Gregor Ocvirk

The Clinical Research Tool: A High-Performance Microdialysis-Based System for Reliably Measuring Interstitial Fluid Glucose Concentration

Background: A novel microdialysis-based continuous glucose monitoring system, the so-called Clinical Research Tool (CRT), is presented. The CRT was designed exclusively for investigational use to offer high analytical accuracy and reliability. The CRT was built to avoid signal artifacts due to catheter clogging, flow obstruction by air bubbles, and flow variation caused by inconstant pumping. For differentiation between physiological events and system artifacts, the sensor current, counter electrode and polarization voltage, battery voltage, sensor temperature, and flow rate are recorded at a rate of 1 Hz. Method: In vitro characterization with buffered glucose solutions (cglucose = 0 − 26 × 10−3 mol liter−1) over 120 h yielded a mean absolute relative error (MARE) of 2.9 ± 0.9% and a recorded mean flow rate of 330 ± 48 nl/min with periodic flow rate variation amounting to 24 ± 7%. The first 120 h in vivo testing was conducted with five type 1 diabetes subjects wearing two systems each. A mean flow rate of 350 ± 59 nl/min and a periodic variation of 22 ± 6% were recorded. Results: Utilizing 3 blood glucose measurements per day and a physical lag time of 1980 s, retrospective calibration of the 10 in vivo experiments yielded a MARE value of 12.4 ± 5.7. Clarke error grid analysis resulted in 81.0%, 16.6%, 0.8%, 1.6%, and 0% in regions A, B, C, D, and E, respectively. Conclusion: The CRT demonstrates exceptional reliability of system operation and very good measurement performance. The ability to differentiate between artifacts and physiological effects suggests the use of the CRT as a reference tool in clinical investigations.

Electrochemical Glucose Biosensors for Diabetes Care

Blood glucose monitoring (BGM) is the most successful application of electrochemical biosensor technology and has motivated tremendous improvements in biology, chemistry, measurement, and fabrication methods of biosensors. The performance of electrochemical biosensors used for BGM has improved greatly over the last four decades. Technological advance has allowed to measure blood glucose (BG) over a wide range of glucose concentration, a wide temperature and hematocrit range in the presence of an abundance of interfering substances with ever-increasing accuracy, and precision in minute sample volumes. The use of optimized enzymes, mediators, and electrochemical measurement methods enables this tremendous progress in performance. Continuous glucose monitoring (CGM) systems based on minimally invasive amperometric sensors, inserted into the subcutaneous tissue, have significantly improved over initial offerings over the last 15 years with regard to time of use, accuracy, reliability, and convenience due to a multitude of parallel advances: materials needed for enzyme immobilization, polymeric cover membranes, and biocompatible coatings needed to tackle the response by the complex body interface have been developed; wireless transfer and processing of unprecedented data volume have been established; effortless and painless insertion schemes of ever smaller sensors have been realized in order to overcome the concerns of persons with diabetes (PwDs) to use a minimally invasive sensor; and scalable manufacturing technologies of miniaturized minimally invasive sensors have allowed for ever improved reproducibility and increased production volume. Looking ahead, the demands on blood glucose system performance are expected to grow even as the pressures to lower the cost of systems increase. The drive for the future is to continue to push the limits on system performance under real-life conditions while lowering cost, all while finding ways to provide the best medical value to PwDs and healthcare providers. Technical issues of commercially available CGM sensors remain to be solved which currently impede reliable hypo- and hyperglycemic alarms, safe insulin dosing recommendations, or insulin pump control at any time of use. It is realistic to assume that continuous glucose monitoring (CGM) systems will be adopted in the future by a larger population of PwDs. Yet it is also clear that BGM systems will remain a major choice of the great majority of PwDs on a global scale. This review offers a technical overview about user, system, and major regulatory requirements and available suitable sensor technology and demonstrated performance of electrochemical BGM and CGM systems from an industrial R&D perspective.