Fully Implantable Arterial Blood Glucose Device for Metabolic Research Applications in Rats for Two Months

Abstract

Original ArticleCurrent options for obtaining glucose measurements in animal studies are limited in terms of the quality and quantity of data available. Glucometers and test strips are perhaps most commonly used. These require tail tip amputation or venipuncture, are stressful to the animal and handler, and often result in high measurement variability due to factors including measurement error, variability in the sampling process, and physiologic stress response. The use of arterial or venous cannulae can help facilitate sample collection and minimize subject and handler stress, but these require routine maintenance with blood loss and offer limited chronic patency. Options for continuous sampling for periods of a few days to 2 weeks include tethered automated blood sampling and some limited use of human continuous glucose monitors (CGMs), which have limited longevity and accuracy.Amperometric electrochemical sensors have been available for over 30 years and originated with the Clark electrode.2,3 The basic principle involves application of a reference voltage to an electrode (typically a noble metal such as platinum) to oxidize a target chemical and measure the current resulting from electron transfer to the electrode. The current is proportional to the availability of the target chemical.Many glucose sensors available today or under development are intended for use in humans with the sensor placed subcutaneously to measure glucose in interstitial fluid. These sensors are targeted at the management of diabetes where patient safety and minimal invasiveness are critical factors, thus precluding placement directly in the blood. These sensors are subject to notable biofouling due to foreign body immune response and are typically overgrown with a fibrous sheath in a matter of days. Background: Chronic continuous glucose monitoring options for animal research have been very limited due to various technical and biological challenges. We provide an evaluation of a novel telemetry device for continuous monitoring of temperature, activity, and plasma glucose levels in the arterial blood of rats for up to 2 months. Methods:In vivo testing in rats including oral glucose tolerance tests (OGTTs) and intraperitoneal glucose tolerance tests (IPGTTs) and ex vivo waterbath testing were performed to evaluate acute and chronic sensor performance. Animal studies were in accordance with the guidelines for the care and use of laboratory animals and approved by the corresponding animal care and use committees (Data Sciences International, Eli Lilly). Results:Results demonstrated the ability to record continuous measurements for 75 days or longer. Bench testing demonstrated a high degree of linearity over a range of 20-850 mg/dL with R 2 = .998 for linear fit and .999 for second order fit (n = 8 sensors). Evaluation of 6 rats over 28 days with 52 daily and OGTT test strip measurements each resulted in mean error of 3.8% and mean absolute relative difference of 16.6%. Conclusions:This device provides significant advantages in the qualit...

Long-term blood glucose monitoring with implanted telemetry device in conscious and stress-free cynomolgus monkeys

“…Fourthly, fixation of subcutaneously inserted sensor for stable data collection in physically active monkeys is very challenging. To stabilize implanted sensor and to avoid any delay of glucose reading, this study used the implanted HD-XG telemetry device to access arterial vasculature and provided real-time blood glucose information [ 12 ].…”

“…In addition, sensing glucose from the blood directly has the potential to reduce or eliminate many issues commonly encountered with interstitial glucose sensing [ 11 ]. The HD-XG implantable glucose device (Data Sciences International, Saint Paul, MN, USA) provides continuous measurement of blood glucose, temperature, and locomotor activity for up to 2 months in rodents [ 12 ]. This study investigated the real-time changes of blood glucose during circadian, meal, stress procedures, and drug exposures by the modified HD-XG transmitter device in conscious, moving-free cynomolgus monkeys ( Macaca fascicularis ) with or without diabetes.…”

Comparison of Continuous Glucose Monitoring between Dexcom G4 Platinum and HD-XG Systems in Nonhuman Primates (Macaca Fascicularis)

“…Fourthly, fixation of subcutaneously inserted sensor for stable data collection in physically active monkeys is challenging. In contrast, the HD-XG telemetry system can stabilize an implanted sensor in an artery and stably provide almost instant glucose readings 16 . However, compared with Dexcom G4 Platinum subcutaneous placement, the HD-XG telemetry method is relatively more invasive as the sensor has to be placed in a main artery.…”

“…Another telemetry system, HD-XG implantable glucose device (Data Sciences International, Saint Paul, MN, USA), provides continuous measurement of blood glucose, temperature and locomotor activity for up to 2 months in rodents and NHPs 16 , 17 . The system has an electrochemical glucose oxidase sensor placed in one main artery for real-time measurements of blood glucose plus temperature and physical activity.…”

Vascular Glucose Sensor Symposium

“…Vascular CGMS failure may occur after several months due membrane degradation, enzyme denaturation, and/or electrode fouling. [146][147][148] Medical Research Group, Inc (acquired by Medtronic) developed a long-term implantable vascular catheter CGMS that utilized glucose-oxidase/catalase enzymes and differential oxygen electrodes to measure the concentration of plasma glucose. A novel mechanical design and multilayered porous membrane ensured an excess supply of oxygen, protected the enzymes from degradation, and compensated for dynamic changes in the ambient oxygen concentration.…”