Abstract: The present methods and apparatus concern the detection and/or identification of target analytes using probe molecules. In various embodiments of the invention, the probes or analytes are attached to one or more cantilevers. Binding of a probe to an analyte results in deflection of the cantilever, detected by a detection unit. A counterbalancing force may be applied to restore the cantilever to its original position. The counterbalancing force may be magnetic, electrical or radiative. The detection unit and the mechanism generating the counterbalancing force may be operably coupled to an information processing and control unit, such as a computer. The computer may regulate a feedback loop that maintains the cantilever in a fixed position by balancing the deflecting force and the counterbalancing force. The concentration of analytes in a sample may be determined from the magnitude of the counterbalancing force required to maintain the cantilever in a fixed position.

Abstract: The present methods and apparatus 100 concern nucleic acid 214 sequencing by incorporation of nucleotides 218 into nucleic acid strands 220. The incorporation of nucleotides 218 is detected by changes in the mass and/or surface stress of the structure 116, 212. In some embodiments of the invention, the structure 116, 212 comprises one or more nanoscale or microscale cantilevers. In certain embodiments of the invention, each different type of nucleotide 218 is distinguishably labeled with a bulky group and each incorporated nucleotide 218 is identified by the changes in mass and/or surface stress of the structure 116, 212 upon incorporation of the nucleotide 218. In alternative embodiments of the invention only one type of nucleotide 218 is exposed at a time to the nucleic acids 214, 220. Changes in the properties of the structure 116, 212 may be detected by a variety of methods, such as piezoelectric detection, shifts in resonant frequency of the structure 116, 212, and/or position sensitive photodetection.

Abstract: The methods and apparatus disclosed herein concern nucleic acid sequencing by enhanced Raman spectroscopy. In certain embodiments of the invention, nucleotides are covalently attached to Raman labels before incorporation into a nucleic acid 13. Exonuclease 15 treatment of the labeled nucleic acid 13 results in the release of labeled nucleotides 16, 130, which are detected by Raman spectroscopy. In alternative embodiments of the invention, nucleotides 16, 130 released from a nucleic acid 13 by exonuclease 15 treatment are covalently cross-linked to silver or gold nanoparticles 140 and detected by surface enhanced Raman spectroscopy (SERS), surface enhanced resonance Raman spectroscopy (SERRS) and/or coherent anti-Stokes Raman spectroscopy (CARS). Other embodiments of the invention concern apparatus 10, 100, 210 for nucleic acid sequencing.