A High-Precision, Low-Cost Hybrid System for Biomedical Multi-Marker Diagnostic Applications

Abstract

Summary Point-of-care biosensing for multiple marker detection requires multiple-site detection, ease of use, portability, and low cost. State-of-the-art measuring systems are based on optical detection, but such techniques demand bulky, expensive, and often delicate instrumentation. Systems based on electronic detection are good candidates for the next generation technology for biosensors. Integration of electrodes and electronics onto the same silicon die for biosensing and molecular diagnostic applications has advantages in terms of high parallelism, small probe volumes and low noise. On the other hand, VLSI solutions have high non-recurring-engineering cost and are not suited for small volume production. Hybrid electronic circuits connected to a passive disposable support featuring a limited number of electrodes represent a more cost-effective solution for moderate-parallelism (less than 100 sites) applications, such as protein biomarker monitoring. The main challenge in this case is lower accuracy and higher noise levels due to connectors and limited device matching. In this work we demonstrate a flexible system based on hybrid electronics for capacitive biosensing that achieves signal-to-noise ratios compatible with micro-fabricated arrays of passive electrodes. Biosensor operating principle Our biosensing approach relies on the principle of chronoamperometry, i.e., the measurement of the time constant associated with the electrical transient which follows the application of a voltage step to a pair of bio-functionalized electrodes immersed in a solution. The system presented in this work is based on a printed circuit board and allows addressing and excitation of multiple electrode couples (in this prototype implementation up to 16), as well as the parallel measurement of the transient characteristics. The key design specification is detection of capacitive impedance variations between 4% and 20%. Results The measurement circuit provides a square wave through a follower stage and switches to excite several sensing sites of the biosensor independently. The response RC decay signal is amplified and sampled by an NI-DAQ acquisition device (sampling rate: 400 kHz). The load resistor and the amplification factor can be selected to tune the decay constant in a certain range (around 100 μsec). The addressing devices on the PCB allow an independent measurement of each site. The switches and the follower stage can be considered transparent to the excitation signal, and the noise is independent of the excitation voltage between −100 mV and 100 mV. Signal distortion caused by the limited bandwidth of the amplifier is negligible for transients longer than 1 μs decay time. Parasitic elements influence the response transient when the measured capacitance is lower than 100 pF. This lower capacitance limit corresponds to an electrode size of 100 μm × 100 μm, which is fully adequate to moderate density arrays. As an example of the use of the system, 1 mm2 gold electrodes with a self-assembled monolayer of ethylene glycols were measured. The response transient was well represented by an exponential, and the capacitance value was 11.6 nF and was determined with a relative standard deviation of 1.5%, which fully meets the design specification.