Abstract
Cell-based assay based on time-stretch imaging is recognized to be well-suited for high-throughput phenotypic screening. However, this ultrafast imaging technique has primarily been limited to suspension-cell assay, leaving a wide range of solid-substrate assay formats uncharted. Moreover, time-stretch imaging is generally restricted to intrinsic biophysical phenotyping, but lacks the biomolecular signatures of the cells. To address these challenges, we develop a spinning time-stretch imaging assay platform based on the functionalized digital versatile disc (DVD). We demonstrate that adherent cell culture and biochemically-specific cell-capture can now be assayed with time-stretch microscopy, thanks to the high-speed DVD spinning motion that naturally enables on-the-fly cellular imaging at an ultrafast line-scan rate of >10MHz. As scanning the whole DVD at such a high speed enables ultra-large field-of-view imaging, it could be favorable for scaling both the assay throughput and content as demanded in many applications, e.g. drug discovery, and rare cancer cell screening.
Highlights
Accessing detailed spatial information of cells, microscopy allows high-content cell-based phenotypic assay, but at a compromised measurement throughput [1,2]
Notable example is imaging flow cytometry in which streamlines cell interrogation by imaging single cells in suspension at a throughput of 1,000’s cells/sec is achieved [2]. This throughput is still at least two-orders-of-magnitude slower than classical non-imaging flow cytometry because of the inherent speed-versus-sensitivity limitation of the camera technologies. This pervasive problem hinders the acceptance of imaging cell-based assay in high-throughput screening (HTS) applications [3,4,5], e.g. phenotypic screening in the early drug discovery pipeline in which tens of thousands compounds per screen are involved; and circulating tumor cell (CTC) screening in which rare cell detection within enormous and heterogeneous population is mandated
This can be verified by the static images of the same area taken by a conventional light microscope using a 10× objective lens (Nikon Eclipse Ni-U)
Summary
Accessing detailed spatial information of cells, microscopy allows high-content cell-based phenotypic assay, but at a compromised measurement throughput [1,2]. Notable example is imaging flow cytometry in which streamlines cell interrogation by imaging single cells in suspension at a throughput of 1,000’s cells/sec is achieved [2] This throughput is still at least two-orders-of-magnitude slower than classical non-imaging flow cytometry because of the inherent speed-versus-sensitivity limitation of the camera technologies. The ultrafast continuous line-scan imaging (at a rate of tens of MHz) naturally favors imaging flow cytometry applications at a throughput which is impossible elsewhere, e.g. detecting rare cancer cells at 100,000 cells/sec [10] Despite this uniquely fast imaging capability, two key challenges remain in the context of cell-based assay. Planar platform allows space-multiplexed chemically specific cell-capture assays, e.g. arraybased immunoassay These assay types have yet been explored in time-stretch imaging
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