Method and apparatus for sensing and characterizing particles

• US 6,111,398 A
• Filed: 07/03/1997
• Issued: 08/29/2000
• Est. Priority Date: 07/03/1997
• Status: Expired due to Term

• Current Assignee: Coulter International Corp.
• Original Assignee: Coulter International Corp.
• Inventors: Graham, Marshall Donnie
• Primary Examiner(s): BROWN, GLENN WARNER
• Application Number:
  US08/887,588
• Time in Patent Office: 1,153 Days
• Field of Search: 324/71.4, 73/61.71
• US Class Current: 324/71.4
• CPC Class Codes: G01N 15/13 Details pertaining to apertures
• CPC Class Codes: G01N 2015/1019 Associating Coulter-counter and optical flow cytometer [OFC]
• CPC Class Codes: G01N 2015/135 Electrodes

Abstract

Apparatus for sensing and characterizing particles (e.g., blood cells or ceramic powders) suspended in a liquid medium comprises a conduit through which the particle suspension is caused to pass simultaneously with an electrical current. According to the invention, the interior wall of the conduit effectively varies in resistivity along the length of the conduit to define a delimited central region of high electrical resistivity which is smoothly contiguous on its opposing boundaries to uninsulated distal elements of lesser electrical resistivity. The delimited central region of the conduit functions as a Coulter volumeter conduit. The uninsulated distal elements of the conduit are made to have a dimension along the conduit wall which is at least equal to the axial extent of the effective ambit electric fields of a traditional Coulter volumeter conduit having a cross-sectional geometry identical to that of the delimited central region of high resistivity in the improved volumeter conduit. According to a preferred embodiment of the invention, the delimited central region of the improved volumeter conduit is defined by a traditional Coulter conduit wafer, i.e., a dielectric wafer containing a central circular conduit, and the distal elements of lesser resistivity are defined by uninsulated, electrically conductive, circular collars attached to opposite sides of the conduit wafer. The conduit in the conduit wafer and the openings in the conductive collars collectively form a hydrodynamically smooth volumeter conduit, in which the electric and hydrodynamic fields of the traditional volumeter conduit are advantageously amended in the manner above noted.

Claims

1. Apparatus for sensing and characterizing particles by the Coulter principle, said apparatus comprising:

(a) a volumeter conduit through which a liquid suspension of particles to be sensed and characterized can be made to pass, said volumeter conduit being hydrodynamically smooth and formed in a solid member having an electrical resistivity which effectively varies along the conduit length to define a conduit having a delimited central region of high electrical resistivity which is smoothly contiguous on its opposing boundaries to uninsulated distal regions of substantially lesser electrical resistivity;

(b) a liquid-handling system for causing said liquid suspension of particles to pass through said volumeter conduit;

(c) a first electrical circuit for producing a nominal electrical excitation current through said volumeter conduit, said excitation current being effective to establish in the vicinity of said volumeter conduit an electric field having a particle-sensitive zone in which changes in said nominal electrical excitation current as produced by particles passing through said volumeter conduit simultaneously with said nominal current are measurable, said uninsulated distal regions independently functioning (i) to shape said electric field so as to substantially confine said particle-sensitive zone within the physical boundaries of said volumeter conduit;

(ii) to enable development of quasi-laminar flow through said sensitive zone so as to increase the proportion of particles per second transiting substantially homogeneous areas of the sensitive zone; and

(iii) to prevent particles that have already passed through said conduit and are on recirculating trajectories from re-entering said particle-sensitive zone; and

(d) a second electrical circuit for monitoring the amplitude of the electrical current through said volumeter conduit to sense the characteristics of particles passing through said conduit.

2. The apparatus as defined by claim 1 wherein said solid member is a three-element structure composed of a layer of material having high electrical resistivity disposed between, and contiguous with, a pair of layers of material of lesser resistivity, and wherein said conduit is formed by through-holes respectively formed in each of said layers, said through-holes being of the same size and shape and being fluidically aligned to form a hydrodynamically continuous and smooth conduit passing through said three-element structure.

3. The apparatus as defined by claim 1 wherein said solid member comprises an intrinsic semiconductor wafer which is suitably doped with an electrically active impurity to provide said delimited central region of high electrical resistivity which is smoothly contiguous on its opposing boundaries to uninsulated distal regions of substantially lesser electrical resistivity.

4. The apparatus as defined by claim 1 wherein said solid member comprises a unitary assembly comprising three complementary and contiguous ceramic elements, the center ceramic element being substantially pure and the outer ceramic elements being either a conductive ceramic or a ceramic infiltrated with a metallic material to enhance the conductivity thereof, and wherein said conduit is formed by through-holes respectively formed in each of said ceramic elements, said through-holes being of the same size and shape and being fluidically aligned to form said hydrodynamically smooth conduit.

5. The apparatus as defined by claim 1 wherein said solid member comprises a unitary assembly comprising three complementary and contiguous elements, the center element being made of a substantially pure ceramic and the outer elements being made of a metallic material, and wherein said conduit is formed by through-holes respectively formed in each of said elements, said through-holes being of the same size and shape and being fluidically aligned to form said hydrodynamically smooth conduit.

6. The apparatus as defined by claim 1 wherein said volumeter assembly comprises a flow cell having a wall of dielectric material which defines said delimited central region of said conduit and a pair of conductive collars which define said distal regions.

7. The apparatus as defined by claim 5 wherein the through-hole formed in one of said outer ceramic elements gradually increases in diameter to provide a trumpet-shaped or radiussed opening through which a particle suspension can readily enter said conduit.

8. The apparatus as defined by claim 1 wherein said volumeter conduit has a circular cross-section.

9. The apparatus as defined by claim 1 wherein said volumeter conduit has a rectangular cross-section.

10. The apparatus as defined by claim 1 wherein said volumeter conduit is defined by (a) a through-hole formed in a wafer of dielectric material, and (b) central openings respectively formed in a pair of electrically-conductive collars, said central openings and said through-hole being of identical size and shape, said collars being disposed on opposite sides of said wafer so that their respective openings and said through-hole collectively form a hydrodynamically smooth conduit.

11. The apparatus as defined by claim 10 wherein said volumeter conduit has a circular cross-section, and wherein each of said collars is circular in shape and has a diameter approximately 1.5 to 10 times the diameter of said volumeter conduit.

12. The apparatus as defined by claim 10 wherein each of said collars has a thickness approximately 1 to 10 times the thickness of said wafer.

13. The apparatus as defined by claim 10 wherein each of said collars comprises a material selected from the group consisting of metals of the platinum group, gold, nickel, tungsten, titanium, alloys of said metals, silicon carbide, titanium carbide, and tungsten carbide.

14. The apparatus as defined by claim 10 wherein at least the central openings of said collars are plated with a metallic material selected from the group consisting of metals of the platinum group, gold, titanium, and alloys of such metals.

15. The apparatus as defined by claim 10 wherein said collars comprise a material selected from the group consisting of sapphire, ruby, alumina, quartz, glass, beryllia, silicon carbide, titanium carbide, and tungsten carbide, and wherein at least the central openings of said collars are plated with a metallic material selected from the group consisting of metals of the platinum group, gold, titanium, and alloys of such metals.

16. The apparatus as defined by claim 10 wherein the material of one collar differs from that of the other collar.

17. The apparatus as defined by claim 10 wherein at least one of said collars constitutes a structural component of said liquid-handling system.

18. The apparatus as defined by claim 10 wherein said collars have substantially the same thickness.

19. The apparatus as defined by claim 10 wherein the thickness of one collar differs from that of the other collar.

20. The apparatus as defined by claim 10 wherein said wafer comprises a material selected from the group consisting of sapphire, ruby, alumina, quartz, glass, beryllia, and lossy dielectrics.

21. Particle -sensing and -characterizing apparatus comprising:

(i) a wafer of electrically insulative material having a through-hole therein through which a liquid suspension of particles is adapted to pass, such liquid suspension of particles comprising a particle-suspending medium having an electrical impedance that differs from that of said particles;

(ii) a pair of electrically conductive collars, each collar having an opening centrally located therein, said collars being attached to opposite sides of said wafer in positions overlying regions surrounding said through-hole, said through-hole and collar openings being of the same size and shape and being arranged to define a hydrodynamically continuous and smooth conduit for the particle suspension;

(iii) a first circuit for causing a nominal electrical current through said conduit, said current being effective to establish an electric field in the vicinity of said conduit; and

(iv) a second circuit for monitoring changes in said nominal electrical current as produced by particles passing through a particle-sensitive portion of said electric field, said collars having a thickness by which said particle-sensitive portion is confined within the geometric dimensions of said conduit.

22. The apparatus as defined by claim 21 wherein said through-hole and said collar openings are circular in cross-section.

23. The apparatus as defined by claim 21 wherein said through-hole and said collar openings are rectangular in cross-section.

24. The apparatus as defined by claim 21 wherein each of said collars comprises a disc-shaped member of substantially the same diameter.

25. The apparatus as defined by claim 24 wherein the diameter of each disc-shaped member is approximately 1.5 to 10 times the diameter of said through-hole.

26. The apparatus as defined by claim 21 wherein thickness of each collar is approximately 1 to 10 times the thickness of said wafer.

27. The apparatus as defined by claim 21 wherein said collars comprise a material selected from the group consisting of metals of the platinum group, gold, nickel, tungsten, titanium, alloys of said metals, silicon carbide, titanium carbide, and tungsten carbide.

28. The apparatus as defined by claim 21 wherein said collars comprise a material selected from the group consisting of sapphire, ruby, alumina, quartz, glass, beryllia, silicon carbide, titanium carbide, and tungsten carbide, and wherein at least the central openings of said collars are plated with a metallic material selected from the group consisting of metals of the platinum group, gold, titanium, and alloys of such metals.

29. The apparatus as defined by claim 21 wherein at least the central openings of said collars are plated with a metallic material selected from the group consisting of metals of the platinum group, gold, titanium, and alloys of such metals.

30. The apparatus as defined by claim 21 wherein the material of one collar differs from that of the other collar.

31. The apparatus as defined by claim 21 wherein at least one of said collars constitutes a structural component of a liquid-handling system for causing a liquid suspension of particles to pass through said through-hole.

32. The apparatus as defined by claim 21 wherein said collars have substantially the same thickness.

33. The apparatus as defined by claim 21 wherein the thickness of one collar differs from that of the other collar.

34. The apparatus as defined by claim 21 wherein said dielectric material comprises a material selected from the group consisting of sapphire, ruby, alumina, quartz, glass, beryllia and lossy dielectrics.

35. A particle-sensing volumeter assembly adapted for use in an apparatus which characterizes particles by the Coulter principle, said volumeter assembly comprising a solid member having a wall defining a hydrodynamically smooth conduit through which particles to be characterized can be made to pass simultaneously with the passage of an electrical current through said conduit, said electrical current being effective to produce in the vicinity of said conduit an electric field having a particle-sensitive zone through which the passage of said particles is detectable, said wall having an electrical resistivity which varies in an axisymmetric manner along the conduit length to define a delimited central region of high electrical resistivity contiguous on its opposing boundaries to uninsulated distal regions of substantially lesser electrical resistivity, said uninsulated distal regions having a length measured along the longitudinal axis of said conduit which is sufficient to independently (i) shape said electric field so as to substantially confine said particle-sensitive zone within the physical boundaries of the conduit;

(ii) enable development of quasi-laminar flow through said particle-sensitive zone so as to increase the proportion of particles per second transiting substantially homogeneous areas of said particle-sensitive zone; and

(iii) prevent particles that have already passed through said conduit and are on recirculating trajectories from re-entering said particle-sensitive zone.

36. The apparatus as defined by claim 35 wherein said solid member is a three-element structure composed of a layer of material having high electrical resistivity disposed between, and contiguous with, a pair of layers of material of lesser resistivity, and wherein said conduit is formed by through-holes respectively formed in each of said layers, said through-holes being of the same size and shape and being fluidically aligned to form a hydrodynamically continuous and smooth conduit passing through said three-element structure.

37. The apparatus as defined by claim 35 wherein said solid member comprises an intrinsic semiconductor wafer which is suitably doped with an electrically active impurity to provide said delimited central region of high electrical resistivity which is smoothly contiguous on its opposing boundaries to uninsulated distal regions of substantially lesser electrical resistivity.

38. The apparatus as defined by claim 35 wherein said solid member comprises a unitary assembly comprising three complementary and contiguous ceramic elements, the center ceramic element being substantially pure and the outer ceramic elements being either a conductive ceramic or a ceramic infiltrated with a metallic material to enhance the conductivity thereof, and wherein said conduit is formed by through-holes respectively formed in each of said ceramic elements, said through-holes being of the same size and shape and being fluidically aligned to form said hydrodynamically smooth conduit.

39. The apparatus as defined by claim 38 wherein the through-hole formed in one of said outer ceramic elements gradually increases in diameter to provide a trumpet-shaped or radiussed opening through which a particle suspension can readily enter said conduit.

40. The apparatus as defined by claim 35 wherein said solid member comprises a unitary assembly comprising three complementary and contiguous elements, the center element being made of a substantially pure ceramic and the outer elements being made of a metallic material, and wherein said conduit is formed by through-holes respectively formed in each of said elements, said through-holes being of the same size and shape and being fluidically aligned to form said hydrodynamically smooth conduit.

41. The apparatus as defined by claim 40 wherein the through-hole formed in one of said outer metallic elements gradually increases in diameter to provide a trumpet-shaped or radiussed opening through which a particle suspension can readily enter said conduit.

42. The apparatus as defined by claim 35 wherein said solid member comprises a flow cell having a wall of dielectric material which defines said delimited central region of said conduit and a pair of electrically conductive collars which define said distal regions.

43. The apparatus as defined by claim 42 wherein the through-hole formed in one of said outer ceramic elements gradually increases in diameter to provide a trumpet-shaped or radiussed opening through which a particle suspension can readily enter said conduit.

44. The apparatus as defined by claim 35 wherein said volumeter conduit has a circular cross-section.

45. The apparatus as defined by claim 35 wherein said volumeter conduit has a rectangular cross-section.

46. The apparatus as defined by claim 35 wherein said volumeter conduit is defined by (a) a through-hole formed in a wafer of dielectric material, and (b) central openings respectively formed in a pair of electrically-conductive collars, said central openings and said through-hole being of identical size and shape, said collars being disposed on opposite sides of said wafer so that their respective openings and said through-hole collectively form a hydrodynamically smooth conduit.

47. The apparatus as defined by claim 46 wherein each of said collars is circular in shape and has a diameter approximately 1.5 to 10 times the diameter of said conduit.

48. The apparatus as defined by claim 46 wherein each of said collars has a thickness approximately 1 to 10 times the thickness of said wafer.

49. The apparatus as defined by claim 46 wherein said collars comprise a material selected from the group consisting of metals of the platinum group, gold, nickel, tungsten, titanium, alloys of said metals, silicon carbide, titanium carbide, and tungsten carbide.

50. The apparatus as defined by claim 46 wherein said collars comprise a material selected from the group consisting of sapphire, ruby, alumina, quartz, glass, beryllia, silicon carbide, titanium carbide, and tungsten carbide, and wherein at least the central openings of said collars are plated with a metallic material selected from the group consisting of metals of the platinum group, gold, titanium, and alloys of such metals.

51. The apparatus as defined by claim 46 wherein at least the central openings of said collars are plated with a metallic material selected from the group consisting of metals of the platinum group, gold, nickel, tungsten, titanium, alloys of such metals.

52. The apparatus as defined by claim 46 wherein the material of one collar differs from that of the other collar.

53. The apparatus as defined by claim 46 wherein at least one of said collars constitutes a structural component of a liquid-handling system for causing a liquid suspension of particles to pass through said through-hole.

54. The apparatus as defined by claim 46 wherein said collars have substantially the same thickness.

55. The apparatus as defined by claim 46 wherein the thickness of one collar differs from that of the other collar.

56. The apparatus as defined by claim 46 wherein the central opening in one collar gradually increases through the thickness of the collar to provide a trumpet-shaped or radiussed opening through which a particle suspension can enter said conduit.

57. The apparatus as defined by claim 46 wherein said wafer comprises a material selected from the group consisting of sapphire, ruby, alumina, quartz, glass, beryllia, and lossy dielectrics.

58. A particle-sensing volumeter assembly adapted for use in an apparatus which characterizes particles by the Coulter principle, said volumeter assembly comprising a solid member having a wall defining a hydrodynamically smooth conduit through which particles to be characterized can be made to pass simultaneously with the passage of an electrical current through said conduit, said electrical current being effective to produce in the vicinity of said conduit an electric field having a particle-sensitive zone through which the passage of said particles is detectable, said wall having an electrical resistivity which varies in an axisymmetric manner along the conduit length to define a delimited first region of high electrical resistivity contiguous on at least one of its opposing boundaries to an uninsulated distal region of substantially lesser electrical resistivity, said uninsulated distal region having a length measured along the longitudinal axis of said conduit which is sufficient to independently (i) shape said electric field so as to substantially confine at least a portion of said particle-sensitive zone within the physical boundaries of the conduit;

and (ii) either enable development of quasi-laminar flow through said particle-sensitive zone so as to increase the proportion of particles per second transiting substantially homogeneous areas of said particle-sensitive zone, or prevent particles that have already passed through said conduit and are on recirculating trajectories from re-entering said particle-sensitive zone.

59. The apparatus as defined by claim 58 wherein said conduit is defined by (a) a through-hole formed in a wafer of dielectric material, and (b) a central opening formed in an electrically-conductive collar, said central opening and said through-hole being of identical size and shape, said collar being disposed on said wafer so that its respective opening and said through-hole collectively form a hydrodynamically smooth conduit.

60. The apparatus as defined by claim 59 wherein said collar is circular in shape and has a diameter approximately 1.5 to 10 times the diameter of said conduit.

61. The apparatus as defined by claim 59 wherein said collar has a thickness approximately 1 to 10 times the thickness of said wafer.

62. The apparatus as defined by claim 59 wherein said collar comprises a material selected from the group consisting of metals of the platinum group, gold, nickel, tungsten, titanium, alloys of said metals, silicon carbide, titanium carbide, and tungsten carbide.

63. The apparatus as defined by claim 59 wherein said collars comprise a material selected from the group consisting of sapphire, ruby, alumina, quartz, glass, beryllia, silicon carbide, titanium carbide, and tungsten carbide, and wherein at least the central openings of said collars are plated with a metallic material selected from the group consisting of metals of the platinum group, gold, titanium, and alloys of such metals.

64. The apparatus as defined by claim 59 wherein at least the central opening of said collar is plated with a metallic material selected from the group consisting of metals of the platinum group, gold, nickel, tungsten, titanium, alloys of such metals.

65. A method for sensing and characterizing particles by the Coulter principle, said method comprising:

(a) passing a liquid suspension of particles to be sensed and characterized through a volumeter conduit formed in a solid material having an electrical resistivity which effectively varies along the conduit length to define a conduit having a delimited central region of high electrical resistivity which is smoothly contiguous on its opposing boundaries to uninsulated distal regions of substantially lesser electrical resistivity;

(b) producing a nominal electrical excitation current through said volumeter conduit and an electric field in the vicinity of said conduit, said electric field having a particle-sensitive zone in which changes in said nominal electrical excitation current as produced by particles passing through said volumeter conduit simultaneously with said nominal current are measurable, said uninsulated distal regions independently functioning (i) to shape said electric field so as to substantially confine said sensitive zone within the physical boundaries of the conduit; and

(ii) to enable development of quasi-laminar flow through said sensitive zone so as to increase the proportion of particles per second transiting substantially homogeneous areas of the sensitive zone; and

(c) monitoring the amplitude of the electrical current through said volumeter conduit to sense the presence and characteristics of particles passing through said conduit.