High throughput screening of crystallization of materials

• US 20020145231A1
• Filed: 06/22/2001
• Published: 10/10/2002
• Est. Priority Date: 04/06/2001
• Status: Active Grant

• Current Assignee: California Institute of Technology, Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: BERGER, JAMES M., Quake, Stephen R., Hansen, Carl L.
• Granted Patent: US 7,052,545 B2
• Time in Patent Office: Days
• US Class Current: 264/267
• CPC Class Codes: B01D 9/00 Crystallisation crystallisation directly from the vapour phase B01D7/02; making single crystals C30B ; crystallisation as part of the Bayer process also classified in C01F7/14
• CPC Class Codes: B01D 9/0072 Crystallisation in microfluidic devices
• CPC Class Codes: B01D 9/0077 Screening for crystallisation conditions or for crystal forms
• 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 2219/00274 Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
• 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 2219/00389 Feeding through valves
• CPC Class Codes: B01J 2219/00418 using pressure
• CPC Class Codes: B01J 2219/00432 Photolithographic masks
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00756 Compositions, e.g. coatings, crystals, formulations
• CPC Class Codes: B01J 2219/00891 Feeding or evacuation
• CPC Class Codes: B01J 2219/00907 using membranes
• CPC Class Codes: B01J 2219/00952 Sensing operations
• 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 2200/10 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 2300/123 : 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 2400/0481 : squeezing of channels or chambers
• 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 3/5025 : for parallel transport of multiple samples
• 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 3/502753 : characterised by bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation separation in general B01D; microapparatus for analysis using electrophoresis G01N27/44791; sample preparation G01N1/28
• 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: B81B 2201/051 : Micromixers, microreactors
• CPC Class Codes: B81B 2201/054 : Microvalves
• CPC Class Codes: B81B 2203/0127 : Diaphragms, i.e. structures separating two media that can control the passage from one medium to another; Membranes, i.e. diaphragms with filtering function
• CPC Class Codes: B81B 2203/0315 : Cavities
• CPC Class Codes: B81C 1/00119 : Arrangement of basic structures like cavities or channels, e.g. suitable for microfluidic systems
• CPC Class Codes: B81C 99/0065 : Process control; Yield prediction
• CPC Class Codes: C30B 29/00 : Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
• CPC Class Codes: C30B 29/54 : Organic compounds
• CPC Class Codes: C30B 29/58 : Macromolecular compounds
• 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 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 99/0046 : using magnets
• CPC Class Codes: F16K 99/0051 : using electrostatic means
• CPC Class Codes: F16K 99/0059 : actuated by a pilot fluid
• CPC Class Codes: Y10T 117/10 : Apparatus
• 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 117/1024 : for crystallization from liquid or supercritical state

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 metering a volume of crystallizing agent for crystallization comprising:

providing a chamber having a volume in an elastomeric block separated from a control recess by an elastomeric membrane;

supplying a pressure to the control recess such that the membrane is deflected into the chamber and the volume is reduced by a calibrated amount, thereby excluding from the chamber a calibrated volume of a crystallization sample.

2. The method of claim 1 further comprising:

providing the crystallizing agent to an opening of the chamber; and

ceasing application of the pressure such that the membrane relaxes back to an original position and the calibrated volume of the crystallizing agent is drawn into the chamber.

3. The method of claim 2 wherein the crystallization sample is a protein solution such that drawing the crystallizing agent into the chamber changes a solubility of the protein.

4. The method of claim 1 further comprising the parallelization of multiple chambers with varying calibrated volumes.

5. The method of claim 1 further comprising the use of a parallel structure to rapidly determine optimal conditions for crystallization.

6. A system for crystallizing a target material comprising:

an elastomeric block including a microfabricated chamber configured to contain a volume of a solution of the target material; and

a microfabricated flow channel in fluid communication with the chamber, the flow channel introducing a volume of a crystallizing agent into the chamber.

7. The crystallization system of claim 6 further comprising an isolation structure, the isolation structure configured to selectively isolate the chamber from the flow channel as the flow channel receives a volume of crystallizing agent, and then to place the chamber into contact with the flow channel to alter a solution condition within the chamber.

8. The crystallization system of claim 6 wherein the volume of crystallizing agent is determined by a dimension of the flow channel.

9. The crystallization system of claim 6 wherein the volume of crystallizing agent is determined by a length of the flow channel.

10. The crystallization system of claim 6 wherein the volume of crystallizing agent is determined by a width of the flow channel.

11. The crystallization system of claim 6 further comprising a control channel overlying the chamber and separated from the chamber by a membrane, the membrane deflectable into the chamber to exclude a calibrated volume of sample solution from the chamber, such that relaxation of the membrane draws the calibrated volume of the crystallizing agent into the chamber.

12. The crystallization system of claim 6 further comprising:

a plurality of first parallel flow channels in fluid communication with a target material; and

a plurality of second parallel flow channels orthogonal to and intersecting the first flow channels to create a plurality of junctions, the second flow channels in fluid communication with a crystallizing agent such that an array of solution environments can be created at the junctions.

14. The crystallization system of claim 13 wherein the crystallization reservoir is formed in a second elastomeric block.

15. The crystallization system of claim 13 wherein the dialysis membrane is present within the elastomeric block.

16. The crystallization system of claim 13 wherein the dialysis membrane comprises a polymer that is introduced between the chamber and the reservoir and then subjected to cross-linking.

17. The crystallization system of claim 13 further comprising an intermediate solution imposed between the chamber and the reservoir to mediate diffusion of crystallizing agent into the chamber.

18. The crystallization system of claim 17 further comprising a second dialysis membrane imposed between the intermediate solution and the reservoir.

20. The method of claim 19 wherein the volume of crystallizing agent is introduced into the chamber by deforming an elastomer membrane overlying the chamber to exclude the volume of the sample from the chamber, followed by relaxing the membrane to cause the volume of a surrounding crystallizing agent to flow into the chamber.

21. The method of claim 19 wherein the volume of crystallizing agent is introduced into the chamber by entrapping a volume of crystallizing agent proximate to the chamber, and then opening an elastomer valve positioned between the chamber and the crystallization agent to allow diffusion of crystallization agent into the chamber.

22. The method of claim 19 wherein the volume of crystallization agent is introduced into the chamber by diffusion across a dialysis membrane.

23. The method of claim 19 wherein the chamber is defined by a junction between a first flow channel orthogonal to a second flow channel, and wherein the sample is flowed through the first flow channel and the crystallization agent flowed through the second flow channel.

24. The method of claim 23 wherein an array of chambers is defined by a junction between a first set of parallel flow channels orthogonal to a second set of parallel flow channels, and wherein samples are flowed through the first flow channels and crystallization agents are flowed through the second flow channels to create an array of solution conditions.

26. The method of claim 25 wherein the surface is a surface of mineral substrate exhibiting a regular morphology.

27. The method of claim 25 wherein the surface is a surface of semiconductor material exhibiting a morphology defined by features patterned by lithography.

29. The method of claim 28 wherein the air pocket is formed by trapping air during charging of the chamber with target material solution and introduction of the recrystallizing agent.

30. The method of claim 28 further comprising creating a hydrophobic material in contact with the air pocket, the hydrophobic material preventing target material solution and crystallizing agent from displacing the air pocket.

31. The method of claim 30 wherein the hydrophobic material is created by microcontact printing an underlying substrate.

32. The method of claim 30 wherein the hydrophobic material is created by flowing a hydrophobic fluid through a junction between the chamber and the crystallizing agent to leave the hydrophobic material as a residue.

13. A system for crystallizing a target material comprising:

an elastomeric block including a microfabricated chamber configured to contain a volume of a solution of the target material; and

a crystallizing agent reservoir in fluid communication with the microfabricated chamber through a dialysis membrane, the dialysis membrane configured to prevent flow of the target material into the crystallizing agent reservoir.

19. A method for crystallizing a target material comprising:

charging a chamber of a microfabricated elastomeric block with a volume of solution of the target material; and

introducing a volume of a crystallization agent into the chamber to change a solvent environment of the chamber.

25. A method for crystallizing a target material comprising introducing a crystallizing agent to a target material solution in the presence of a surface having a morphology calculated to serve as a template for formation of a crystal of the target material.

28. A method for crystallizing a target material by vapor diffusion comprising:

providing a target material solution within a microfabricated chamber;

providing a recrystallizing agent in fluid communication with the microfabricated chamber;

providing an air pocket between the chamber and the recrystallization agent, such that the crystallizing agent diffuses in the vapor phase across the air pocket into the target material solution.