Objective
To date, there are no systems that monitor ketones in a continuous and real-time fashion and provide timely feedback necessary for supporting DKA treatment decisions. The goal of the proposed research is to optimize, characterize, demonstrate, test and validate a fully integrated and user friendly wearable microneedle electrochemical sensor array, capable of monitoring simultaneously ketone bodies (via beta-hydroxybutyrate, BHB) and glucose. The tiny enzyme-functionalized microneedle sensors will be inserted painlessly underneath the skin to contact the interstitial biofluid where they will collect clinically relevant information regarding changing BHB and glucose levels in real time. By developing a stand-alone skin-worn integrated CKM/CGM sensor patch and critically validating its accuracy using T1D patients, the proposed project will advance state-of-the-art in early DKA detection and assessment and treatment of DK/DKA, and of diabetes management technology, in general. To realize this objective, we will finalize and optimize the design elements and operation of the skin-worn microneedle system and demonstrate its attractive analytical performance in vitro within the initial 18 months. Subsequently, in the following 18 months, we will implement a clinical trial demonstrating and validating the accuracy of this device across a wide spectrum in patients living with T1D. Upon completion of the project, we will deliver a functional continuous ketone monitor, ready for use by T1D patients, providing early diagnosis of DKA and transforming the management of diabetes and the patient outcomes.
Background Rationale
Motivated by the biomedical importance of achieving continuous detection of diabetes biomarkers in the body, we propose here to develop a wearable microneedle sensor for real-time monitoring of ketone bodies along with glucose. Diabetic ketoacidosis (DKA) is a life threatening complication of both type 1 and type 2 diabetes mellitus that continues to have high rates of morbidity and mortality. Ketone bodies are commonly tested in-vitro by using capillary blood meters which measure β-hydroxybutyrate (BHB), as the most important index in DKA diagnosis. However, such test strips cannot track the trends and dynamic fluctuations of BHB concentrations and hence cannot lead to timely treatment. Among the recently introduced wearable chemical sensing platforms, microneedle sensors have received considerable attention for simple, rapid, continuous, painless, transdermal sensing of various biomarkers in the body interstitial fluid (ISF). The PI’s team has pioneered the field of microneedle electrochemical biosensors for transdermal monitoring of metabolites over the past decade and recently described a proof-of-concept microneedle detection of the key DKA biomarker BHB. This pioneering study lays the foundation for the current proposal. Unlike common single-analyte (glucose) CGM systems, microneedle sensor array platforms offer a distinct advantage of performing multiplexed simultaneous detection of multiple biomarkers on the same footprint. By designing and optimizing a microneedle sensor array of individually addressable electrodes, functionalized with enzymes specific to BHB and glucose, we will thus introduce a minimally-invasive dual-analyte platform for simultaneous real-time monitoring of glucose/BHB markers in ISF towards effective assessment of DK/DK and toward multiplexed detection multiple diabetes-related biomarkers and diabetes management, in general.
Description of Project
Diabetic ketoacidosis (DKA) is a severe life-threatening complication of diabetes mellitus with potentially fatal consequence and a significant risk for people living with T1D. Detection of ketones is critical to avoid the onset of DKA, yet to date, there are no systems that monitor ketones in a continuous and real-time fashion. The development of such reliable miniaturized diagnostic system is the ultimate goal of this project. Specifically, we propose to optimize, characterize, demonstrate, test and validate a fully integrated wearable microneedle electrochemical sensor array capable of monitoring ketone bodies (via beta-hydroxybutyrate, BHB) and glucose. Microneedle sensors are skin-worn microscale devices that have garnered considerable recent attention due to their ability to obtain continuously useful molecular diagnostic information concerning numerous disease markers. Our main effort will focus on developing a reliable, stable and selective real-time detection of the dominant ketone biomarker BHB in connection to a specific (enzymatic) recognition reaction occurring at the at the microneedle tip. The systematic optimization of the microneedle BHB microneedle sensor will be followed by critical characterization of its analytical performance. The ketone microneedle sensor will subsequently be expanded to provide a real-time dual-analyte glucose/BHB detection using the same physical footprint. This will be realized by functionalizing a neighboring microneedle electrode with a glucose-specific enzyme. The integrated continuous ketone/glucose monitoring (CKM/CGM) will undergo critical clinical testing and validation using human subjects with T1D across a wide range of ketone concentrations, as well as home wear testing of the user experience in non-clinical settings. Upon completion of the project, we will introduce and deliver a fully integrated compact and user-friendly functional ketone monitor that is ready for full clinical development and thus rapidly available to individuals living with T1D.
Anticipated Outcome
The ultimate goal of this project is to achieve two outcomes. First, to finalize development of a wearable stand-alone continuous ketone and glucose meter. Second, is to test this device in a clinical setting to determine the accuracy of the device. The ultimate deliverable of this proposal will be a highly reliable, stable, biocompatible, fully integrated microneedle wireless wearable sensing device that will measure continuously BHB, along with glucose, every 10 min for a period of at least 5 days (as initial goal, with an extended 10-12 day operation in the future).
We will utilize a novel, “microneedle array” technology that will allow for the following capabilities of the device:
• Offer ketone measurements ate 10 min intervals.
• Enable full wireless delivery of collected data to a smartphone for recording and display.
• Can track dynamic BHB changes and alert for potential risks.
• Rely on applicator to accelerate the skin insertion of the microneedle array to achieve reproducible penetration.
• Rely on short ~1 mm microneedle sensors, compared to the 8-10 mm length common in CGM systems.
• Offer continuous 5 days operation (with future extension to 12 days).
• Rely on scalable fabrication method, along with reusable and disposable components, towards a cost-effective compact final product.
This compact system will then be tested in a clinical trial in which patients with T1D will be admitted to our research clinic and have their insulin pumps removed for several hours. Removing patient insulin pumps will cause an increase in ketone levels. During this time, they will be wearing our continuous ketone meter and will have frequent blood samples obtained for ketone levels. The lab obtained ketone levels will be compared to the device readings to determine accuracy. Our group has performed this procedure multiple times and can ensure it will be done safely.
Thus, at the conclusion of the project, we will have taken this wearable device from the research lab to patient care. From this point, our device could be further developed by our group or in collaboration with other device companies.
Relevance to T1D
Continuous glucose monitors (CGMs) have revolutionized T1D care by improving glycemic control, lowering the risk of hypoglycemia, and improving quality of life. However, these devices measure glucose alone and do not measure ketone levels, which are the cause of diabetes ketoacidosis (DKA). DKA is an acute metabolic complication of diabetes mellitus that is life threatening. DKA remains far too common with ~5-7% of patients living with T1D experiencing an episode each year. Therefore, an urgent need exists to develop reliable tools to detect ketones in real-time so that patients can appropriately respond to changing ketone levels to reduce the risk of DKA. DKA has become a topic of renewed interest given the clinical development of SGLT-2i medications. These medications are oral pills that have numerous benefits for patients with type TWO diabetes. Namely they improve glucose levels, lower weight, lower blood pressure, reduce cardiovascular disease, and reduce kidney complications of diabetes. Unfortunately, these medications are not currently approved for type ONE diabetes given they increase the risk of DKA. Therefore, the development of a continuous ketone meter will not only reduce the risk of DKA in general, but also open the door for the safe use of these extremely beneficial medications. Our goal with this project is twofold. First, we will finalize development of a continuous ketone meter. Second, we will test the accuracy of the device in patients living with T1D. By the conclusion of this project, we will have developed the first dual continuous glucose and ketone meter and tested it in patients.