorbing substrate patch can be carried out by depositing a volume of reacting solution (e.g. hydro-organic mixture such as water/methanol mixture, enzymes, derivatization reagents or stabilizers), typically 5-50 ⁇ (e.g. 15 ⁇ ), on the surface of the sample absorbing substrate patch before adding a volume of an extraction solvent into the container portion of the recipient system of a sample handling device in order to facilitate extraction of analytes of interest or to biologically and chemically modify the analytes of interest.
  • a volume of reacting solution e.g. hydro-organic mixture such as water/methanol mixture, enzymes, derivatization reagents or stabilizers
  • an extraction solvent into the container portion of the recipient system of a sample handling device in order to facilitate extraction of analytes of interest or to biologically and chemically modify the analytes of interest.
  • the dried body fluid spot on the absorbent substrate patch is pre-wetted by depositing a volume of a wetting solvent (e.g. mixture of water and organic solvent such as water/methanol mixtures), typically 5-50 ⁇ (e.g. 15 ⁇ ), on the surface of the sample absorbing substrate patch before adding a volume of an organic solvent non-miscible to the wetting solvent (e.g. hexane, MTBE, ethyl acetate, hexane/MTBE mixture (e.g. 1/1), MTBE/ethyl acetate (e.g. 1/1)), typically 50-1500 ⁇ (e.g.
  • a wetting solvent e.g. mixture of water and organic solvent such as water/methanol mixtures
  • an organic solvent non-miscible to the wetting solvent e.g. hexane, MTBE, ethyl acetate, hexane/MTBE mixture (e.g. 1/1), MTBE/eth
  • the removable cover portion is then closed and the liquid medium is homogenized, typically by shaking or sonication (e.g. for 15 minutes).
  • the wetting phase remains trapped/supported by the sample absorbing substrate patch and the wetting phase and the extraction phase are brought in contact during this homogenization step such that the analytes of interest are transferred from one phase to the other through a liquid-liquid extraction process within the container portion of the recipient system of the sample handling device.
  • the invention provides a method for preparing non-card format dried body fluid spots comprising:
  • the invention provides a method for analysing non-card format dried body fluid spots comprising:
  • step (i) Providing a dried body fluid sample spot obtainable under step (ii) of a method for preparing non-card format dried body fluid spots according to the invention
  • the invention provides a method for analysing non-card format dried body fluid spots according to the invention further comprising, before step (ii), a pre-wetting step (ia) of the dried body fluid spot, by depositing a volume of the extraction solvent used under step (ii) or a volume of a wetting solvent which is non-miscible to the extraction solvent on the surface of the sample absorbing substrate patch.
  • the invention provides a method for analysing non-card format dried body fluid spots according to the invention further comprising a pre-wetting step (ia) of the dried body fluid spot with a volume of a wetting solvent which is non- miscible to the extraction solvent on the surface of the sample absorbing substrate patch.
  • the invention provides a method for analysing non-card format dried body fluid spots according to the invention further comprising a step of comparing the amount of said at least one analyte analysed under step (v) with a predetermined reference value for this analyte (e.g. value of the amount of the analyte present in a reference sample such as a sample from an healthy individual, from an individual carrying the sought marker, from the same individual before treatment, at an earlier stage of the treatment, or containing the sought substance).
  • a predetermined reference value for this analyte e.g. value of the amount of the analyte present in a reference sample such as a sample from an healthy individual, from an individual carrying the sought marker, from the same individual before treatment, at an earlier stage of the treatment, or containing the sought substance.
  • the invention provides a method according the invention wherein the sampling device is such that the one or several cover portions 51 comprises a perforable portion 52 further comprising a step of perforating the perforable portion 52 of the one or several cover portions 51 for analysing the analytes present on the said sample absorbing patch 2 of the sample handling device.
  • the step of perforating the perforable portion 52 of the one or several cover portions 51 of a method according to a method according to the invention may carried out after step (i) for either adding the extraction solvent or analysing the analytes present in the liquid within the said one or several container portions of the sample handling device when the extraction solvent has been already added or during the pre-wetting step of the dried body fluid spot for analysing the analytes present on the said sample absorbing patch 2 of the sample handling device.
  • the invention provides a method according to the invention wherein the body fluid sample is selected from saliva, blood and serum.
  • the invention provides a method according to the invention wherein the body fluid sample is blood.
  • BzEcg (Benzylecgonine), CE (Colision Energy), CocEt (Cocaethylene), DP (Declustering Potential), HPLC (high performance liquid chromatography), LC (liquid chromatography), MA (methylamphetamine), MDA (3,4-methylene-dioxy- amphetamine), MDEA (3,4-methylene-dioxy-ethylamphetamine), MDMA (3,4- methylene-dioxy-methylamphetamine), MS (mass spectrometry), MTBE (methyl t- (Saquinavir).
  • Example 1 Preparation of dried blood spot in a sample handling device according to the invention
  • a blood sample typically 5 ⁇
  • a circular paper filter (Whatman 903®, 5 mm internal diameter) fixed by pression on the surface of the removable closing element facing the interior of the fluid container portion of a sample handling device according to the invention as shown on Figure 2A and let for complete drying (typically overnight).
  • a dried blood spot is then formed and can be stored by closing the removable closing element and/or further analysed by re-solubilization in-situ of the dried blood spot by a method according to the invention.
  • Example 2 In situ extraction of analytes from a dried blood spot formed in a sample handling device according to the invention by solid-liquid extraction (SLE) or micro liquid-liquid extraction (ixLLE)
  • a dried blood spot is formed as described under Example 1 where a cocktail of the following 18 analytes representative of 5 distinct groups of analytes was mixed with a liquid blood sample prior deposition of blood on the circular paper filter:
  • Extraction of the dried blood spot was then achieved by transferring the analytes of interest into liquid phase within the sample handling device according to the invention by solid-liquid extraction method as shown on Figures 5A and 5C through the addition of 350 ⁇ of an extraction solvent (e.g. methanol) into the receptacle of the sample collection device according to the invention used for the preparation and storage of said dried blood spot, with or without a pre-wetting step of depositing about 15 ⁇ of an extraction solvent (e.g. methanol) on the surface of the dried blood spot, typically 0-5 min before the addition of the extraction solvent into the receptacle of the sample collection device ( Figure 5B1).
  • an extraction solvent e.g. methanol
  • Process efficiencies are calculated as the ratio of the peak area obtained with DBS extract over the peak area of an hydro-organic standard solution of the 18 analytes cocktail. The concentration of the latter (5ng/ml) takes into account the dilution occurring during the reconstitution step. Process efficiencies are calculated with the mean of 3 determinations and are reported together with corresponding coefficients of variations in Table 1 below.
  • Extraction of the dried blood spot is alternatively achieved by transferring the analytes of interest into liquid phase within the sample handling device according to the invention by liquid-liquid extraction method as shown on Figures 5A, 5B2 and 5C through the addition of about 15 ⁇ of a wetting solvent (e.g. mixture of water/methanol in proportion of 100/0; 75/25; 50/50; 25/75; 0/100) on the surface of the dried blood spot (Figure 5B2), typically 0-5 min before the addition of 350 ⁇ of an extraction solvent non-miscible with the wetting solvent (e.g.
  • a wetting solvent e.g. mixture of water/methanol in proportion of 100/0; 75/25; 50/50; 25/75; 0/100
  • LC-MS detection of analytes relies on their capacity to be ionized and this ability can be altered by the co-elution of interfering compounds from the sample matrix ("matrix effects").
  • Phospholipids are endogenous compounds of the blood and plasma, and comprise a large variety of chemical structures.
  • Phosphatidyl cholines (PC) and sphingomyelines (SM) are the most abundant phospholipids and represent more than 70% of the total lipid content.
  • Figures 6A and B show the extracted analytes and the residual phospholipids when the DBS as described above is extracted by SLE or by ⁇ ⁇ , respectively. It clearly shows that ⁇ extraction allows the removal of a large quantity of phospholipids (PC and SM) which remain in minority amounts as compared the analytes, while their amount remains majoritary as compared to the analytes after extraction by SLE.
  • PC and SM phospholipids
  • a sample collection device and methods according to the invention by offering the possibility to extract analytes from dried body fluid spots by ⁇ , ⁇ present the advantage to allow a better selectivity in the extraction than classical SLE methods, especially for phospholipid removal, which improve the analytical sensitivity, notably for LC-MS detection.
  • Example 3 In situ analysis of a dried blood spot formed in a sample handling device according to the invention for the Quantification of saquinavir by LC-MS/MS
  • LC-MS/MS analysis was applied for the quantitation of saquinavir (antiretroviral drug) present on a DBS prepared and extracted using either a SLE or a ⁇ extraction process as described in Example 2 in a device according to the invention.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention porte sur un dispositif de traitement d'échantillon pour préparer et stocker une tache de liquide organique séché dans un format non de carte et pour analyser in situ un échantillon de liquide organique provenant de ladite tache de liquide organique séché dans un format non de carte. La présente invention porte également sur des procédés associés.
PCT/IB2012/050498 2011-02-03 2012-02-03 Dispositifs à format non de carte pour recueillir, stocker et analyser des taches de liquides organiques séchés et procédés associés Ceased WO2012104812A2 (fr)

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EP11153161A EP2484448A1 (fr) 2011-02-03 2011-02-03 Dispositifs au format non carte pour la collecte, le stockage et l'analyse de tâches de fluide corporel séchées et procédés correspondants
EP11153161.2 2011-02-03

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