Nano-plasmonics and electronics co-integration in CMOS enabling a pill-sized multiplexed fluorescence microarray system

The ultra-miniaturization of massively multiplexed fluorescence-based bio-molecular sensing systems for proteins and nucleic acids into a chip-scale form, small enough to fit inside a pill (∼ 0.1cm³), can revolutionize sensing modalities in-vitro and in-vivo. Prior miniaturization techniques have been limited to focusing on traditional optical components (multiple filter sets, lenses, photo-detectors, etc.) arranged in new packaging systems. Here, we report a method that eliminates all external optics and miniaturizes an entire multiplexed fluorescence system into a 2 × 1 mm² chip through co-integration for the first time of massively scalable nano-plasmonic multi-functional optical elements and electronic processing circuitry realized in an industry standard complementary-metal-oxide semiconductor (CMOS) foundry process with absolutely ‘no change’ in fabrication or processing. The implemented nano-waveguide based filters operating in the visible and near-IR realized with the embedded sub-wavelength multi-layer copper-based electronic interconnects inside the chip show for the first time a sub-wavelength surface plasmon polariton mode inside CMOS. This is the principle behind the angle-insensitive nature of the filtering that operates in the presence of uncollimated and scattering environments, enabling the first optics-free 96-sensor CMOS fluorescence sensing system. The chip demonstrates the surface sensitivity of zeptomoles of quantum dot-based labels, and volume sensitivities of ∼ 100 fM for nucleic acids and ∼ 5 pM for proteins that are comparable to, if not better, than commercial fluorescence readers. The ability to integrate multi-functional nano-optical structures in a commercial CMOS process, along with all the complex electronics, can have a transformative impact and enable a new class of miniaturized and scalable chip-sized optical sensors.