The For applications of clinically relevant biosensors

The latest development in Blood Glucose Monitoring and Detection.
Diabetes mellitus is an incurable disease resulting from an insufficiency of insulin in the body, causing elevated blood-glucose levels, known as hyperglycaemia, or reduced glucose concentrations, known as hypoglycaemia. A plethora of biosensors have been developed to provide diagnostic information regarding patient’s health status. Many different types of sensors have been investigated, and a 2010 review by Toghill and Compton provides a great insight into enzymatic and non-enzymatic electrochemical glucose sensing approaches studied over the past decade. Spectroscopic methods for non-invasive glucose detection have also been growing in popularity, with Raman and infrared spectroscopy being the focus of particular attention . For applications of clinically relevant biosensors the reader is directed to excellent reviews by Corrie et al. and Yoo et al.
However, the real challenge that remains is the creation of biosensors for daily use by patients in personalised monitoring . Several reviews focusing on sensor integration into wearable platforms have been published recently ,therefore, this review focuses solely on recent advances pertaining to biological fluids other than blood, such as interstitial fluid, sweat, breath, saliva and ocular fluid, and focusing particularly on non-invasive approaches which may enable continuous glucose monitoring for diabetics.
Electrochemical sensors were chosen for blood-glucose measurements due to their high sensitivity, on the order of µM to mM, good reproducibility and ease of fabrication at relatively low cost. GOx was employed as the enzymatic basis for the sensor, owed to its high selectivity for glucose. Less common enzymes, such as hexokinase and glucose-1-dehydrogenase were also used for glucose measurements, but GOx can tolerate extreme changes in pH, temperature and ionic strength in comparison with other enzymes. Withstanding these conditions can be important during any manufacturing processes,making it a prime candidate for glucose monitoring devices. In the design of first generation sensors, oxygen was employed as the electron-acceptor, which can result in errors from variations in oxygen tension and limitations, known as the oxygen deficit.
Intraoral dental accessories have also been of interest for non-invasive and continuous monitoring to provide information regarding a patient’s health status. A tooth has the potential to act as a continuous monitoring device as it is in constant contact with the patient’s saliva. Mannoor et al. have developed a bacterial detection approach whereby a graphene-based nanosensor was printed on to water-soluble silk and transferred on to tooth enamel. This sensing tooth incorporates a resonant coil to prevent the need for a power source and external connections. The device operates by the self-assembly of antimicrobial peptides on to the single sheet of graphene, where the bio-selective analysis of bacteria can be performed at a single cellular level. Preliminary results showed great specificity, response time and single-molecule detection abilities for this sensor, however this sensing application must still be tested on-body for real-time analysis. This approach could potentially be adapted for detection of other analytes such as glucose, by means of a chemical glucose sensor immobilised on to a water-soluble silk layer attached to the tooth enamel.
Gao et al. recently reported a non-invasive and continuous wearable glucose-sweat sensing device . Sensors integrated in to this Bluetooth-enabled wristband detect skin temperature, sodium, potassium, lactate and glucose concentrations in sweat. An advantage of this approach is the use of multiple sensors which overcomes limitations of single, stand-alone sensors . Due to the complex nature of sweat, multiple sensors are required to provide a more comprehensive profile of sweat composition and enable data cross-comparisons. For example, it is known that the potassium concentration in sweat is quite stable during basal and exercising states. As a result, potassium levels can be used as a reference for comparing the fluctuating concentrations of other analytes, such as glucose and enable real fluctuations to be distinguished from artefacts . This device was designed to exhibit similar form factors of existing devices, such as the fitness wristbands by Fitbit Inc. thereby encouraging user uptake to create a pathway to commercialisation. The sensors were tested individually in situ and collectively in the device. The sensors were placed close to the skin, to allow for immediate analysis of sweat as it emerged. Sweat was absorbed into a water-absorbent thin rayon pad for stable and reliable glucose readings, placed between the electrode sensors and skin. This flexible wearable Sensors sensing system is a promising platform for tracking multiple physiological analytes during exercise.
The continuous and non-invasive glucose detection in saliva, using everyday dental platforms, including mouth guards and dentures, as well as novel devices, such as dental tattoos . Several research groups, including that of Kim et al. have investigated the potential use of a mouth guard as a minimally invasive continuous monitoring platform for metabolite sensing in saliva. This sensing platform encompasses a printable enzymatic electrode, based on lactate oxidase, for the detection of salivary lactatewith high sensitivity, selectivity and stability in human saliva samples. This amperometric electrochemical sensing approach uses a poly-orthophenylenediamine (PPD) or lactate oxidase reagent layer with a printable Prussian-blue transducer, where the Prussian-blue reagent acts as the ‘artificial peroxidase’ to offer a highly selective detection approach for hydrogen peroxide in the catalytic reaction.

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