MODULAR MICROFLUIDIC DEVICE

Abstract

Described is a modular microfluidic device (MMD) for producing an analyte composition from a biological fluid sample, said device comprising: (a) a reagent module (RM) comprising a reagent reservoir containing a reagent and an eluent reservoir containing an eluent, said reagent and eluent reservoirs being coupled to one or more RM microchannels; and (b) a sample preparation module (SPM) comprising a SPM microchannel adapted to couple with the RM microchannel whereby fluid continuity between SPM and RM microchannels is produced on coupling, and: (i) a sample inlet for receiving said biological fluid sample; (ii) an outlet for delivering said analyte composition; (iii) a mixing chamber; (v) a metering chamber; (vi) an eluent chamber; (vii) a valve; (viii) a solid phase extraction element (SPE); and (ix) an aspirator in fluid communication with the sample inlet of the SPM for withdrawing an aliquot of said biological fluid when contained in a sample vessel, said aspirator being operably coupled to a pneumatic fluid level sensor.

Claims

1. A modular microfluidic device (MMD) for producing an analyte composition from a biological fluid sample, said device comprising: (a) a reagent module (RM) comprising a reagent reservoir containing a reagent and an eluent reservoir containing an eluent, said reagent and eluent reservoirs being coupled to one or more RM microchannels; and (b) a sample preparation module (SPM) comprising a SPM microchannel adapted to couple with the RM microchannel whereby fluid continuity between SPM and RM microchannels is produced on coupling, and: (i) a sample inlet for receiving said biological fluid sample; (ii) an outlet for delivering said analyte composition; (iii) a mixing chamber; (v) a metering chamber; (vi) an eluent chamber; (vii) a valve; (viii) a solid phase extraction element (SPE); and (ix) an aspirator in fluid communication with the sample inlet of the SPM for withdrawing an aliquot of said biological fluid when contained in a sample vessel, said aspirator being operably coupled to a pneumatic fluid level sensor.

2. The device of claim 1 wherein the SPM is directly or indirectly coupled to the aspirator, for example being indirectly coupled via a microchannel in the RM and/or a fluid passage in the processing head.

3. The device of claim 1 wherein the aspirator is rigid and suitable for piercing the septum of a self-sealing biological sample vessel, for example being a needle or cannula.

4. The device of claim 1 further comprising a processing head, said processing head comprising: (a) said pneumatic fluid level sensor; and (b) a gas supply/vacuum means adapted to couple with an MMD microchannel for driving or sucking fluid through said microchannel, said processing head pump being further adapted to couple with the sample inlet of the SPM for drawing a liquid aliquot from a primary biological sample contained in a sample vessel.

5. The device of claim 1 wherein said pneumatic fluid sensor comprises: (a) a two way gas supply/vacuum means connected to said aspirator and adapted to provide a low pressure air flow therethrough during movement of said aspirator toward said biological fluid when contained in a sample vessel; and (b) a pressure sensor adapted to detect a back pressure developed therein as said aspirator approaches the surface of said biological fluid.

6. The device of claim 5 wherein said pressure sensor is a pressure transducer.

7. The device of claim 1 wherein said gas supply/vacuum means comprises a source of compressed gas.

8. The device of claim 1 wherein said gas supply/vacuum means comprises a pump.

9. The device of claim 8 wherein said pump is a syringe pump.

10. The device of claim 1 wherein said two way gas supply/vacuum means is adapted to deliver pulsed low pressure air flow through the aspirator.

11. The device of claim 1 wherein said two way gas supply/vacuum means is adapted to deliver continuous low pressure air flow through the aspirator.

12. The device of claim 1 further comprising means for moving said aspirator toward and away from the surface of said biological fluid when contained in a sample vessel, optionally wherein the device further comprises means responsive to the fluid level being sensed for moving the aspirator into the biological sample a predetermined distance appropriate for the aliquot size to be aspirated.

13. A modular microfluidic device (MMD) for producing an analyte composition from a biological fluid sample, said device comprising: (a) a reagent module (RM) comprising a reagent reservoir containing a reagent and an eluent reservoir containing an eluent, said reagent and eluent reservoirs being coupled to one or more RM microchannels; and (b) a sample preparation module (SPM) comprising a SPM microchannel adapted to couple with the RM microchannel whereby fluid continuity between SPM and RM microchannels is produced on coupling, and: (i) a sample inlet for receiving said biological fluid sample; (ii) an outlet for delivering said analyte composition; (iii) a pressure sensor component; (iv) a mixing chamber; (v) a metering chamber; (vi) an eluent chamber; (vii) a valve; and (viii) a solid phase extraction element (SPE); and. (c) a processing head, said processing head comprising: (i) a pump adapted to couple with an MMD microchannel for driving or aspirating fluid through said microchannel, said processing head pump being further adapted to couple with the sample inlet of the SPM for drawing a liquid aliquot from a primary biological sample contained in a sample vessel; and (ii) a sensor component adapted to form a pressure sensor in conjunction with the SPM pressure sensor component; wherein the sample inlet of the SPM is coupled to an aspirator for drawing a liquid aliquot from a biological sample contained in a sample vessel.

14. The device of claim 13 wherein said pressure sensor is a pneumatic fluid level sensor operably coupled to said aspirator, optionally wherein the device further comprises means responsive to the fluid level being sensed for moving the aspirator into the biological sample a predetermined distance appropriate for the aliquot size to be aspirated.

15. The device of claim 1 wherein the SPM is directly or indirectly coupled to the aspirator, for example being indirectly coupled via a microchannel in the RM and/or a fluid passage in the processing head.

16. The device of claim 1 wherein the aspirator is rigid and suitable for piercing the septum of a self-sealing biological sample vessel, for example being a needle or cannula.

17. The device of claim 1 wherein the RM and SPM are physically linked but not in fluid communication.

18. The device of claim 17 wherein the RM and SPM are physically linked by retaining means on the RM and/or the SPM.

19. The device of claim 18 wherein the retaining means provides a loose fit between RM and SPM.

20-68. (canceled)

69. A kit of parts comprising: (a) two or more different, analyte-specific RMs, each comprising a different reagent but being otherwise as defined in any one of the preceding claims, and each RM being adapted for use in the preparation of a particular analyte composition from a biological fluid sample; and (b) an SPM as defined in any one of the preceding claims, wherein the SPM is a universal SPM having a microchannel adapted to couple with the RM microchannel of any one of the two or more RMs, wherein any one of the two or more RMs may be coupled with the SPM to form a microfluidic device for producing a selected analyte composition from a biological fluid sample.

70-88. (canceled)

Description

EXEMPLIFICATION

[0184] Embodiments of the present invention will now be described by way of example with reference to the accompanying drawings in which:

[0185] FIG. 1 shows a perspective view of an CMMD according to the invention.

[0186] FIG. 2 illustrates schematically apparatus embodying the present invention.

[0187] FIG. 3 schematically illustrates an CMMD of the invention.

EXAMPLE 1: MICROFLUIDIC DEVICE

[0188] Referring now to FIG. 1, the CMMD comprises a reagent module (RM) 2 comprising several reagent reservoirs 4 each containing a reagent (not shown) and an eluent reservoir 6 containing an eluent (not shown), said reagent and eluent reservoirs being coupled to RM microchannels 8 and a sample preparation module (SPM) 10 comprising a SPM microchannel (not shown) coupled with the RM microchannel whereby fluid continuity between SPM and RM microchannels is established. The SPM has a sample inlet 12 connected to an aspirator 16 for receiving a biological fluid sample contained in a sample vessel 18, an outlet for delivering analyte composition, a sensor component, a mixing chamber, a metering chamber, an eluent chamber, a number of valves (not shown), a solid phase extraction elements (SPE) 20 and metering chamber valve head 21. The CMMD is provided with several interface sites 22 for coupling with a processing head (not shown).

EXAMPLE 2: MICROFLUIDIC PLATFORM

[0189] Referring now to FIG. 2, the apparatus comprises a platform 30 comprising a drum carousel 32 containing a plurality of stacked MMDs 33 and a conveyer 34 containing a chain of vessels 36 each containing a biological sample. A processing head 38 is coupled with an MMD 39 loaded from the carousel by automated robot (not shown), during which the RM and SPM modules are themselves also coupled to form a CMMD 40, while an individual sample vessel 42 is brought into registration with an aspirator on the CMMD (not shown).

EXAMPLE 3: VITAMIN D PREPARATION SEQUENCE

[0190] Referring now to FIG. 3, the dotted lines indicate the RM having seven reagent reservoirs A-G containing reagents as follows: [0191] A: Methanol (100 μl) [0192] B: Standard (40 μl)+methanol (500 μl) [0193] C: Buffer (200 μl) [0194] D: Methanol (100 μl) [0195] E: Water (100 μl) [0196] F: 70% methanol in water (100 μl) [0197] G: Water (40 μl)

[0198] The aspirator (not shown) is pushed through the rubber septum of a sealed vessel containing a sample of serum (not shown). The aspirator is lowered towards the surface of the serum sample while pulses of air at low pressure air are driven through it. A pressure transducer (not shown) measures back pressure and thereby permits monitoring of the approach of the aspirator to the surface of the serum sample.

[0199] Once the surface of the serum sample is detected, pulsing of low pressure air through the aspirator is terminated and the aspirator tip further lowered a predetermined distance beneath the surface of the serum. 200 μl of serum is then drawn into sample inlet (50) along microchannel 51 into metering chamber 53 containing a filling loop 54 until determined to be full using sensor 55.

[0200] A valve head on the metering chamber (not shown) is then rotated by a rotating valve head actuator in a processing head (not shown) so that ports are aligned with microchannel 57. The serum is then pushed into the mixing chamber 56 along with the contents of reagent reservoirs B and C along microchannel 57 and their arrival and absence of entrained bubbles confirmed with sensor 58. The contents of the mixing chamber are then mixed with bead 60.

[0201] The SPE 63 with a two port rotating valve head 62 is then conditioned with: (a) the contents of reagent reservoir D along microchannel 66; then (b) the contents of reagent reservoir E along microchannel 68, the valve head 62 being rotated to bring the ports into alignment with the appropriate microchannels with a rotating valve head actuator in a processing head (not shown) with excess being collect in waste chamber 70.

[0202] 500 μl of sample from the mixing chamber 56 is then loaded onto the SPE 63 along microchannel 64 with excess being collect in waste chamber 70. The SPE 63 is then washed with the contents of reservoir F along microchannel 74. SPE 63 is then dried with 250 μl of air.

[0203] The analyte is then eluted from the SPE 63 into eluent chamber 76 with the contents of reservoir A along microchannel 78. Polarization of the analyte composition in the eluent chamber 76 is then improved by adding the contents of reservoir G along microchannel 80. The polarized analyte composition is then injected into an LC-MS device (not shown) via outlet 82 for analysis.

EQUIVALENTS

[0204] The foregoing description details presently preferred embodiments of the present invention which are therefore to be considered in all respects as illustrative and not restrictive. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents, modifications and variations to the specific embodiments of the invention described specifically herein. Such equivalents, modifications and variations are intended to be (or are) encompassed in the scope of the following claims.