DEVICES AND METHODS FOR MEASURING VISCOELASTIC CHANGES OF A SAMPLE

Abstract

The present invention provides an apparatus for use in viscoelastic analysis, for example in coagulation testing of sample liquids, such as blood and/or its elements. In the apparatus for use in viscoelastic analysis, the rotating means are provided below the cup, pin and cup receiving element. The present invention further provides capacitive detection means and temperature control devices, which may be used in the apparatus for use in viscoelastic analysis. The present invention further provides a method of performing viscoelastic analysis, e.g. coagulation analysis, on a sample using the devices and apparatuses.

Claims

1. An apparatus (221, 321, 721) for measuring the coagulation characteristics of a sample (201, 301, 701) comprising: a cup (202, 302, 702) suitable for receiving the sample (201, 301, 701); a cup receiving element (210, 310, 710) providing (detachable) fixing for the cup (202, 302, 702) in measurement position; a pin (203, 303, 703) suitable to be dipped into said sample (201, 301, 701) in said cup (202, 302, 702), wherein the pin (203, 303, 703) is rotational symmetric, the rotational symmetry axis of the pin (203, 303, 703) forms a vertical axis (212, 312, 712), and the pin (203, 303, 703) is attached to supporting means (209, 313, 709); rotating means comprising a shaft (206, 306, 706), which extends along the vertical axis (212, 312, 712), which is rotatable around the vertical axis (212, 312, 712), and which is attached to the cup receiving element (210, 310, 710) or to supporting means (313) for the pin (203, 303, 703), such that a rotation of the shaft (206, 306, 706) causes a rotation of the cup receiving element (210, 310, 710) or of the supporting means (313) for the pin (203, 303, 703), and/or vice versa; and detection means (5, 105, 211, 311, 711) capable of detecting a rotation around said vertical axis (212, 312, 712) and/or variations in a rotation around said vertical axis (212, 312, 712); wherein the rotating means are provided below the cup (202, 302, 702), pin (203, 303, 703) and cup receiving element (210, 310, 710).

2. The apparatus (221, 321, 721) according to claim 1, wherein the rotating means comprise a an elastic coupling element (208, 308, 708), which provides a rotation to the shaft (206, 306, 706).

3. The apparatus (221, 321, 721) according to claim 2, wherein the elastic coupling element (208, 308, 708) is selected from a spring wire, a piezoelectric bending element, and a field-based forcing element using an electric force or using a magnetic force.

4. The apparatus (221, 321, 721) according to any one of claims 1 to 3, wherein the rotating means comprise a bearing (207, 307, 707), preferably with low friction torque.

5. The apparatus (221, 321, 721) according to claim 4, wherein the bearing (207, 307, 707) is selected from a ball bearing, a roll bearing, a magnetic bearing, and an air-lubricated bearing.

6. The apparatus (221, 321, 721) according to claim 4 or 5, wherein the bearing (207, 307, 707) is disposed in a base support member (220, 320, 720).

7. The apparatus (221, 321, 721) according to claim 6, wherein the shaft (206, 306, 706) extends through the base support member (220, 320, 720).

8. The apparatus (221, 321, 721) according to any one of claims 1 to 7, wherein the pin (203, 303, 703) has a cylindrical shape.

9. The apparatus (221, 321, 721) according to any one of claims 1 to 8, wherein the cup receiving element (210, 310, 710) comprises temperature control means to control the temperature of the cup (202, 302, 702) and/or of the sample (201, 301, 701).

10. The apparatus (221, 321, 721) according to any one of claims 1 to 9, wherein the cup receiving element (210, 310, 710) comprises a cup receiver for fixing the cup and fixation means for attaching the cup receiver to the shaft (206, 306, 706) or to other portions of the apparatus (221, 321, 721), in particular to immovable portions of the apparatus (221, 321, 721).

11. The apparatus (221, 321, 721) according to any one of claims 1 to 10, wherein the pin (203, 303, 703) is attached to supporting means (209, 313, 709) in a detachable manner.

12. The apparatus (221, 321, 721) according to any one of claims 1 to 11, wherein the shaft (206, 306, 706) is attached to the cup receiving element (210, 310, 710), in particular to the bottom portion of the cup receiving element (210, 310, 710), such that a rotation of the shaft (206, 306, 706) causes a rotation of the cup receiving element (210, 310, 710) and/or vice versa.

13. The apparatus (221, 321, 721) according to claim 12, wherein the supporting means (209, 709) for the pin (203, 303, 703) are immovable, such that the pin (203, 303, 703) attached to the supporting means (209, 709) is immovable.

14. The apparatus (221, 321, 721) according to claim 12 or 13, wherein the supporting means (209, 709) for the pin (203, 303, 703) are a cover (209, 709).

15. The apparatus (221, 321, 721) according to any one of claims 1 to 11, wherein the shaft (206, 306, 706) is attached to supporting means (313) for the pin (203, 303, 703), such that a rotation of the shaft (206, 306, 706) causes a rotation of the supporting means (313) for the pin (203, 303, 703), and/or vice versa.

16. The apparatus (221, 321, 721) according to claim 15, wherein the cup receiving element (210, 310, 710) is immovable, such that the cup (202, 302, 702) fixed to the cup receiving element (210, 310, 710) is immovable.

17. The apparatus (221, 321, 721) according to claim 15 or 16, wherein the supporting means (313) for the pin (203, 303, 703) are a frame (313).

18. The apparatus (221, 321, 721) according to any one of claims 1 to 17, wherein the detection means (5, 105, 211, 311, 711) are selected from optical, electrical, or magnetic detection means.

19. The apparatus (221, 321, 721) according to claim 18, wherein the detection means (5, 105, 211, 311, 711) are optical detection means (5, 105), preferably comprising a light emitter and a light sensor.

20. The apparatus (221, 321, 721) according to any one of claims 1 to 19, wherein the detection means (5, 105, 211, 311, 711) are disposed below the cup (202, 302, 702), pin (203, 303, 703) and cup receiving element (210, 310, 710), preferably the detection means (5, 105, 211, 311, 711) are disposed below the base support member (220, 320, 720).

21. The apparatus (221, 321, 721) according to any one of claims 1 to 20, wherein the detection means (5, 105, 211, 311, 711) are connected to the shaft (206, 306, 706).

22. The apparatus (221, 321, 721) according to any one of claims 1 to 20, wherein the detection means (211, 311, 711) comprise one or more capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 411a, 411b, 511a, 511b, 611a, 611b).

23. The apparatus (221, 321, 721) according to claim 22, wherein the capacitor element (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 411a, 411b, 511a, 511b, 611a, 611b) comprises an electrically non-conductive support, which preferably extends essentially perpendicularly to the vertical axis (212, 312, 412, 512, 612, 712) and at least one electrically conductive and rotatable layer disposed on the support, which preferably rotates with the same angular amplitude as the shaft (206, 306, 406, 506, 606, 706).

24. The apparatus (221, 321, 721) according to claim 22 or 23, wherein the detection means (211, 311, 411, 511, 611, 711) further comprises an electrical circuit capable of detecting a rotation of at least +/2 with an accuracy of at least 0.2 on a time frame of at most 5 seconds.

25. Capacitive detection means (211, 311, 411, 511, 711) for detecting variations in a rotation around a vertical axis (212, 312, 412, 512, 612, 712) caused by blood coagulation comprising a rotatable capacitor element (11a, 11a, 11a, 11a, 411a, 511a) capable of rotating around the vertical axis (212, 312, 412, 512, 612, 712); at least one fixed capacitor element (11b, 11b, 11b, 11b, 411b, 511b); and an electrical circuit, which is preferably connected to the at least one fixed capacitor element (11b, 11b, 11b, 11b, 411b, 511b); wherein each of the capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 411a, 411b, 511a, 511b) comprises at least one electrically conductive element, which does not have a circular shape with the vertical axis as center, and wherein the rotatable capacitor element (11a, 11a, 11a, 11a, 411a, 511a) and the at least one fixed capacitor element (11b, 11b, 11b, 11b, 411b, 511b) are arranged such that the at least one electrically conductive element of the rotatable capacitor element (11a, 11a, 11a, 11a, 411a, 511a) faces the at least one electrically conductive element of the at least one fixed capacitor element (11b, 11b, 11b, 11b, 411b, 511b).

26. The capacitive detection means (211, 311, 411, 511, 711) according to claim 25, wherein the electrical circuit is capable of detecting a rotation of the rotatable capacitor element around the vertical axis of at least +/2 with an accuracy of at least 0.2 in a time frame of at most 5 seconds.

27. The capacitive detection means (211, 311, 411, 511, 711) according to claim 25 or 26, wherein at least one of the capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 411a, 411b, 511a, 511b) comprises an electrically non-conductive support, which preferably extends essentially perpendicularly to the vertical axis (212, 312, 412, 512, 612, 712) and wherein the at least one electrically conductive element of said at least one of the capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 411a, 411b, 511a, 511b) is disposed on the support.

28. The capacitive detection means (211, 311, 411, 511, 711) according to any of claims 25-27, wherein the electrically non-conductive support material of the capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 411a, 411b, 511a, 511b) is lightweight material having less than 2.5 g/cm.sup.3 mass density.

29. The capacitive detection means (211, 311, 411, 511, 711) according to any of claims 25-28, wherein the electrically non-conductive support material of the capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 411a, 411b, 511a, 511b) is selected from PCB material, plastic, ceramic, glass and carbon fiber.

30. The capacitive detection means (211, 311, 411, 511, 711) according to any one of claims 25 to 29, wherein the electrically conductive element is made of a material having an electric conductivity of more than 5.10.sup.4 S/m.

31. The capacitive detection means (211, 311, 411, 511, 711) according to any one of claims 25 to 30, wherein the electrically conductive element is made of metal, metal alloy, metal-containing material, such as conductive silver paste, graphite, graphene, conductive polymers, or dotted semiconductors with increased conductivity, or of any combination thereof.

32. The capacitive detection means (211, 311, 411, 511, 711) according to any one of claims 25 to 31, wherein the electrically conductive element is in the shape of a spot, a square, a circle, a segment of a circle, a triangle, or an ellipse.

33. The capacitive detection means (211, 311, 411, 511, 711) according to any one of claims 25 to 32, wherein the electrically conductive element is disposed on the electrically non-conductive support by photochemical coating, sputtering, metal evaporation, or screen printing.

34. The capacitive detection means (211, 311, 411, 511, 711) according to any one of claims 25 to 33, wherein the at least one fixed capacitor element (11b, 11b, 11b, 11b, 411b, 511b) is arranged essentially in parallel to the rotatable capacitor element (11a, 11a, 11a, 11a, 411a, 511a).

35. The capacitive detection means (211, 311, 411, 511, 711) according to any one of claims 25 to 34, wherein rotatable capacitor element (11a, 11a, 11a, 11a, 411a, 511a) has essentially a plate-like, disk-like or cylindrical shape.

36. The capacitive detection means (211, 311, 411, 511, 711) according to any one of claims 25 to 35, wherein the at least one fixed capacitor element (11b, 11b, 11b, 11b, 411a, 511a) comprises a sine oscillator electrode (S), a cosine oscillator electrode (C), and a pickup electrode (P).

37. The capacitive detection means (211, 311, 411, 511, 711) according to claim 36, wherein the at least one fixed capacitor element (11b, 11b, 11b, 11b, 411a, 511a) comprises at least three sine oscillator electrodes (S), at least three cosine oscillator electrodes (C), and at least three pickup electrodes (P).

38. The capacitive detection means (211, 311, 411, 511, 711) according to claim 37, wherein the at least three sine oscillator electrodes (S), the at least three cosine oscillator electrodes (C), and the at least three pickup electrodes (P) are disposed on the support in an alternating manner.

39. The capacitive detection means (211, 311, 411, 511, 711) according to any one of claims 35 to 38, further comprising at least one ground electrode (G) located on the at least one fixed capacitor element (11b, 11b, 11b, 11b, 411a, 511a) (i) between a sine oscillator electrode (S) and a pickup electrode (P); or (ii) between a cosine oscillator electrode (C) and a pickup electrode (P).

40. The capacitive detection means (211, 311, 411, 511, 711) according to any one of claims 25 to 39, wherein the capacitive detection means (211, 311, 411, 511, 711) has a weight of 15 g or less.

41. The capacitive detection means (211, 311, 411, 511, 711) according to any one of claims 25 to 40, wherein the rotatable capacitor element (11a, 11a, 11a, 11a, 411a, 511a) can be attached to a shaft (206, 306, 706) of an apparatus (221, 321, 721) for measuring the coagulation characteristics of a sample (201, 301, 701), which shaft (206, 306, 706) is rotatable around the vertical axis (212, 312, 712), such that a rotation of the shaft (206, 306, 706) causes a rotation of the rotatable capacitor element (11a, 11a, 11a, 11a, 411a, 511a)and/or vice versa.

42. Capacitive detection means (211, 311, 611, 711) for detecting variations in a rotation around a vertical axis (212, 312, 612, 712) caused by blood coagulation comprising a rotatable dielectric element (617), which is capable of rotating around the vertical axis (612) and which does not have a circular shape with the vertical axis as center; two fixed capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b); and an electrical circuit, preferably connected to a fixed capacitor element (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b); wherein each of the two fixed capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b)comprises at least one electrically conductive element; the the two fixed capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b) are arranged such that the electrically conductive elements of the capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b) face each other; and the dielectric element (617) is at least partially placed between the two fixed capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b)

43. The capacitive detection means (211, 311, 611, 711) according to claim 42, wherein the electrical circuit is capable of detecting a rotation of the rotatable dielectric element (617) around the vertical axis of at least +/2 with an accuracy of at least 0.2 in a time frame of at most 5 seconds.

44. The capacitive detection means (211, 311, 611, 711) according to claim 42 or 43, wherein the capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b)comprise an electrically non-conductive support, which preferably extends essentially perpendicularly to the vertical axis (212, 312, 612, 712) and at least one electrically conductive element disposed on the support.

45. The capacitive detection means (211, 311, 611, 711) according to any of claims 42 to 44, wherein the electrically non-conductive support material of the capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b)is lightweight material having less than 2.5 g/cm.sup.3 mass density.

46. The capacitive detection means (211, 311, 611, 711) according to any of claims 42 to 45, wherein the electrically non-conductive support material of the capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b) is selected from PCB material, plastic, ceramic, glass and carbon fiber.

47. The capacitive detection means (211, 311, 611, 711) according to any one of claims 42 to 46, wherein the electrically conductive element is made of a material having an electric conductivity of more than 5.10.sup.4 S/m.

48. The capacitive detection means (211, 311, 611, 711) according to any one of claims 42 to 47, wherein the electrically conductive element is made of metal, metal alloy, metal-containing material, such as conductive silver paste, graphite, graphene, conductive polymers, or clotted semiconductors with increased conductivity, or of any combination thereof.

49. The capacitive detection means (211, 311, 611, 711) according to any one of claims 42 to 48, wherein the electrically conductive element is in the shape of a spot, a square, a circle, a segment of a circle, a triangle, or an ellipse.

50. The capacitive detection means (21 1, 311, 611, 711) according to any one of claims 42 to 49, wherein the electrically conductive element is disposed on the electrically non-conductive support by photochemical coating, sputtering, metal evaporation, or screen printing.

51. The capacitive detection means (211, 311, 611, 711) according to any one of claims 42 to 50, wherein the two fixed capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b)are arranged in an essentially parallel manner to each other and to the rotatable dielectric element (617).

52. The capacitive detection means (211, 311, 611, 711) according to any one of claims 42 to 51, wherein the capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b) have essentially a plate-like or disk-like shape.

53. The capacitive detection means (211, 311, 611, 711) according to any one of claims 42 to 52, wherein the capacitor elements (11a, 11b, 11a, 11b, 11a, 11b, 11a, 11b, 611a, 611b) comprise at least one sine oscillator electrode (S), at least one cosine oscillator electrode (C), and/or at least one pickup electrode (P).

54. The capacitive detection means (211, 311, 611, 711) according to claim 53, wherein the upper capacitor element (11a, 11a, 11a, 11a, 611a) comprises a pickup electrode (P) and the lower capacitor element (11b, 11b, 11b, 11b, 611b) comprises a sine oscillator electrode (S), and a cosine oscillator electrode (C).

55. The capacitive detection means (211, 311, 611, 711) according to claim 54, wherein the upper capacitor element (11a, 11a, 11a, 11a, 611a) comprises at least three pickup electrodes (P) and the lower capacitor element (11b, 11b, 11b, 11b, 611b) comprises at least three sine oscillator electrodes (S), and at least three cosine oscillator electrodes (C).

56. The capacitive detection means (211, 311, 611, 711) according to claim 53, wherein the upper capacitor element (11a, 11a, 11a, 11a, 611a) comprises a sine oscillator electrode (S) and a cosine oscillator electrode (C) and the lower capacitor element (11b, 11b, 11b, 11b, 611b) comprises a pickup electrode (P).

57. The capacitive detection means (211, 311, 611, 711) according to claim 56, wherein the upper capacitor element (11a, 11a, 11a, 11a, 611a) comprises at least three sine oscillator electrodes (S) and at least three cosine oscillator electrodes (C) and the lower capacitor element (11b, 11b, 11b, 11b, 611b) comprises at least three pickup electrodes (P).

58. The capacitive detection means (211, 311, 611, 711) according to claim 55 or 57, wherein the at least three sine oscillator electrodes (S), the at least three cosine oscillator electrodes (C), and the at least three pickup electrodes (P) are disposed on the support in an alternating manner.

59. The capacitive detection means (211, 311, 611, 711) according to any one of claims 42 to 58, wherein the capacitive detection means (211, 311, 611, 711) has a weight of 15 g or less.

60. The capacitive detection means (211, 311, 611, 711) according to any one of claims 42 to 59, wherein the rotatable dielectric element (617) can be attached to a shaft (206, 306, 606, 706) of an apparatus (221, 321, 721) for measuring the coagulation characteristics of a sample (201, 301, 701), which shaft (206, 306, 606, 706) is rotatable around the vertical axis (212, 312, 612, 712), such that a rotation of the shaft (206, 306, 606, 706) causes a rotation of the rotatable dielectric element (617) and/or vice versa.

61. The capacitive detection means (211, 311, 611, 711) according to any one of claims 42 to 60, wherein the dielectric element (617) is made of a material selected from the group consisting of a polymer material, such as polyethylene (PE) or polytetrafluorethylene (PTFE); a ceramic material, such as steatite; a glass material, aluminium oxide; mica; silicon dioxide; and any combination thereof.

62. The capacitive detection means (211, 311, 611, 711) according to any one of claims 42 to 61, wherein the dielectric element (617) has essentially a disk-like or plate-like shape.

63. An apparatus (221, 321, 721) for measuring the coagulation characteristics of a sample (201, 301, 701) comprising the capacitive detection means (211, 311, 411, 511, 611, 711) according to any one of claims 25 to 62.

64. The apparatus (221, 321, 721) according to claim 63, wherein the apparatus (221, 321, 721) is the apparatus according to any one of claims 1 to 24.

65. A temperature control device (718, 719) for controlling the temperature of a cup (702) and/or of a cup receiving element (710) while measuring the coagulation characteristics of a sample (701) in a thromboelastic measurement apparatus (721) comprising: (a) a heating (719) comprising an electromagnetic radiation emitting element emitting radiation with an emission maximum in the wavelength range from 300 to 3,000 nm; (b) a temperature sensing element (718) for contactless measurement of thermal radiation in the wavelength range from more than 3,000 nm to 30,000 nm; and (c) optionally, controlling means for activating or deactivating the heating (719) depending on the temperature measured by the temperature sensing element (718), which has preferably an accuracy of at least +/3 C.

66. The temperature controlling device according to claim 65, wherein the electromagnetic radiation emitting element is a diode.

67. The temperature controlling device according to claim 66, wherein the diode is an LED or a near-IR diode.

68. The temperature controlling device according to any one of claims 65 to 67, wherein the temperature sensing element is a pyro-electric detector, a photoresistor, or a photodiode.

69. The temperature controlling device according to any one of claims 65 to 68, wherein the controlling means comprise a feedback loop for the heater current, voltage, or pulse width..

70. An apparatus (721) for measuring the coagulation characteristics of a sample (701) comprising the temperature control device (718, 719) according to any one of claims 65 to 69.

71. The apparatus (721) according to claim 70, wherein the apparatus (721) further comprises the capacitive detection means (211, 311, 411, 511, 611, 711) according to any one of claims 25 to 62.

72. The apparatus (721) according to claim 70 or 71, wherein the apparatus (721) is according to any of claims 1 to 24 and 63 to 64.

73. The apparatus (721) according to any of claims 70-72, wherein the surface of the shaft and/or of the cup receiver, which is targeted by the electromagnetic radiation emitted from the heating (719) is dark and/or roughened.

74. Use of the temperature control device (718, 719) according to any one of claims 65 to 69 in measuring the coagulation characteristics of a sample (701).

75. The use according to claim 74, wherein the sample (701) is a blood sample.

76. A method for measuring the coagulation characteristics of a sample (201, 301, 701) by means of an apparatus (221, 321, 721) according to any one of claims of claims 1 to 24, 63 to 64, and 70 to 73, comprising the following steps: (a) measuring variations in the rotation around the vertical axis (212, 312, 712) by means of the detection means (211, 311, 411, 511, 611, 711); (b) converting said measured rotation/variation values to clot firmness values (CFV) of a viscoelastic measurement curve by the following formula:
CFV=(A.sub.0A)*100/A.sub.0 wherein A.sub.0 is the difference between maximum and minimum signal at the two turning points of the oscillatory movement before measurement start, and A is the difference between maximum and minimum signal at the two turning points of the oscillatory movement at a certain time point during the measurement; and (c) plotting the CFV's over the corresponding time points to obtain a measurement graph.

77. The method according to claim 76 comprising the use of the capacitive detection means (211, 311, 411, 511, 611, 711) according to any one of claims 25 to 62.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0220] In the following a brief description of the appended figures will be given. The figures are intended to illustrate the present invention in more detail. However, they are not intended to limit the subject matter of the invention in any way.

[0221] FIG. 1 is a schematic drawing of the measurement principle for early viscoelastic testing devices with optical detection means.

[0222] FIG. 2 is a schematic drawing of the measurement principle for viscoelastic testing devices with reduced sensitivity to environmental distortions like vibrations or shocks and with optical detection means.

[0223] FIG. 3 is an exemplary diagram showing a typical thromboelastometric measurement.

[0224] FIG. 4 is a schematic drawing of an apparatus according to a first preferred exemplary embodiment of the present invention.

[0225] FIG. 5 is a schematic drawing of an apparatus according to a second preferred exemplary embodiment of the present invention.

[0226] FIG. 6 is a schematic drawing of a movement detection system according to a preferred exemplary embodiment of the present invention.

[0227] FIG. 7 is a schematic drawing of an electrical circuit that creates an electrical detection signal from the movement detection system of FIG. 6.

[0228] FIG. 8 is a schematic drawing of alternative electrode arrangements regarding number and symmetry.

[0229] FIG. 9 is a schematic drawing of an alternative electrode arrangement according to a preferred exemplary embodiment of the present invention.

[0230] FIG. 10 is a schematic drawing of an alternative electrode arrangement according to a further preferred exemplary embodiment of the present invention.

[0231] FIG. 11 is schematic drawing of a combination of preferred exemplary embodiments of the present invention.

EXEMPLARY EMBODIMENTS

[0232] In the following, the present invention is illustrated in various exemplary embodiments. However, the present invention shall not to be limited in scope by the specific embodiments described in the following. The exemplary embodiments are given to enable those skilled in the art to more clearly understand and to practice the present invention. The present invention, however, is not limited in scope by the exemplary embodiments, which are intended as illustrations of selected aspects of the invention only, and methods which are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention in addition to those described herein will become readily apparent to those skilled in the art from the foregoing description, accompanying figures and the exemplary embodiments below. All such modifications fall within the scope of the appended claims.

[0233] FIG. 4 shows a schematic drawing of an apparatus (221) according to a first preferred exemplary embodiment of the present invention (rotating cup embodiment). According to this embodiment shown in FIG. 4, the apparatus (221) for measuring the coagulation characteristics of a sample (201), in particular a test liquid, preferably blood (or elements/components, comprises a cup (202) for receiving said sample. Furthermore, the apparatus comprises a pin (203), which can be placed inside the cup (202). In contrast to prior art measurement technologies, in the apparatus shown in FIG. 4 the pin (203) ispreferably detachablyfixed during the measurement regarding all spatial orientations/directions. This means in particular that the pin (203) cannot move in any direction. This is an important difference to the prior-art technologies described in FIG. 1 and FIG. 2: In the apparatus (21) shown in FIG. 1 the pin (3) is mounted via a wire (4) and can thus move in nearly any direction within the cup (2), which makes the measurement sensitive for shock or vibration. In the prior-art technology described in FIG. 2, the pin (103) is rotatable around the central vertical axis of the shaft (106).

[0234] In the first preferred exemplary embodiment shown in FIG. 4 the pin (203) can be for example fixed by attaching it to a cover (209). The cover (209) itself may for example be fixed, e.g. mounted, to a part of the apparatus, e.g. to a base support member (220), such as a base plate. Another possibility to fix the pin is to provide pin and cover in one piece (which includes both, pin and cover) and to attach that pin/cover piece directly to a base support member, such as a base plate. Preferably, said cup and pin are made of a polymeric material, which polymer preferably includes (meth)acrylic and/or styrene monomers, e.g. PMMA, MABS, ABS, PS, or any mixed co-polymer thereof.

[0235] According to the first preferred exemplary embodiment shown in FIG. 4, the cup (202) is rotatable, in particular around its vertical rotation axis (212). Preferably, the cup (202) is not movable along the axis (212), but only rotatable around axis (212). The rotation is enabled by providing a cup receiving element (210), which is connected to a shaft (206) and which is rotatable mounted into a base support member (220), such as a base plate, e.g., by at least one bearing (207). Similar to the cup (202), also the cup receiving element (210) is preferably not movable along the axis (212), but only rotatable around axis (212). In particular, a complete (full) rotation of 360 around axis (212) is not even requiredtypically a small angular movement (partial rotation; circular motion) of, for example, +/2.5 around axis (212) (i.e., in both directions) is sufficient for viscoelastic testing. Such a (partial) rotation is driven by an elastic coupling element (208), such as a spring wire, attached to the shaft (206), for example above or below said bearing (207).

[0236] During coagulation testing the blood sample typically forms a blood clot. After formation of the clot between cup (202) (e.g., a cuvette) and pin (203), the clot itself is stretched by the movement of the cup (202) relative to the pin (203). The detection of the characteristic parameters of the clot is based on the mechanical coupling of cup (202) and pin (203) by the clot. During a viscoelastic measurement, the pin (203) is fixed and the cup (202) rotates gently and slowly around the axis (212) by means of the elastic coupling element (208) and the cup receiving element (210). The movement of the cup (202) can be measured by various methods, for example by means of capacitive detection means (211), such as capacitor plates. In operation, the pin (203) is stationary and the rotatable shaft (206) and cup (202) placed in the cup receiver (210) are rotated back and forth by the elastic element (208, e.g. a spring wire), for example in an angular range of about 5. The rotation is transmitted by the coupling of the shaft (206) to the cup receiving element (210). When the blood clot forms an increasing torque acts against the oscillating movement of the cup (202), such that the cup/cup receiving element is oscillating in a decreased angular range of <5. This decrease in angular (oscillating) movement can be detected by suitable detection means (211) disposed below the pin (203) and cup (202)/cup receiving element (210).

[0237] This first preferred exemplary embodiment shown in FIG. 4 allows filling of the cup (202) with reagent and sample while being placed in the (optionally temperature-controlled) measurement position. It further avoids the need to attach a separate cup holder with cup and sample to the measurement device after filling the sample into the cup and before measurement start (as for example described in U.S. Pat. No. 5,777,215). Additionally, the first preferred exemplary embodiment shown in FIG. 4 further avoids the need to put the pin onto a small shaft before the measurement procedure starts (as for example described in U.S. Pat. No. 6,537,819 B2). Both improvements result in easier handling for the user and reduce in this way the risk for potential user mistakes.

[0238] Another advantage of the first preferred exemplary embodiment shown in FIG. 4 is that the lower end of the shaft (206) can also be used for a movement detection unit, enabling new options of movement detection technologies (in addition to the prior art optical detection as shown in FIG. 1). For example, in the first preferred exemplary embodiment shown in FIG. 4, field-based detection by means of capacitive detection means (211), such as capacitor plates, e.g. in an oscillatory circuit, may be employed. Nevertheless, also a movement detection by light beam deflection would be still applicable in this first embodiment.

[0239] In contrast to the existing measurement technologies, in the preferred embodiment shown in FIG. 4 the pin is (optionally detachably) fixed and thus essentially immobile in all orientations. This is in contrast to prior-art apparatuses (see FIG. 1 and FIG. 2), where pin can either move in any direction (cf. FIG. 1 where the pin (3) is mounted via a spring wire (4)) or is rotatable around the vertical axis (cf. FIG. 2). This novel design according to the present invention has the advantage of allowing the filling of the cup with reagent and sample while being placed in its measurement position and at the measurement temperature. It thus avoids the filling of the cup outside of the measurement apparatus (and at a different temperature) and subsequently placing it in its measurement position (e.g. as described in U.S. Pat. No. 5,777,215). It is also obviates the need to mount the pin to a pin neck prior to measurement (e.g. as described U.S. Pat. No. 6,537.819). Thus, the apparatus enables easier handling and thereby reduces the risk for potential usage errors. Another advantage of this embodiment is that the distal end of the shaft is free and can be used for an alternative detection technology, in particular, for capacitive detection as described herein.

[0240] FIG. 5 shows a schematic drawing of an apparatus (321) according to a second preferred exemplary embodiment of the present invention (rotating pin embodiment). According to this embodiment shown in FIG. 5, the cup (302) is now (preferably detachably) fixed, e.g. to a base plate, by means of a cup receiving element (310). This means in particular that the cup (302) cannot move in any direction. However, the pin (303) is rotatable, in particular around its vertical rotation axis (312). Preferably, the pin (303) is not movable along the axis (312), but only rotatable around axis (312). Again, in particular a complete (full) rotation of 360 around axis (312) is not even requiredtypically a small angular movement (partial rotation; circular motion) of, for example, +/4 around axis (312) (i.e., in both directions) is sufficient for viscoelastic testing. For example, the pin (303) can be (preferably detachably) fixed to a frame (313), which is connected to a shaft (306) and which is rotatable mounted into a base support member (320), such as a base plate, e.g., by at least one bearing (307). The frame (313) can be formed, for example, by an essentially rectangular arrangement of rods or tubes, e.g. comprising two or, more preferably, four metal rods or tubes, or by an essentially rectangular formed (single) rod or tube, which extends through corresponding openings (323) in the upper plate (322). The openings (323) in the upper plate (322) are preferably shaped such that they allow for an partial rotation/angular movement of the frame (313) of at least +/2, more preferably at least +/4. Similar to the embodiment shown in FIG. 4, the (partial) rotation (here: of the frame and, thus, the pin) is enabled by an elastic coupling element (308), such as a spring wire, attached to the shaft (306), which is connected to the frame (313). The elastic coupling element (308) can be mounted above or below said bearing (307).

[0241] Thus, in contrast to the prior art apparatus shown in FIG. 2, in the second preferred exemplary embodiment of the present invention shown in FIG. 5 rotatable fixing of the pin (303) is not realized by a shaft that is supported by a bearing above the cup/cup receiving element, but by a frame (313) attached to a shaft (306) that is supported by a bearing (307) below the cup/cup receiving element. In this way, the sample (301) can be filled into the cup (302) while being placed in the final measurement positionwhereas in measurement apparatuses of the prior art, e.g. as described in U.S. Pat. No. 5,777,215, the bearing is positioned directly above the cup, which makes filling of the cup in the measurement position impossible. Moreover, due to the provision of the rotating means, such as the ball bearing, below the cup/cup receiving element (instead of above), the center of mass of the entire apparatus is considerably lower and, thus, the apparatus is less susceptible to vibrations, tilting, and similar environmental influences, which may otherwise influence the measurement.

[0242] In addition, the placement of the rotation means, such as the bearing (307) and/or the spring (308) below the cup/cup receiving element enables new movement detection means due to the resulting available space at the lower end of the shaft (306), similarly to the embodiment in FIG. 4. Accordingly, movement of the pin may be detected by optical means as described in the prior art (see FIG. 2) or by field-based detection by means of capacitive detection means (311), such as capacitor plates, e.g. in an oscillatory circuit.

[0243] In summary, also the second embodiment of the present invention as depicted in FIG. 5, realizes the three advantages mentioned above for the first embodiment as shown in FIG. 4, namely, (i) it allows filling of the cup (302) with the sample (and, optionally reagents) while being placed in the measurement position; (ii) it avoids the need to attach a separate cup holder, which holds the cup receiving element in measurement position after addition of the sample; and (iii) it enables the use of new movement detection means, such as capacitor plates. In addition, the apparatus' center of mass is considerably lower making the apparatus more robust and more easy to handle.

[0244] FIG. 6 shows a preferred embodiment of the detection system according to the present invention, which may be used in viscoelastic measurements and which can be easily combined with the apparatus according to the present invention, for example with the preferred exemplified embodiment thereof shown in FIG. 4 or with the preferred exemplified embodiment thereof shown in FIG. 5. FIG. 6 shows schematically a cup (402) with a sample (401) and a pin (403). Below the cup (402) is a bearing (407) and a shaft (406), to which an elastic coupling element (408) is attached for providing rotation. The lower end of the shaft (406) is connected to a rotatable capacitor element (411a), which is preferably light-weight.

[0245] Most preferably, the capacitor element (411a) is a disk. It is also preferred that the rotatable capacitor element (411a), in particular the disk, is rotational symmetric to facilitates rotation of the rotatable capacitor element (411a).

[0246] Preferably, the rotatable capacitor element (411a) is attached to the lower end of the shaft (406), such that shaft (406) is essentially perpendicular to the rotatable capacitor element (411a). The rotatable capacitor element (411a) has electrically conductive elements (shaded areas in the capacitor element (411a) shown in FIG. 6), which are preferably arranged in an rotationally symmetric manner. Said capacitor element (411a) can be obtained, for example, from standard PCB (printed circuit board) material, or from special lightweight PCB material known in the art, e.g. by etching the corresponding electrically conductive elements out of the conductive layer of the PCB material. Alternatively, said rotatable capacitor element (411a) can be obtained by applying a metal coating onto a support material, e.g., ceramics (for example by screen printing using a mask to obtain electrically conductive elements).

[0247] In parallel to the rotatable capacitor element (411a) another capacitor element (411b) is provided. In general, a capacitor element refers in particular to one or more conductive elements arranged on a support. Said capacitor element (411b) can also be obtained by, for example, etching PCB material or by applying metal to a support material, such as ceramics. Said capacitor element (411b) is fixed, while the rotatable capacitor element (411a) follows the rotating movement of shaft (406). In other words, rotatable capacitor element (411a) typically rotates with the rotating shaft. Said fixed capacitor element (411b) is electrically connected to a circuitry, while the conductive elements on rotatable capacitor element (411a) are electrically insulated from all other parts and from each other. The movement of the shaft (406) can thus be detected by the relative movement of the capacitor element (411a) (which rotates with shaft (406)) in respect to the fixed capacitor element (411b).

[0248] The fixed capacitor element (411b) may for example comprise three kinds of electrodes: Sine oscillator (S), Cosine oscillator (C), and Pickup electrode (P). The electrodes S and C can then be connected to a rectangular oscillating voltage with a 90-phase shift between S and C. Other phase shifts and/or a frequency shift between the two signals are also possible. Depending on the angular position of shaft (406) and the corresponding exact position of the conductive element on the connected disk, the capacitance C.sub.SP from electrode S to electrode P and the capacitance C.sub.CP from electrode C to electrode P is changed in opposite directions. Accordingly, the actual angle of the rotatable conductive element can be calculated from the difference of C.sub.SP and C.sub.CP after scaling to the sum of C.sub.SP and C.sub.CP. This scaling provides high insensitivity to external mechanical distortions like distance changes, vibrations, tilting of the axis, and the like.

[0249] FIG. 7 shows schematically a preferred exemplary embodiment of a circuitry forming an oscillating circuit to measure capacitance differences between the electrodes S and C and the pickup electrode P. Electrodes S, C, and P are electrically conductive elements of the fixed electrode, whereas Z represents an electrically conductive element of the rotatable capacitor element. In this way, an electrical voltage signal can be generated that is proportional to the angular displacement between the isolated conductive layers on the rotatable capacitor element (411a) and the fixed capacitor element (411b), e.g. shown in FIG. 6: The alternating electrode voltages at S and C as provided by a frequency generator (14) induce charge fluctuations on both electrodes, and, due to the capacitor effect, also at electrode P. Thereby, the fluctuations on P depend on the electric environment around the electrodes S and C, which changes significantly by rotating the conductive element(s) Z on said disk. In particular, direct capacitive charge variations at P inducible without the loop way over said conductive elements can optionally be minimized by additional grounded electrodes between electrodes S and P, and between electrodes C and P, respectively.

[0250] Said charge fluctuations on electrode P can be amplified by a charge amplifier (15) and detected synchronously to the initial alternating voltages at electrodes S and C in a synchronized detector (16). In this way, two voltages U.sub.S and U.sub.C are generated and subsequently send through separated low-pass filters to reduce noise. Both resulting voltage signals, X and Y, allow calculation of a signal proportional to the angular displacement D of the capacitor element (11a) by D=(XY)/X+Y). To provide this signal as recordable data stream, the initial signals X and Y could be also digitized in an ADC (analog/digital converter) and then further processed digitally.

[0251] Other configurations in the fixed array of conductive electrodes are also conceivable without changing the general measurement principle. For example, one sine oscillator electrode (S) could be combined with two pickup electrodes (P1 and P2) at each side of S, separated again by ground electrodes to prevent directly induced charge fluctuations without the loop way via the rotatable conductive elements. In this case, the angular movement of said conductive elements would result in charge increase at one of the two pickup electrodes and in charge decrease at the other pickup electrode.

[0252] FIG. 8A-D shows preferred exemplary embodiments of the arrangement of the electrodes on the rotatable capacitor element (11a, 11a, 11a, 11a; left) and on the fixed capacitor element (11b, 11b, 11b, 11b; right). The exemplary embodiment shown in FIG. 8A represents the simplest approach of electrode arrangement. Such an arrangement may be sensitive to even slight tilting of the shaft holding the rotatable electrodes. The exemplary embodiment shown in FIG. 8B is insensitive to tilting of the shaft in one direction (i.e., tilting in the directions where the electrodes are placed), but not insensitive to tilting in other directions. The exemplary embodiment shown in FIG. 8C is the simplest approach that is insensitive to tilting of the shaft in any possible direction parallel to the electrodes plane. However, electrodes cover not yet all of the available space on the rotating disk. The exemplary embodiment shown in FIG. 8D is insensitive to shaft tilting in any direction and makes use of nearly all available space on the rotating disk for electrodes. This approach increases the resulting signal and considerably improves therefore the signal to noise ratio of the setup.

[0253] In summary, there is a high variability in number, arrangement and symmetry of employed electrodes. As a general principle, the precision and insensitivity against external distortions is improved by increasing the electrode number for each type S, C, and P from 1 to at least 3.

[0254] FIG. 9 shows another preferred exemplary embodiment of the capacitor elements (511a, 511b) of a detection system according to the present invention, wherein the capacitor elements (511a, 511b) have a cylindrically shaped geometry. In cylindrical geometry, the conductive elements can be for example directly printed (or metal-evaporated) on a rotating, nonconductive shaft (506) to save weight. Alternatively, another cylindrical element serving as rotatable capacitor element (511a) may be attached to the shaft (506), for example a sleeve made of non-conductive material. Electrodes of type S, C and P are placed at a fixed position surrounding the rotating axis (512). The number of electrodes is again variable.

[0255] FIG. 10 shows another preferred exemplary embodiment of the detection system according to the present invention, wherein the dielectric variation of the capacitance between fixed capacitor elements (611a, 611b) is used. Instead of using a rotating capacitor element relative to a fixed capacitor element to induce variations in capacitance as described above, in the present exemplary embodiment the electrodes S and C are aligned face-to-face to an electrode P in fixed positions. In this setup, the axis (612) is equipped with a segmented disk made of a dielectric material (617) that moves between the electrodes in dependence of the angular orientation of the axis. The dielectric material can be for example a polymer material like polyethylene (PE) or polytetrafluorethylene (PTFE), a ceramic material like steatite, or another dielectric material like aluminum oxide, mica, or silicon dioxide.

[0256] FIG. 11 shows a schematic drawing of an apparatus (721) according to a preferred exemplary embodiment of the present invention equipped with a temperature control device (718, 719) according to the present invention. In general, the apparatus (721) corresponds to the preferred exemplary embodiment shown in FIG. 4 (see above), however, additionally equipped with a temperature control device (718, 719). Accordingly, the apparatus (721) comprises a cup (702) with a sample (701), which is attached to a cup receiving element (710). The immobile pin (703) is fixed to a cover (709). The cup receiving element (710) is attached to a shaft (706), which is rotatable mounted into a base support member (720), such as a base plate, e.g., by at least one bearing (707). Accordingly, the cup receiving element (710) and the cup (702) can (partially) rotate around axis (712). Such a (partial) rotation is driven by an elastic coupling element (708), such as a spring wire, attached to the shaft (706), for example above or below said bearing (707).

[0257] A heating (719), in particular a radiation element, which emits electromagnetic radiation in the wavelength range below 3 m (3000 nm), more preferably below 1 m (1000 nm), is placed in close vicinity (preferably not more than 75 mm distance) of the shaft (706) and/or the cup-receiving element (710). Such a radiation element (719) may be, for example, a light emitting diode (preferably having a wavelength range 450-780 nm), a near-IR diode (preferably having a wavelength range 780-1500 nm), or a UV diode (preferably having a wavelength range 300-450 nm). A portion of the emitted energy (indicated by the dotted arrow in FIG. 11) is converted into heat in the shaft (706) and/or in the cup-receiving element (710) by absorption. This energy absorption is dependent on surface properties: the more dark (e.g., black) and the rougher the surface of the shaft (706) and/or the cup-receiving element (710) is/are made, the more radiation can be absorbed. In the theoretical approximation of an ideally black body, radiation absorption is independent from the wavelength.

[0258] The upper cut-off of the spectral range of emitted radiation (wavelength of 3 m, preferably 1 m) is important, because the emitted radiation should not interfere with the spectral range of thermal radiation according to Planck's law. This law describes that thermal radiation is emitted only in the range above 3 m for an (ideally black) body at a temperature between 30 and 40. The thermal radiation (as indicated by the dotted arrow in FIG. 11) directed to the shaft (706) and/or the cup-receiving element (710) can then be used to measure the temperature of the shaft (706) and/or the cup-receiving element (710) in a nearby (preferably maximum 75 mm distance) temperature sensor (718). The temperature sensor (718) may be, for example, a (calibrated) photodiode or photoresistor, or a pyro-electric sensor. Usually, these sensors absorb thermal radiation only in a certain spectral range that depends on the temperatures to be measured. In particular, sensors intended to measure temperatures between 20 and 50 C. typically have a spectral sensitivity in the range between 3 m and 30 m, because the thermal radiation according to Planck's law on thermal radiation peaks in this range.

[0259] For example, a near-IR diode with emission maximum around 850 nm (2 W total power, OSRAM SSH4715AS) was used as a heating (719) and a pyro-electric detector with spectral sensitivity between 5.5 and 14 m (MELEXIS MLX 90615) was used as temperature sensor (719). Shaft (706) and cup receiving element (710) were blackened by conventional blackboard color to increase absorption of thermal radiation. Non-movable surrounding metal parts were heated to 37 C. by 2 conventional thermo-resistors (5 W power in total) and controlled to maintain this value by a conventional thermo-regulation consisting of said thermo-resistors and a thermocouple as sensor. The IR diode enabled additional heating of the cup receiving element and the cup from 35.5 C. (as achieved by thermal radiation from the surrounding non-movable parts) to 37 C. (as required to perform a thromboelastometric measurement at typical body temperature) within less than 30 seconds. An alternative radiation source, a light emitting diode with emission maximum at 660 nm (CREE, Xlamp XP, XPEPHR-L 1-0000-00901) and an average output power of 0.35 W, was also able to heat the cup receiving element (710) and cup (702) from 35.5 C. to 37 C. with less than 30 seconds. The maximum achievable temperature difference between surrounding metal parts and cup was about 16 C. for the diode emitting at 850 nm maximum and about 12 C. for the diode emitting at 660 nm maximum.