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We report the development of a sensitive label-free, cost-effective detection system with simultaneous multi-channel measurement of open circuit potential (OCP) variations for the detection of prostate specific antigen (PSA). We demonstrate a significant increase of 600 times in the sensitivity as compared to the reported literature. To accurately measure OCP variations, a complete monolithic field-effect transistor (FET)-input ultra-low input bias current instrumentation amplifier is used to form the electronic circuit to measure the variation between a working electrode and a reference electrode. This amplifier electronic system setup provides a differential voltage measurement with high input impedance and low input bias current. Since no current is applied to the electrochemical system, a true and accurate measurement of the variation can be performed. This is the first report on the use of DNA aptamers with an OCP system where we employed a DNA aptamer against PSA. An optimised ratio of anti-PSA DNA aptamer with 6-mercapto-1-hexanol (MCH) was used to fabricate the aptasensor using gold electrodes. The electrodes are hosted in a cell with an automated flow system. A wide range of concentrations of PSA (0.1 to 100 ng/mL) were injected through the system. The sensor could potentially differentiate 0.1 ng/mL PSA from blank measurement, which is well below the required clinical range (>1 ng/mL). The sensor was also challenged with 4% human serum albumin and human kallikrein2 as control proteins where the sensor demonstrated excellent selectivity. The developed system can be further generalised to various other targets using specific probes.