Abstract
In order to reduce medical facility overload due to the rise of the elderly population, modern lifestyle diseases, or pandemics, the medical industry is currently developing point-of-care and home medical device systems. Diabetes is an incurable and lifetime disease, accountable for a significant mortality and socio-economic public health burden. Thus, tight glucose control in diabetic patients, which can prevent the onset of its late complications, is of enormous importance. Despite recent advances, the current best achievable management of glucose control is still inadequate, due to several key limitations in the system components, mainly related to the reliability of sensing components, both temporally and chemically, and the integration of sensing and delivery components in a single wearable platform, which is yet to be achieved. Thus, advanced closed-loop artificial pancreas systems able to modulate insulin delivery according to the measured sensor glucose levels, independently of patient supervision, represent a key requirement of development efforts. Here, we demonstrate a minimally invasive, transdermal, multiplex, and versatile continuous metabolites monitoring system in the subcutaneous interstitial fluid space based on a chemically modified SiNW-FET nanosensor array on microneedle elements. Using this technology, ISF-borne metabolites require no extraction and are measured directly and continuously by the nanosensors. Due to their chemical sensing mechanism, the nanosensor response is only influenced by the specific metabolite of interest, and no response is observed in the presence of potential exogenous and endogenous interferents known to seriously affect the response of current electrochemical glucose detection approaches. The 2D architecture of this platform, using a single SOI substrate as a top-down multipurpose material, resulted in a standard fabricated chip with 3D functionality. After proving the ability of the system to act as a selective multimetabolites sensor, we have implemented our platform to reach our main goal for in vivo continuous glucose monitoring of healthy human subjects. Furthermore, minor adjustments to the fabrication technique allow the on-chip integration of microinjection needle elements, which can ideally be used as a drug delivery system. Preliminary experiments on a mice animal model successfully demonstrated the single-chip capability to both monitor glucose levels as well as deliver insulin. By that, we hope to provide in the future a cost-effective and reliable wearable personalized clinical tool for patients and a strong tool for research, which will be able to perform direct monitoring of clinical biomarkers in the ISF as well as synchronized transdermal drug delivery by this single-chip multifunctional platform.
Highlights
In order to reduce medical facility overload due to the rise of the elderly population, modern lifestyle diseases, or pandemics, the medical industry is currently developing point-of-care and home medical device systems
These systems require catheters that must be inserted in the subcutaneous tissue and replaced occasionally, and potential chemical interferences hamper their application. Other approaches such as sweat and exhalation sampling, skin IR spectroscopy, and even contact lenses were investigated for metabolites monitoring, but they all lack the high blood correlation, metabolites variety, and sampling repeatability required for clinical applications.[10−12] it has been shown that interstitial fluid (ISF) glucose concentrations parallel those of blood glucose concentration, and the same holds for additional metabolites such as lactate, amino acids, drugs, and more.[13−15] In this context, the main challenge is the extraction of the extracellular fluid sample, since it is hard to separate this fluid from the surrounding cells in the tissue.[16,17]
The use of three separate needles enables multiplex sensing, and the redundancy of the sensors in our platform allows for selfcalibration by the use of enzyme-free microneedle elements; a shift caused by a nonspecific reaction would be referred to as part of the baseline
Summary
In order to reduce medical facility overload due to the rise of the elderly population, modern lifestyle diseases, or pandemics, the medical industry is currently developing point-of-care and home medical device systems.
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