Nanoscale biosensors have remarkable theoretical sensitivities, but often suffer from sub-optimal limits of detection in practice. This is in part because the sensing area of nanoscale sensors is orders of magnitude smaller than the total device substrate. Current strategies to immobilize probes (capture molecules) functionalize both sensing and non-sensing regions, leading to target depletion and diminished limits of detection. The difference in topography between these regions on nanoscale biosensors offers a way to selectively address only the sensing area. We developed a bottom-up, topographically selective approach employing self-assembled poly(N-isopropylacrylamide) (PNIPAM) hydrogel nanoparticles as a mask to preferentially bind target to only the active sensing region of a photonic crystal (PhC) biosensor. This led to over one order of magnitude improvement in the limit of detection for the device, in agreement with finite element simulations. Since the sensing elements in many nanoscale sensors are topographically distinct, this approach should be widely applicable.

We report on a modified solid-state nanopore measurement scheme to probe alcohol-soluble proteins. Taking advantage of the intrinsic alcohol solubility of LiCl as an electrolyte, we show that the devices can be operated in azeotropic mixtures of ethanol and water. We first characterize nanopore conductivity across a range of ethanol content as a function of both nanopore diameter and salt concentration, showing ionic response that can be understood through established models. Then, as a demonstration of resistive-pulse sensing, we measure and interpret electrical translocations of zeins, a class of alcohol-soluble maize protein.