Desktop drug screening system

• US 20030087309A1
• Filed: 08/27/2002
• Published: 05/08/2003
• Est. Priority Date: 08/27/2001
• Status: Abandoned Application

• Current Assignee: GenoSpectra, Inc. (Thermo Fisher Scientific Incorporated)
• Original Assignee: GenoSpectra, Inc. (Thermo Fisher Scientific Incorporated)
• Inventors: Chen, Shiping
• Application Number:
  US10/229,571
• Publication Number:
  US 20030087309A1
• Time in Patent Office: Days
• US Class Current: 435/7.1
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00286 Reactor vessels with top and bottom openings
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00511 Walls of reactor vessels
• CPC Class Codes: B01J 2219/00522 in a multiple parallel arrangement
• CPC Class Codes: B01J 2219/00524 in the shape of fiber bundles
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00702 Processes involving means for analysing and characterising the products
• CPC Class Codes: B01J 2219/0072 Organic compounds
• CPC Class Codes: B01J 2219/0074 Biological products
• CPC Class Codes: B01L 2200/027 for microfluidic devices
• CPC Class Codes: B01L 2200/0605 Metering of fluids
• CPC Class Codes: B01L 2200/0642 Filling fluids into wells by specific techniques
• CPC Class Codes: B01L 2300/0654 Lenses; Optical fibres
• CPC Class Codes: B01L 2300/0819 Microarrays; Biochips
• CPC Class Codes: B01L 2400/0688 surface tension valves, capillary stop, capillary break
• CPC Class Codes: B01L 2400/086 using baffles or other fixed flow obstructions
• CPC Class Codes: B01L 3/0262 using touch-off at substrate or container
• CPC Class Codes: B01L 3/5025 for parallel transport of multiple samples
• CPC Class Codes: B01L 3/50857 using arrays or bundles of open capillaries for holding samples
• CPC Class Codes: C40B 60/12 : for screening libraries

Abstract

Systems and methods involved in extreme high throughput screening of compounds which have an affinity for a biological target are disclosed. The system is based on a capillary bundle with two distinguishable ends wherein capillaries on one end are connected to compounds stored in discrete reservoirs and capillaries on the other end are bound and processed to form a two dimensional microarray. A capillary bundle having reaction wells for hybridization and compound reaction in one end of the capillaries is disclosed. Also disclosed are various methods of identifying a target compound in a liquid using this capillary bundle as well as methods of fabricating the bundle. A novel surface tension guided reaction chamber is also provided. Methods and chemistry for fabrication and use of a surface tension guided reaction chamber in binding and hybridization assays are also disclosed. Methods and systems for precise metering of fluids within the capillaries and at the reaction chambers, including the surface tension guided “virtual” reaction well are provided.

Claims

1. A method for high throughput screening (HTS) of a compound library of one or more probes for a property of interacting with a target, the method comprising:

providing the compound library in a capillary array comprising a plurality of channels assembled in a substrate, wherein each capillary channel is capable of holding an amount of a probe and further wherein the first ends of a plurality of channels form a first face of the capillary array;

providing a reaction well adjacent one end of the capillary such that a probe in the capillary is capable of interacting with a target molecule in the reaction well;

providing at least one target molecule in the reaction well; and

detecting an interaction of a probe with the target molecule.

2. The method of claim 1, wherein the reaction well comprises a separate assay array assembled in a substrate, wherein the probe in a capillary array is capable of being in fluid communication with a channel in the assay array.

3. The method of claim 2, wherein the assay array has an identical pitch and pattern of capillaries as the capillary array.

4. The method of claim 2, wherein a first face of the assay array is coupled to the capillary array and a second face of the assay array is pneumatically coupled to a pressure chamber.

5. The method of claim 1, wherein the reaction well comprises a micro reaction well fabricated at a first end of each channel of the capillary array, wherein the probe in a capillary array is capable of being in fluid communication with the micro reaction well.

6. The method of claim 1, wherein the reaction well comprises a virtual reaction well fabricated at a first end of each channel of the capillary array, wherein the reaction well is formed on the first face of the capillary array, the reaction well being defined by a hydrophilic region at the first end of the channel and a hydrophobic region surrounding the hydrophilic region.

7. A method for screening a compound according to claim 6, wherein the reaction well has a cross-sectional area greater than a cross-sectional area of its corresponding channel.

8. The method of claim 1, wherein each capillary channel is capable of holding a metered amount of the probe.

9. The method of claim 8, wherein the probe in a solution is provided within the channel by drawing a metered amount of the probe solution into the channel by a force selected from the group consisting of a capillary force, pressure, gravity, a magnetic force and an electrical force.

10. The method of claim 1, wherein the first face of the array is accessible to liquid handling and detecting apparatus and a second distal face of the array is coupled to a pressure chamber.

11. The method of claim 1, wherein the interaction of the probe with the target is detected using an optical method.

12. The method of claim 1, wherein the substrate is a transparent material.

13. The method of claim 10, further comprising providing a target reagent to the reaction well by a fluid delivery nozzle.

14. The method of claim 10, further comprising:

pumping a probe solution to the reaction well by applying a suitable pressure differential between the pressure chamber and the first face of the array.

15. The method of claim 10, further comprising:

pumping a probe solution to the reaction well by inserting a liquid immiscible with the probe into the pressure chamber; and

moving the probe solution between the channel and the reaction well by displacing a volume of the inert fluid in the pressure chamber.

16. A method for high throughput screening (HTS) of one or more probes for an enzymatic activity, the method comprising:

(a) providing a capillary array comprising a plurality of channels assembled in a substrate, wherein each capillary channel is capable of holding an amount of a probe and further wherein the first ends of a plurality of channels form a first face of the capillary array;

(b) providing a virtual reaction well adjacent one end of the capillary, wherein the reaction well is formed on the first face of the capillary array and further wherein the reaction well is defined by a hydrophilic region at the first end of the channel and a hydrophobic region surrounding the hydrophilic region;

(c) applying a target solution to the first face of the capillary array in a flooding manner such that droplets of the target solution are retained in the reaction wells after excess solution is allowed to run off;

(d) applying a negative pressure to a pressure chamber to draw a metered amount of substrate into the channel, wherein a second distal face of the array is coupled to the pressure chamber;

(e) removing excess substrate fluid from the reaction well;

(f) applying a metered amount of an enzyme to the reaction by a method comprising steps (c) through (e) wherein the solution contains the enzyme;

(g) applying a positive pressure in the pressure chamber to push a metered amount of enzyme, target and compound into the micro-reaction well; and

(h) detecting the enzymatic activity of a probe in a channel.

17. The method of claim 16, wherein excess substrate fluid is removed from the reaction well by a method selected from the group consisting of capillary force, squeegeeing, wiping, absorption, gravity, centrifugation, air pressure, air knife blowing and vacuum force.

18. The method of claim 16, wherein the reaction is detected using optical methods.

19. The method of claim 16, wherein the substrate is transparent.

20. A desktop high throughput screening (HTS) system for detecting a property of one or more probe compounds to interact with a target, the system comprising:

(a) a compound library of probes in a capillary array comprising;

a plurality of channels assembled in a substrate, wherein each capillary channel is capable of holding an amount of a probe and further wherein the first ends of a plurality of channels form a first face of the capillary array; and

a reaction well adjacent one end of the capillary such that a probe in the capillary is capable of interacting with a target molecule in the reaction well; and

(b) a desktop HTS station comprising;

a pressure chamber capable of connecting to the capillary array;

a chamber for reacting metered amounts of probes and at least one target; and

a detector for detecting an interaction of a probe with the target molecule.

21. The system of claim 20, further comprising:

(c) a compound loading station comprising a plurality of probe compounds stored individually in a plurality of reservoirs, such that each reservoir is fluidically coupled to a channel in the capillary array.

22. The system of claim 20, wherein the reaction well comprises a separate assay array assembled in a substrate, wherein the probe in a capillary array is capable of being in fluid communication with a channel in the assay array.

23. The system of claim 20, wherein the reaction well comprises a micro reaction well fabricated at a first end of each channel of the capillary array, wherein the probe in a capillary array is capable of being in fluid communication with the micro reaction well.

24. The system of claim 20, wherein the reaction well comprises a virtual reaction well fabricated at a first end of each channel of the capillary array, wherein the reaction well is formed on the first face of the capillary array, the reaction well being defined by a hydrophilic region at the first end of the channel and a hydrophobic region surrounding the hydrophilic region.

25. The system of claim 20, wherein the desktop HTS system comprises a mechanism for removal of excess substrate fluid from the reaction well by a method selected from the group consisting of capillary force, squeegeeing, wiping, absorption, gravity, centrifugation, air pressure, air knife blowing and vacuum force.

26. The system of claim 20, wherein capillaries comprising the channels are lined with optical fiber.

27. The system of claim 20, wherein the detector detects the interaction of the target and chemical compounds by fluorescence emission, fluorescence polarization, luminescence, absorption, surface plasmon resonance (SPR).

28. The system of claim 20, wherein the detector is a CCD based imaging system, CMOS based imaging system or a scanning based fluorescence system.