Paper-Based Electrochemical Diagnostics for Blood, Urine, and Saliva: Matrix Effects, Miniaturization Constraints, and Engineering Strategies

Paper-based electrochemical diagnostics have emerged as promising point-of-care (POC) platforms for rapid, low-cost analysis of biofluids such as blood, urine, and saliva. Compared to colorimetric assays, electrochemical detection enables more objective and quantitative readouts while preserving portability and capillary-driven operation. This review summarizes recent advances in integrating electrochemical sensing with paper-based platforms, including microfluidic paper-based analytical devices and lateral flow systems, and their use in techniques such as voltammetry and impedance spectroscopy. Key challenges to reliable performance in real samples are identified, particularly biological matrix effects and miniaturization constraints. Variability in biofluid composition, including hematocrit, protein fouling, ionic strength, and viscosity, can disrupt mass transport, alter conductivity, and reduce signal stability. These effects are amplified in miniaturized systems, where small volumes and reduced electrode areas increase susceptibility to noise and drift. Engineering strategies to address these challenges include antifouling surface modifications, integrated sample conditioning, electrode optimization, redox-mediated signal enhancement, and matrix-aware calibration. Overall, future progress depends on integrated device designs that ensure reproducibility and reliability in real-world samples.