An integrated wearable microneedle array for the continuous monitoring of multiple biomarkers in interstitial fluid.

Implementations of wearable microneedle-based arrays of sensors for the monitoring of multiple biomarkers in interstitial fluid have lacked system integration and evidence of robust analytical performance. Here we report the development and testing of a fully integrated wearable array of microneedles for the wireless and continuous real-time sensing of two metabolites (lactate and glucose, or alcohol and glucose) in the interstitial fluid of volunteers performing common daily activities. The device works with a custom smartphone app for data capture and visualization, comprises reusable electronics and a disposable microneedle array, and is optimized for system integration, cost-effective fabrication via advanced micromachining, easier assembly, biocompatibility, pain-free skin penetration and enhanced sensitivity. Single-analyte and dual-analyte measurements correlated well with the corresponding gold-standard measurements in blood or breath. Further validation of the technology in large populations with concurrent validation of sensor readouts through centralized laboratory tests should determine the robustness and utility of real-time simultaneous monitoring of several biomarkers in interstitial fluid.

Microneedle-Based Detection of Ketone Bodies along with Glucose and Lactate: Toward Real-Time Continuous Interstitial Fluid Monitoring of Diabetic Ketosis and Ketoacidosis.

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 ß-hydroxybutyrate (HB) as the dominant biomarker of ketone formation. Such real-time HB detection has been realized using the ß-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 µM), 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.