Abstract:
A test system includes an optical medium, a binding agent capable of capturing a target complex, and a light detector. The optical medium provides a light path, and the binding agent is positioned to hold the target complex in an evanescent field created by propagation of light along the light path. The complex interacts with the evanescent field and emits light that the detector positioned to detect. The optical medium and the detector can be included in an optical integrated circuit where detected light passes through the optical medium transverse to the direction of the light path.

Description:
BACKGROUND 
       [0001]    Diagnostic test kits have been developed for detection or analysis of target biological and environmental species in samples. Such test kits provide convenience since they may be used at a point of care such as a home, a medical facility, or elsewhere. For example, in a work place, a drug test kit can be used to detect one or more specific drugs or drug metabolites in a sample from an employee, a potential employee, or any other person that has agreed to be tested. Diseases, blood chemistry, DNA sequencing, and conditions such as pregnancy can similarly be quickly and conveniently detected using diagnostic test kits at home or wherever the test is desired. 
         [0002]    Many diagnostic tests employ binding assay techniques. In a typical binding assay, a liquid sample is introduced to a flow matrix, e.g., into a test strip, where a labeling substance such as an antibody with an attached dye or florescent material binds to the target species. The complex thus created then flows to an indicator region that is treated to capture and hold the specific complex containing the target species and the labeling substance. The presence of the target species can then be detected through a change in the properties in the indicator region. For example, an accumulation of dye causing the indicator region to change color marks the presences of the target species in the sample. 
         [0003]    Human observation has traditionally been used to determine the test results indicated by the change or lack of change in indicators of a diagnostic test kit. However, automated or electronic test evaluation may more reliably provide results, and integrated test systems or ICs are sought to provide test results without requiring human judgment. Such test systems would ideally be efficient and low cost for economic use in the widest variety of test situations. 
       SUMMARY 
       [0004]    In accordance with an aspect of the invention, a test system can detect the presence of a target species in a sample from light emitted in a direction transverse to the direction of input radiation. The test system can be integrated into a compact and low cost configuration. 
         [0005]    One specific embodiment of the invention includes a light guide and a binding agent positioned to trap a target species or complex in an evanescent field of the light guide. The target species or complex when present interacts with the evanescent field of light propagating through a waveguide and emits light in a direction transverse to the waveguide, for example, by fluorescence or scattering. A detector positioned to detect the emissions transverse to the waveguide can generate a signal indicating a test result. The system can be integrated into an optical integrated circuit containing the waveguide and optionally the detector and a light source, and the binding agent can be coated on an exposed surface of the waveguide and exposed to the sample through a flow matrix. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0006]      FIG. 1  shows an embodiment of a test system in accordance with an embodiment of the invention that detects emissions transverse to the direction of excitation radiation. 
           [0007]      FIG. 2  shows a test system in accordance with an embodiment of the invention in which a lighting system, a waveguide, and a detector are integral parts of an optical integrated circuit that detects transverse emissions. 
           [0008]      FIG. 3  shows a test system in accordance with an embodiment of the invention that detects transverse emissions from multiple indicator regions. 
       
    
    
       [0009]    Use of the same reference symbols in different figures indicates similar or identical items. 
       DETAILED DESCRIPTION 
       [0010]    A compact configuration for a diagnostic test system can be achieved by detecting indicator emissions that are transverse to a direction of input excitation.  FIG. 1  shows an exemplary embodiment of a test system  100 . Test system  100  includes a test strip  110 , lighting system  120 , an optical medium  130 , and a detector  140 . 
         [0011]    Test strip  110  can be of conventional design and may, for example, be made of a hydrophilic fibrous or matt material that provides a flow matrix for transport of a liquid sample by wicking. Test strip  110  also includes one or more labeling substances that are adapted or selected to enter the sample and attach to a target species to form a complex *O. Such labeling substances are well known and may include fluorescent molecules, fluorescent particles, or quantum dots. 
         [0012]    Lighting system  120  introduces electromagnetic radiation (i.e., light) into optical medium  130 . A suitable lighting system  120  can be implemented using an active light source such as a flash lamp, a light emitting diode (LED), a laser diode (e.g., a VCSEL) and/or passive optical elements such as reflectors, lenses, and diffractive elements that collect light and direct that light into optical medium  130 . The electromagnetic radiation input from lighting system  120  includes radiation of an excitation wavelength chosen to excite the labeling substance or the complex *O including the labeling substance, causing the complex *O to fluoresce or otherwise emit light. To reduce background light at the emitted wavelength, lighting system  120  may employ a filter that blocks light having the emitted wavelength while transmitting light having other wavelengths including the excitation wavelength. As described further below, while optical medium  130  controls propagation of light so that light from lighting system  120  propagates only in a plane of optical medium  130 , emissions from the excited complex *O can be in any direction including transverse to the plane of the excitation radiation. 
         [0013]    Optical medium  130  can be any medium capable of guiding the light from lighting system  120 . Some examples of structures suitable for optical medium  130  include but are not limited to an optical light pipe, a thin polymer substrate, or a waveguide that may have a serpentine pattern extending under all or a portion of the area of test strip  110 . Such optical mediums generally include cladding or variations in refractive index that prevent light from escaping the optical medium. However, a well known property of electromagnetic propagation in a waveguide or similar medium is the presence of an evanescent field that extends outside the waveguide. The strength of the evanescent field generally falls exponentially with distance from the interface and depends on the refractive indices of the waveguide and its surroundings. Optical medium  130  is such that the light propagating through optical medium  130  produces such an evanescent field that extends a sufficient distance from the interface to provide a coupling with any of the labeling substance found close to optical medium  130 . 
         [0014]    At the interface of test strip  110  and optical medium  120  are binding agents Y. Binding agents Y may be or contain ligands, antibodies, antigens, proteins, nucleic acid, or other material that is selected to capture and hold the target species or the complex *O including the target species and a labeling substance. Binding agents Y can be coated on optical medium  120 , part of test strip  110 , or otherwise held at a position such that any of the target species or complex *O that binding agent Y captures are held within the evanescent field around optical medium  130 . 
         [0015]    The target species or complex *O as noted above is of a type that interacts with the evanescent field just outside optical medium  130  and then emits at least some light in a direction transverse to optical medium  130 . In an exemplary embodiment of the invention, the target species or complex *O is fluorescent or contains a quantum dot or similar structure that absorbs energy from the evanescent field around optical medium  120  and then emits light or radiation in random directions. Transversely emitted radiation can pass through optical medium  130  and reach detector  140 . If desired, a reflector (not shown) can be provided in or above test strip  110  to reflect light emitted in a direction away from optical medium  130  back through optical medium  130  to be read by detector  140 . 
         [0016]    The input radiation is normally confined to optical medium  130  and an absorber  135  can be provided at the end or edges of optical medium  130  to avoid stray reflection that might reach detector  140 , causing noise. However, with a fluorescent label or quantum dot, a test operation can direct excitation radiation through the optical medium  130  for a limited time and then observe the transverse radiation emitted after the excitation radiation is shut off. This technique can reduce the background or noise signal that might otherwise result from stray reflections or leakage from optical medium  120  while the excitation radiation propagates through optical medium  120 . Alternatively, light emitted from the target complex *O while the excitation radiation is on may provide a measurable signal, so that a label that fluoresces with long decay time is not required, and a target complex *O that merely scatters light from the evanescent field may be also be suitable. 
         [0017]    Detector  140  is a general light detector suitable for detecting the frequency of light emitted from the target complex *O and, for example, may be a PIN photodiode, an avalanche photodiode, an amorphous silicon detector, or a detector array, such as a CCD array or CMOS sensor. Additionally, an emission filter  145  can be employed to reduce signal noise by blocking wavelengths that differ from the wavelength of light emitted from the target complex *O. Emission filter  145  can be, for example, an optical band pass filter or long pass filter with wavelength parameters selected according to the properties of the target complex *O. Conventional optical filter types such as absorbing filters or interference filters can be used for emission filter  145 , but an interference filter may require collimation of the input light, which a micro-channel plate (not shown) between emission filter  145  and binding agents Y might provide. 
         [0018]    Test system  100  can be implemented using discrete or integrated components and may be packaged in a test kit including the elements shown in  FIG. 1  and perhaps a power source and/or a results display or printer. In one embodiment, each of test strip  110 , lighting system  120 , optical medium  130 , and detector  140  are separately fabricated and then assembled to form test system  100 . Alternatively, two or more of the components  110 ,  120 ,  130 , and  140  can be fabricated as part of an integrated structure. 
         [0019]      FIG. 2  illustrates an embodiment of a test system  200  including an optical integrated circuit  210  that incorporates a lighting system  220 , an optical medium  230 , an absorber  235 , a detector  240 , and an emission filter  245 . Lighting system  220 , optical medium  230 , absorber  235 , detector  240  and emission filter  245  perform substantially the same functions and may have substantially the same structure as described above respectively for lighting system  120 , optical medium  130 , absorber  135 , detector  140  and emission filter  145 . However, in test system  200 , lighting system  220  and detector  240  are specifically electronic devices that are fabricated in a substrate and overlying layers of an integrated semiconductor structure. Additional electronic test elements  250  can also be fabricated in integrated circuit  210  using know integrated circuit processing techniques. Such elements  250  may include but are not limited to control circuits for activation and use of test system  200 , signal processing circuits that evaluate electrical signals from detector  240  to determine a test result, light emitting diodes (LEDs) and/or driver circuits for displays or printers providing visual or printed indications of test results, or interface circuits for signal I/O including output of electrical signal indicating test results. Optical medium  230 , absorber  235 , emission filter  245  are optical elements that can be fabricated in or on the semiconductor structure using known techniques. The fabrication process for optical integrated circuit  210  leaves a surface of optical medium  230  available for a coating containing binding agents Y. Test strip  110  can then be attached to optical integrated circuit  210 , and the system can be packaged as desired for convenient use. 
         [0020]    The exemplary embodiments of  FIGS. 1 and 2  illustrate test systems capable of detecting a single target species. Alternative configurations can test simultaneously for multiple species.  FIG. 3  shows an example of a test system  300  capable of simultaneously detecting multiple target species in a liquid sample. The multiplex geometry test system  300  is alternatively or additionally able to provide indicators for both positive and negative controls, which may be required for diagnostic assays. To test for two target species or positive and negative controls, test system  300  includes an optical integrated circuit  310  containing the same elements as described above for optical integrated circuit  210  of  FIG. 2 , except that optical integrated circuit  310  includes an additional light detector  340  and an associated emission filter  345  for detection of a second target species as described further below. To test for two target species, a test strip  310  contains two labeling substances that are adapted or selected to respectively attach to the two different target species to form two distinct complexes *O and *O′. Alternatively, a single labeling substance may be able to form one complex *O or *O′ with one target species attached and a second complex *O′ or *O if a different target species or no target species is attached (i.e., for a negative control.) 
         [0021]    Two different binding agents Y and Y′ are coated on separated indicator regions  312  and  313  on optical medium  230 . The indicator region  312  containing one binding agent Y captures and holds one complex *O in the evanescent field adjacent optical medium  230 , and the indicator  313  region containing the other binding agent Y′ similarly captures and holds the other complex *O′ in the evanescent field adjacent optical medium  230 . 
         [0022]    As illustrated in  FIG. 3 , indicator  312  and  313  regions are respectively positioned so that light emitted in a transverse direction from complex *O reaches detector  240  and light emitted in a transverse direction from complex *O′ reaches detector  340 . Independent electrical signals from detectors  240  and  340  can then respectively indicate the presence and/or quantity of respective complexes *O and *O′. To avoid cross-talk noise, indicator regions  312  and  313  can be laterally separated from each other and optical medium  230  may have a serpentine structure, baffles, or other light blocking structures to prevent light from indicator region  312  from reaching detector  340  and prevent light from indicator region  313  from reaching detector  240 . Alternatively, indicator regions  312  and  313  may be on completely separate waveguides in optical medium  230 . Baffles or separations may be alternatively or additionally be employed in lighting system  220  or between lighting system  220  and optical medium  230  to separate light beams. Emission filters  245  and  345  can also be used to distinguish targeted emitted light when complexes *O and *O′ emit light of different frequencies. 
         [0023]    Although the invention has been described with reference to particular embodiments, the description is only an example of the invention&#39;s application and should not be taken as a limitation. Various adaptations and combinations of features of the embodiments disclosed are within the scope of the invention as defined by the following claims.