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Electrochemical glucose sensing – is there still room for improvement? Emilia Witkowska Nery, Magdalena Kundys, Paulina Sonia Jele#, and Martin Jönsson-Niedzió#ka Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.6b03151 • Publication Date (Web): 25 Oct 2016 Downloaded from http://pubs.acs.org on October 28, 2016
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Analytical Chemistry
Electrochemical glucose sensing –is there still room for improvement? EmiliaWitkowska Nery*, Magdalena Kundys, Paulina S. Jeleń, Martin Jönsson-Niedziółka Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland ABSTRACT:As diabetes is considered one of the biggest health care challenges of the coming decades substantial effort is being made to develop novel glucose monitoring systems, this includes thousands of articles which are being published every year. To the question in the title, we answer an unequivocal “yes”, but maybe not necessarily in the areas where most of the published research is focused.
1000 diabetic persons per year) and neurological conditions12– . The WHO estimates that 1.5 million deaths were directly caused by diabetes in 2012, with additional 2.2 million related to higher-than-normal blood glucose levels. Addressing this problem the World Health Day 2016 entitled “Beat diabetes” was devoted to this disease15. Novel glucose sensors are constantly described in the literature. However, despite diabetes often being cited as a motivation, in most cases the analyte is chosen not because of potential future applications, but because of price, easy handling, non-toxicity etc. Thus glucose serves only as a model analyte to present novel electrode modification methods. In this review we would like to approach the applicability of such systems; comparing them to commercially available sensors used in glucometers, and analyzing their potential utility for noninvasive methods of measurement based for example on samples such as sweat and tears. We would also like to take a closer look on low-cost diagnostic devices made from paper or thread, which are gathering considerable attention recently. A short analysis of requisites for implantable systems and future trends are presented. 14
INTRODUCTION More than 50 years have passed since the announcement of the first glucose enzyme electrodes by Clark and Lyons in 19621. Currently, around 85% of the biosensor market is formed by glucose sensors2, and glucose is also one of the most popular analytes in the scientific literature with more than 1000 publications per year related to this topic (Scopus search, terms “glucose” and “sensor”, years 2011-2015).Therefore, it is of no surprise that many excellent reviews are already available. Reviews related to electrochemical glucose sensing include ones focused on principles of operation2,3, practical issues of home glucose monitoring2,3, implantable devices2–4 and noninvasive sensing methods4 as well as history5, key developments and examples of successful commercialization4,6–8. Readers interested in optical sensing methods are referred to publications by Steiner et al.9 and Yadav et al.10. Nowadays glucose concentration is mostly assessed in blood, however determination in other body fluids such as urine, sweat, saliva, tears and exhaled air is also possible and this topic was recently reviewed by Makaram et al.11. The interest behind glucose monitoring is of course related to diabetes, a chronic, metabolic disease resulting in abnormal levels of blood glucose. According to a recent report by the World Health Organization (WHO)12 around 422 million people around the world suffer from this illness, 90% of whom are diagnosed with type 2 diabetes. Not counting gestational diabetes, which is a transient state often ending together with the delivery, two types of diabetes are distinguished: Type 1 is an autoimmune disorder in which the immune system wrongly identifies and attacks pancreatic beta cells responsible for the production of insulin. This type requires insulin treatment (insulin triggers liver and skeletal muscle to take up and store glucose). In type 2, persistent overexposure to glucose leads to diminished sensitivity of the organism to insulin. Apart from that, the strain induced on beta cells can result in their permanent failure. As the second type is often associated with behavioral and environmental risk factors treatment is in most cases based on lifestyle changes, such as change of diet, exercise etc. as well as administration of small molecule pharmaceuticals. Regardless the cause of the disease, the complications related to elevated glucose levels are equal for both types and include damage of capillary blood vessels which, depending on the location, can lead to loss of vision (35% of diabetic patients suffer from retinopathy), kidney problems (80% endstage renal disease caused by diabetes), cardiovascular disease (2-3 times higher prevalence rate than non-diabetic), nonhealing wounds (1.5 to 3.5 of lower limb amputations per
GLUCOSE MONITORING -USERS POINT OF VIEW The reluctance of people to make changes to their lifestyle, which could potentially prevent diabetes, also extends to the analysis and control of blood sugar levels in patients already diagnosed with the disease. Many promising systems never reach the market, or are withdrawn from it, due to inconvenient handling, painful sampling or irritation caused during usage or even because of incomprehensible ways of presentation of the results. The ideal system from the user’s point of view should be painless, should not necessitate constant maintenance, provide measurement along the way of other daily activities and present the results in an easy to understand fashion. Having this in mind, systems for continuous monitoring such as teeth-tattoos or implants, contact lenses and watches or skin-tattoos, which do not cause skin irritation have the highest chance of implementation. This trend is clearly supported by corporate giants such as Google and Novartis, currently working on glucose sensing contact lenses, and Apple developing its glucose monitoring watch. The user friendliness issue was already addressed by several companies and has resulted in the creation of numerous helpful smartphone applications. These provide graphical information regarding fluctuations of glucose levels, recommendations and alerts in case of alarming results or even gamification in the form of points and virtual prizes for consistent
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testing habits. Bayer went as far as to connect its glucometer (DIDGET) to a Nintendo gaming platform, which would automatically reward the user with new game levels and options granted for keeping the measurement schedule. On the other hand, different trends will be observed for developing regions, where not only people have to be convinced to use the test, but the measurement system has to be accessible to begin with. The number of diabetic patients is growing most rapidly in low- and middle-income countries, and only in 50% of those low-income countries primary care settings provide access to blood glucose measurements12. Although current disposable test strips are extremely low-cost they are still based on two components, the strip and an electronic reader, which increases the chance of their malfunction in resource limited settings. Current printing and manufacturing technolo-
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gies, and the prototype all-printed device with integrated reader presented by the Acreo Company16 let us believe that one component, extremely low cost systems will be soon available. A third group of patients is formed by people dependent on insulin-therapy. In those cases, the sought after system is the implantable artificial pancreas, combining continuous glucose monitoring with an automatic insulin pump. Although some achievements were already made in this field, current implantable CGM systems still need to be recalibrated at least twice a day and have short working lifetime. The state of the art and possible future directions of the development of those main groups of glucose sensors, are summarised in Fig. 1. Subsequent sections will describe each of these groups in more detail, but first a few words will be given on modern methodologies of electrode modification.
Figure 1 State of the art and future directions of different types of glucose sensors.
ELECTRODES AND THEIR MODIFICATIONS The search for novel enzymatic and non-enzymatic means of glucose sensing is set to intensify due to constantly stricter standards regarding the accuracy of test strips intended for self-monitoring. The new ISO 15197:2013 standard (applicable from May 2016) states that the accuracy of the test strips should be within ± 20% of laboratory results for concentrations above 5.6 mmol/L and within ± 0.83 mmol/L for lower concentrations. As it was shown that some of the commercially available glucose test strips after approval are not meeting even the less rigorous criteria from the ISO 2003 standard17 we can presume that novel electrode materials (enzymatic and non-enzymatic) and configurations (e.g. redundant sensor arrays) aimed at accuracy enhancement are indeed necessary.
ENZYMATIC GLUCOSE SENSING Each body fluid in which the amount of glucose is proportional to its concentration in blood might be analytically useful; the only prerequisite is that other species in the sample should not affect the measurement, either by passivation of the elec-
trode or by acting as electroactive interferents. Highly selective enzymatic reactions can be used to diminish the influence of those interfering species. Glucose oxidase (GOx) – the most popular enzyme used for glucose detection – is able to reduce oxygen to hydrogen peroxide while at the same time transforming glucose to D-glucono-1,5-lactone. Quantification of glucose can be achieved based on either the detection of the hydrogen peroxide produced or the oxygen consumed. Three generations of glucose oxidase biosensors were proposed until now. The first generation is based on measuring peroxide formation and necessitates oxygen, the second uses an additional mediator which transports electrons from the enzyme active site to the electrode, and the third is based on direct electron transfer between GOx and the electrode2. Glucose measurements can also involve interaction with other enzymes such as hexokinase18 or glucose-1-dehydrogenase (GDH) which do not depend upon dissolved oxygen2. When compared with GOx, the most popularly used GDH with FAD co-enzyme (flavin adenine dinucleotide) presents lower specificity and stability but a higher turnover rate19. Most of the commercially available glucose sensors rely on disposable,
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Analytical Chemistry
screen-printed, enzymatic, electrochemical test strips produced by the following major companies: Abbot, Bayer, Johnson &Johnson, and Roche Diagnostics. They can usually be stored for one year or more in up to ~45oC and are extremely lowcost (0.02–0.06 USD per strip)8. Their biggest disadvantages are sampling, which, as they are based on blood is often considered painful and inconvenient, and the relatively low accuracy. Regarding the construction of commercial electrodes, products manufactured by Abbot use FAD-GDH and NAD-GDH (nicotinamide adenine dinucleotide), Bayer uses FAD-GDH, Johnson & Johnson uses both FAD-GDH and GOx and Roche Diagnostics mainly PQQ-GDH (pyrroloquinoline quinone)3. The chosen mediator should re-oxidize at relatively low potentials (
