Search

Significant progress in the field of solid-state biosensors has occurred over the last decade. Various types of sensing devices with high-density integration and flexible configuration, as well as new applications for clinical diagnosis and healthcare, have been developed using blood, serum, and other body fluids such as sweat, tears, and saliva. In this review, we focus on the recent progress of solid-state biosensors in the biomedical field. New concepts, technical achievements, and practical applications of the sensors are described and discussed from the perspective of sensing materials, sensor structures, design of biomolecular recognition, and biomedical applications. Several challenges remain before the solid-state biosensors are realized for point-of-care testing in clinical diagnosis and healthcare. Collaboration among researchers, integration of technologies, and knowledge from different fields are necessary to tackle the remaining challenges.

An organic electrochemical transistor (OECT) with a trisaccharide-grafted conductive polymer channel was developed for human influenza A virus detection under aqueous conditions. A target recognition element was introduced into the electrochemical amplifier of the OECT for highly sensitive, selective, and label-free virus sensing. 3,4-Ethylenedioxythiophene (EDOT) and its derivative bearing an oxylamine moiety (EDOTOA) were electrochemically copolymerized on the channel region composed of a PEDOT:PSS thin film. The trisaccharides composed of Sia-α2,6′-Gal-Glu (2,6-sialyllactose), a specific receptor for the hemagglutinin used as a spike protein on the surface of human influenza A virus, were covalently introduced into the EDOTOA unit. Changes in the drain current of the OECT were observed following virus adsorption onto the 2,6-sialyllactose-functionalized channel. A signal transduction mechanism involving a doping effect due to the adsorption of negatively-charged virus nanoparticles is proposed. The limit of detection was more than two orders of magnitude lower than commercial immunochromatographic influenza virus assays over the same detection time. Because of its processability with printing technologies and low power consumption, the OECT device developed here may be suitable for the wearable monitoring of influenza virus infection.

Conductive polymers, such as poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS), can be used for specific biosensing after its surface is modified with functional groups. Herein, we report a simple two-step surface modification method for commercially available PEDOT:PSS films printed on a flexible substrate. The derivatization process involves: (1) the introduction of an ethylenediamine linker for conjugation with the biorecognition element by activating the sulfonate group in PSS with an acid chloride reaction; and (2) the introduction of FPBA into the ethylenediamine linker. As a proof of concept, 4-carboxy-3-fluorophenylboronic acid (carboxy FPBA) is covalently introduced to the side chain of the PSS dopant in the conductive layer. FPBA serves as a selective molecular recognition element for diol compounds, including glucose, at neutral pH. Continuous glucose monitoring is achieved by label-free potentiometry using FPBA-functionalized commercial PEDOT:PSS films. Negative potential responses with glucose are successfully achieved in ideal and realistic buffer solutions with or without 1% fetal bovine serum (FBS) because of the complexation of FPBA. The dynamic range of the enzyme-free sensor covered physiologically relevant blood glucose levels of 70–140 mg/dL. The developed method is suitable and cost effective for the mass production of biosensors as it can be applied to a large surface area at once. Furthermore, various ligands and receptors can be introduced onto commercial PEDOT:PSS films using this technique. Hence, the proposed method has potential applications in wearable and implantable biosensors.

A planar amperometric oxygen sensor has been developed using a printing method for an Ag anode and a four-layered structure for an electrolyte solution. The sensor consists of four glass substrates stuck together by epoxy resin. A Pt cathode and an Ag anode are deposited on one of these glass substrates by r.f. sputtering and by printing, respectively. An internal electrolyte solution is enclosed in the structure and sealed off by an oxygen-permeable membrane. A linear relationship is obtained between the reduction current and the partial pressure of oxygen in the range 0–600 mmHg. The current at an oxygen pressure of 100 mmHg is stable for more than 2000 h. The amount of Ag anode patterned by the printing method is found to be sufficient for continuous long-term use. Based on methods and structures similar to those described in this paper, it should be possible to fabricate miniaturized oxygen sensors and biosensors.

A urea sensor based on an ammonium-ion-sensitive field-effect transistor has been realized in combination with an immobilized urease membrane. The effect of buffer concentrations on the response characteristics of the sensor is investigated. The lower detection limit, as given by the calibration curve, is strongly affected by the concentrations of potassium and sodium ions, while its slope in the appropriate buffer solution is independent of the buffer concentration in a limited urea concentration range. Although the slope in physiological saline solution is only 18 mV/dec, the dynamic range of the sensor covers the physiological range of urea in blood. The small slope and the narrow dynamic range are found to be due to poor selectivity of the ammonium-ion-selective membrane over sodium and potassium ions. It is, therefore, possible to improve the sensor response characteristics by improving the selectivity of the ammonium-ion-selective membrane.

An integrated chemical sensor with multiple ion and gas sensors, composed of four ISFETs (pH, Na + , K + and Cl − ) and two gas sensors ( P O 2 and P CO 2 ) on a 4 mm × 4 mm chip, is realized using semiconductor processing. The ISFETs are based on an Si 3 N 4 -gate ISFET, and use polymeric membrane except for the pH ISFET. The P O 2 sensor is a miniaturized Clark-type sensor, consisting of a Pt cathode and Ag/AgCl anode patterned by the lift-off process. The P CO 2 sensor is a miniaturized Severinghaus-type sensor using a pH ISFET. All of the ISFETs show sensitivities over 50 mV/decade, and a linear range between 1 × 10 −4 and 5 × 10 −1 mol/l. The sensitivities of the P O 2 and P CO 2 sensors are 0.35 nA/mmHg and 42 mV/decade, respectively, and their response times are 30 s and 1 min, respectively. The integrated chemical sensor with multiple ion and gas sensors could be used for clinical analysis.

A novel concept of high pressure liquid chromatography is presented, involving a silicon chip with an open-tubular column and a conductometric detector, a chip holder and a pressure pulse driven injector using a conventional liquid chromatography pump and valves. The design and optimization of the chromatograph and the chip are discussed. A 5 × 5 mm chip containing an open-tubular column of 6 μm × 2 μm × 15 cm was fabricated, which has theoretical separation efficiencies of 8000 and 25 000 plates in 1 and 5 min, respectively. The total column volume is 1.5 nanoliter and the detection cell volume 1.2 picoliter.