Biological analysis arrangement and approach therefor

• US 8,709,788 B2
• Filed: 11/19/2012
• Issued: 04/29/2014
• Est. Priority Date: 09/16/2002
• Status: Expired due to Fees

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Inventors: El Gamal, Abbas, Eltoukhy, Helmy, Salama, Khaled
• Primary Examiner(s): Bhat, Narayan
• Application Number:
  US13/680,796
• Publication Number:
  US 20130078623A1
• Time in Patent Office: 526 Days
• Field of Search: 435/6.1, 435/283.1, 435/287.1, 435/287.2, 356/246, 356/440, 422/82.01, 422/82.05, 536/23.1, 536/24.3
• US Class Current: 435/283.1
• CPC Class Codes: B01L 2300/0654 Lenses; Optical fibres
• CPC Class Codes: B01L 2300/0819 Microarrays; Biochips
• CPC Class Codes: B01L 2300/0877 Flow chambers
• CPC Class Codes: B01L 2300/1822 using Peltier elements
• CPC Class Codes: B01L 3/5027 by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00
• CPC Class Codes: B01L 3/502715 characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: C12Q 1/66 involving luciferase
• CPC Class Codes: G01N 21/253 for batch operation, i.e. multisample apparatus analytical automats G01N35/00
• CPC Class Codes: G01N 21/6454 using an integrated detector array

Abstract

Characteristics of a chemical or biological sample are detected using an approach involving light detection. According to an example embodiment of the present invention, an assaying arrangement including a light detector is adapted to detect light from a sample, such as a biological material. A signal corresponding to the detected light is used to characterize the sample, for example, by detecting a light-related property thereof. In one implementation, the assaying arrangement includes integrated circuitry having a light detector and a programmable processor, with the light detector generating a signal corresponding to the light and sending the signal to the processor. The processor provides an output corresponding to the signal and indicative of a characteristic of the sample.

Claims

1. An apparatus comprising:

an integrated circuit chip configured and arranged as a one-sided biological sensing architecture that includes

a substrate of the integrated circuit chip having a first side;

a plurality of test sites that are recessed into the first side of the integrated circuit chip substrate and configured and arranged in a planar array;

a plurality of photodiodes that are integrated into the recesses of the plurality of test sites and that are configured and arranged with a diffusion doping region having a dopant concentration and junction depth sufficient to detect firefly luciferase light produced during a pyrosequencing reaction within the plurality of test sites and generated from a sample contained within the test sites;

an analog to digital converter circuit fabricated as part of the integrated circuit chip and configured and arranged to convert analog voltages from the plurality of photodiodes into digital values; and

a memory circuit configured and arranged to store the digital values and that is fabricated as part of the integrated circuit chip.

2. The apparatus of claim 1, wherein the substrate is a P-type substrate and wherein the plurality of photodiodes each include an N-type diffusion doping region that has the dopant concentration and junction depth sufficient to detect firefly luciferase light produced during a pyrosequencing reaction within the test sites, wherein the P-type substrate has a first dopant concentration of a first dopant species per cm³ and the N-type diffusion region has a second dopant concentration of a second dopant species per cm³ and wherein a ratio between the first dopant concentration and the second dopant concentration is sufficient to detect firefly luciferase light produced during a pyrosequencing reaction.

3. The apparatus of claim 1, wherein the substrate is a P-type substrate and wherein the plurality of photodiodes each include an N-type diffusion doping region that has the junction depth sufficient to detect firefly luciferase light produced during a pyrosequencing reaction within the test sites and wherein the junction depth is at least about 3 micrometers.

4. The apparatus of claim 1, further including processing circuitry that is configured and arranged to reduce non-ideal characteristics of signals generated by the plurality of photodiodes and that is fabricated as part of the integrated circuit chip.

5. The apparatus of claim 1, further including processing circuitry adapted to reduce thermally-generated noise in signals generated by the plurality of photodiodes and that is fabricated as part of the integrated circuit chip.

6. The apparatus of claim 1, further including signal averaging circuitry that is configured and arranged to lower shot noise for individual photodiodes of the plurality of photodiodes by averaging inputs from the plurality of photodiodes.

7. The apparatus of claim 1, further including one or more reset switches configured and arranged to reset the plurality of photodiodes to a known state.

8. The apparatus of claim 1, wherein the planar array includes a plurality of columns and rows and wherein the apparatus further includes column and row decoder circuits that are configured and arranged to address a photodiode corresponding to each test site.

9. The apparatus of claim 1, further including processing circuitry that is configured and arranged to process input from each test site as a pixel of a plurality of pixels.

10. The apparatus of claim 9, wherein the processing circuitry is further configured and arranged to process data from the pixels in groups corresponding to different detected characteristics.

11. The apparatus of claim 10, further including at least one filter for a particular group of pixels, the filter being configured and arranged to filter out a specific wavelength of light.

12. The apparatus of claim 1, further including circuitry for sampling charge from the plurality of photodiodes in parallel to produce a digital signal.

13. The apparatus of claim 1, further including a plurality of channels that are fluidly coupled to the plurality of test sites and that are configured and arranged to deliver reagents to the plurality of test sites.

14. An apparatus comprising:

an integrated circuit chip configured and arranged as a one-sided biological sensing architecture that includes

a substrate of the integrated circuit chip having a first side;

a plurality of test sites that are recessed into the first side of the integrated circuit chip substrate and configured and arranged in a planar array;

a plurality of photodiodes that are integrated into the recesses of the plurality of test sites and that are configured and arranged with a diffusion doping region having a dopant concentration and junction depth sufficient to detect firefly luciferase light produced during a pryosequencing reaction within the plurality of test sites and generated from a sample contained within the test sites;

an analog to digital converter circuit fabricated as part of the integrated circuit chip and configured and arranged to convert analog voltages from the plurality of photodiodes into digital values;

a memory circuit configured and arranged to store the digital values and that is fabricated as part of integrated circuit chip; and

wherein the substrate is a P-type substrate with a dopant concentration of about 10¹⁵ dopant species per cm³ and wherein the plurality of photodiodes each include an N-type diffusion with a dopant concentration of about 5*10¹⁵ dopant species per cm³.

15. A method of detecting luciferase light generation, the method comprising:

providing a reagent to a plurality of test sites that are recessed into a first side of an integrated circuit chip substrate and that are arranged in a planar array;

measuring charge accumulation in a plurality of photodiodes that are integrated into the recesses of the plurality of test sites and that are configured and arranged with a diffusion doping region having a dopant concentration and junction depth sufficient to detect firefly luciferase light produced during a pyrosequencing reaction within the plurality of test sites and generated responsive to interaction between the reagent and test samples contained within the plurality of test sites;

converting the measured charge accumulation to a digital value using an analog to digital converter circuit that is fabricated as part of the integrated circuit chip substrate; and

storing the digital values in a memory circuit that is fabricated as part of the integrated circuit chip substrate.

16. The method of claim 15, further including a step of reducing shot noise from individual photodiodes of the plurality of photodiodes by averaging inputs from the plurality of photodiodes using signal averaging circuitry.

17. The method of claim 15, wherein the step of converting the measured charge accumulation to a digital value is accomplished by sampling charge from the plurality of photodiodes in parallel.

18. The method of claim 15, wherein the reagent is dNTP and the test samples are DNA sequences.