On-chip whole-animal manipulation for high-throughput subcellular-resolution in-vivo drug/genetic screening

Techniques for rapid and automated small-animal manipulation and immobilization are necessary for high-throughput in vivo genetic/drug screens using cellular and sub-cellular features in multicellular organisms. We present a suite of technologies for complex high-throughput whole-animal genetic and drug screens. We demonstrate a high-speed microfluidic sorter that can isolate and immobilize Caenorhabditis elegans in a well-defined geometry, an integrated chip containing individually addressable screening chambers for incubation and exposure of individual animals to biochemical compounds, and a device for delivery of compound libraries in standard multiwell plates to microfluidic devices. The immobilization stability obtained by these devices is comparable to that of chemical anesthesia and the immobilization process does not affect lifespan, progeny production, or other aspects of animal health. The high-stability enables the use of a variety of key optical techniques. We use this to demonstrate femtosecond-laser nanosurgery and three-dimensional multiphoton microscopy to study neural regeneration at sub-cellular resolution in vivo.