Feasibility of Continuous Ketone Monitoring in Subcutaneous Tissue Using a Ketone Sensor

Abstract

Background: The feasibility of measuring β-hydroxybutyrate in ISF using a continuous ketone monitoring (CKM) sensor using a single calibration without further adjustments over 14 days is described.

Methods: A CKM sensor was developed using wired enzyme technology with β-hydroxybutyrate dehydrogenase chemistry. In vitro characterization of the sensor was performed in phosphate buffered saline at 37°C. In vivo performance was evaluated in 12 healthy participants on low carbohydrate diets, who wore 3 ketone sensors on the back of their upper arms to continuously measure ketone levels over 14 days. Reference capillary ketone measurements were performed using Precision Xtra® test strips at least 8 times a day.

Results: The sensor is stable over 14 days and has a linear response over the 0-8 mM range. The operational stability of the sensor is very good with a 2.1% signal change over 14 days. The first human study of the CKM sensor demonstrated that the sensor can continuously track ketones well through the entire 14 days of wear. The performance with a single retrospective calibration of the sensor showed 82.4% of data pairs within 0.225 mM/20% and 91.4% within 0.3 mM/30% of the capillary ketone reference (presented as mM at <1.5 mM and as percentage at or above 1.5 mM). This suggests that the sensor can be used with a single calibration for the 14 days of use.

Conclusions: Measuring ketones in ISF using a continuous ketone sensor is feasible. Additional studies are required to evaluate the performance in intended patient populations, including conditions of ketosis and diabetic ketoacidosis.

Keywords: continuous ketone monitoring; diabetes ketoacidosis; factory calibration; ketogenic; β-hydroxybutyrate.

Figure 1.

Change in the sensor response with sequential addition of ketone aliquots (solid line is the mean and shaded area is 1 standard deviation of the data from 16 sensors). Sensors were immersed in PBS at 37°C while aliquots of 1 M ketone were added to produce step responses: 1, 2, 3, 4, 6, and 8 mM.

Figure 2.

Plot of calibrated sensor response as a function of ketone concentration.

Figure 3.

Change in sensor response (solid line is the mean and shaded area is 1 standard deviation of the data from 16 sensors) at 8 mM ketone held at 37°C for 14 days.

Figure 4.

Response of 3 sensors simultaneously worn by 1 subject with changing concentration of ketone in the body over the 14 days (336 hours). The reference ketone measurements are overlaid with the sensor responses.

Figure 5.

Plot of ISF ketone values measured by the sensors against capillary ketone strip reference measurements. Number of Paired data points is 3132.