Optical detection of label-free biomolecular interactions using microreplicated plastic sensor elements

• US 6,951,715 B2
• Filed: 01/28/2002
• Issued: 10/04/2005
• Est. Priority Date: 10/30/2000
• Status: Expired due to Term

• Current Assignee: X-Body Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Sru Biosystems Incorporated
• Inventors: Lin, Bo, Li, Peter, Cunningham, Brian T., Pien, Homer, Pepper, Jane, Qiu, Jean
• Primary Examiner(s): Chin, Christopher L.
• Application Number:
  US10/058,626
• Publication Number:
  US 20030027327A1
• Time in Patent Office: 1,345 Days
• Field of Search: 264/1.31, 264/1.9, 359/130, 359/566, 359/569, 359/570, 359/571, 359/572, 359/576, 385/12, 385/37, 385/130, 385/131, 422/82.11, 427/2.11, 427/2.13, 427/162, 435/4, 435/5, 435/6, 435/7.2, 435/7.32, 436/501, 436/518, 436/524, 436/525, 436/527, 436/531, 436/164, 436/165, 436/805, 436/811, 436/813
• US Class Current: 435/4
• CPC Class Codes: B01L 2300/0636 Integrated biosensor, microarrays
• CPC Class Codes: B01L 2300/0654 Lenses; Optical fibres
• CPC Class Codes: B01L 2300/0829 Multi-well plates; Microtitration plates
• CPC Class Codes: B01L 3/5085 for multiple samples, e.g. microtitration plates
• CPC Class Codes: G01N 21/253 for batch operation, i.e. multisample apparatus analytical automats G01N35/00
• CPC Class Codes: G01N 21/4788 Diffraction for sizing particles G01N15/0205
• CPC Class Codes: G01N 21/7743 the reagent-coated grating coupling light in or out of the waveguide
• CPC Class Codes: G01N 33/54373 involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
• CPC Class Codes: G02B 5/1809 with pitch less than or comparable to the wavelength
• CPC Class Codes: G02B 5/1852 using mechanical means, e.g. ruling with diamond tool, moulding
• CPC Class Codes: G02B 6/02061 Grating external to the fibre and in contact with the fibre, e.g. evanescently coupled, gratings applied to the fibre end mechanically induced in the fibre G02B6/02071, surface relief on the fibre G02B6/02066
• CPC Class Codes: Y10S 436/805 Optical property

Abstract

Methods and compositions are provided for detecting biomolecular interactions. The use of labels is not required and the methods can be performed in a high-throughput manner. The invention also provides optical devices useful as narrow band filters.

Claims

1. A method of producing a biosensor comprising:

dispensing a liquid optical cement between a master grating structure and a substrate, wherein the master grating structure comprises features having a depth and a period;

causing the liquid optical cement to harden forming a hardened liquid, wherein the hardened liquid adheres to the substrate;

separating the substrate and the hardened liquid from the master grating structure, the hardened liquid replicating the master grating structure, the hardened liquid thus forming an optical grating that replicates the features of the master grating structure,

depositing a coating onto the hardened liquid, a coating having a higher refractive index than the hardened liquid to form an optical grating; and

immobilizing one or more specific binding substances on the optical grating form a biosensor;

wherein, when the biosensor is illuminated, a resonant grating effect is produced on the reflected radiation spectrum, and wherein the depth and period of the optical grating are less than the wavelength of the resonant grating effect.

2. The method of claim 1, further comprising:

creating the master grating structure by selectively etching a silicon wafer to create optical features having a depth and a period.

3. The method of claim 1, wherein hardening the optical cement comprises exposure to UV light.

4. The method of claim 1, wherein a narrow band of optical wavelengths is reflected from the biosensor when the biosensor is illuminated with a broad band of optical wavelengths.

5. The method of claim 1, wherein the optical grating comprises a repeating pattern having a period of about 0.01 microns to about 1 micron and a depth of about 0.01 microns to about 1 micron.

6. The method of claim 1, wherein the one or more specific binding substances are arranged in an array of distinct locations.

7. The method of claim 1, wherein the one or more specific binding substances are bound to their binding partners.

8. The method of claim 1, wherein the one or more specific binding substances are selected from the group consisting of protein solutions, peptide solutions, DNA solutions, RNA solutions, solutions of combinatorial chemical libraries, nucleic acids, polypeptides, antigens, polyclonal antibodies, monoclonal antibodies, single chain antibodies (scFv), F(ab) fragments, F(ab′

)₂ fragments, Fv fragments, small organic molecules, cells, viruses, bacteria, and biological samples.

9. The method of claim 8, wherein the biological sample is selected from the group consisting of blood, plasma, serum, gastrointestinal secretions, homogenates of tissues or tumors, synovial fluid, feces, saliva, sputum, cyst fluid, amniotic fluid, cerebrospinal fluid, peritoneal fluid, lung lavage fluid, semen, lymphatic fluid, tears, and prostatitc fluid.

10. The method of claim 1 further comprising attaching the optical grating to a liquid-containing vessel such that the optical grating forms an internal surface of the liquid-containing vessel.

11. The method of claim 10, wherein the liquid-containing vessel is a microtiter plate, a test tube, a petri dish or a microfluidic channel.

12. The method of claim 1, wherein the features of the master grating structure comprise a repeating pattern of shapes selected from the group consisting of continuous parallel lines, squares, circles, ellipses, triangles, ovals, trapezoids, sinusoidal waves, rectangles, and hexagons.

13. The method of claim 1, wherein the features of the master grating structure have a period of about 0.01 microns to about 1 micron and a depth of about 0.01 microns to about 1 micron.

14. The method of claim 1 wherein the substrate comprises plastic.

15. The method of claim 1, wherein the coating having a higher refractive index than the hardened liquid is selected from the group consisting of zinc sulfide, titanium dioxide, tantalum oxide, and silicon nitride.

16. A method of producing a biosensor comprising:

creating a master grating structure by selectively etching a silicon wafer to create optical features having a depth and a period;

dispensing liquid optical cement between the master grating structure and a substrate;

curing the liquid optical cement by exposing it to UV light to form cured optical cement, wherein the cured optical cement adheres to the substrate;

separating the substrate and the cured optical cement from the master grating structure, the cured optical cement replicating the master grating structure,

coating the cured optical cement by depositing a thin film of material selected from the group consisting of silicon nitride, titanium dioxide, zinc sulfide, or tantalum oxide onto the cured optical cement to form an optical grating; and

immobilizing one or more specific binding substances on the optical grating to form a biosensor;

wherein, when the biosensor is illuminated, a resonant grating effect is produced on the reflected radiation spectrum, and wherein the depth and the period of the optical grating are less than the wavelength of the resonant grating effect.