Biosensing with holographic smart chips

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The ability to rapidly detect chemical and biological molecules is essential for diverse applications, ranging from biochemical analysis, medical diagnostics, pharmaceutical screening and defence. Most current biosensors, for example DNA-chips or enzyme-linked immunosorbent assays, rely on labelling the sample under investigation with a fluorescent or radioactive tag, which is expensive, time consuming and can potentially perturb the three-dimensional structure of the protein under investigation. While alternative label-free technologies, such as quartz crystal microbalance and surface plasmon resonance, are typically limited by their mass resolution, it has recently been shown that when picomoles of biological molecules react on one side of a microfabricated silicon beam, in-plane surface stresses cause the cantilever to bend. The novel nanomechanical actuation mechanism has important advantages, because cantilevers are microfabricated by standard low-cost silicon technology and, by virtue of the size achievable, are extremely sensitive to detect small molecule chemical and biological interactions, detecting femtomoles of DNA and proteins.In the London Centre for Nanotechnology we have co-developed the first multiple array cantilever biosensor system in the UK in collaboration with Veeco Instruments Inc. However this technology relies on measuring the deflection of the free-end of a fixed cantilever, using a laser-beam. The ability to detect multiple biomolecules is therefore limited to the number of fixed-end cantilevers that can be microfabricated. In addition, the physical measurement apparatus cannot be separated from the biochemical environment, making everyday clinical use challenging. Also, as in all fixed array-based combinatorial methods where scale-up is derived from increasing the number and density of elements in the array, chemical crosscontamination and physical cross-talk represent significant hurdles. Our speculative engineering proposal promises to resolve all of these problems by separating the delicate measurement tool entirely from the much cruder biomechanically active elements, the cantilevers. The radical departure that we are seeking to implement is to untether the cantilevers from the substrate which anchors them in the traditional scheme, and simply to measure their bending when they are free objects in solution. The underlying idea is to use advanced optics to measure the surface normals at several points simultaneously as the chips tumble in a flow moving through a narrow channel, and from that, to reconstruct the bending. Our scheme will be able to search for many different oligonucleotides and proteins in a single fluid specimen because different biological receptors can be tethered to different chips, and the chips themselves can be labelled with unique holographic tags. In clinical application, we envision the mixture of tens of thousands of such chips with the biological solution, followed by pumping of the resultant slurry through a microfluidic reader (essentially a miniaturised supermarket barcode scanner) with on-board integrated optics and associated digital processing to perform the shape determination. To conclude, the ability to rapidly detect biomolecules using holographic smart chips forges a radically new approach to high-throuput proteomics, biosensing and medical diagnostics.