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Isolating live cells after high-throughput, long-term, time-lapse microscopy

Researchers led by Johan Paulsson have engineered a high-throughput microfluidic device for multigenerational culturing, imaging, and tracking of single-cell lineages. The platform is highly customizable and is compatible with many cell types, ranging from bacteria to mammalian cells. Growing cells can be observed across complex and changing environmental conditions by virtually any type of microscopy, and any individual cell(s) of interest can be recovered for further downstream processing such as multi-omics or functional profiling. The team hopes to partner with an industry collaborator to demonstrate high-throughput phenotypic screening and subsequent isolation of select cells in a commercial context.

The device addresses shortcomings with current single-cell screening methods. Cytometry-based techniques often struggle to disentangle genetically heritable states from transient phenotypic variability since only single snapshots are considered, failing to capture dynamic processes. Screens that rely on microplates in turn suffer from limited throughput and require arrayed library formats. Pooled techniques that implicate genetic barcodes require upstream molecular cloning and severely limit the complexity and range of variants that can be characterized. The invention presented here resolves even slight phenotypic differences with quantitative multi-image classifications; operates at high-throughput due to scalable microfluidic designs that allow for parallelized screening; and accepts cellular populations of arbitrary diversities, including pooled genetic libraries and ecological samples, as variants are physically accommodated and collected.

The team believes that the detailed phenotyping and live-cell extraction features – coupled with high throughput and low cost of fabrication – give the technology significant potential to complement, and even supplant in many instances, conventional cytometry- and microplate-based screening tools. A supplementary capability for on-chip intracellular delivery, followed by immediate observation and sorting of top-performing clones, further broadens the scope of applications and may prove to be invaluable for the development of cell-based therapeutics.

This work was published in Nature Methods.

Intellectual Property Status: Patent(s) Pending