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    • 1. 发明申请
    • CORRELATION CONFOCAL MICROSCOPE
    • 相关协同显微镜
    • WO2011136857A2
    • 2011-11-03
    • PCT/US2011/020186
    • 2011-01-05
    • TRUSTEES OF BOSTON UNIVERSITYSIMON, DavidSERGIENKO, AlexanderGOLDSTEIN, Lee, EdwinWEBB, Robert, H.
    • SIMON, DavidSERGIENKO, AlexanderGOLDSTEIN, Lee, EdwinWEBB, Robert, H.
    • G02B21/00G01B9/04
    • G02B21/0004G02B21/0056G02B21/0084
    • A correlation confocal microscope uses correlated photon pairs to improve resolution. It employs a source of a light beam converging to a point location on a sample, and an objective that gathers light from the point location and generates an image beam. A modulator applies a spatial pattern of modulation to the source light beam to define spatially correlated photons whose spatial correlations are preserved in modulated light gathered from the sample. A filter applies a modulation-selective filter function to the image light beam to generate a filtered light beam of like-modulated photons. A coincidence detector detects temporally coincident photon pairs in the filtered light beam, generating a pulse output that indicates the magnitude of a light-detectable property (such as transmissivity or reflectivity) of the sample at the point location. The modulator may apply phase modulation and the filter may be a phase-sensitive component such as an interferometer.
    • 相关共焦显微镜使用相关的光子对来提高分辨率。 它采用会聚到样本上的点位置的光束源,以及从点位置收集光并产生图像束的目标。 调制器将调制空间模式应用于源光束以限定空间相关光子,其空间相关性保留在从样本收集的调制光中。 滤波器将调制选择滤波器功能应用于图像光束以产生经过调制的光子的滤波光束。 符合检测器检测滤波光束中的时间上重合的光子对,产生指示样品在点位置处的可光可检测特性(例如透射率或反射率)的幅度的脉冲输出。 调制器可以进行相位调制,并且滤波器可以是诸如干涉仪之类的相敏元件。
    • 3. 发明申请
    • READING OF FLUORESCENT ARRAYS
    • 读出荧光阵列
    • WO2004017374A2
    • 2004-02-26
    • PCT/US2003/025702
    • 2003-08-18
    • CLINICAL MICROARRAYS, INC.MONTAGU, Jean, I.WEBB, Robert, H.
    • MONTAGU, Jean, I.WEBB, Robert, H.
    • H01L
    • G01N21/6452B01J2219/00315B01J2219/00387B01J2219/00533B01J2219/00605B01J2219/00612B01J2219/00637B01J2219/00641B01J2219/00722B01J2219/00725B01J2219/0074C40B40/06C40B40/10C40B60/14G01N21/274G01N21/6428G01N21/6456G01N33/54393G01N33/582
    • Reading of fluorescent arrays (103) in clinical settings is made possible by a reader (110) constructed to employ dark field illumination of the array, and mapping an image of the array onto a solid state sensor array (146) with image dimensions (D;) of the same order magnitude as the dimensions (D() of the fluorescent array, preferably with reduction of image. High intensity illumination is employed, non uniformities of which being compensated by normalization employing intensity calibration features (164) in the array itself, that are sensed during imaging of the array. Preferably high intensity light emitting diodes (122, 132, 402, 404), such as used in traffic lights, are employed for excitation of the array, preferably the excitation being introduced to the array via a solid internally reflecting homogenizer (130). Intermediate depth of field collection and imaging optics enable substantial collection of light, with NA in the range of 0.30 to 0.60, preferably in the range of 0.4 to 0.55. The resultant relatively large depth of field is in some advantageous cases compensated by absorbing light that tends to travel beyond the spots being imaged and would otherwise create noise fluorescence, the absorption produced e.g., by an opaque metal oxide coating (304) that is interposed between a substrate (302), preferably an ultra-thin substrate, on which the array lies, and the much thicker glass or other rigid support (306). For clinical purposes the arrays comprise fewer than 1000 spots, as is appropriate for protein, one example being an array of fewer than 500 spots. Relatively large spot sizes are employed, i.e. of the order of at least 80 or 100 micron diameter spots or preferably larger, 150 or 300 micron spots. Resolution of such spots to at least 50 pixels on the solid state detector array enables suitable binning and other manipulations leading to highly accurate results. Novel methods of assays and diagnosis such as cancer diagnosis employ the reader in detecting a set of markers related to the disease, for instance ovarian cancer.
    • 临床设置中的荧光阵列(103)的读取可以由构造为采用阵列的暗场照明的读取器(110)进行,并且将阵列的图像映射到具有图像尺寸(D)的固态传感器阵列(146)上 )与荧光阵列的尺寸(D())相同的数量级,优选地具有图像的降低。采用高强度照明,其非均匀性通过使用阵列本身中的强度校准特征(164)的归一化来补偿 优选地,在交通灯中使用的高强度发光二极管(122,132,402,404)用于激励阵列,优选地,激励被引入阵列通过 内部反射均匀器(130),中间景深采集和成像光学元件可实现大量的光收集,其中NA在0.30至0.60的范围内,优选在0.4 t o 0.55。 所产生的相对较大的景深在一些有利的情况下通过吸收倾向于超过被成像的斑点的光而被补偿,否则将产生噪声荧光,例如通过不透明的金属氧化物涂层(304)产生的吸收,所述不透明金属氧化物涂层 阵列所在的衬底(302),优选地是超薄衬底,以及更厚的玻璃或其它刚性支撑件(306)。 对于临床目的,阵列包含少于1000个点,如适用于蛋白质,一个实例是少于500个点的阵列。 使用相对较大的光斑尺寸,即大约至少80或100微米直径的斑点或优选较大的150或300微米光点。 在固态检测器阵列上将这样的斑点分辨率至少为50像素使得能够进行合适的合并和其他操作,从而获得高度准确的结果。 新的测定和诊断方法如癌症诊断使用读者检测与疾病相关的一组标志物,例如卵巢癌。