Non-invasive Bioelectronic Devices for Diabetes Management

<p dir="ltr">Diabetes is an ancient disease that has been longstanding in human history for thousands of years. It was named and described of symptoms in the 2nd century AD during the Greco-Roman era. Diabetes is characterized by impaired utilization of glucose, which is the primary cellular energy source. Poor management of diabetes can result in various complications and even death. Centuries of research and exploration have enriched the understanding of diabetes, but the exact cause has not yet been fully uncovered. To date, diabetes patients require lifelong management through careful monitoring of blood glucose levels and preventing diabetic complications. </p><p dir="ltr">Biosensing techniques are vital for monitoring in diabetes management, the representative one is glucose sensing. However, current commercially available glucose meters are still invasive, painful, and can damage skin tissues, posing risks of infection. The pursuit of non-invasive sensing technologies for glucose is crucial to enhance the comfort of long-term diabetes management. Additionally, sensing techniques for other biomarkers have been applied in diagnosing diabetic complications, but these tests are only available at centralized facilities such as hospitals and laboratories. My doctoral research focuses on exploring non-invasive biosensing technologies for applications in diabetes management. This research encompasses three main projects covering four different biomarkers related to various aspects of diabetes. </p><p dir="ltr">The first project is the optical sensing technique for glucose. Utilizing glucose absorbance of near-infrared (NIR) light, the optical sensing approach can quantitatively detect glucose concentrations. Optical sensing technique is inherently non-invasive but faces challenges from water absorption of NIR light. In this work, the spectroscopic analysis identified four glucose absorption peaks counter with water interference: 1605, 1706, 2145 and 2275 nm. Furthermore, a miniaturized glucose optical sensor was fabricated using 1600-1700 nm light, which was decided by the most prominent peaks at 1605 and 1706 nm. The device successfully detects glucose in aqueous solutions within the physiological range of 50-400 mg/dL, attaining a limit of detection (LOD) as low as 10 mg/dL. This work provides a foundational design for future non-invasive glucose sensing, by offering functional light wavelengths and a simplified optical detection system.</p><p dir="ltr">The second project focuses on an inflammatory biomarker, Tumor Necrosis Factor-alpha (TNF-alpha). This biomarker has been confirmed by clinical research for its significance in monitoring diabetic complications and its association with insulin resistance, one cause for type 2 diabetes. Inspired by home-use blood glucose meters and the widely used COVID saliva test kits during the pandemic, the second project proposes a conductometric sensor measuring TNF-alpha levels in saliva. This sensor enables rapid detection, easily accessible resistance signals and conversion to TNF-alpha concentration. The fabricated TNF-alpha sensor has a broad detection range covering levels from 10 to 3000 femtomolar (fM) with a low LOD of 10 fM. Additionally, a Bluetooth-integrated microcontroller successfully measured the resistance of a TNF-alpha sensor and observed the readings on a smart phone. This approach of TNF alpha sensing and reading forms an initial prototype for transforming conventional time consuming and laboratory-based tests. With further research on TNF-alpha and diabetes, this self monitoring method holds the potential to be used together with blood glucose meters in future. It can evaluate diabetic complications, assessing insulin resistance, and optimizing diabetes treatment plans from another focus beyond limitation to monitoring glucose levels only.</p><p dir="ltr">The third project is detecting biomarkers related to kidneys, because kidney disease is one major diabetic complication. About 40% of diabetes patients develop kidney disease, termed diabetic nephropathy. For assessment of kidney function, conductometric sensors for creatinine and cystatin C (cysC) were developed. The sensors successfully detected creatinine and cysC in both phosphate buffer saline (PBS) and artificial saliva in nanomolar (nM) range. The detection limit for both creatinine and cysC was determined as 0.01 nM, which is more than 500× and 1000× times lower than critical concentrations to diagnosis kidney disease by using these two biomarkers, respectively. Moreover, creatinine and cysC sensors were both fabricated following one protocol, with the only difference at antibody immobilization step. A battery-free miniaturized thin-film device for reading sensors signals was fabricated as a proof-of-concept of the ease of use. The outcome and analysis of the third project provide a potential route for assessing kidney function in home and a scalable fabrication process of conductometric sensors for different biomarkers.</p><p dir="ltr">The outcomes of these three projects are all associated with non-invasive sensing techniques for biomarkers related to diabetes management. As searching for a definitive cure for diabetes would be a long-lasting process, these research works would contribute to the transformation of biosensing in diabetes to be a painless, rapid and easily accessible process.</p>