TDI imaging system for kinetic studies

#This invention generally relates to imaging objects or particles for purposes of detection and analysis, and more specifically, to a system and method for analyzing the spectral composition, spatial characteristics, and temporal behavior of objects, such as cells, which may be in motion.

#Development of new drugs to treat diseases and other medical problems is an expensive and time-consuming process. The efficiency of the drug discovery process is hindered by the limitations of current cell and particle analysis technology. These limitations affect drug discovery at every stage, including: target discovery, target validation, screening, lead optimization, and clinical development. Cell and particle analysis technology is an important aspect of this problem, because one of the goals of the drug discovery process is to understand the biological effect of potential drug compounds on targeted cell types and the collateral effects on other cell types.

#In many cases, fluorescent tags are used to label both potential drug compounds and various cellular components in order to detect and analyze binding interactions in both in vitro and in vivo assays. In order to distinguish different compounds and biological targets, each can be labeled with a different fluorescent tag. Therefore, the number of compounds and targets that can be simultaneously studied is limited by the number of colors that can be discriminated. Binding interactions in biological systems are dynamic processes that require evaluation at different points in time. Such interactions can occur over intervals of only a few microseconds. Hence, the ability to discriminate the time sequence of events in an assay is a function of the speed with which repeated fluorescent measurements can be made.

#The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same becomes better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein:

#FIGS. 1A, 1B, and 1C are respectively a plan view, an elevational view, and an isometric view of an exemplary imaging system suitable for implementing the present invention, in which particles conveyed by a fluid stream are imaged on a TDI detector;

#FIGS. 2A-2F are a plurality of images of an object produced on the TDI detector over time, for a first embodiment of the present invention in which an object is detected continuously, and the signals produced by the TDI detector in response to the images of the object are rapidly clocked;

#The present invention offers considerable advantages over systems employed for cell and particle analysis in the prior art. In some embodiments of the present invention, these advantages arise from the use of an optical dispersion system in combination with a TDI detector to produce an output signal in response to the images of cells and other objects that are directed onto the TDI detector. Multiple objects can be imaged on the TDI detector at the same time. In addition, the image of each object can be spectrally decomposed to discriminate object features by absorption, scatter, reflection, or probe emissions, using a common TDI detector for the analysis.

#The present invention can be employed to determine morphological, photometric and spectral characteristics of cells and other objects by measuring optical signals including light scatter, reflection, absorption, fluorescence, phosphorescence, luminescence, etc. Morphological parameters include nuclear area, perimeter, texture or spatial frequency content, centroid position, shape (i.e., round, elliptical, barbell-shaped, etc.), volume, and ratios of any of these parameters. Similar parameters can also be determined for the cytoplasm of cells with the present invention. Photometric measurements with the invention enable the determination of nuclear optical density, cytoplasm optical density, background optical density, and the ratios of any of these values. An object being imaged with the present invention can be stimulated into either fluorescence or phosphorescence to emit light, or may be luminescent, producing light without stimulation. In each case, the light from the object is imaged on the TDI detector of the present invention, and the output signal of the detector is analyzed to determine the presence and amplitude of the emitted light, the number of discrete positions in a cell or other object from which the light signal(s) originate(s), the relative position of the signal sources, and the color (wavelength or waveband) of the light emitted at each position in the object.

#An initial application of the imaging system comprising the present invention will likely be as a cell analyzer to determine one or more of the parameters listed above, for cells entrained in a fluid flowing through the imaging system. However, it should also be understood that this invention can be used for imaging other types of moving objects.