Bioanalysis systems including optical integrated circuit

Medicilon offers comprehensive and FDA/CFDA GLP-compliant bioanalysis services to support preclinical and clinical development for small molecule drugs, biologics, vaccines and biomarkers. Email:marketing@medicilon.com.cn Web:www.medicilon.com

The present invention generally relates to bioanalysis systems and methods, such as Surface Plasmon Resonance systems, involving optical circuits. In particular, the present invention relates to using optical circuits to improve management of light in bioanalysis systems such as Surface Plasmon Resonance and providing improved sample arrays.

The following presents a simplified summary of the invention in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the invention. It is intended to neither identify key or critical elements of the invention nor delineate the scope of the invention. Rather, the sole purpose of this summary is to present some concepts of the invention in a simplified form as a prelude to the more detailed description that is presented hereinafter.

The present invention provides systems and methods that mitigate problems associated with the inefficient management of light in conventional SPR systems. In this connection, the inventors have discovered that many of the concerns associated with SPR are attributable to the inefficient management of light. Optical Integrated Circuits (OICs) are integrated into SPR systems to provide advances such as high throughput and high sensitivity which consequently make SPR a much more attractive technology in drug discovery. The bioanalysis systems and methods of the present invention permit faster and simpler discovery of new targets for drugs, identification of such targets, and screening candidate entities as directed to the targets. Moreover, the present invention enables the identification of receptors for targets of unknown function.

One aspect of the invention relates to a bioanalysis assay system, such as an SPR system, containing a light source; a metallic support; a light detector, such as reflectance spectrophotometer; and at least one OIC. Another aspect of the invention relates to a method of monitoring a binding event, involving directing light at a metallic support, detecting light reflected from the metallic support, and analyzing properties of the reflected light, wherein directing light and/or detecting light involves the use of an OIC, or the light detector may be part of the OIC.

Another aspect of the invention relates to a disposable microwell array for the bioanalysis system, such as the SPR system, containing a silicon substrate having an insulation layer formed thereover; a plurality of wells formed on a top surface of the silicon substrate; and a metallic layer on the silicon substrate within each of the wells. A first member of a binding pair may be attached to the metallic layer in some cases with appropriate intermediate linking layers while a second member of a binding pair is contacted with the first member simply by exposure to a sample solution and a second reagent. A glass or plastic substrate may be employed in place of the silicon substrate.

Another aspect of the invention relates to a method analyzing distribution in a Z direction and orientation of mass relative to a planar or graded (continuous or not continuous) SPR surface using at least one of multiple wavelengths, physical surface modification, depth profiling, and polarization analysis. The Z direction is normal to the SPR surface. The method permits the evaluation of specific binding versus nonspecific absorption and concentration and binding profiles of specifically bound mass.

To the accomplishment of the foregoing and related ends, certain illustrative aspects of the invention are described herein in connection with the following description and the annexed drawings. These aspects are indicative, however, of but a few of the various ways in which the principles of the invention may be employed and the present invention is intended to include all such aspects and their equivalents. Other advantages and novel features of the invention will become apparent from the following detailed description of the invention when considered in conjunction with the drawings.

The sensitivity in index measurement is directly related to the measurement sensitivity of SPR for molecules. In one embodiment, the about 1×107 or more index sensitivity translates to detection of molecules with a mass of less than about 750 Daltons at less than about 50% coverage. In another embodiment, the about 1×107 or more index sensitivity translates to detection of molecules with a mass of less than about 500 Daltons at less than about 50% coverage. Even higher molecular sensitivity can be achieved with a design that allows detection sensitivity for about 10% or less coverage.

The SPR systems of the present invention facilitate monitoring and measuring protein interactions. Proteins are large molecules with molecular masses in the range of thousands of Daltons. Such a large mass can lead to a large change of index. However partial coverage of the SPR surface is frequently the case and the high sensitivity of the SPR systems of the present invention allows the detection of low coverage. In a kinetic measurement, the rate sensitivity is dependent on the initial low coverage range. The high sensitivity enables more accurate kinetic measurement rates for protein binding.

The use of OICs in the SPR systems of the present invention allows enhanced dynamic range to be achieved along with the enhanced sensitivity as described above. A large change in sample refractive index (or thickness) shifts the point of minimum reflectivity outside of the wavelength range for the initial linewidth of the SPR signal. The AWG that is used, for example, in one embodiment, has a high sensitivity but also has a wide dynamic range. The AWG works in a high defractive order, typically higher than about 50. Also associated with the design is the free spectral range that gives the scanning range for a single high resolution scan. By coupling an appropriate wavelength source to a different input waveguide a different diffractive order may be used. Consequently, the same high resolution can be obtained in a separated wavelength channel. As an example, by shifting the wavelength source by 150 nm, the same resolution of about 1×10−7 index or more can be obtained even though the index has changed by about 0.05. In one embodiment, the dynamic range for measurement is thus at least about 1:500,000 in index. In another embodiment, the dynamic range for measurement is thus at least about 1:500,000,000 in index. With such a dynamic range, index changes smaller than about 1×107 in index can be distinguished.

The SPR systems of the present invention facilitate nonspecific background (NSB) rejection. Another aspect of the invention relates to a method analyzing distribution in a Z direction and orientation of mass relative to a planar or graded (continuous or not continuous) SPR surface using at least one of multiple wavelengths, physical surface modification, depth profiling, and polarization analysis. The Z direction is normal to the SPR surface. The method permits the evaluation of specific binding versus nonspecific absorption and concentration and binding profiles of specifically bound mass.