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Diabetes is one of the most prolific diseases in human history, claiming almost 2 million lives every year. It affects the cells ability to uptake glucose present in the blood to produce energy, which can lead to hyperglycemia and other co-morbidities if left untreated. Thus, the monitoring of these glucose levels is a key management strategy and is an ongoing challenge faced by people suffering from diabetes mellitus daily. The technology and knowledge necessary for this has progressed rapidly, allowing for a quick and reliable measure of blood glucose levels through the measurement of the serum marker HBA1c that relates to the level of glycated hemoglobin in the blood. However, modern glucometers are invasive and need a fresh sample of blood, this requirement is a major factor in diminished patient compliance with treatment and regulation. Developments in non-invasive glucose monitoring can remove this issue by using technology that detects changes in the blood glucose such as iontophoresis and spectroscopy. These methods, while not perfect, have already seen some success in technological trials and future research into the potential for self-regulation of glucose levels within a closed loop system is promising.
Diabetes mellitus (DM) is a pandemic that has affected over 451 million people worldwide in 2017 and is expected to affect and estimated 693 million by 2045 (GAIL FERNANDES, 2018). It affects the bodys ability to produce and utilize insulin, leading to hyperglycemia as cells are unable to use glucose for energy (Florez, 2016). The monitoring of blood glucose is has evolved from obscure methods such as urine tasting used in the past, to modern blood glucose strips of colorimetry. As technology improved, more advanced glucometers were developed, eventually self-calibrated precise self-monitored blood glucose biosensors are available (Kranti Shreesh Khadilkar, 2013). Glycated hemoglobin (HBA1c) estimation remains the gold standard for monitoring glucose as an endpoint for drug intervention studies (SK, 2012). Additionally, performing these tests frequently (up to 4 times a day) is an essential part of chronic diabetes management. As almost all commercially successful blood glucose monitoring devices are invasive, such self-testing technique depend on inconvenient and painful sampling of blood from the tip of the finger which has been shown to compromise patient compliance (Trisha Dunning, 2013). Thus, there is a tremendous need to develop non-invasive blood glucose monitoring devices that will alleviate the pain and suffering of diabetics associated with frequent measurements. Numerous developments in non-invasive technological field have been taking place over the past decade, emphasizing the need for a critical review of the current methods and its potential future applications.
DM can be split into two types. Type 1, earlier referred to as ‘juvenile-onset diabetes’, accounts for 5-10% of diabetes and is caused by cell-mediated autoimmune destruction of pancreatic ²-cells which produce insulin (GAIL FERNANDES, 2018). It usually presents as extreme hyperglycemia and ketoacidosis, and as the body is unable to produce insulin, the only current therapy is to provide regular injections throughout the day. Further research into the cause of this auto-immune destruction is needed, but it is known to be linked to the HLA gene, which regulates the expression of the immune system (Florez, 2016). Type 2 on the other hand, is more widespread, accounting for 90-95% of all cases. The patients affected show insulin resistance and relative insulin deficiency, rather than a complete absence (Surendra S. Borgharkar, 2019). As such, they may not need insulin therapy to treat it and a combination of medication and a healthy lifestyle has been shown to mitigate the effects (Mahbub Alam, 2019). With age, obesity, and absence of physical activity, the risk of developing type 2 DM rises. In some racial / ethnic subgroups (African American, American Indian, Hispanic/Latino, and Asian American) it occurs more frequently (Florez, 2016). A genetic predisposition is often observed, more so than type 1, however the genetic basis for the disease is still poorly understood and the presumed family genetic history can be explained by the shared lifestyle and environmental factors associated with DM.
HBA1c is a glycated type of hemoglobin that is increased in patients with DM (Trisha Dunning, 2013). It measures a physiological mechanism of non-enzymatic glycation, a surrogate for glycation for other proteins in the body and a precursor to the complications that arise from diabetes. Serum HBA1c levels are not affected by short term changes in diet and can therefore be used as a measurable biomarker to provide an indirect estimate of the progressive onset of DM (Kranti Shreesh Khadilkar, 2013). However, all circumstances affecting the lifespan of red blood cells and haemoglobinopathies can lead to non-glycemic differences and unreliable HBA1c measurements. Therefore, HBA1c must therefore be cannot be reliably used circumstances that result in conditions such as anemia and chronic kidney disease (Surendra S. Borgharkar, 2019). Another significant restriction is that it does not portray the glycemic variability in the short term, it is therefore of no value for taking acute or short-term decisions. It may not be appropriate in instances where there is a need to monitor and regulate glycemic control in a short time, such as gestational DM (Kranti Shreesh Khadilkar, 2013).
Iontophoresis has been studied as a potential method of non-invasive glucose measurement (NGM). It is a process already used as accepted in the medical community as a method to deliver transdermal drugs using voltage gradient (Mahbub Alam, 2019). This method can be modified by reverse iontophoresis to transport glucose in the opposite direction to the electric potential. The glucose molecules in the interstitial fluid are uncharged, and thus are carried from the anode to the cathode by the movement of charged ions, where they are collected and measured using a standard glucometer (SK, 2012). A recent proof of concept has taken this concept and applied it into a tattoo which consists of anodic and cathodic contingent inks. The potential of this research is massive as once realized, it could allow the patient to monitor their glucose levels without having to carry a separate device or take blood in public, which carries a certain stigma within society (Wenzhao Jia, 2014). However, while it has been successfully adopted into technology, there are some drawbacks to its use compared to HBA1c measurement. The primary goal of NGM to reduce pain is challenged, as frequent exposure to the electrical currents has been shown to cause skin irritation in trials. The sensor is also heavily affected by the salt ions present in sweat, so they must be stationary for the duration of the measurement (SK, 2012). A potential solution to the electricity induced irritation problem can be seen in recently patented technology; a method for the continuous monitoring of blood glucose (CGM) in a patient’s blood vessel using a non-invasive sensor composed of a radio band patch antenna. The device determines the blood glucose concentration in a blood vessel based on the non-invasive antenna sensor’s resonant frequency shift based on the level of glucose within. It uses non-ionizing electro-magnetic radiation and poses no danger of provoking adverse side effects in the patient (USA Patent No. US20190231237A1, 2019).
When light is focused on biological samples, it reflects, disperses and transmits on the basis of the sample’s structural and chemical composition (SK, 2012). Consequently, some NGM methods are aimed at determining the optical signature of glucose, allowing it to be differentiated from and measured within the blood non-invasively. The concentration of glucose within the blood plasma has been seen to affect red blood cells (RBCs) membrane, bioimpedance spectroscopy is utilized in such a manner to detect changes within a red blood cells membrane and relate it to the level of glucose in the blood. However, the results can be affected based on the water content of the blood as well as by diseases that affect the membranes of RBCs (Mahbub Alam, 2019). Raman spectroscopy is a solution to this problem as it measures the wavelengths of scattered light within blood to detect signals specific to glucose. Water has a low scattering index and does not interfere with this method (SK, 2012).
Non-invasive continuous blood glucose management is a step that science will need to take if the problem of DM is to be solved for good. HBA1c monitoring, while functional and usable by a majority of patients is reliant on patient compliance and self-regulation. A continuous glucose monitoring device connected to an insulin pump in a closed loop forms the fundamental background of an artificial pancreas, which is the end goal of diabetes management, and is an unrealistic dream with todays technology. However, with an optimistic outlook, along with future research into non-invasive measurements can eventually realize this dream of a self-regulating pancreas and the eventual elimination of diabetes as a major worldwide threat.
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