Periodic Reporting for period 2 - ELSAH (Electronic smart patch system for wireless monitoring of molecular biomarkers for healthcare and well-being) Reporting period: 2020-10-01 to 2022-03-31 Summary of the context and overall objectives of the project ELSAH is an EU-funded collaborative project in the area of electronic smart systems that started in January 2019. Our objective is to develop and demonstrate an integrated wearable sensor system (the ‘ELSAH-patch’) for continuous monitoring of molecular biomarker concentrations. By adding molecular detection to their sensing capabilities, we will for the first time realize wearables that provide truly evidence-based support to healthy living. This will lead to better health and well-being, which in turn can be expected to also cause a reduction in the prevalence of diseases of affluence like obesity, cardiovascular diseases, high blood pressure or type 2 diabetes.While currently available wearables rely on monitoring physiological parameters such as the heart rate, an in-depth analysis requires continuous quantification of molecular biomarkers, which naturally entails direct contact with the user’s biofluids. To that end, blood is generally regarded as the gold reference biofluid, but blood sampling is an invasive technique that is incompatible to the needs of wearables users. To overcome this hurdle, a number of wearables are currently in development that make use of non-invasive biofluids such as sweat, saliva or ocular fluid, but these systems generally struggle with specific challenges linked to the nature of the non-invasive sample type, including for example ill-defined correlations of biomarker concentrations. In ELSAH, we are targeting minimally invasive sampling of the dermal interstitial fluid (ISF), which has been proven to be highly similar in biomarker composition to blood. We will probe the ISF by microneedles that have been validated as pain-free. Consequently, we are positive that our approach is most promising for integrating continuous monitoring of biomarkers into wearables for healthcare and well-being applications. We will realize a flexible and integrated smart patch-based wearable sensor system (‘ELSAH-patch’) that quantifies several molecular biomarkers in parallel by minimally invasive microneedle-based sampling and electrochemical detection. The ELSAH-patch will be fully self-sustained by integrating the microneedle biosensor with a microchip, a printed battery and printed electronics (interconnects and antenna structures), thereby enabling independent measurements and secure wireless data transmission to the user’s mobile phone. To demonstrate our ELSHA-patch, we choose the two biomarkers glucose and lactate, which are amongst the most established and prominent biomarkers to support a healthy lifestyle.The ELSAH project consortium unites the interdisciplinary expertise required to achieve our ambitious objectives and brings together ten leading partners from five European countries, including three research institutions, two universities and five companies (two large companies and three SMEs). Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The ELSAH project is structured around realising and validating three system generations of increasing complexity and integration level, with the final 3rd generation system resembling the ELSAH-patch that will be evaluated by volunteers.The 1st and 2nd generation ELSAH system have been assembled and characterized. In the 2nd generation system, on the same flexible PET substrate, the components developed in ELSAH have been integrated: microneedle-biosensor with Glucozyme-based biofunctionalization, microchip-board, printed antennas and printed battery. Measurements performed with the microchip and with a commercial potentiostat showed comparable results. The Master Specification Document (MSD) containing also the proposed layout and process flow for the fabrication of the 3rd generation ELSAH system has been prepared following a design process methodology to align to the requirements for a medical device prototype. Regarding the single components of the ELSAH system, following results have been obtained:- Microneedle biosensor. Polymeric microneedles of the target dimensions have been manufactured from medical-grade polymeric materials. Only platinum (no more gold) will be used for the working and counter electrodes. Direct electron transfer (DET) enzymes for glucose and lactate detection were developed. Development of enzymatic hydrogel-based microneedle biofunctionalisation by dispensing showed first good results. The sterilization process using e-beam resulted compatible with the biosensors and first cytotoxicity tests showed no issues with the biofunctionalization.- Microchip. The ELSAH-microchip integrating all defined specifications on a single low-power silicon chip has been designed, fabricated and integrated. - Printed battery. Two generations of printed batteries supplying to the microchip the required voltage and current for the sensing application have been developed. The battery for the 2nd generation ELSAH-system is already flexible.- Antenna. Two generations of NFC and UHF antennas have been developed and characterised. The improvement of the NFC antenna is in progress for the 3rd generation. 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) Main results achieved beyond the state of the art and expected ones are:- The main aim of ELSAH is the realisation of a flexible and integrated smart patch-based wearable sensor system (‘ELSAH-patch’) for continuous monitoring of health and well-being that quantifies several molecular biomarkers in parallel by minimally invasive microneedle-based sampling and electrochemical detection.- Polymeric microneedles have been manufactured from rigid medical-grade polymeric materials. The use of flexible medical-grade polymeric materials is in development.- Microneedle biofunctionalisation by electropolymerisation of oxidase enzymes for the detection of glucose and lactate has been performed. Direct electron transfer (DET) enzymatic hydrogel-based microneedle biofunctionalisation by dispensing is in development.- A highly integrated and energy-efficient silicon microchip enabling biosensor measurements, data acquisition, data storage as well as secure wireless data transmission has been designed, fabricated and characterised.- Printed eco-friendly battery and printed antennas complying with the required dimensional and electrical parameters are in development.The potential impacts are:- The development of the smart ELSAH-patch system for continuous monitoring of multiple molecular biomarkers will substantially enhance the applicability and usability of wearables in the health and well-being sector, thereby opening up entirely new application areas (e.g. personalised medicine through closed-loop theranostics).- The ELSAH-patch system can support self-care of chronic disease patients and of healthy men / women to prevent the onset of chronic diseases.- The ELSAH-patch system will be of great societal benefit to hobby sportsmen and women as well as to athletes. It will, for the first time, be possible to measure lactate in real-time in an easy to use, cost-effective and noninvasive manner for everyone.- Benefits to healthcare professionals include a reduced danger of infection by using a non-invasive measurement technique. The minimally-invasive nature of microneedle technologies incorporated into the ELSAH-patch means that no blood is drawn, and so the risk of is blood-borne infection is eliminated. The ELSAH-patch for healthcare and well-being. (c) AIT/Purtscher
