Ultra high throughput microfluidic analytical systems and methods
First Claim
1. An illumination and detection system for use in illuminating a plurality of samples in a plurality of microchannels located in a detection region on a microfluidic device, and for detecting radiation emitted from the detection region, wherein the microchannels are substantially parallel along a first direction within the detection region, the system comprising:
- an illumination source for providing an excitation beam having two or more excitation wavelengths;
focussing optics for focussing the excitation beam onto a first plane defined by the plurality of microchannels in the detection region such that the focussed excitation beam is elongated, having a major axis substantially perpendicular to the first direction, wherein the excitation beam impinges upon the detection region at a non-normal angle of incidence relative to the first plane, and wherein the excitation beam simultaneously excites the samples in at least two of the microchannels so as to cause the excited samples to emit radiation;
two or more detectors, wherein each detector detects a specific range of radiation wavelengths; and
detection optics for directing radiation from the samples toward the detectors such that the wavelengths of the emitted radiation within each specific radiation wavelength range are directed toward the corresponding detector.
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Abstract
Analytical systems and methods that use a modular interface structure for providing an interface between a sample substrate and an analytical unit, where the analytical unit typically has a particular interface arrangement for implementing various analytical and control functions. Using a number of variants for each module of the modular interface structure advantageously provides cost effective and efficient ways to perform numerous tests using a particular substrate or class of substrates with a particular analytical and control systems interface arrangement. Improved optical illumination and detection system for simultaneously analyzing reactions or conditions in multiple parallel microchannels are also provided. Increased throughput and improved emissions detection is provided by the present invention by simultaneously illuminating multiple parallel microchannels at a non-normal incidence using an excitation beam including multiple excitation frequencies, and simultaneously detecting emissions from the substances in the microchannels in a direction normal to the substrate using a detection module with multiple detectors.
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Citations
65 Claims
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1. An illumination and detection system for use in illuminating a plurality of samples in a plurality of microchannels located in a detection region on a microfluidic device, and for detecting radiation emitted from the detection region, wherein the microchannels are substantially parallel along a first direction within the detection region, the system comprising:
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an illumination source for providing an excitation beam having two or more excitation wavelengths;
focussing optics for focussing the excitation beam onto a first plane defined by the plurality of microchannels in the detection region such that the focussed excitation beam is elongated, having a major axis substantially perpendicular to the first direction, wherein the excitation beam impinges upon the detection region at a non-normal angle of incidence relative to the first plane, and wherein the excitation beam simultaneously excites the samples in at least two of the microchannels so as to cause the excited samples to emit radiation;
two or more detectors, wherein each detector detects a specific range of radiation wavelengths; and
detection optics for directing radiation from the samples toward the detectors such that the wavelengths of the emitted radiation within each specific radiation wavelength range are directed toward the corresponding detector. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61)
two or more laser sources, wherein each laser source emits a radiation beam having one of the excitation wavelengths; and
illumination optics for combining each of the radiation beams into the excitation beam.
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3. The system of claim 1, wherein the excitation beam is polarized in a direction parallel to the major axis.
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4. The system of claim 1, wherein the illumination source includes:
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a first laser that emits a radiation beam having a first primary wavelength;
a second laser that emits a radiation beam having a second primary wavelength;
a third laser that emits a radiation beam having a third primary wavelength; and
wherein the illumination optics includes optical elements for combining the first, second and third radiation beams so as to form the excitation beam.
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5. The system of claim 4, wherein the illumination source further includes a fourth laser that emits a radiation beam having a fourth primary wavelength, and wherein the optical elements combine the fourth radiation beam into the excitation beam.
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6. The system of claim 4, wherein the optical elements include:
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a first beamsplitter element for combining the radiation beam of the first laser with the radiation beam of the second laser so as to form a first combined radiation beam;
a second beamsplitter element for combining the first combined radiation beam with the radiation beam of the third laser so as to form the excitation beam.
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7. The system of claim 4, wherein the first, second and third primary wavelengths are different, and wherein each of the first, second and third primary wavelengths are one of approximately 633 nm, approximately 457 nm, approximately 532 nm, and approximately 355 nm.
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8. The system of claim 1, wherein the detection optics includes:
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one or more beamsplitter elements, wherein each beamsplitter element is associated with one of the detectors, and wherein each beamsplitter element directs radiation having the specific range of wavelengths associated with one of the detectors toward that detector; and
a focusing element that focuses and directs the emitted radiation from the excited samples to the beamsplitter elements.
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9. The system of claim 8, wherein the focusing element is positioned between the detection region and the beamsplitter elements, and wherein the beamsplitter elements are linearly positioned relative to the focussing element and the detection region so as to form a linear arrangement.
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10. The system of claim 8, wherein the focusing element and the beamsplitter elements are positioned such that the linear arrangement is normal to the first plane.
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11. The system of claim 1, wherein each of the detectors includes a CCD array.
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12. The system of claim 1, wherein each of the detectors provides an output signal proportional to the radiation received from the detection region within its specific range of wavelengths, and wherein the system further includes a processor coupled to each of the detectors for analyzing the output signals of the detectors.
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13. The system of claim 1, wherein the microfluidic device includes at least two intersecting microchannels.
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14. The system of claim 1, wherein each of the plurality of microchannels has at least one cross-sectional dimension between about 0.1 and about 500 micrometers.
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15. The system of claim 1, wherein the microfluidic device comprises:
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a fluid reservoir for holding a conducting fluid;
a conducting capillary for supplying the fluid to the reservoir, wherein one end of the capillary is positioned at a first location in the reservoir;
a voltage source having a first terminal and a second terminal;
a first lead connecting the first terminal to the conducting capillary; and
a second lead connecting the second terminal to a second location in the reservoir;
wherein when the level of the fluid within the reservoir is at least at the first location, an electric current is present between the first and second terminals, and wherein when the fluid level is below the first location such that there is no contact between the fluid and the capillary, no electric current between the first and second terminals is present.
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16. The system of claim 15, wherein the first terminal is positive and the second terminal is negative.
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17. The system of claim 15, further including a fluid monitoring element in fluid communication with the capillary, wherein the fluid monitoring element provides fluid to the reservoir through the capillary when no electric current between the first and second terminals is present.
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18. The system of claim 15, wherein the fluid monitoring device provides a predetermined amount of fluid to the reservoir when no electric current between the first and second terminals is present.
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19. The system of claim 17, wherein the fluid monitoring device includes a syringe pump.
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20. The system of claim 1, wherein the microfluidic device comprises:
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a fluid reservoir for holding a conducting fluid;
a conducting capillary for supplying the fluid to the reservoir, wherein one end of the capillary is positioned at a first level within the reservoir;
a voltage source having a first terminal and a second terminal;
a first lead connecting the first terminal to the conducting capillary;
a second lead connecting the second terminal to a location at a second level within the reservoir, wherein the second level is below the first level; and
a fluid monitoring element for providing fluid to the reservoir from a fluid source;
wherein an electric current is present between the first and second terminals only when the level of fluid in the reservoir is at least at the level associated with the first location, and wherein the fluid monitoring device provides fluid to the reservoir through the capillary when no current is present.
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21. The system of claim 20, wherein the fluid monitoring element provides a predetermined amount of fluid to the reservoir when no electric current between the first and second terminals is present.
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22. The system of claim 20, wherein the fluid monitoring element includes a syringe pump.
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23. The system of claim 1, further comprising:
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a sample substrate having a plurality of substrate reservoirs and the plurality of microchannels disposed thereon, wherein the plurality of microchannels connects the plurality of substrate reservoirs, and wherein two or more of the microchannels are substantially parallel in a detection region on the substrate; and
a modular interface, having two or more removably attachable interface modules, for interfacing with a plurality of instrument connectors, the interface including;
a substrate interface module having at least one fluid reservoir disposed therein, wherein the substrate interface module is removably attached to the substrate, and wherein the at least one fluid reservoir is positioned so as to provide increased capacity to one of the substrate reservoirs; and
an instrument interface module having a plurality of first connectors for connecting to one or more of the plurality of instrument connectors, and a plurality of second connectors for providing a connection between the instrument connectors and the substrate interface module when the substrate interface module is removably attached to the instrument interface module.
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24. The system of claim 23, wherein the modular interface further includes a fluid supply module removably attached between the instrument and substrate interface modules, the fluid supply module including at least one fluid supply reservoir, wherein the fluid supply module also provides a connection between the substrate interface module and the second connectors of the instrument interface module.
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25. The system of claim 24, wherein the fluid supply module includes a plurality of third connectors for connecting to the plurality of second connectors of the instrument interface module, and a plurality of fourth connectors for providing the connection between the second connectors and the substrate interface module.
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26. The system of claim 25, wherein the number of fourth connectors is greater than the number of second connectors.
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27. The system of claim 25, wherein the plurality of fourth connectors includes a pin electrode positioned to directly engage fluid present in the at least one fluid reservoir of the substrate interface module.
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28. The system of claim 24, wherein the capacity of the fluid supply reservoir is substantially greater than the capacity of the substrate reservoir and the at least one fluid reservoir combined.
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29. The system of claim 24, wherein the fluid supply module includes at least one fluid connector positioned to provide fluid communication between the fluid supply reservoir and the at least one fluid reservoir of the substrate interface module.
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30. The system of claim 29, wherein the at least one fluid connector includes a capillary for providing fluid from the fluid supply reservoir to the at least one fluid reservoir of the substrate interface module.
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31. The system of claim 23, wherein the instrument connectors, first connectors and second connectors each include one or more connectors selected from the group consisting of vacuum ports, electrical connectors, pressure ports and temperature control electrodes.
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32. The system of claim 31, wherein the pin electrode provides temperature control to the fluid in the at least one fluid reservoir.
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33. The system of claim 31, wherein the pin electrode provides a voltage to the fluid in the at least one fluid reservoir.
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34. The system of claim 23, wherein the instrument interface module is removably attached to the substrate interface module, and wherein the plurality of second connectors includes a pin electrode positioned to directly engage fluid present in the at least one fluid reservoir of the substrate interface module.
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35. The system of claim 34, wherein the pin electrode provides temperature control to the fluid in the at least one fluid reservoir.
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36. The system of claim 34, wherein the pin electrode provides a voltage to the fluid in the at least one fluid reservoir.
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37. The system of claim 23, wherein the number of second connectors is greater than the number of first connectors.
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38. The system of claim 23, wherein each of the substrate interface and instrument interface modules includes an optical interface area aligned with the detection region on the substrate to allow radiation to pass to and from the detection region.
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39. The system of claim 38, wherein each optical interface area includes one of an optical window and an opening defined within its respective module.
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40. The system of claim 23, wherein each of the plurality of microchannels has at least one cross-sectional dimension between about 0.1 and about 500 micrometers.
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41. The system of claim 23, wherein at least two of the plurality of microchannels intersect.
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42. The system of claim 23, wherein the substrate further includes a plurality of sampling capillary connection regions for interfacing with one or more sampling capillaries, wherein the sampling capillary connection regions are connected to the plurality of microchannels.
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43. The system of claim 1, wherein the microfluidic device is arranged on a sample substrate, and wherein the device comprises:
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a plurality of substrate reservoirs disposed on the substrate;
wherein the plurality of microchannels are disposed on the substrate, wherein the plurality of microchannels connects the plurality of substrate reservoirs, and wherein two or more of the microchannels are substantially parallel in the detection region on the substrate; and
a non-linear arrangement of a plurality of sampling capillary connection regions disposed on the substrate for interfacing with one or more sampling capillaries, wherein the sampling capillary connection regions are connected to the plurality of microchannels.
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44. The system of claim 43, wherein the non-linear arrangement of sampling capillary connection regions includes:
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a first linear arrangement of sampling capillary connection regions; and
a second linear arrangement of sampling capillary connection regions, wherein the first and second arrangements are substantially parallel.
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45. The system of claim 44, wherein the first and second linear arrangements are spaced approximately 18 mm apart, and wherein the sampling capillary connection regions of each of the first and second arrangements are spaced approximately 4.5 mm apart.
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46. The system of claim 44, wherein each of the first and second linear arrangements includes three, four, five or six sampling capillary connection regions.
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47. The system of claim 46, wherein the plurality of substrate reservoirs includes 30 reservoirs.
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48. The system of claim 44, wherein each of the first and second linear arrangements includes one or two sampling capillary connection regions.
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49. The system of claim 48, wherein the plurality of substrate reservoirs includes 16 reservoirs.
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50. The system of claim 44, wherein the first and second linear arrangements are substantially parallel to the two or more parallel microchannels in the detection region.
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51. The system of claim 43, wherein each of the plurality of microchannels has at least one cross-sectional dimension between about 0.1 and about 500 micrometers.
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52. The system of claim 43, wherein at least two of the plurality of microchannels intersect.
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53. The system of claim 44, wherein the sampling capillary connection regions of each of the first and second linear arrangements are spaced approximately 9.0 mm apart.
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54. The system of claim 44, wherein the sampling capillary connection regions of each of the first and second linear arrangements are spaced approximately 2.25 mm apart.
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55. The system of claim 1, wherein the microfluidic device is arranged on a sample substrate, and wherein the device comprises:
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a plurality of substrate reservoirs disposed on the substrate;
wherein the plurality of microchannels are disposed on the substrate, wherein the plurality of microchannels connects the plurality of substrate reservoirs; and
two linear arrangements of two or more sampling capillary connection regions disposed on the substrate for interfacing with one or more sampling capillaries, the sampling capillary connection regions being connected to the plurality of microchannels, wherein for each linear arrangement, the sampling capillary connection regions are space approximately n*2.25 mm apart, where n is an integer having a value of from 1 to 24, inclusive.
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56. The system of claim 55, wherein the value of n is one of 1, 2 and 4.
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57. The system of claim 1, wherein the detection optics includes:
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one or more beamsplitter elements, wherein each beamsplitter element is associated with one of the detectors, and wherein each beamsplitter element directs radiation having a specific polarization toward the associated detector; and
a focusing element that focuses and directs the emitted radiation from the excited samples to the beamsplitter elements.
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58. The system of claim 1, wherein the microfluidic device comprises:
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a fluid reservoir for holding a conducting fluid;
a capillary for supplying the fluid to the reservoir;
a voltage source having a first terminal and a second terminal;
a first electrode connected to the first terminal, wherein the first electrode is positioned at a first location in the reservoir; and
a second electrode connected to the second terminal, wherein the second electrode is positioned at a second location in the reservoir;
wherein when the level of the fluid within the reservoir is at least at the first location, an electric current is present between the first and second terminals, and wherein when the fluid level is below the first location such that there is no contact between the fluid and the first electrode, no electric current between the first and second terminals is present.
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59. The system of claim 58, further comprising a fluid monitoring device, wherein the fluid monitoring device provides a predetermined amount of fluid to the reservoir through the capillary when no electric current between the first and second terminals is present.
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60. The system of claim 1, wherein the microfluidic device comprises:
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a first fluid reservoir for holding a conducting fluid;
a second fluid reservoir for holding the conducting fluid, wherein the first fluid reservoir is in fluid communication with the second fluid reservoir;
a capillary for supplying the fluid to the first reservoir;
a voltage source having a first terminal and a second terminal;
a first electrode connected to the first terminal, wherein the first electrode is positioned in the first reservoir; and
a second electrode connected to the second terminal, wherein the second electrode is positioned in the second reservoir;
wherein when the level of the fluid within one of the first and second reservoirs is at least at a first level, an electric current is present between the first and second terminals, and wherein when the fluid level is below the first level such that there is no contact between the fluid and one of the first and second electrodes, no electric current between the first and second terminals is present.
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61. The system of claim 60, further comprising a fluid monitoring device, wherein the fluid monitoring device provides a predetermined amount of fluid to the first reservoir through the capillary when no electric current between the first and second terminals is present.
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62. An analytical system comprising:
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an analysis chip having a plurality of microchannels disposed thereon, wherein at least two of the plurality of microchannels are located in a detection region;
an optical illumination and detection subsystem including;
an illumination source for illuminating the at least two microchannels in the detection region with an excitation beam at a non-normal angle of incidence, said excitation beam having at least two excitation wavelengths, wherein the excitation beam simultaneously excites samples in the at least two microchannels in the detection region; and
at least two detectors, wherein each detector detects a specific range of wavelengths;
an instrument array including a plurality of interface components for providing control of analyses performed on the chip;
ana modular interface structure, including at least one module, for holding the chip and for interfacing the chip with the instrument array, wherein the at least one module is configured to interface with at least one of the interface components.
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63. An illumination and detection system for use in illuminating a plurality of samples in a plurality of microchannels located in a detection region on a microfluidic device, and for detecting radiation emitted from the detection region, wherein the microchannels are substantially parallel along a first direction within the detection region, the system comprising:
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an illumination source for providing an excitation beam, wherein the illumination source is configured so that excitation beam impinges at a non-normal angle of incidence onto a first plane defined by the plurality of microchannels in the detection region, wherein on the first plane the excitation beam is elongated, having a major axis substantially perpendicular to the first direction, and wherein the excitation beam simultaneously excites the samples in at least two of the microchannels so as to cause the excited samples to emit radiation;
one or more detectors, wherein each detector detects a specific range of radiation wavelengths; and
detection optics for directing radiation from the samples toward the one or more detectors such that the wavelengths of the emitted radiation within each specific radiation wavelength range are directed toward the corresponding detector.
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64. An illumination and detection system for use in illuminating a plurality of samples in a plurality of microchannels located in a detection region on a microfluidic device, and for detecting radiation emitted from the detection region, wherein the microchannels are substantially parallel along a first direction within the detection region, the system comprising:
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an illumination source for providing an excitation beam having two or more excitation wavelengths;
focussing optics for focussing the excitation beam onto a first plane defined by the plurality of microchannels in the detection region such that the focussed excitation beam is elongated, having a major axis substantially perpendicular to the first direction, wherein the excitation beam impinges upon the detection region at a non-normal angle of incidence relative to the first plane, and wherein the excitation beam simultaneously excites the samples in at least two of the microchannels so as to cause the excited samples to emit radiation;
two or more detectors, wherein each detector detects a specific range of radiation wavelengths and a specific polarization; and
detection optics for directing radiation from the samples toward the detectors such that the emitted radiation having both the specific polarization and wavelengths within the specific radiation wavelength range are directed toward the corresponding detector. - View Dependent Claims (65)
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Specification