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Multiple capillary biochemical analyzer    
United States Patent5439578   
Link to this pagehttp://www.wikipatents.com/5439578.html
Inventor(s)Dovichi; Norman J. (Edmonton, CA); Zhang; Jian Z. (Edmonton, CA)
AbstractA multiple capillary analyzer allows detection of light from multiple capillaries with a reduced number of interfaces through which light must pass in detecting light emitted from a sample being analyzed, using a modified sheath flow cuvette. A linear or rectangular array of capillaries is introduced into a rectangular flow chamber. Sheath fluid draws individual sample streams through the cuvette. The capillaries are closely and evenly spaced and held by a transparent retainer in a fixed position in relation to an optical detection system. Collimated sample excitation radiation is applied simultaneously across the ends of the capillaries in the retainer. Light emitted from the excited sample is detected by the optical detection system. The retainer is provided by a transparent chamber having inward slanting end walls. The capillaries are wedged into the chamber. One sideways dimension of the chamber is equal to the diameter of the capillaries and one end to end dimension varies from, at the top of the chamber, slightly greater than the sum of the diameters of the capillaries to, at the bottom of the chamber, slightly smaller than the sum of the diameters of the capillaries. The optical system utilizes optic fibres to deliver light to individual photodetectors, one for each capillary tube. A filter or wavelength division demultiplexer may be used for isolating fluorescence at particular bands.
   














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Drawing from US Patent 5439578
Multiple capillary biochemical analyzer - US Patent 5439578 Drawing
Multiple capillary biochemical analyzer
Inventor     Dovichi; Norman J. (Edmonton, CA); Zhang; Jian Z. (Edmonton, CA)
Owner/Assignee     The Governors of the University of Alberta (Edmonton, CA)
Patent assignment
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Publication Date     August 8, 1995
Application Number     08/072,096
PAIR File History     Application Data   Transaction History
Image File Wrapper   Patent Term   Fees
Litigation
Filing Date     June 3, 1993
US Classification     204/603 204/604 356/318 356/344 356/417
Int'l Classification     G01N 027/26 G01N 027/447
Examiner     Niebling; John
Assistant Examiner     Starsiak Jr.; John S.
Attorney/Law Firm     Devinsky; Paul
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Parent Case    
Priority Data    
USPTO Field of Search     422/68.1 422/82.05 356/344 204/180.1 204/180.2 204/180.9 204/182.8 204/299 R
Patent Tags     multiple capillary biochemical analyzer
   
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The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the seconds ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

an electrophoretic voltage source connected across said capillary tubes to force said organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes, said flow chamber being held essentially at ground potential;

a detector positioned to detect organic sample in the individual sample streams emerging from the capillary tubes; and

an outlet for draining said sheath flow fluid and entrained streams directly from said flow chamber to waste, said outlet having a substantially larger flow area than said capillary tubes to thereby permit non-capillary flow therethrough.

2. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the seconds ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

an electrophoretic voltage source to force said organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes; said electrophoretic voltage source being connected across the length of the capillary tubes whereby said flow chamber is held essentially at ground potential; and

a detector positioned to detect organic sample in the individual sample streams emerging from the capillary tubes.

3. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the seconds ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force said organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes;

a detector positioned to detect organic sample in the individual sample streams emerging from the capillary tubes;

an exit port in said flow chamber for draining said sheath flow fluid and entrained streams directly from said flow chamber to waste, said exit port having a substantially larger flow area than said capillary tubes to thereby permit non-capillary flow therethrough; and

means to prevent drop formation at said exit port.

4. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the seconds ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force said organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes; said means including an electrophoretic voltage source connected across the length of the capillary tubes;

a detector positioned to detect organic sample in the individual sample streams emerging from the capillary tubes;

an exit port in said flow chamber for drawing sheath fluid from said chamber; and

means to prevent drop formation at said exit port.

5. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the seconds ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force said organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes;

a detector positioned to detect organic sample in the individual sample streams emerging from the capillary tubes, said detector being selected from the group comprising thermo-optical absorption detectors and electrochemical detectors; and

an outlet for draining said sheath flow fluid and entrained streams directly from said flow chamber to waste, said outlet having a substantially larger flow area than said capillary tubes to thereby permit non-capillary flow therethrough.

6. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the seconds ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force said organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes; said means including an electrophoretic voltage source connected across the length of the capillary tubes; and

a detector positioned to detect organic sample in the individual sample streams emerging from the capillary tubes, said detector being selected from the group comprising thermo-optical absorption detectors and electrochemical detectors.

7. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the seconds ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force said organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes, said means to force being selected from the group comprising pumps and gas pressure;

a detector positioned to detect organic sample in the individual sample streams emerging from the capillary tubes; and

an outlet for draining said sheath flow fluid and entrained streams directly from said flow chamber to waste, said outlet having a flow area substantially larger than that of the capillary tubes to thereby permit non-capillary flow therethrough.

8. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the seconds ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force said organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes;

a detector positioned to detect organic sample in the individual sample streams emerging from the capillary tubes;

an outlet for draining said sheath flow fluid and entrained streams directly from said flow chamber to waste, said outlet having a flow area substantially larger than that of the capillary tubes to thereby permit non-capillary flow therethrough; and

wherein said plurality of capillary tubes is arranged in a two-dimensional array and wherein said detector comprises a mass spectrometer having an ionization chamber, the second ends of said capillary tubes being disposed within said ionization chamber.

9. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the seconds ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force said organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes; said means including an electrophoretic voltage source connected across the length of the capillary tubes;

a detector positioned to detect organic sample in the individual sample streams emerging from the capillary tubes; and

wherein said plurality of capillary tubes is arranged in a two-dimensional array and wherein said detector comprises a mass spectrometer having an ionization chamber, the second ends of said capillary tubes being disposed within said ionization chamber.

10. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent to and abutting each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the second ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that organic sample from the capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes; and

a detector to detect organic sample emerging in the individual sample streams from the capillary tubes.

11. The analyzer according to claim 10, wherein the detector includes a source of collimated electromagnetic radiation having a wavelength that may excite the sample to emit radiation, said source being aligned to provide collimated light through the organic sample drawn from the capillary tubes by the sheath fluid.

12. The analyzer of claim 11 in which the detector includes an optical system aligned to receive emitted radiation from the organic sample.

13. The analyzer according to any one of claims 1 or 2, wherein said flow chamber is at ground potential.

14. The analyzer according to claim 13, wherein said chamber is at least partially formed of a transparent material and includes a recessed portion wherein the transparent material is exposed; and wherein said detector includes a source of collimated radiation and means for receiving emitted radiation from said sample streams; and wherein said source of collimated radiation and means for receiving emitted radiation are positioned in said recessed portion and adjacent to said transparent material.

15. The analyzer of claim 11 in which the detector is an optical system that receives scattered radiation from contaminants carried by the sample.

16. The analyzer of claim 11, in which said capillary tubes are arrayed in a linear array.

17. The analyzer of claim 11 in which the chamber includes an upper portion and a lower portion, and the means to supply sheath fluid includes a tube connected to the upper portion of the chamber, and the lower portion of the chamber encircles the second ends of the capillary tubes.

18. The analyzer according to claim 12, wherein a least a portion of the lower portion of the chamber is made of transparent material, said portion being adjacent the second ends of the capillary tubes.

19. The apparatus according to claims 17, wherein said detector further comprises a source of collimated electromagnetic radiation for generating electromagnetic radiation in a first direction which is generally orthogonal with respect to the direction of flow of said sample streams and an optical collection means positioned to receive radiation emitted from said sample streams in a second direction which is generally orthogonal with respect to the direction of flow of said sample streams.

20. The analyzer according to claim 10, wherein the means to force the organic sample through the capillary tubes includes an electrophoretic voltage source connected across the length of the capillary tubes.

21. The analyzer according to claim 10, wherein said capillary tubes are arrayed in a linear array.

22. The analyzer according to claim 10, wherein the means to supply sheath flow into said interior cavity includes a reservoir of sheath fluid syphon coupled to the chamber.

23. The analyzer according to claim 10, wherein said flow chamber comprises a side wall at least partially encircling said interior cavity and wherein at least a segment of the side wall is transparent to electromagnetic radiation radiating away from organic sample drawn from the capillary tubes by the sheath fluid.

24. The apparatus according to claim 23, wherein said detector further comprises a source of collimated electromagnetic radiation for generating electromagnetic radiation in a first direction which is generally orthogonal with respect to the direction of flow of said sample streams and an optical collection means positioned to receive radiation emitted from said sample streams in a second direction which is generally orthogonal with respect to the direction of flow of said sample streams.

25. The analyzer according to claim 10, wherein said chamber comprises a side wall at least partially encircling said interior cavity and wherein at least a segment of the side wall is transparent to electromagnetic radiation radiating away from organic sample drawn from the capillary tubes by the sheath fluid and in which at least a further segment of the side wall is transparent to the collimated electromagnetic radiation.

26. The apparatus according to claim 25, wherein said detector further comprises a source of collimated electromagnetic radiation for generating electromagnetic radiation in a first direction which is generally orthogonal with respect to the direction of flow of said sample streams and an optical collection means positioned to receive radiation emitted from said sample streams in a second direction which is generally orthogonal with respect to the direction of flow of said sample streams.

27. The analyzer according to claim 10, wherein each of said capillary tubes has an inside diameter on the order of about 50 .mu.m and an outside diameter on the order of about 150 .mu.m.

28. The analyzer according to claim 10, wherein said means to force an organic sample through the capillary tube comprises an electrophoretic voltage source of on the order of 30 kv connected across said capillary tubes and said flow chamber.

29. The analyzer according to claim 10, wherein the organic material is carried in said capillaries by a fluid, said fluid having essentially the same index of refraction as the sheath fluid.

30. The analyzer according to claim 10, wherein the volumetric flow of sheath fluid through said chamber is on the order of less than about 10 mL/hr.

31. The analyzer according to claim 10, wherein the rate flow of sheath fluid through said chamber is on the order of less than about 4 mm/sec.

32. The analyzer according to claim 10, further comprising an exit port in said flow chamber for drawing sheath fluid from said chamber and means to prevent drop formation at said exit port.

33. The analyzer according to any one of claim 3 or 4, wherein said means to prevent drop formation comprises a container, at least partially filled with fluid, connected to said exit port and into which the fluid from said chamber drains.

34. The analyzer according to claim 10, wherein said detector comprises a thermo-optical absorption detector.

35. The analyzer according to any one of claims 34, 6 or 7, wherein said organic samples are carried in said capillary tubes in a fluid and said detector comprises:

a first laser, aligned with said array of capillary tubes for simultaneously exciting the organic samples in said individual sample streams and for heating said fluid;

a second laser for passing a laser beam through each of said individual sample streams in a direction generally orthogonal to the direction of alignment of said first laser; and

an optical system for receiving emitted light from said individual sample streams.

36. The analyzer according to claim 10, wherein said detector comprises an electrochemical detector.

37. The analyzer according to any one of claims 36, 5 or 6, wherein said chamber is made of an inert, non-conducting material and further comprising an array of electrodes aligned with said array of capillary tubes and disposed in said chamber downstream, in the direction of sheath fluid flow from the second ends of said capillary tubes;

means, connected to each of said electrodes, for electrochemically analyzing each of said individual sample streams.

38. The analyzer according to claim 10, wherein said means for forcing the organic sample through said capillary tubes comprises a pump.

39. The analyzer according to claim 10, wherein the means to force the organic samples through the capillary tubes comprises gas pressure.

40. The analyzer according to claim 10, wherein said plurality of capillary tubes is arranged in a two-dimensional array and wherein said detector comprises a mass spectrometer having an ionization chamber, the second ends of said capillary tubes being disposed within said ionization chamber.

41. The analyzer according to any one of claims 40, 8 or 9, wherein a portion of the second capillary tubes extends into said ionization chamber, said portion being formed of an electrically conductive material.

42. The analyzer according to claim 10, wherein said plurality of capillary tubes are arranged side by side-in abutting relationship.

43. The analyzer according to claim 11, wherein a fluid acceleration region is formed downstream of the second ends of said capillaries, and wherein said source of collimated electromagnetic radiation is positioned to direct said radiation at the fluid acceleration region.

44. The apparatus according to claim 11, wherein said detector further comprises an optical collection means positioned to collect radiation emitted by said sample in a direction generally orthogonal to the direction of flow of said sample streams.

45. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source

a flow chamber having an interior cavity, the seconds ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force said organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes; and

a detector, including a source of collimated electromagnetic radiation having a wavelength that may excite the sample to emit radiation to detect organic sample emerging in the individual sample streams from the capillary tubes; said source being aligned to provide collimated light through the organic sample drawn from the capillary tubes by the sheath fluid, said detector further comprising an optical system aligned to receive emitted radiation from the organic sample, said optical system including plural photodetectors, one for each capillary tube.

46. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the second ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force the organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes; and

a detector including a first source of collimated electromagnetic radiation having a wavelength that may excite the sample to emit radiation to detect organic sample emerging in the individual sample streams from the capillary tubes, said source being aligned to provide collimated light through organic sample drawn from the capillary tubes by the sheath fluid, said detector further comprising a second source of collimated electromagnetic radiation aligned to direct a beam of radiation at each of said sample streams, further comprising an optical system aligned to detect radiation from said sample streams.

47. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the second ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in said capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force the organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes;

a detector including a source of collimated electromagnetic radiation having a wavelength that may excite the sample to emit radiation to detect organic sample emerging in the individual sample streams from the capillary tubes; said source being aligned to provide collimated light through the organic sample drawn from the capillary tubes by the sheath fluid; and

wherein the means to force sample through the capillary tubes comprises a pump and the capillary tubes are filled with chromatographic packing material.

48. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the second ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in the capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes;

a detector to detect organic sample emerging in the individual sample streams from the capillary tubes; and

wherein said plurality of capillary tubes are arrayed in a two-dimensional array formed of plural rows of capillary tubes, each row of capillary tubes terminating at a different level from any other row of capillary tubes.

49. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other and the first ends being connectable to a source of organic sample;

a flow chamber having an interior cavity, the second ends of the capillary tubes terminating inside the interior cavity;

means to supply sheath fluid into the interior cavity of said flow chamber to provide a flow of sheath fluid past the second ends of the capillary tubes such that any organic sample in the capillary tubes is drawn by the flow of sheath fluid in individual sample streams from the second ends of the capillary tubes;

means to force organic sample through the capillary tubes from the first ends of the capillary tubes to the second ends of the capillary tubes;

a detector, including a source of collimated electromagnetic radiation having a wavelength that may excite the sample to emit radiation to detect organic sample emerging in the individual sample streams from the capillary tubes, said source being aligned to provide collimated light through the organic sample drawn from the capillary tubes by the sheath fluid, and;

wherein said capillary tubes are arrayed in a two-dimensional array formed of plural rows of capillary tubes, each row of capillary tubes terminating at a different level from any other row of capillary tubes.

50. An analyzer for analyzing an organic sample, the analyzer comprising:

a plurality of capillary tubes arrayed side by side, each capillary tube having first and second ends, the second ends of the capillary tubes terminating adjacent each other