Abstract: Fouling on the surface of biomaterials and medical devices by proteins and microorganisms in the body severely hinders device functionality and drastically shortens lifetime. Currently, there is high demand for coatings that mitigate this biofouling. In this invention, the use of polyacrylamides has been explored in hydrogel coatings by building the largest library of acrylamide-based copolymer anti-biofouling hydrogels (>160 combinations) to date. A combinatorial approach was used, exploiting the ease of hydrogel synthesis to examine a high-throughput screening of platelet adhesion, precursor to thrombosis and a common culprit in biofouling. Applicability has been demonstrated of top-performing polyacrylamide-based hydrogel by (i) coating affinity-based electrochemical biosensors in vitro in a whole blood assay, and (ii) through coating an electrochemical aptamer-based device for real-time monitoring of analytes in an in vivo closed-loop system.