High throughput screening of crystallization materials

• US 8,382,896 B2
• Filed: 01/29/2007
• Issued: 02/26/2013
• Est. Priority Date: 06/27/2000
• Status: Expired due to Term

• Current Assignee: California Institute of Technology, Regents of the University of California (University of California)
• Original Assignee: California Institute of Technology, Regents of the University of California (University of California)
• Inventors: Hansen, Carl L., Quake, Stephen R., Berger, James M.
• Primary Examiner(s): Kunemund, Bob M
• Application Number:
  US11/668,263
• Publication Number:
  US 20070209572A1
• Time in Patent Office: 2,220 Days
• Field of Search: 117/68, 117/69, 117/70
• US Class Current: 117/68
• CPC Class Codes: B01J 2219/00274 Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
• CPC Class Codes: B01L 2200/025 Align devices or objects to ensure defined positions relative to each other
• 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 2200/10 Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
• CPC Class Codes: B01L 2300/0681 Filter
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0861 Configuration of multiple channels and/or chambers in a single devices
• CPC Class Codes: B01L 2300/0864 comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
• CPC Class Codes: B01L 2300/0887 Laminated structure
• CPC Class Codes: B01L 2300/123 Flexible; Elastomeric
• CPC Class Codes: B01L 2300/14 Means for pressure control
• CPC Class Codes: B01L 2300/18 Means for temperature control
• CPC Class Codes: B01L 2300/1827 using resistive heater
• CPC Class Codes: B01L 2400/0481 squeezing of channels or chambers
• CPC Class Codes: B01L 2400/049 vacuum
• CPC Class Codes: B01L 2400/0638 membrane valves, flap valves
• CPC Class Codes: B01L 2400/0655 pinch valves
• CPC Class Codes: B01L 2400/0688 surface tension valves, capillary stop, capillary break
• CPC Class Codes: B01L 3/06 : Crystallising dishes
• CPC Class Codes: B01L 3/502707 : characterised by the manufacture of the container or its components by shaping or joining plastic parts B29C59/00, B29C65/00; by laminating B32B37/00; manufacture of microstructural devices in general B81C
• CPC Class Codes: B01L 3/50273 : characterised by the means or forces applied to move the fluids micropumps F04B19/006, of the membrane type F04B43/043
• CPC Class Codes: B01L 3/502738 : characterised by integrated valves microvalves F16K99/0001
• CPC Class Codes: B01L 3/502761 : specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• CPC Class Codes: B01L 7/54 : using spatial temperature gradients
• CPC Class Codes: B01L 9/527 : for microfluidic devices, e.g. used for lab-on-a-chip
• CPC Class Codes: C12Q 1/6874 : involving nucleic acid arrays, e.g. sequencing by hybridisation
• CPC Class Codes: C12Q 2535/125 : Allele specific primer extension
• CPC Class Codes: C30B 7/08 : by cooling of the solution
• CPC Class Codes: C30B 7/14 : the crystallising materials being formed by chemical reactions in the solution
• CPC Class Codes: F04B 43/043 : Micropumps
• CPC Class Codes: F04B 43/14 : having plate-like flexible members
• CPC Class Codes: F16K 2099/0074 : using photolithography, e.g. etching
• CPC Class Codes: F16K 2099/0078 : using moulding or stamping
• CPC Class Codes: F16K 2099/008 : Multi-layer fabrications
• CPC Class Codes: F16K 2099/0084 : Chemistry or biology, e.g. "lab-on-a-chip" technology
• CPC Class Codes: F16K 2099/0094 : Micropumps
• CPC Class Codes: F16K 99/0001 : Microvalves microdevices B81B1/00; manufacture or treatment of devices or systems in or on a substrate B81C1/00; microfluidic structures B01L3/5027; micropumps F04B19/006
• CPC Class Codes: F16K 99/0015 : Diaphragm or membrane valves
• CPC Class Codes: F16K 99/0026 : Valves using channel deformation
• CPC Class Codes: F16K 99/0034 : Operating means specially adapted for microvalves
• CPC Class Codes: F16K 99/0059 : actuated by a pilot fluid
• CPC Class Codes: Y10T 117/1004 : with means for measuring, testing, or sensing
• CPC Class Codes: Y10T 117/1008 : with responsive control means
• CPC Class Codes: Y10T 137/0318 : Processes
• CPC Class Codes: Y10T 137/0396 : Involving pressure control

Abstract

High throughput screening of crystallization of a target material is accomplished by simultaneously introducing a solution of the target material into a plurality of chambers of a microfabricated fluidic device. The microfabricated fluidic device is then manipulated to vary the solution condition in the chambers, thereby simultaneously providing a large number of crystallization environments. Control over changed solution conditions may result from a variety of techniques, including but not limited to metering volumes of crystallizing agent into the chamber by volume exclusion, by entrapment of volumes of crystallizing agent determined by the dimensions of the microfabricated structure, or by cross-channel injection of sample and crystallizing agent into an array of junctions defined by intersecting orthogonal flow channels.

Claims

1. A method of priming an elastomeric microfluidic device with a liquid material, the method comprising:

loading a plurality of wells on an upper surface of the elastomeric microfluidic device with the liquid material;

biasing a holder piece against the upper surface such that a continuous raised rim of the holder piece presses against the upper surface surrounding the wells, such that a chamber is created over the wells; and

applying a positive pressure to the chamber to drive the material from the wells into an active area of the elastomeric microfluidic device.

2. The method of claim 1 wherein the raised rim deforms to engage the upper surface.

3. The method of claim 1 wherein upper surface deforms to engage the raised rim.

11. The method of claim 1, wherein the active area of the elastomeric microfluidic device comprises a dead-ended chamber or channel.

4. A method of actuating a valve within a microfluidic elastomer device, the method comprising:

applying a holder piece having a continuous raised rim against a surface of the microfluidic device having a plurality of control line outlets to create a chamber over the outlets; and

applying a positive or negative pressure to the chamber to control a pressure within a control line and thereby actuate an elastomeric valve membrane of the microfluidic device that is in communication with the control line.

5. The method of claim 4 wherein the raised rim is elastic and deforms to engage the surface.

6. The method of claim 4 wherein the surface is elastic and deforms to engage the raised rim.

7. A method of exercising temporal control over diffusion between two fluids, the method comprising:

providing a microfluidic flow channel in an elastomer material, a membrane portion of the elastomer material positioned within the flow channel to define a valve;

priming a first portion of the flow channel on one side of the membrane with a first fluid;

priming a second portion of the flow channel on the opposite side of the membrane with a second fluid; and

repeatedly moving the elastomer membrane into and out of the flow channel over time to allow diffusion between the first fluid and the second fluid across the valve.

8. The method of claim 7 wherein the elastomer membrane is moved into and out of the flow channel in response to a reduced pressure within a control recess positioned in the elastomer material adjacent to the membrane.

9. The method of claim 7 wherein the first fluid is a crystallizing agent and the second fluid is a crystallization target solution, such that the elastomer membrane is repeatedly displaced to alter a solution environment of the flow channel to promote crystallization of a target material.

10. The method of claim 7 wherein a combined volume of the first fluid and the second fluid is 50 nL or less.