Ultra-fast nucleic acid sequencing device and a method for making and using the same

• US 6,413,792 B1
• Filed: 08/31/2000
• Issued: 07/02/2002
• Est. Priority Date: 04/24/2000
• Status: Expired due to Term

• Current Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Original Assignee: Gulf Research and Development Company
• Inventors: Sauer, Jon Robert, Van Zeghbroeck, Bart Jozef
• Primary Examiner(s): Chaudhuri, Olik
• Assistant Examiner(s): KIELIN, ERIK J
• Application Number:
  US09/653,543
• Time in Patent Office: 670 Days
• Field of Search: 438/49, 257/253, 435/6, 435/287.2, 204/450, 204/451, 204/455, 204/601, 436/72
• US Class Current: 438/49
• CPC Class Codes: B01L 2200/0663 Stretching or orienting elongated molecules or particles
• CPC Class Codes: B01L 2300/0645 Electrodes
• CPC Class Codes: B01L 2400/0436 acoustic forces, e.g. surface acoustic waves [SAW]
• CPC Class Codes: B01L 3/502761 specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• CPC Class Codes: C12Q 1/6825 Nucleic acid detection involving sensors
• CPC Class Codes: C12Q 1/6869 Methods for sequencing
• CPC Class Codes: C12Q 2565/501 being an array of oligonucleotides
• CPC Class Codes: C12Q 2565/607 being a sensor, e.g. electrode
• CPC Class Codes: G01N 27/414 Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
• CPC Class Codes: G01N 33/48721 Investigating individual macromolecules, e.g. by translocation through nanopores Coulter counters in general G01N15/12; fabrication methods for nanoscale apertures B81B1/00; sequencing of nucleic acids C12Q1/68
• CPC Class Codes: H01L 2924/00 Indexing scheme for arrangements or methods for connecting or disconnecting semiconductor or solid-state bodies as covered by H01L24/00
• CPC Class Codes: H01L 2924/0002 Not covered by any one of groups H01L24/00, H01L24/00 and H01L2224/00

Abstract

A system and method employing at least one semiconductor device having at least one detecting region which can include, for example, a recess or opening therein, for detecting a charge representative of a component of a polymer, such as a nucleic acid strand, proximate to the detecting region, and a method for manufacturing such a semiconductor device. The system and method can thus be used for sequencing individual nucleotides or bases of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA). The semiconductor device includes at least two doped regions, such as two n-type regions implanted in a p-type semiconductor layer or two p-type regions implanted in an n-type semiconductor layer. The detecting region permits a current to pass between the two doped regions in response to the presence of the component of the polymer, such as a base of a DNA or RNA strand. The current has characteristics representative of the component of the polymer, such as characteristics representative of the detected base of the DNA or RNA strand.

Claims

1. A system for detecting at least one polymer, comprising:

at least one semiconductor device comprising at least one detecting region having an opening through which said polymer can pass, said opening having a cross-sectional dimension of less than about 100 nm and being configured such that while said at least one polymer passes through said opening, a charge of at least a component of said polymer creates image charges in said region, said image charges being sufficient to increase the conductivity of said region by an amount related to said charge of said component.

2. A system as claimed in claim 1, wherein:

said component includes a base in a nucleic acid strand; and

said detecting region is adapted to detect said charge representative of said base in said nucleic acid strand.

3. A system as claimed in claim 1, wherein:

said detecting region is further adapted to generate a signal representative of said detected charge.

4. A system as claimed in claim 1, wherein:

said cross-sectional dimension of said opening has a size which is adapted to prevent a plurality of said polymers to pass therethrough alongside of each other.

5. A system as claimed in claim 1, further comprising:

an excitation device, adapted to generate movement in said semiconductor device to facilitate movement of said polymer through said opening.

6. A system as claimed in claim 1, wherein:

said component includes a mer of said polymer.

7. A system as claimed in claim 1, wherein:

said semiconductor device includes a plurality of said detecting regions; and

each said detecting region is adapted to detect a charge representative of a component of said at least one polymer proximate thereto.

8. A system as claimed in claim 1, wherein:

said semiconductor device further includes at least two doped regions; and

said detecting region is adapted to pass a current between said two doped regions in response to a presence of said component proximate to said detecting region.

9. A system as claimed in claim 1, wherein:

said semiconductor device includes a plurality of doped regions, and a respective detecting region associated with each respective pair of said doped regions, such that each said respective detecting region is adapted, in response to a presence of a component proximate thereto, to pass a respective current between its said respective pair of doped regions.

10. A system as claimed in claim 1, further comprising:

a plurality of said semiconductor devices.

11. A system as claimed in claim 1, further comprising:

a detector, adapted to detect a signal generated by said detecting region in response to said component proximate thereto.

33. A system as claimed in claim 1, wherein:

said opening is substantially circular, and said cross-sectional dimension is a diameter of less than 100 nm.

34. A system as claimed in claim 33, wherein:

said diameter is within a range of about 1 nm to about 10 nm.

35. A system as claimed in claim 1, wherein:

said cross-sectional dimension is within a range of about 1 nm to about 10 nm.

12. A method for detecting at least one polymer, comprising the steps of:

moving a portion of said polymer through an opening in a detecting region of at least one semiconductor device, said opening having a cross-sectional dimension of less than about 100 nm, to enable a charge of at least a component of said polymer to create image charges in said region while said portion of said polymer passes through said opening, said image charges being sufficient to increase the conductivity of said region by an amount related to said component charge;

applying a potential across said region to generate a current through said device; and

identifying said component based on said current.

13. A method as claimed in claim 12, wherein:

said component includes a base in a nucleic acid strand; and

said detecting step detects said charge representative of said base in said nucleic acid strand.

14. A method as claimed in claim 12, further comprising the step of:

generating at said detecting region a signal representative of said detected charge.

15. A method as claimed in claim 12, wherein:

said cross-sectional dimension of said opening has a size which is adapted to prevent a plurality of said polymers to pass therethrough alongside of each other.

16. A method as claimed in claim 12, further comprising the step of:

generating movement in said semiconductor device to facilitate movement of said polymer through said opening.

17. A method as claimed in claim 12, wherein:

said component includes a mer of said polymer.

18. A method as claimed in claim 12, wherein:

said semiconductor device includes a plurality of said detecting regions; and

said detecting step includes the step of detecting, at each said detecting region, a charge representative of a component of said at least one polymer proximate thereto.

19. A method as claimed in claim 12, wherein:

said semiconductor device further includes at least two doped regions; and

said method further includes the step of passing a current between said two doped regions in response to a presence of said component proximate to said detecting region.

20. A method as claimed in claim 12, wherein:

said semiconductor device includes a plurality of doped regions, and a respective detecting region associated with each respective pair of said doped regions; and

said method further includes the step of passing, at each said respective detecting region in response to a presence of a component proximate thereto, a respective current between its said respective pair of doped regions.

21. A method as claimed in claim 12, where in:

said positioning step positions a respective portion of each of a plurality of said polymers proximate to a respective detecting region of a respective semiconductor device; and

said detecting step detects, at each said respective detecting region, a charge representative of a component of said respective polymer proximate to said respective detecting region.

22. A method as claimed in claim 12, further comprising the step of:

detecting a signal generated by said detecting region in response to said component proximate thereto.

36. A method as claimed in claim 12, wherein:

said opening is substantially circular, and said cross-sectional dimension is a diameter of less than 100 nm.

37. A method as claimed in claim 36, wherein:

said diameter is within a range of about 1 nm to about 10 nm.

38. A method as claimed in claim 12, wherein:

said cross-sectional dimension is within a range of about 1 nm to about 10 nm.

23. A method for manufacturing a device for detecting a polymer, comprising the steps of:

providing a semiconductor structure comprising at least one semiconductor layer; and

creating a detecting region in said semiconductor structure having an opening through which said polymer can pass, said opening having a cross-sectional dimension of less than about 100 nm, said detecting region being configured to enable a charge of at least a component of said polymer to create image charges in said region while said polymer passes through said opening, said image charges being sufficient to increase the conductivity of said region by an amount related to said charge of said component.

24. A method as claimed in claim 23, wherein:

said component includes a base in a nucleic acid strand; and

said creating step creates said detecting region which is adapted to detect said charge representative of said base in said nucleic acid strand.

25. A method as claimed in claim 23, wherein:

said cross-sectional dimension of said opening has a size which is adapted to prevent a plurality of said polymers to pass therethrough alongside of each other.

26. A method as claimed in claim 23, wherein said opening creating step includes the step of:

forming an insulating layer on a wall of said semiconductor layer forming said opening to decrease said cross-section of said opening.

27. A method as claimed in claim 23, wherein:

said component includes a mer of said polymer.

28. A method as claimed in claim 23, further comprising the steps of:

creating at least two doped regions in said semiconductor layer, said doped regions being positioned with respect to said detecting region such that said detecting region is adapted to pass a current between said doped regions in response to said component of said polymer proximate thereto.

29. A method as claimed in claim 28, wherein:

said doped region creating step creates said doped regions having a first doping such that said doped regions are separated by a portion of said semiconductor layer having a second doping.

30. A method as claimed in claim 28, wherein:

said doped region creating step creates said doped regions as a stack of doped regions, each having a first doping and being separated by a layer having a second doping.

31. A method as claimed in claim 28, wherein:

each of said doped regions includes a p-type doping.

32. A method as claimed in claim 28, wherein:

each of said doped regions includes an n-type doping.

39. A method as claimed in claim 23, wherein:

said opening is substantially circular, and said cross-sectional dimension is a diameter of less than 100 nm.

40. A method as claimed in claim 39, wherein:

said diameter is within a range of about 1 nm to about 10 nm.

41. A method as claimed in claim 23, wherein:

said cross-sectional dimension is within a range of about 1 nm to about 10 nm.