Diabetic ketoacidosis (DKA), a severe complication of diabetes mellitus with potentially fatal consequences, is characterized by hyperglycemia and
metabolic acidosis due to the accumulation of ketone bodies, which requires people with diabetes to monitor both glucose and ketone bodies. However,
despite major advances in diabetes management mainly since the emergence of new-generation continuous glucose monitoring (CGM) devices capable of in
vivo monitoring of glucose directly in the interstitial fluid (ISF), the continuous monitoring of ketone bodies is yet to be addressed. Here, we present the first
use of a real-time continuous ketone bodies monitoring (CKM) microneedle platform. The system is based on the electrochemical monitoring of betahydroxybutyrate
(HB) as the dominant biomarker of ketone formation. Such real-time HB detection has been realized using the beta-hydroxybutyrate
dehydrogenase (HBD) enzymatic reaction and by addressing the major challenges associated with the stable confinement of the enzyme/cofactor couple
(HBD/NAD(+)) and with a stable and selective low-potential fouling-free anodic detection of NADH. The resulting CKM microneedle device displays an
attractive analytical performance, with high sensitivity (with low detection limit, 50 mu M), high selectivity in the presence of potential interferences, along
with good stability during prolonged operation in artificial ISF. The potential applicability of this microneedle sensor toward minimally invasive monitoring
of ketone bodies has been demonstrated in a phantom gel skin-mimicking model. The ability to detect HB along with glucose and lactate on a single
microneedle array has been demonstrated. These findings pave the way for CKM and for the simultaneous microneedle-based monitoring of multiple
diabetes-related biomarkers toward a tight glycemic control.