BIOSENSOR

• US 20100015649A1
• Filed: 12/27/2007
• Published: 01/21/2010
• Est. Priority Date: 12/28/2006
• Status: Active Grant

• Current Assignee: Highland Biosciences Limited
• Original Assignee: Highland Biosciences Limited
• Inventors: Day, Richard
• Granted Patent: US 8,845,968 B2
• Time in Patent Office: Days
• US Class Current: 435/13
• CPC Class Codes: G01N 11/16 by measuring damping effect upon oscillatory body
• CPC Class Codes: G01N 2291/014 Resonance or resonant frequency
• CPC Class Codes: G01N 2291/022 Liquids
• CPC Class Codes: G01N 2291/0255 (Bio)chemical reactions, e.g. on biosensors
• CPC Class Codes: G01N 2291/02818 Density, viscosity
• CPC Class Codes: G01N 2291/0427 Flexural waves, plate waves, e.g. Lamb waves, tuning fork, cantilever
• CPC Class Codes: G01N 2291/101 one transducer
• CPC Class Codes: G01N 29/022 Fluid sensors based on microsensors, e.g. quartz crystal-microbalance [QCM], surface acoustic wave [SAW] devices, tuning forks, cantilevers, flexural plate wave [FPW] devices microdevices per se B81B
• CPC Class Codes: G01N 29/036 by measuring frequency or resonance of acoustic waves
• CPC Class Codes: G01N 29/222 Constructional or flow details for analysing fluids optoacoustic fluid cells G01N29/2425
• CPC Class Codes: G01N 29/245 Ceramic probes, e.g. lead zirconate titanate [PZT] probes
• CPC Class Codes: G01N 29/4427 with stored values, e.g. threshold values
• CPC Class Codes: G01N 33/49 Blood chemical methods for determining blood cell populations G01N33/5094; chemical analysis of blood groups or blood types G01N33/80
• CPC Class Codes: G01N 33/4905 Determining clotting time of blood by chemical methods G01N33/86, C12Q1/54
• CPC Class Codes: G01N 9/002 using variation of the resonant frequency of an element vibrating in contact with the material submitted to analysis G01N9/34 takes precedence

Abstract

The present application provides apparatus (300, 400) and methods for determining the density of a fluid sample. In particular, it provides a sensor device which can be loaded with a fluid sample such as blood, and which further comprises at least one oscillating beam member or resonator (108, 109, 110). Exposure of the blood sample to clotting agents allows a clotting reaction to commence. The device allows the density of the sample fluid to be monitored with reference to the oscillation of the vibrating beam member, thus allowing the monitoring of the clotting of the fluid sample.

Claims

1. A sensor device for monitoring changes in the density and/or viscosity of a fluid sample before, during and after a chemical reaction, the device comprising:

a plurality of layers, wherein one of said layers comprises a base substrate,

at least two beam members which are conjoined to the base substrate at each end of their length,

at least one vibration excitory element for use in providing the selective oscillation of at least one of said at least two beam members,

a sensor element for use in determining the frequency of oscillation of at least one of said at least two beam members, and

a reaction chamber, said reaction chamber defining an internal volume which is suitable for receiving and retaining the fluid sample, and wherein said reaction chamber accommodates said at least two beam members in a manner which allows the unimpeded oscillation of said at least two beam members.

2. A device as claimed in claim 1 wherein the at least two beam members are defined by and are integral to the base substrate.

3. A device as claimed in claim 1 wherein the device comprises three or more beam members.

4. A device as claimed in claim 1 wherein the at least two beam members are spaced equidistantly apart.

5. A device as claimed in claim 1 wherein the at least two beam members are arranged parallel to each other.

6. A device as claimed in claim 1 wherein the at least two beam members are composed of a material which is selected from the group consisting of:

silicon, tungsten, titanium, palladium, gold, platinum, and stainless steel.

7. A device as claimed in claim 2 wherein the at least two beam members are formed by a technique selected from the group consisting of:

etching, laser treatment, and mechanical punching.

8. A device as claimed in claim 1 wherein the vibratory element comprises a piezoelectric element.

9. A device as claimed in claim 8 wherein the vibratory element causes at least one of the at least two beam members to resonate in a transverse direction.

10. A device as claimed in claim 8 wherein the piezoelectric element causes oscillation of the beam member to which it is conjoined at the fundamental frequency.

11. A device as claimed in claim 1 wherein the sensor element comprises a piezoelectric element.

12. A device as claimed in claim 1 wherein the at least two beam members are provided within a reaction chamber, said reaction chamber being defined by an internal volume formed about said at least two beam members.

13. A device as claimed in claim 12 wherein the reaction chamber is defined about said at least two beam members by means of upper and lower substrates provided about the base substrate.

14. A device as claimed in claim 13 wherein the upper and lower substrate layers are positioned above and below the planar faces of the based substrate.

15. A device as claimed in claimed in claim 13 wherein said upper and lower substrate layers comprise a plurality of components.

16. A device as claimed in claim 13 wherein the upper and lower substrate layers comprise a plurality of sub-layers.

17. A device as claimed in claim 13 wherein at least one of the upper and/or lower substrate members is shaped to allow for the formation of at least one channel or opening through which the fluid sample can ingress into the reaction chamber.

18. A device as claimed in claim 13 wherein said upper and lower substrate layers define at least one channel and opening suitable to permit the entry of the fluid sample into the reaction chamber and/or the displacement of air therethrough upon the filling of the reaction chamber with a fluid sample.

19. A device as claimed in claim 18 wherein the channel and opening are of suitable dimensions such that the fluid sample can enter into said reaction chamber by means of capillary action.

20. A device as claimed in claim 12 wherein at least one of the surfaces of the reaction chamber exhibits a low surface tension.

21. A device as claimed in claim 12 wherein at least one internal surface of the reaction chamber is provided with a hydrophilic surface.

22. A device as claimed in claim 12 wherein the internal volume defined by the reaction chamber is not more that ten microlitres.

23. A device as claimed in claim 12 wherein additional layers are provided about said upper and lower substrate layers in order to confer further strength and/or rigidity to the structure.

24. A device as claimed in claim 1 wherein the fluid sample is a biological fluid.

25. A device as claimed in claim 24 further comprising a reagent comprising at least one blood clotting agent, said blood clotting agent being provided in an amount suitable to induce haemostasis of a blood sample provided within said reaction chamber.

26. A device as claimed in claim 25 wherein said reagent is provided on the base substrate.

27. A device as claimed in claim 25 wherein said reagent is provided on a surface of at least one of the at least two beam members.

28. A device as claimed in claim 1 wherein the length of the at least one of said at least two beam member is around eighteen millimeters.

29. A device as claimed in claim 1 comprising three beam members, wherein the width of the central beam member is around two millimeters.

30. A device member as claimed in claim 29 wherein the width of the outer beam members is around one millimeter.

31. A device as claimed in claim 1 wherein the device comprises three beam members, and wherein the width of the central beam member is the sum of the width of the outer two beam members.

32. A method for determining changes in the density and/or viscosity of a fluid sample, the method comprising:

providing a fluid sample,

loading the reaction chamber of a sensor device according to claim 1,

oscillating a first beam member provided within the reaction chamber,

determining the simultaneous oscillation of at least one further beam member provided within the reaction chamber, and

determining the density and/or viscosity of the fluid sample with reference to the frequency of oscillation of the at least one further beam member.

33. A method as claimed in claim 32 further comprising using a change in resonance frequency of the oscillation of the at least one further beam member to detect when the reaction chamber of the sensor is filled with the fluid sample.

34. A method as claimed in claim 32 further comprising using a change in amplitude of the oscillation of the at least one further beam member to detect when the reaction chamber of the sensor is filled with the fluid sample.

35. A method as claimed in claim 32 further comprising using a change in the resonant frequency of the oscillation of the at least one further beam member to measure the progress of a chemical reaction occurring in the fluid sample.

36. A method as claimed in claim 32 further comprising using a change in amplitude of the oscillation of the at least one further beam member to measure the progress of a chemical reaction occurring in the fluid sample.

37. A method as claimed in claim 32 further comprising using changes in a quality factor of at least one of the beam members to measure the progress of a chemical reaction occurring in the fluid sample.

48. Use of a sensor device as claimed in claim 1 for determining at least one of the following:

density and/or viscosity of a fluid sample,

a blood clotting time,

level of anti-coagulant in a blood sample,

the haematocrit level of a blood sample.

38. A method of determining the level of anti-coagulant in a blood sample, the method comprising:

loading a reaction chamber comprising at least two beam members with the blood sample,

oscillating a first beam member,

bringing the blood sample into contact with a reagent which causes blood clotting,

determining the oscillation of at least one second beam member,

determining the density of the blood sample by determining the oscillation frequency of the at least one second beam member, and

comparing the density of the blood sample to a standard in order to determine the level of anti-coagulant in the blood sample.

39. A method as claimed in claim 38 further comprising using a change in resonant frequency of the oscillation of the at least one second beam member to detect when the reaction chamber is filled with a blood sample.

40. A method as claimed in claim 38 further comprising using a change in amplitude of the oscillation of the at least one second beam member to detect when the reaction chamber is filled with a blood sample.

41. A method as claimed in claim 38 further comprising using a change in the resonant frequency of the oscillation of the at least one second beam member to measure the progress of a chemical reaction occurring in the blood sample.

42. A method as claimed in claim 38 further comprising using a change in amplitude of the oscillation of the at least one second beam member to measure the progress of a chemical reaction occurring in the blood sample.

43. A method as claimed in claim 38 further comprising using changes in a quality factor of at least one of the beam members to measure the progress of a chemical reaction occurring in the blood sample.

44. A method as claimed in claim 38 further comprising bringing the blood sample into contact with at least one clotting agent.

45. A method as claimed in claim 44 further comprising bringing the blood sample into contact with the at least one clotting agent within the reaction chamber.

46. A method as claimed in claim 45 wherein the reagent is an enzyme which induces precipitation of the blood sample.

47. A method as claimed in claim 38 further comprising determining the level of haematocrit in the blood sample prior to bringing the blood sample into contact with a reagent which causes blood clotting.

49-51. -51. (canceled)