On chip dilution system

• US 20030210607A1
• Filed: 06/25/2002
• Published: 11/13/2003
• Est. Priority Date: 05/08/2002
• Status: Active Grant

• Current Assignee: Cytonome/St, Llc (Cytonome Inc.)
• Original Assignee: Coventor, Inc. (Lam Research Corporation)
• Inventors: Deshpande, Manish, Gilbert, John
• Granted Patent: US 6,883,957 B2
• Time in Patent Office: Days
• US Class Current: 366/152.1
• CPC Class Codes: B01F 23/483 using water for diluting a liquid ingredient, obtaining a predetermined concentration or making an aqueous solution of a concentrate
• CPC Class Codes: B01F 23/49 Mixing systems, i.e. flow charts or diagrams
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01F 35/13 using one or more of the components of the mixture to wash-out the mixer
• CPC Class Codes: B01F 35/145 Washing or cleaning mixers not provided for in other groups in this subclass; Inhibiting build-up of material on machine parts using other means
• CPC Class Codes: B01L 2200/148 Specific details about calibrations
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0867 Multiple inlets and one sample wells, e.g. mixing, dilution
• CPC Class Codes: B01L 2400/0655 pinch valves
• CPC Class Codes: B01L 2400/082 Active control of flow resistance, e.g. flow controllers
• CPC Class Codes: B01L 3/502738 characterised by integrated valves microvalves F16K99/0001
• CPC Class Codes: Y10T 137/2499 Mixture condition maintaining or sensing
• CPC Class Codes: Y10T 137/7736 Consistency responsive
• CPC Class Codes: Y10T 137/87676 With flow control
• CPC Class Codes: Y10T 137/87684 Valve in each inlet
• CPC Class Codes: Y10T 436/10 Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
• CPC Class Codes: Y10T 436/25625 Dilution

Abstract

An on-chip chemical compound dilution system for providing dilution of a chemical compound in a microfluidic application includes at least one sample well for providing a selected chemical compound to be diluted, a dilution well for providing a diluent for diluting the chemical compound, a network of channels for carrying the chemical compound and diluent, a first syringe pump for effecting dilution, a second syringe pump, a detector and a plurality of valves for selectively controlling the flow of liquid through the channels. The dilution system may be a multiple-stage dilution system for precisely mixing a plurality of chemical compounds in a diluent. The dilution system allows for accurate calibration to compensate for variations due to manufacturing, thereby providing precise dilution ratios. The dilution system further enables flushing to allow re-use of the system with another chemical compound.

Claims

1. A dilution system for diluting a chemical compound, comprising:

a sample well for providing a chemical compound;

a dilution well for providing a diluent;

a dilution channel for transmitting the diluent;

a sample channel for transmitting the chemical compound to the dilution channel to form a diluted chemical compound; and

a variable flow valve for varying the flow of diluent through the dilution channel, thereby varying a ratio of the diluent to the chemical compound in the diluted chemical compound.

2. The dilution system of claim 1, further comprising a second dilution channel for mixing the diluent with the chemical compound to form the diluted chemical compound.

3. The dilution system of claim 2, further comprising a detector for analyzing the diluted chemical compound.

4. The dilution system of claim 3, further comprising a detector channel for passing the diluted chemical compound to the detector.

5. The dilution system of claim 4, further comprising a first on-off valve for selectively blocking flow of the diluted chemical compound to the detector channel.

6. The dilution system of claim 5, further comprising a second on-off valve in the second dilution channel, a third on-off valve in the first dilution channel between the sample channel and the second dilution channel for creating an aliquot in the second dilution channel to facilitate mixing of the diluent and the chemical compound.

7. The dilution system of claim 6, further comprising a fourth on-off valve for selectively blocking flow from the diluent well.

8. The dilution system of claim 1, further comprising a constant flow source for pulling flow from the sample well and the dilution well to perform dilution of the chemical compound.

9. The dilution system of claim 1, wherein the ratio is between about one and about ten.

10. A method for diluting a sample, comprising:

providing a dilution system having;

a sample well for providing a sample which may be a known chemical standard;

a dilution well for providing a diluent;

a dilution channel for transmitting the diluent;

a sample channel for transmitting the known chemical standard to the dilution channel to form a diluted chemical standard;

a high precision variable flow valve for varying the flow of diluent through the dilution channel, wherein the variable flow valve has a plurality of settings corresponding to different dilution ratios; and

a detector capable measuring the ratio of standard chemicals to diluent when chemical standards are introduced into the system through the sample well; and

introducing one or more predetermined chemicals into the system so that the observed dilution at the detector can be correlated with each setting of the precision variable flow valve.

11. A method of calibrating an on-chip dilution system, comprising:

providing a dilution system comprising a sample well for providing a chemical compound, a dilution well for providing a diluent, a dilution channel for transmitting the diluent, a sample channel for transmitting the chemical compound to the dilution channel to form a diluted chemical compound, a variable flow valve for controlling the flow of diluent through the dilution channel and a detector for analyzing the diluted chemical standard; and

calibrating the variable flow valve to correlate a setting on the variable flow valve to a dilution ratio for the system.

12. The method of claim 11, wherein the step of calibrating comprises the steps of:

providing a known chemical standard in the sample well;

providing a diluent in the dilution well;

setting the variable flow valve to a first setting;

diluting the known chemical standard with diluent to form a diluted chemical standard having a first dilution ratio;

detecting the diluted chemical standard to determine the first dilution ratio; and

correlating the first setting to the first dilution ratio.

13. The method of claim 12, wherein the step of calibrating further comprises:

setting the variable flow valve to a second setting;

diluting the known chemical standard with diluent to form a diluted chemical standard having a second dilution ratio;

detecting the diluted chemical standard to determine the second dilution ratio; and

correlating the second setting to the second dilution ratio.

14. The method of claim 13, further comprising the step of generating a calibration curve graphing a relationship between a plurality of settings of the variable flow valve and the dilution ratio for the system.

15. The method of claim 11, wherein the variable flow valve comprises an aperture formed in a side wall of the dilution channel, a membrane covering the aperture and an external actuator for deflecting the membrane through the aperture a predetermined amount to vary the resistance of the dilution channel to flow.

16. The method of claim 15, wherein the step of calibrating comprises determining a relationship between the dilution ratio of the system and an amount of deflection of the membrane in the variable flow valve.

17. A dilution system for diluting a plurality of chemical compounds, comprising:

a first dilution module comprising a first sample well for providing a first chemical compound, a first dilution well for providing a first diluent, a first dilution channel for transmitting the first diluent, a first sample channel for transmitting the first chemical compound to the first dilution channel to form a first diluted chemical compound, and a first variable flow valve for varying the flow of diluent through the dilution channel;

a second dilution module comprising a second dilution channel for receiving the first diluted chemical compound, a second sample well for providing a second chemical compound, a second sample channel for transmitting the second chemical compound to the second dilution channel to mix the second chemical compound with the diluted first chemical compound to form a diluted mix, and a second variable flow valve for regulating the flow of the second chemical compound; and

a bi-stable valve for selectively blocking flow between the first dilution module and the second dilution module.

18. The dilution system of claim 17, further comprising a detector for analyzing the diluted chemical compound.

19. The dilution system of claim 17, further comprising a detector channel for passing the diluted first chemical compound from the first dilution module to the second dilution module.

20. The dilution system of claim 19, wherein the detector channel transmits the diluted mix to the detector.

21. The dilution system of claim 17, further comprising a constant flow source for pulling flow from the sample well and the dilution well to perform dilution of the chemical compound.

22. A variable flow valve for regulating liquid flow through a channel, comprising

an aperture formed in a side wall of the channel;

a membrane covering the aperture; and

an external actuator for deflecting the membrane through the aperture a predetermined amount to vary the resistance of the channel to flow, comprising a base and a cylindrical head for contacting the membrane.