High throughput microfluidic systems and methods

United States Patent [w]

Kercso et al.

US006132685A [ii] Patent Number: 6,132,685 [45] Date of Patent: Oct. 17,2000

[54] HIGH THROUGHPUT MICROFLUIDIC SYSTEMS AND METHODS

[75] Inventors: Joseph E. Kercso, Palo Alto; Steven A.

Sundberg, San Francisco; Jeffrey A.
Wolk, Hall Moon Bay; Andrew W.
Toth, Sunnyvale; Calvin Y. H. Chow,
Portola Valley; J. Wallace Parce, Palo
Alto, all of Calif.

[73] Assignee: Caliper Technologies Corporation,

Mountain View, Calif.

[21] Appl. No.: 09/132,096 [22] Filed: Aug. 10, 1998

[51] Int. CI. G01N 35/02

[52] U.S. CI 422/104; 422/63; 422/65;

436/43; 436/47

[58] Field of Search 422/104, 102,

422/65, 63; 436/43, 47

[56] References Cited

U.S. PATENT DOCUMENTS

Bao et al., "Ultramicro enzyme assays in a capillary elec

troporetic system" /. Chromatog. (1992) 608:217-224.

Bunin et al., "A general and expedient method for the

solid-phase synthesis of 1,4—benzodiazepine derivatives"

(1992)/. Am. Chem. Soc. 114:10997-10998.

Cho et al., "An unnatural biopolymer" Science (1993)

261:1303-*1305.

Chu et al., "Affinity capillary electrophoresis-mass spectrometry for screening combinatorial libraries" /. Am. Chem. Soc. (1996) 118:7827-7835.

(List continued on next page.)

Primary Examiner—Long V. Le

Attorney, Agent, or Firm—Townsend Townsend & Crew LLP; Mark D. Barrish, Esq.

[57] ABSTRACT

The invention provides improved systems, devices, and methods for analyzing a large number of sample compounds contained in standard multiwell microtiter plates or other array structures. The multiwell plates travel along a conveyor system to a test station having a microfluidic device. At the test station, each plate is removed from the conveyor and the wells of the multiwell plate are sequentially aligned with an input port of the microfiuidic device. After at least a portion of each sample has been input into the microfiuidic channel system, the plate is returned to the conveyor system. Pre and/or post testing stations may be disposed along the conveyor system, and the use of an X-Y-Z robotic arm and novel plate support bracket allows each of the samples in the wells to be input into the microfiuidic network through a probe affixed to a microfiuidic chip. A clamshell structure having a hinged lid can releasably support the chip while providing and/or accommodating the electrical, optical, structural, and other interface connections between the microfiuidic device and the surrounding system.

13 Claims, 10 Drawing Sheets

U.S. PATENT DOCUMENTS

5,140,161 8/1992 Hillman et al. .

5,144,139 9/1992 Hillman et al. .

5,164,598 11/1992 Hillman et al. .

5,171,132 12/1992 Miyazaki et al. .

5,171,534 12/1992 Smith et al. .

5,188,963 2/1993 Stapleton .

5,192,405 3/1993 Petersen et al. .

5,271,724 12/1993 van Lintel .

5,273,718 12/1993 Skold et al 422/101

5,277,556 1/1994 van Lintel .

5,278,048 1/1994 Parce et al. .

5,294,795 3/1994 Lehtinen et al 250/328

5,296,375 3/1994 Kricka et al. .

5,304,487 4/1994 Wilding et al. .

5,324,591 6/1994 Georger, Jr. et al. .

5,375,979 12/1994 Trah .

5,380,493 1/1995 Chavez et al 422/104

5,384,261 1/1995 Winkler et al. .

5,395,503 3/1995 Parce et al. .

5,427,946 6/1995 Kricka et al. .

5,429,734 7/1995 Gajar et al. .

5,445,939 8/1995 Anderson .

5,483,843 1/1996 Miller et al 73/864.23

5,486,335 1/1996 Wilding et al. .

5,496,697 3/1996 Parce et al. .

5,498,392 3/1996 Wilding et al. .

5,519,635 5/1996 Miyake et al. .

5,571,410 11/1996 Swedberg et al. .

5,585,069 12/1996 Zanzucchi et al. .

5,592,289 1/1997 Norris 356/244

5,593,838 1/1997 Zanzucchi et al. .

5,605,662 2/1997 Heller et al. .

5,620,894 4/1997 Barger et al 435/286.2

5,637,469 6/1997 Wilding et al. .

5,650,075 7/1997 Haas et al. .

5,654,200 8/1997 Copeland et al 436/46

5,658,723 8/1997 Oberhardt .

5,773,298 6/1999 Lynggaard et al. .

5,780,754 7/1998 Karlberg et al. .

5,955,028 9/1999 Chow .

5,993,746 11/1999 Priha et al 422/104

OTHER PUBLICATIONS

Dasgupta et al., "Electroosmosis: A reliable fluid propulsion system for flow injection analysis" Anal. Chem. (f994) 66:f792-f798.

Harmon et al., "Mathematical treatment of electrophoretically mediated microanalysis" Anal. Chem. (f993) 65:2655-2662.

Harmon et al., "Selectivity in electrophoretically medicated microanalysis by control of product detection time" Anal. Chem. (f994) 66:3797-3805.

Harrison et al., "Capillary electrophoresis and sample injection systems integrated on a planar glass chip" Anal. Chem. (f992) 64:f926-f932.

Harrison et al., Micromachining a miniaturized capillary electrophoresis-based chemical analysis system on a chip Science (f 993) 26f :895-897.

Jacobson et al., "Effects of injection schemes and column geometry on the performance of microchip electrophoresis devices" Anal. Chem. (1994) 66:1107-1113. Jacobson et al., "High-speed separations on a microchip" Anal. Chem. (1994) 66:1114-1118.

Jacobson et al., "Open channel electrochromatography on a microchip" Anal. Chem. (1994) 66:2369-2373. Jacobson et al., "Microchip electrophoresis with simple stacking" Electrophoresis (1995) 16:481^186.

Jacobson et al., "Fused quartz substrates for microchip electrophoresis" Anal. Chem. (1995) 67:2059-2063.

Jung et al., "Multiple peptide synthesis methods and their applications" Angew. Chem. Int. Ed. Engl. (1992) 31:367-383.

Kikuchi et al., "Optically accessible microchannels formed in a single-crystal silicon substrate for studies of blood rheology" Microvascular Res. (1992) 44:226-240.

Koutny et al., "Microchip electrophoretic immunoassay for serum Cortisol" Anal. Chem. (1996) 68:18-22.

Linhares et al., "Use of an on-column fracture in capillary zone electrophoresis for sample introduction" Anal. Chem. (1991) 63:2076-2078.

Manz et al. "Miniaturized total chemical analysis systems: A novel concept for chemical sensing" Sensors and Actuators (1990) Bl:244-248.

Manz et al. "Micromachining of monocrystalline silicon and glass for chemical analysis systems. A look into next century's technology or just a fashionable craze?" Trends in Anal. Chem. (1991) 10(5):144-148.

Manz et al. "Electroosmotic pumping and electrophoretic separations for miniaturized chemical analysis systems" /. Micromech. Microeng.(1994) 4:257-265.

Pavia et al., "The generation of molecular diversity" Bioorgan. Med. Chem. Lett. (1993) 3(3):387-396.

Ramsey et al. "Microfabricated chemical measurement systems" Nature Medicine (1995) 1 (10):1093-1096.

Schmalzing et al., "Solution-phase immunoassay for determination of Cortisol in serum by capillary lectrophoresis" Clin. Chem. (1995) 41(9):1403-1406.

Seiler et al. "Planar glass chips for capillary electrophoresis: Repetitive sample injection, quantitation, and separation efficiency" Anal. Chem. (1993) 65:1481-1488.

Seller et al., "Electroosmotic pumping and valveless control of fluid flow within a manifold of capillaries on glass chip" Anal. Chem. (1994) 66:3485-3491.

Simon et al., "Peptoids: A modular approach to drug discovery" Proc. Natl. Acad. Sci. USA (1992) 89:9367-9371.

Song et al., "Multisample analysis using an array of microreactors for an alternatiin-current field-enhanced latex immunoassay" Anal. Chem. (1994) 66 (6):778-781.

Weaver et al., "Gel microdroplets: Rapid detection and enumeration of individual microorganisms by their metabolic activity" Bio/technology (1988) 6:1084-1089.

Wiley et al., "Peptidomimetics derived from natural products" Medicinal Research Reviews (1993) 13(3)327-384.

Wooley et al., "Ultra-high-speed DNAfragment separations using microfabricated capillary array electrophoresis chips" Proc. Natl. Acad. Sci. USA (1994) 91:11348-11352.

Zuckerman et al., "Efficient method for the preparation of peptoids [oligo(N-substituted glycines)] by submonomer sold-phase synthesis" /. Am. Chem. Soc. (1992) 114:10646-10647.