Smart Wearable Diabetic Healthcare Materials and Devices

Abstract

Diabetes is a chronic disease that prevents the body from regulating blood glucose properly. The basis for the management of diabetes is blood glucose measurements at least three times a day. Continuous glucose monitoring systems (CGMs) can measure blood glucose fluctuation over time through glucose in interstitial fluids with the minimally invasive method. However, a CGM patch has disadvantages of infection risk and biofouling on the surface of the glucose sensor. To overcome these limitations, non-invasively electrochemical CGMs that measure blood glucose from the glucose concentration of body fluids such as sweat, interstitial fluids, tears, and saliva have been actively researched. Among them, tears constantly produce and drain a certain amount of basal tear every day without an additional circulation system unlike other body fluids such as sweat and saliva, making them suitable as samples for CGMs. In my thesis, Part I presents an overall introduction to CGMs including non-invasive electrochemical CGMs and smart contact lens for CGMs and then parts II-IV describe my Ph.D. research on the development of smart contact lens for diabetic diagnosis with continuous glucose monitoring as described in more detail below. Part II describes an highly sensitive wireless non-invasive glucose sensors with hyaluronate-gold nanoparticle/glucose oxidase (HA-AuNP/GOx) complex. Non-invasive real-time biosensors to measure glucose levels in the body fluids have been widely investigated for continuous glucose monitoring of diabetic patients. However, they suffered from low sensitivity and reproducibility due to the instability of nanomaterials used for glucose biosensors. Here, we developed a HA-AuNP/GOx complex and an ultra-low power application specific integrated circuit (ASIC) chip for noninvasive and robust wireless patch-type glucose sensors. The HA-AuNP/GOx complex was prepared by the facile conjugation of thiolated HA to AuNPs and the following physical binding of GOx. The wireless glucose sensor with exhibited slow water evaporation (0.11 μl·min-1), fast response (5 sec), high sensitivity (247.4 μA·cm-2·mmol-1) and selectivity, low detection limit (0.5 mg·dl-1), and highly stable enzymatic activity (~ 14 d). We successfully demonstrated the strong correlation between glucose concentrations measured by a commercially-available blood glucometer and the wireless patch-type glucose sensor. Taken together, we could confirm the feasibility of the wireless patch-type robust glucose sensor for non-invasive and continuous diabetic diagnosis. Part III describes a smart contact lens for diabetic diagnosis and theraphy. Among various wearable devices, a smart contact lens is especially promising for healthcare applications, because it can be used as an excellent platform to facilitate the interface between the human body and an electronic device. Despite wide investigations on smart contact lenses for diagnostic applications, however, there has been no report on electrically controlled drug delivery in combination with real-time biometric analysis. Here, we developed a smart contact lens for both continuous glucose monitoring and treatment of diabetic retinopathy. The smart contact lens device, built on a biocompatible polymer, contains ultrathin, flexible electrical circuits and a microcontroller chip for real-time electrochemical biosensing, on-demand controlled drug delivery, wireless power management and data communication. In diabetic model rabbits, we could measure tear glucose levels to be validated by the conventional invasive blood-glucose tests and trigger drugs to be released from reservoirs for the treatment of diabetic retinopathy. Taken together, we successfully demonstrated the first example of smart contact lenses for non-invasive and continuous diabetic diagnosis and diabetic retinopathy therapy. Part IV describes a bimetallic nanocatalysts immobilized in nanoporous hydrogels for long-term robust CGM of smart contact lens. Smart contact lenses for CGM have great potential for huge clinical impact. To date, their development has been limited by challenges in accurate detection of glucose without hysteresis for tear glucose monitoring to track the blood glucose levels. Here, we demonstrate that hyaluronated gold@platinium bimetallic nanocatalysts (HA-Au@Pt BiNCs) immobilized in nanoporous hydrogels in smart contact lenses enable reliable CGM in diabetic rabbits. After redox reaction of glucose oxidase, the nanocatalysts facilitate rapid decomposition of hydrogen peroxide and nanoparticle-mediated charge transfer with drastically improved diffusion via rapid swelling of nanoporous hydrogels. The ocular glucose sensors result in high sensitivity, fast response time, low detection limit, low hysteresis, and rapid sensor warming-up time. In diabetic rabbits, smart contact lens can detect tear glucose levels consistent with blood glucose levels measured by a glucometer and a CGM device, reflecting rapid concentration changes without hysteresis. The CGM in a human demonstrates the feasibility of smart contact lenses for further clinical applications. Part V describes a hyaluronated gold/platinum (HA-Au/Pt) bimetallic electrode for long-term stable and accurate smart contact lens for CGMs. CGMs with wearable devices have received much attention as new paradigm medical devices that effectively manage diabetes by non-invasively measuring the trend of blood glucose change over time in body fluids. The duration and accuracy of the CGM system are greatly affected by the stability of electrodes in the glucose sensor. Platinum (Pt) and gold (Au) electrodes with high sensitivity and stability have been mainly used for biosensors that diagnose and monitor a very small amount of biomarkers. However, the low ductility of Pt and large difference of thermal expansion coefficient between Pt and polymer substrate lead to critical defects during strain and heat process, resulting from electrical disconnection. Also, Au electrodes have a problem of corrosion and dissolution due to an electrochemical reaction with chloride ions contained in body fluids. Here, we developed the HA-Au/Pt bimetallic electrodes for long-term stable and accurate smart contact lens for CGMs. The Au thin-film that has low surface energy, a similar lattice constant with Pt and thermal expansion coefficient between polymer substrate and Pt is suitable for stress relaxation layer of Pt thin-film electrode. We prevented the dissolution of the gold electrode by chloride ion in tears by passivating the edge of the Au/Pt bimetallic electrode with branched sulfide hyaluronic acid (branched HA-SH). In diabetic and normal rabbits, we demonstrated that the smart contact lens applied HA-Au/Pt bimetallic electrodes have a high correlation (ρ=0.875) with 98.6 % clinically acceptable data for 3 weeks. Taken together, the smart contact lens with long-term stable HA-Au/Pt bimetallic electrodes will pave to the clinical applications of non-invasive wearable CGMs. Taken together, my PhD thesis reports the successful development of ultra-sensitive and long-term robust smart contact lens for diabetes diagnosis with continuous glucose monitoring. The successful development of smart contact lens for diabetic diagnosis appeared to greatly contribute for the drastically improved performance of noninvasive continuous glucose monitoring systems, showing the feasibility for futuristic medical devices applications.