Broad range light detection system

• US 6,992,761 B2
• Filed: 05/22/2003
• Issued: 01/31/2006
• Est. Priority Date: 09/20/1997
• Status: Expired due to Term

• Current Assignee: Molecular Devices
• Original Assignee: Molecular Devices
• Inventors: Stumbo, David P., Modlin, Douglas N., French, Todd E., Petersen, Jonathan F., Stellmacher, Rick V.
• Primary Examiner(s): EVANS, FANNIE L
• Application Number:
  US10/445,292
• Publication Number:
  US 20040239922A1
• Time in Patent Office: 985 Days
• Field of Search: 356/306, 356/317, 356/318, 356/319, 356/326, 356/328, 356/417, 250/458.1, 250/459.1, 250/461.1, 250/461.2
• US Class Current: 356/317
• CPC Class Codes: G01N 21/6428 Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" in vivo A61B5/00; immunoassay G01N33/53
• CPC Class Codes: G01N 21/6452 Individual samples arranged in a regular 2D-array, e.g. multiwell plates
• CPC Class Codes: G01N 21/76 Chemiluminescence; Bioluminescence

Abstract

Broad-range light-detection systems, including components and methods of use thereof. These systems may include apparatus and methods for detecting light with increased speed and/or detection efficiency, particularly in applications involving repeated analysis of the same sample and/or successive analysis of different samples, and particularly when the sample or samples have a wide range of light intensities. These systems also may include apparatus and methods for detecting light with increased accuracy over a broad range of intensities. These systems also may include vapparatus and methods for automatically scaling detection range to improve detection based on the intensity of the detected light.

Claims

1. A light detection device, comprising:

a detector configured to receive light from a sample;

an accumulator configured to generate an accumulator signal corresponding to the total light received by the detector from the sample during a sampling period;

a timer configured to measure elapsed time during the sampling period; and

a controller configured to terminate the sampling period after the accumulator signal reaches a predetermined accumulator value or after the elapsed time reaches a predetermined detection time limit, whichever occurs first.

2. The device of claim 1, wherein a target measurement precision is used to calculate the predetermined accumulator value.

3. The device of claim 2, wherein a model of measurement noise further is used to calculate the predetermined accumulator value.

4. The device of claim 3, wherein the model of measurement noise is shot noise.

5. The device of claim 2, wherein an estimated measurement result further is used to calculate the predetermined accumulator value.

6. The device of claim 5, wherein the estimated measurement result is calculated using light received from the sample prior to or during the sampling period.

7. The device of claim 1, wherein the device is configured to receive light automatically and sequentially from a plurality of samples.

8. The device of claim 7, wherein the plurality of samples are disposed at different positions in a microplate or a microarray.

9. The device of claim 7 further comprising an automatic sample handler configured to advance samples for analysis, wherein the time between beginning to analyze successive samples is shorter if the accumulator signal reaches the predetermined accumulator value before the elapsed time reaches the predetermined detection time limit.

10. The device of claim 7, wherein the device is configured to receive light automatically from each of the plurality of samples during first and second sampling periods.

11. The device of claim 7, wherein the predetermined detection time limit is calculated using a user-inputted maximum total time for receiving light from the plurality of samples.

12. The device of claim 1, wherein the device is configured to receive light from the sample automatically during first and second sampling periods.

13. The device of claim 12, wherein the first and second sampling periods are sequential.

14. The device of claim 12, wherein the first and second sampling periods are at least partially overlapping.

15. The device of claim 12, wherein the controller is configured to terminate the first and second sampling periods independently after an accumulator signal for each period reaches a predetermined accumulator value or after the elapsed time for each period reaches a predetermined detection time limit, whichever occurs first.

16. The device of claim 12, wherein the duration of the second sampling period is determined at least in part by the duration of the first sampling period.

17. The device of claim 16, wherein the controller is configured to terminate the second sampling period such that it has at least substantially the same duration as the first sampling period.

18. The device of claim 16, wherein the controller is configured to terminate the second sampling period such that it has a duration equal to about twice the predetermined detection time limit minus the duration of the first sampling period.

19. The device of claim 12, wherein the device is configured such that the light received during the first and second sampling periods is of at least substantially the same wavelength.

20. The device of claim 12, wherein the device is configured such that the light received during the first and second sampling periods is of at least substantially different wavelengths.

21. The device of claim 12, wherein the device is configured such that the light received during the first and second sampling periods is of at least substantially different polarization.

22. The device of claim 12, further comprising a processor configured to compute a quantity related to the polarization of the light received during the first and second sampling periods.

23. The device of claim. 22, wherein the quantity is a luminescence polarization or a luminescence anisotropy.

24. The device of claim 12 further comprising a processor configured to compute a quantity related to resonance energy transfer efficiency in the sample based on the light received during the first and second sampling periods.

25. The device of claim 12 further comprising a processor configured to compute a quantity related to a ratio of the light received during the first and second periods.

26. The device of claim 1 further comprising an excitation source configured to excite emission of light from the sample.

27. The device of claim 26, wherein the excitation source is a light source.

28. The device of claim 26, wherein the excitation source is an electrical potential or current.

29. The device of claim 1, the detector, accumulator, accumulator signal, and sampling period being a first detector, a first accumulator, a first accumulator signal, and a first sampling period, respectively, further comprising:

a second detector configured to receive light from the sample; and

a second accumulator configured to generate a second accumulator signal corresponding to the total light received by the second detector from the sample during a second sampling period.

30. The device of claim 1, wherein the accumulator is discrete and generates the accumulator signal by counting pulses from the detector corresponding to quanta of detected light.

31. The device of claim 1, wherein the accumulator is analog and generates the accumulator signal by charging an integration capacitor, the charge on the capacitor corresponding to the amount of detected light.

32. The device of claim 31, the accumulator including a plurality of integration capacitors having substantially different capacities from one other, wherein the amount of detected light required to generate an accumulator signal equal to the predetermined accumulator value is selectable by choosing a particular one of the integration capacitors.

33. The device of claim 31, the accumulator also including a discrete accumulator that accumulates the signal by counting pulses from the detector corresponding to quanta of detected light, wherein the device switches between the discrete and analog accumulators based on the amount of light detected.

34. The device of claim 1, wherein the accumulator is digital and generates the accumulator signal by digitally measuring and summing the output of the detector at a plurality of discrete times during the sampling period.

35. The device of claim 1 further including a plurality of accumulators simultaneously operatively connected in parallel to the detector, each accumulator being configured to generate an integration value proportional to the integrated output of the detector during the sampling period, wherein the proportionality between the accumulator signal and the amount of detected light is substantially different for the different accumulators.

36. The device of claim 1, wherein the detector is selected from a group consisting of photomultiplier tubes, photodiodes, avalanche photodiodes, and charge-coupled devices.

37. The device of claim 1, wherein the device is adapted to switch between digital and analog counting modes, depending on the amount of detected light.

38. The device of claim 1, wherein the predetermined detection time limit is measured by pulses of a flash lamp.

39. A method of detecting light from a sample, comprising:

detecting photons incident on a detector during a sampling period;

collecting data representative of the cumulative number of photons detected during the sampling period; and

terminating the sampling period when the cumulative number of photons detected during the sampling period reaches a predetermined threshold or a predetermined sample time expires, whichever occurs first.

40. The method of claim 39, further comprising calculating the predetermined threshold based on a target measurement precision.

41. The method of claim 39, further comprising repeating the steps of detecting, collecting, and terminating for the same sample.

42. The method of claim 41, further comprising computing a polarization based on the detected light.

43. The method of claim 41, further comprising computing a resonance energy transfer efficiency based on the detected light.

44. The method of claim 41, further comprising computing a ratio based on the detected light.

45. The method of claim 39, further comprising repeating the steps of detecting, collecting, and terminating for a second sample.

46. A light detection device, comprising:

means for receiving light from a sample;

means for generating an accumulator signal corresponding to the total light received by the detector from the sample during a sampling period;

means for measuring elapsed time during the sampling period; and

means for terminating the sampling period after the accumulator signal reaches a predetermined accumulator value or after the elapsed time reaches a predetermined detection time limit, whichever occurs first.