A Critical Review on Current Devloping Non-Invasive Glucose Monitoring Technologies and Devices


Ajay I Patel, Jenish Rachhadiya, Purvi Vadariya, Amitkumar J. Vysh, Ashok B. Patel

Tapan Heights, C-304, Near Matuki Restaurent 80 Feet Ring Road, Vavdi Rajkot - 04 Gujarat.

*Corresponding Author E-mail: jenishrachhadiya77@gmail.com



Diabetes mellitus both type I and type II, is a dangerous and lifelong disorder marked by unusually high blood glucose levels caused by a failure of insulin synthesis or a loss in insulin sensitivity and function. Diabetes have become more common over time, and it is now considered one of the primary causes of high death and morbidity rates. Complications from diabetes can be avoided by regularly monitoring and keeping blood glucose levels within the normal range. Despite the fact that practically all commercially effective blood glucose monitoring devices are invasive, there is an urgent need to create non-invasive glucose monitoring (NGM) devices that would relieve diabetics' pain and suffering associated with repeated skin pricking for glucose testing. It also discusses the most common non-invasive glucose monitoring technologies as well as the most relevant devices. The technology name, the underlying physical principle, and the technological limitation in the human body. There are eleven technologies and five devices in all. Despite numerous fascinating and promising ideas and devices, the review concluded that a suitable solution to the non-invasive glucose monitoring problem still required more work.


KEYWORDS: Types of diabetes, Method for Glucose Measurement, Non-invansive techniques, Glucose Monitoring Devices.




Diabetes Mellitus is a dangerous condition that arises when the body's ability to regulate the quantity of dissolved sugar in the bloodstream is impaired. Diabetes mellitus is a metabolic disorder marked by an increase in blood glucose levels. Glucose is the primary energy transporter in the human body, with optimal values in whole or capillary blood ranging from 4.9 to 6.9 mmol/L1,2. Human meals are converted to glucose as part of the natural digesting process. After being converted, glucose enters the bloodstream, causing the level of dissolved glucose in the blood to rise.


The dissolved glucose is subsequently carried by the bloodstream to the body's numerous tissues and cells. Despite the fact that glucose is present in the blood, adjacent cells cannot access it without the help of a chemical hormone called insulin. Insulin works as a key to unlock the cells, allowing them to take in and use glucose3. In the presence of insulin, cells absorb glucose from the blood, lowering blood sugar levels as sugar leaves the circulation and enters the cells. A lack of insulin production or insulin sensitivity causes diabetes mellitus. The number and type of meals people consume determine the amount of glucose accessible in their bloodstream at any given time. Diabetes is a leading cause of death and morbidity in all countries3.


By 2045, there will be 700 million adults living with diabetes, up from 422 million in 20214. Diabetes mellitus is an incurable disease with a slew of consequences, including heart disease, nephropathy, neuropathy, retinopathy, and amputations. Dietary control of blood glucose levels, oral medication, and insulin injection are among the therapeutic options; nevertheless, all of these have negative consequences for the patient's quality of life5.


Types of diabetes1,3:

The three main types of diabetes are:

A)  Type I Diabetes

B)   Type II Diabetes

C)   Gestational Diabetes


A)  Type 1 diabetes:

Type I diabetes is thought to be caused by an autoimmune reaction. Type I diabetes is characterized by a lack of insulin production caused by T-cell-mediated autoimmunity that destroys pancreatic -cells. The harm is irreversible. It is most commonly diagnosed in children, adolescents, and young adults, but it can strike anyone at any age. It is less common than type II diabetes, with only approximately 5% of individuals who suffer from it.


B)   Type 2 diabetes:

One of the two major kinds of diabetes, in which the pancreas' beta cells produce insulin however the body is unable to utilize it efficiently because the body's cells are resistant to insulin's action. Type II diabetes necessitates calorie restriction, a reduction in simple carbohydrates and fat consumption, and an increase in complex carbohydrates and fiber consumption.


C)  Gestational diabetes:

Insulin blocking hormones released during pregnancy causes gestational diabetes.


Method for diabetes measurement:

The monitoring of blood glucose levels is essential for blood glucose control. Diabetic patients are advised to monitor their blood glucose levels multiple times per day; the most popular method is to use a finger-prick glucose meter. Finger-pricking has a number of drawbacks5. Furthermore, the finger-prick glucose metre is a one-time glucose measuring instrument that is not suitable for continuous blood glucose monitoring. Between measurements, some cases of hyperglycemia or hypoglycemia may go unnoticed. As a result, the resulting monitoring is unable to accurately reflect the blood glucose trend5.


Almost every commercial blood glucose monitoring device (BGMD) uses a low-cost electrochemical biosensor that can be mass-produced and responds quickly to glucose detection6 In the previous few decades, great progress has been made in developing improved BGMD with a blood sample requirement of less than 1 litre. The pain is reduced by using alternate sampling locations, 32 gauge lancets, and a variety of other ways that are not detrimental to the patient.


Glucose monitoring methods are classified into three categories2,7:

A)  Invasive:

The most often used blood glucose devices are invasive, causing pain to the patient, increasing the risk of infection, and disrupting the diabetes patient's everyday life. Repeated blood draws are uncomfortable and might lead to infection.


B)   Minimal invasive:

The minimally invasive monitoring method is an alternative that causes the least amount of skin damage. Because the human skin is made up of numerous layers, different technologies require different transduction processes to obtain enough blood samples for analysis.


C)  Non-invasive:

Non-invasive glucose monitoring systems are more desirable and effective technology mentioned above. This could make millions of people feel more at ease with having their blood glucose levels checked on a regular basis. Non-invasive glucose testing has been tried on bio-fluids such as saliva, urine, perspiration, and tears in addition to blood glucose testing. Tissue locations such as the tongue, oral mucosa, lip, tympanic membrane, and skin can be used to measure it.


Figure 1: Glucose Measurement Techniques


Non–invasive glucose monitoring techniques:

The majority of non-invasive techniques rely on absorption or transmittance. For different wavelengths, blood glucose has a different absorption spectrum. The substitution of blood with other fluids that may contain glucose, such as saliva, urine, perspiration, or tears, is one possibility for painless alternating glucose management. Reverse Iontophoresis, Raman, light absorption, polarimetry, ultrasound, metabolic heat conformation, thermal emission, electromagnetic, light acoustic, and Bioimpedance spectroscopy have all been used in non-invasive studies7,8.


Iontophoresis / reverse iontophorosis:


Iontophoresis (or, more precisely, reverse Iontophoresis) is based on the flow of a low electrical current through the skin between an anode and a cathode on the skin's surface. The anode and cathode are connected by an electric potential, which causes sodium and chloride ions to migrate from beneath the skin to the cathode and anode, respectively. Sodium ion movement, in particular, is the principal source of current9. Convective flow carries uncharged molecules like glucose together with the ions. Interstitial glucose is transferred across the skin by this flow, and is collected at the cathode, where a standard glucose sensor is positioned for direct glucose concentration detection10,11.



The main disadvantages of this technique are it causes skin-irritation but this may be avoided by reducing time of potential. If patient is sweating significantly so it is not used12.


Near-infrared spectroscopy (Near-IR):


It is a spectroscopic approach that employs light in the near-infrared (750–2500 nm) part of the electromagnetic spectrum. Combination overtone band (2000–2500 nm), first overtone band (1400–2000 nm), and second or higher overtone band (750–1400 nm) are the three primary bands in the NIR spectrum13. It can monitor glucose under the skin to a depth of a few millimetres.  With increasing wavelength, light penetration into the skin reduces. Because of interactions with chromophores within the tissue, light is partially absorbed and dispersed as it interacts with it. Glucose absorption information dominates the combination and initial overtone regions, while scattering information dominates the shorter wavelength region14,15.



Despite over two decades of development, no practical and accurate non-invasive NIR glucose monitoring system has yet to be produced. Because of the dynamic and varied background signals, detecting a non-invasive signal created by low glucose levels is difficult16.


Mid-infrared spectroscopy (Mid-IR):


The absorption of light in the 2500–10,000 nm area of the spectrum is measured in mid-infrared spectroscopy (MIRS) it follows same principal as NIR17. The peaks of glucose and other chemicals in the mid-infrared band are significantly sharper than those in the near-infrared region, which are generally broad and weak. On the other hand, a possible advantage of Mid-IR compared to NIR is that the Mid-IR bands produced by glucose, as well as other compounds, are sharper than those of NIR, which are often broad and weak14.



The fundamental limitation of MIR is its low penetration due to significant light absorption by water and other blood chromospheres. As a result, only reflected light may be evaluated because limited penetration prevents light from passing through a body segment18.


Electromagnetic sensing:


Changes in blood glucose concentration alter its dielectric properties, which can be detected using Eddy current-based electromagnetic sensors.  At a resonant frequency of 2.664 MHz, conductivity-based detection of static and moving blood glucose samples inside a plastic tube showed a sensitivity of 4.4 mmol L1 glucose. Localized nuclear magnetic resonance has been shown to detect glycogen metabolism in the human brain19,20.



Variations in temperature and changes in the dielectric properties of blood caused by other physiological components have a significant impact on glucose measurements with this technology.


Fluorescence technology:


The method involves the stimulation of tissues with precise frequencies of ultraviolet light, followed by the measurement of fluorescence at a given wavelength21. Fluorescence-based glucose sensing in tears has been achieved utilising polymerized crystalline colloidal arrays that respond to varying glucose concentrations via visible light diffraction22. In another experiment, an ultraviolet laser light was utilised to stimulate the glucose solution, and the ensuing fluorescence was observed at 380 nm and was proportionate to the glucose concentration7,23.


Impedance spectroscopy:


A current flow of known intensity through a tissue can be used to determine its impedance. The impedance (dielectric) spectrum can be calculated by repeating the experiment with alternating currents at different wavelengths. The dielectric spectrum is measured in the 100 Hz to 100 MHz frequency range24. Changes in plasma glucose concentration cause a decrease in sodium ion concentration and an increase in potassium ion concentration in red blood cells25. These differences produce changes in the membrane potential of red blood cells, which may be approximated using the dielectric spectrum to determine the permittivity and conductivity of the cell membrane19.



Specific issues, such as the effect of bodily water content and dehydration, as well as some disease conditions, remain unsolved.


Optical coherence tomography:


The optical coherence tomography (OCT) is based on the use of a low coherence light, such as a super luminescent light, The light scatter technique, on the other hand, is based on the delay of backscattered light compared to the light reflected by the reference arm mirror, whereas the backscattered light delay technique is based on the intensity of collected light. A low coherence light is used, as well as an interferometer with a reference and sample arm, a moving mirror in the reference arm, and a photo-detector for measuring the interferometry signal26. The glucose concentrations assessed by OCT using scattering coefficients were comparable to those determined using the light scatter method. A block diagram of the experimental system is reported in Fig. 9. Moving the mirror in the reference arm of the interferometer allows scanning the tissues up to a depth of about 1 mm. By moving the mirror into the sample arm scanning of the tissue surface is obtained. Therefore, this technique has unique capability of in-depth and lateral scanning to obtain two-dimensional images with high resolution. It was used to determine the concentration of glucose in the interstitial fluid of the upper dermis of the forearm's skin19.



It is sensitive to motion arefacts and changes in skin temperature, it has limits27.


Ocular spectroscopy:


Using a hydrogel-bound contact lens, this method monitors the glucose concentration in tears. The contact lens was coated with a 7-meter-thick boronic acid derivatives-based hydrogel wafer, which forms reversible covalent connections with glucose in tears28. A light source illuminates the lens, and a spectrometer detects the change in wavelength of reflected light, which is related to the amount of glucose in tears29.



It is a time difference between glucose in the blood and glucose in tears. Furthermore, while using contact lenses is a non-invasive procedure, it may be painful for some people30.

Polarization changes:


When polarized light passes through a solution containing optically active solutes such as chiral molecules, the light rotates its polarization plane by a particular angle, which is proportional to the concentration of the optically active solutes. Because glucose is a chiral molecule, its light rotation features have long been recognised31. The first proposed non-invasive technique for glucose detection in people is said to be an investigation of the polarization changes generated by glucose. This technology has the advantage of being able to employ readily accessible visible light and optical components that can be easily downsized19



The specificity of this approach is weak since various optically active substances, such as aslbumin, are present in human fluids containing glucose and interfere with the reading. Variations in temperature and pH of the solution might cause inaccuracies32.


Raman spectroscopy:


Using a visible to MIR range laser radiation source, Raman spectroscopy examines scattered light in transparent samples with a longer wavelength and lower intensity than the original light. Because of its low scattering indices, water does not interfere with Raman spectra. Because the Raman spectra are narrow and contain distinct peaks, signal separation is simple33. The spectrum was obtained by focusing a 785 nm laser on the anterior chamber of porcine eyes using an optical fiber. In addition to reducing spectrum acquisition time, surface-enhanced Raman spectroscopy may improve glucose detection sensitivity19,34.



The main drawbacks are laser wavelength and intensity instability, as well as extended spectrum acquisition periods.


Ultrasound technology:


Ultrasound technology uses low-frequency ultrasound to penetrate the skin and monitor blood glucose levels. While this method has theoretical potential, it appears that no more research has been done since Lee's group published their rat skin laboratory findings.  Photoacoustic spectroscopy, a version based on the employment of a laser light for the stimulation of a fluid and measurement of the ensuing acoustic response, is being used.A brief laser pulse excites the fluid at a wavelength that is absorbed by a specific molecular species in the fluid.Light absorption induces localised microscopic heating in the medium, which causes an ultrasonic pressure wave to be recorded by a microphone.The photoacoustic approach works on the principle of an energy source irradiating the skin surface and inducing thermal expansion in the illuminated area. The energy of thermal expansion causes an auditory wave to be released. The detection of glucose with this technique is based on monitoring variations in the signal's peak-to-peak value, which varies depending on the blood glucose content35.



The technique is sensitive to chemical interferences from some biological compounds and to physical interferences from temperature and pressure changes. A technological disadvantage is that the instrumentation is still custom made, expensive and sensitive to environmental parameters35.



The information categories approvals, technology, Internet reference are reported in Figure 2 for all the devices. When no information is available for a device on a specific category, the category is not reported.



The metre is designed in the style of a wristwatch. It uses a disposable pad that hooks onto the back of the metre to test glucose via the skin. The pad adheres to the skin via an adhesive, allowing it to come into contact with a minor electrical current, resulting in reverse Iontophoresis. Warm-up time for the metre is two-three hours9. Following that, it measures glucose every tebminutes, followed by Three minutes of electrical stimulation and 7 minutes of glucose measurement. An alert is also triggered if there is a sudden shift in blood sugar of more than 35% from any previous reading in the last hour, if you are sweating, or if any measurements are above or below the patient's goal levels36. When the current reading is more than 18mg/dl higher or lower than the prior measurements, a trend indicator appears to illustrate the direction of the blood sugar37.



The metre is designed for real-time and continuous blood glucose monitoring with alarms, according to the manufacturer. It is based on the use of ultrasounds, which are produced by lighting tissue with laser pulses of various wavelengths (photoacoustics). Ultrasound is also used to locate the measured volume inside a blood vessel and to eliminate the impact of the skin's outer layers. Photoacoustics, according to the company, is better to standard optical technologies because it obtains blood glucose readings directly from inside the blood vessels and enables for increased glucose measurement specificity (identification) and sensitivity (detection of level changes).20



Gluco TrackTM:

It is a hand-held metre that uses ultrasonic readings to determine the blood glucose level. The metre additionally measures tissue conductivity and heat capacity for added accuracy and precision. To the best of his knowledge, the company's technique of combining three technologies is unique36. The metre is made up of two parts: the main unit, which contains the display, transmitter, receiver, and processor, and the "Earring" Unit, which contains sensors and calibration electronics and is attached to the earlobe (externally clipped). The metre generally monitors spot glucose levels, but a continuous mode can be selected to automatically make sequential measurements, revealing trends. Visual and audio alerts are triggered by extreme levels defined by each user. Through a USB port or an IR interface, the measured data can be downloaded for further processing38.



Figure 2: Different type of glucose monitoring devices along with non-invasive techniques39


SpectRx Inc.

The metre is primarily made up of two units: the first is a portable laser that generates micropores in the skin's outer, dead layer. The micropores are about the same size as a hair. The glucose-containing interstitial fluid travels through the micropores and is collected by a patch. Then it gets to the second item, which is a glucose sensor. A conventional sensor can be employed because the sensor is in direct touch with the interstitial fluid. (30) The metre also has a transmitter that sends glucose readings wirelessly to a handheld display device. His process is referred described as "biophotonic technology" by the company.


Hitachi Ltd.

Based on the detection of physiological factors related to human metabolism using specific sensors Thermal energy supplied by metabolic reactions in the human body, in fact, represents a balance between blood sugar levels and local oxygen supply, according to substantial Company research. As a result, the level of blood sugar can be determined by measuring the thermal energy generated by metabolic reactions in combination with other characteristics such as haemoglobin oxygen saturation and blood flow. Sensors in the fingertip are used to measure various temperatures and light properties.



Figure 3: Glucose Measurement Devices (A- Glucowatch. B- Glucotrack. C-Hitachi)403741



In this review, discussed several types of diabetes, their prevalence, and descriptions of non-invasive glucose monitoring technology and devices. All non-invasive tests still require a higher signal-to-noise ratio. A new generation of transducer and procedures should be used to accomplish this. Simultaneous monitoring of bioimpedance and near-infrared spectroscopy in the skin has already been reported in preliminary research. Some of the technologies have yet to be implemented in a device, while others have resulted in a device that is at least in the prototype stage. The difficulty is to develop robust calibration models that can accurately measure in a patient's everyday life. Finally, the new generation of bloodless glucose instruments should include technologies that eliminate interfering species and competing biochemical pathways while maintaining low costs, quick response, accuracy, and simple calibration procedures, enhancing patient comfort and avoiding long-term complications.



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Received on 18.02.2022       Modified on 21.04.2022

Accepted on 23.06.2022   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Ana. 2022; 12(4):264-270.

DOI: 10.52711/2231-5675.2022.00044