Molecular interferometric imaging.

Common-path in-line shearing interferometry, combined with pixel-array imaging, provides a surface metrology that achieves 15 pm surface height resolution. An eighth-wave thermal oxide on silicon generates a reference wave locked in the condition of phase quadrature for phase-to-intensity conversion that makes surface height or index variations directly detectable by an imaging system. The scaling surface mass sensitivity for the surface metrology application is S(scal) = 7 fg/mm under 40x magnification with a molecular resolution of approximately 12 IgG molecules within a pixel, limited by the surface roughness of the substrate. When applied to reverse-phase immunoassays in an antibody microarray format under 7x magnification, the current limit of detection is 10 ng/ml for 1 hour incubation, limited by biological and chemical variability. The biosensor is compatible with real-time binding measurements under active flow conditions with a binding dynamic range per well of 10(3) and a mass sensitivity of 2 pg/mm(2).