Non-Invasive Fluorescence-based Tear Glucose Sensor Integrated to a Smartphone

Project Information

GlucoTear

Grant agreement ID: 751249

DOI

10.3030/751249

Project closed

EC signature date 30 March 2017

Start date 1 March 2018

End date 29 February 2020

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 170 121,60

EU contribution

€ 170 121,60

Coordinated by

UNIVERSITAT JAUME I DE CASTELLON
Spain

Periodic Reporting for period 1 - GlucoTear (Non-Invasive Fluorescence-based Tear Glucose Sensor Integrated to a Smartphone )

Reporting period: 2018-03-01 to 2020-02-29

Summary of the context and overall objectives of the project

"Diabetes is the most common endocrine metabolic disorder that is currently afflicting nearly half a billion people worldwide according to IDF diabetes atlas 2019. It is associated with elevated blood glucose levels and causes complications such as heart diseases, retina degeneration, kidney failure among others. Diabetes patients must therefore regularly monitor blood glucose to maintain glycemic balance as a regimen or prophylactic measure. Up to now, the glucose meters commonly used for this purpose involve painful finger pricking about 4-5 times a day to obtain blood samples. Since diabetes is a lifelong health compilation, the problems caused by continuous finger pricking cannot be overemphasized. The general implication is that it leads to patient non-compliance and hence poor diabetes management. The other alternative to this painful point-sample self-monitoring is the continuous glucose monitoring using implantable devices. However, the present generations of these devices require routine replacement and calibration by the finger pricking method. Additionally, they are expensive and therefore tightly regulated by insurance companies. A viable option for general public interest is non-invasive blood glucose self-monitoring which has remained a worldwide goal despite over 4 decades of innovation in this field. In the GlucoTear project, the objective is to develop fluorescence-based glucose sensor that is integrated to a Smartphone and utilizing fluorescent carbon particles capable of detecting glucose concentration in tear samples. This would avoid finger-pricking method and instead use tear samples that are obtained non-invasively. Overall objectives include: (i) to generate non-toxic fluorescent carbon nanoparticles using laser-based technologies, which are innovative ""green""approaches in the field of nanomaterial synthesis, (ii) to develop a non-invasive, reliable and portable tear glucose sensor based on the fluorescence signals to be detected by a smartphone camera, (iii) to correlate the results of the fluorescence-based tear glucose testing with that of the clinically approved blood glucose sensor in pursuit of a homecare/POC device. The project achieved most of its objectives and milestones for the period, with relatively minor deviations. Further clinical study for the validation of the developed tear glucose sensor is required."

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In GlucoTear project, the following work packages (WP) were performed: WP 1 involved photonic synthesis of 'green' nanocomposites to be utilized in fluorescence glucose sensing. The aim was to obtain highly fluorescent material that also has high glucose sensitivity. Consequently, boronic acid functionalized fluorescent carbon quantum dots (CQDs) were prepared. Boronic acid molecular groups are use for glucose sensing because they form selective/specific reversible covalent complexes with 1,3 diols of glucose molecules leading to changes in fluorescence signal. This work was done at UJI using one-step laser irradiation of precursor molecules dissolved in water which resulted to formation of CQDs with high fluorescence quantum yield of 58 %. The glucose sensing substrate developed in WP1 was validated in WP2. This was done by measuring fluorescence signal of the samples before and after adding different concentration of glucose dissolved in water. The change in fluorescence intensity (ΔF) showed linear correlation with glucose concentrations over a wide range (Figure 1) with detection limit down to 1.0 mg/dl which is in the range of glucose levels in tears. Preliminary test of the glucose sensor using real tear samples was done in WP3. The results showed that the sensor could detect glucose in tears with concentration of about 5.0 mg/dl. WP 4 involved integrating this sensor onto a Smartphone. In brief a mobile phone application for quantifying changes of fluorescence light intensity using either the phone camera or light sensor was developed alongside with a 3D printed sample holder to be attached onto the Smartphone. Part of this results have been disseminated in a journal publication under the title ‘Nonlinear Optics to Glucose Sensing: Multifunctional Nitrogen/Boron Doped Carbon Dots with Solid-State Fluorescence in Nanoporous Silica Films’ in the Journal of Particle and Particle System Characterization. A patent has also been submitted to the European patent office under the title ‘carbon dots with improved optical properties’ file No 19382521.3-1105. This submission is now under revision. Technical fields in which these results can be exploited include: non-invasive glucose sensing, LEDs, solar cells and high-resolution imaging. The project was done at Universtat Jaume I (UJI) in collaboration with Hospital General Universitari de Castelló (HGUC) and BQ Mobile Phone Company.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

By employing a new CQDs synthetic route developed during GlucoTear project, boronic acid functionalized CQDs with high fluorescence quantum yield 58 % were obtained. Additionally these CQDs have the following improved optical properties: (ii) high stability against photobleaching when illuminated continuously by light of wavelength 405 nm for a long period of time up to 15 hours. (iii) triple color (blue, green, red) fluorescence emission which is suitable for many applications including biological imaging, sensing and light emitting diodes. (iv) high fluorescence emission in the solid state (quantum yield 46 %).

This project therefore presents an advancement in fabrication of CQDs using environmentally green laser technologies especially because it offers the possibility to monitor CQDs formation which is not possible with other common methods of CQDs formation such as hydrothermal treatment, solvothermal and microwave synthesis. In terms of socio-economic impact and the wider societal implications, the project has addressed the issue of environmentally green production of nanoparticles by using laser technologies as opposed to wet chemical synthesis. In fact relevant innovation activities during implementation of the project involved production of desired functionalized carbon nanoparticles in water medium by laser ablation. In this way, chemical wastes and emission to the environment were minimized. This therefore contributes to European policy of environmentally ‘green’ and clean manufacturing in the field of nanotechnology.

By use of a mobile phone as a glucose sensor, the project has also contributed to the possibility to achieve personalized e-health in the field of non-invasive point-of-care diabetes diagnostics and monitoring. Besides glucose sensing, other potential users of the fabricated fluorescent carbon dots would be manufacturers of solar cells, Light emitting diodes (LEDs), intense laser protection devices (for human eyes and optical installations) and dyes for high resolution imaging microscopy.

A plot of change of fluorescence of CQDs against glucose concentration