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Abstract and Figures

Diabetes is a chronicle disease where the body of a human is irregular to dissolve the blood glucose properly. The diabetes is due to lack of insulin in human body. The continuous monitoring of blood glucose is main important aspect for health care. Most of the successful glucose monitoring devices is based on methodology of pricking of blood. However, such kind of approach may not be advisable for frequent measurement. The paper presents the extensive review of glucose measurement techniques. The paper covers various non-invasive glucose methods and its control with smart healthcare technology. To fulfill the imperatives for non-invasive blood glucose monitoring system, there is a need to configure an accurate measurement device. Noninvasive glucose-level monitoring device for clinical test overcomes the problem of frequent pricking for blood samples. There is requirement to develop the Internet-Medical-Things (IoMT) integrated Healthcare Cyber-Physical System (H-CPS) based Smart Healthcare framework for glucose measurement with purpose of continuous health monitoring. The paper also covers selective consumer products along with selected state of art glucose measurement approaches. The paper has also listed several challenges and open problems for glucose measurement.
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1
Everything You Wanted to Know About
Noninvasive Bloodless Glucose Monitoring
Prateek Jain Amit M. Joshi Saraju P. Mohanty
Dept. of ECE Dept. of ECE Computer Science and Engineering
MNIT, Jaipur, India MNIT, Jaipur, India University of North Texas, USA
prtk.ieju@gmail.com amjoshi.ece@mnit.ac.in smohanty@ieee.org
Abstract
Diabetes is a chronicle disease where the body of a human is irregular to dissolve the blood glucose
properly. The diabetes is due to lack of insulin in human body. The continuous monitoring of blood
glucose is main important aspect for health care. Most of the successful glucose monitoring devices is
based on methodology of pricking of blood from ear lobe or finger. There is requirement to develop
the Internet-Medical-Things (IoMT) integrated Healthcare Cyber-Physical System (H-CPS) based Smart
Healthcare framework for glucose measurement with purpose of continuous health monitoring. To fulfill
the imperatives for non-invasive blood glucose monitoring system, there is a need to configure an accurate
measurement device. Noninvasive glucose-level monitoring device for clinical test overcomes the problem
of frequent pricking for blood samples.
Index Terms
Smart Healthcare, Internet-of-Medical-Things (IoMT), Healthcare Cyber-Physical System (H-CPS),
Diabetes, Glucose measurement, Non invasive measurement, Spectroscopy and calibration
I. INTRODUCTION
The glucose is considered as important source of energy for the human body. The body requires blood
glucose of normal range (80 to 150 mg/dl) in order to perform the daily activities [1]. However, the higher
or lower value of glucose would lead to various complication inside the body. At the same time, insulin
is also crucial hormone generated inside the body from the food intake. The glucose is produced from
the food digestion which enters the blood cell to supply the energy and also helps in the growth. In case,
the insulin is not properly generated then blood would accumulate the high glucose concentration. Fig. 1
illustrates the closed-loop of glucose generation and consumption in human body [2]. A consistently high
blood glucose concentration is possible if the generation of αcells is larger as compared to that of the
βcells. Because of this condition, enough insulin is not secreted in the body for glucose consumption.
This condition refers to as the Diabetes Mellitus. Diabetes is termed as chronic disease which defines
high blood glucose levels inside the human body. The unbalanced glycemic profile is main reason for
the cause of diabetic condition. The rate of prevalence for Non Communicable Diseases (NCD)/Chronic
Disease has increased with many fold from last several years. There are around 20 million death reported
yearly through cardiovascular disease, for which high blood glucose is significant predisposing factors.
Moreover, people with diabetes are more affected during the viral pandemic outbreaks [3], [4], [5].
There has been exponential growth of diabetes patients over past few years because of obesity, unhealthy
diet plan, old-age population, and inactive lifestyle. Diabetes is considered as one of the fastest growing
health challenges, with the number of adults living with diabetes having more than tripled over the past
2 decades (Refer Fig. 2) [6]. The prevalence of diabetes around the world was 9.3% during 2019 with
approximate 463 million people. It is expected to rise to 578 million by 2030 with 10.2% prevalence
arXiv:2101.08996v1 [physics.med-ph] 22 Jan 2021
2
Insulin Secretion
by βCells
Glucose
Consumption
by Insulin
Food Intake Exercise
Discharge
Glucagon
by αCells
Glucose Deliverance
by Liver
CGM by
iGLU
High Glucose Concentration
Food Intake
CGM by
iGLU Normal Blood
Glucose Concentration
Fig. 1: Illustration of the closed loop form of glucose generation and consumption [2].
rate and the same would be 10.9% with 700 million population by 2045. It has been observed that
prevalence is quite higher in urban to 10.8% whereas 7.2% in rural region. Almost half of the diabetes
patients unaware about their situation due to lack of knowledge. The diabetes has indeed global outbreak
which has affected presently almost 1 in 10 people around the world. It is projected that more than 0.5
billion adults would suffer from the diabetes in the next decade [7]. As per the report from International
Diabetes Federation (IDF), the death from diabetes has large number than combined death from Malaria
(0.6mio), HIV/AIDS (1.5mio) and tuberculosis (1.5mio) [8]. There are around 8 million new patients are
being added to diabetic community every year. This has grown the demands immensely for the effective
diabetic management. It is important to monitor the blood glucose over time to time for avoiding late-
stage complication from diabetes. This has necessitate the design of various reliable and robust solutions
for efficient diabetes management. The market of diabetes devices has also grown rapidly with significant
requisite for frequent glucose measurement for better glycemic profile control.
Diabetes is one of the major chronic disease which has long-term impact of the well-being life of
a person. Diabetes Mellitus (DM) is considered as physiological dysfunctions with high blood glucose
because of insufficient insulin, insulin resistance, or excess generation of glucagon [9]. It is the critical
health issue of 21st century. Type 2 Diabetes (T2DM) has shown rapid growth around the world from
past few years. Any form of diabetes may lead to complications in various body parts which increase the
possibility of premature death. The higher value of blood glucose known as hyperglycemia, would lead
to thickening of blood vessels which could resulted in kidneys damage and loss of sight and some times
even to these organs failure. Diabetes is also associated with limb amputation, peripheral vascular diseases
and myocardial. Contrary, the low blood glucose defined as hypoglycemia may occur in Type 1 Diabetes
Patients (T1DM) for excessive insulin dosage [10]. The most common symptoms for hypoglycemia
pateints are dizziness, sweating and fatigue and in the worst case it can lead to coma and death. The
diabetic patients would have several common symptoms such as thirsty, tiredness, changes in vision,
consistently hungriness, unexpected weight loss and the excretion of urine within short durations [11].
If the diabetes remain untreated over the period of time, it may cause blindness, heart stroke, kidney
disease, lower limb amputation and blindness. It would lead to increase the probability of death almost
50% higher in comparison of the patients without diabetes. The diabetes also brings the additional financial
burden for the treatment and point of care. The diabetic patients could also result in loss of productivity
at workplace and may lead to disability. There are several health issues which may also arise from
3
Estimations
Projections
Chronological Year
Population in Millions
Fig. 2: Global trend of Diabetes, Adopted from [6].
diabetes like depression, digestive problem, anxiety disorders, mood disorder and eating habits change.
The diabetes could be controlled with proper diet plan, through some physical exercise, insulin dosage
and medicines. The early stage of diabetes is possible to control with oral medicines. The diabetes control
also helps to reduce the associated risk of high blood pressure, cardiovascular and amputation.
The rest of the article is organized in the following manner: Section II briefly presents different
types of diabetes while making case for the need of glucose level monitoring. Section III presents
overview of various types of glucose-level measurement mechanisms. Section IV provides details of
available approaches for noninvasive glucose-level monitoring. Section V has discussions on various
post-processing and calibration techniques for noninvasive glucose-level monitoring. Section VI briefly
discusses various consumer products for noninvasive glucose level measurement. Section VII presents
the approaches for glucose-level control and corresponding consumer products. Section VIII provides the
Internet-of-Medical-Things (IoMT) perspectives of glucose level measurements and control in healthcare
Cyber-Physical Systems (H-CPS) that makes smart healthcare possible. Section IX outlines the shortcom-
ings and open problems of glucose-level measurements and control. Section X summarizes the learning
of this comprehensive review work.
II. TH E HEA LTH ISSUE OF DIABETE S AN D NEE D FO R GLU CO SE -LEV EL MEASUREMENT
This Section presents details of different types of diabetes, the health issues arise due to diabetes,
while making case for the need of glucose level monitoring.
A. Types of Diabetes
The diabetes occurs because of insufficient insulin with respect to glucose generated inside the body.
The insulin from body is either insufficient or not any which is generated from beta cells of the pancreas.
In case of diabetes, the cells of liver, muscles and fat unable to balance glucose insulin effectively. The
4
diabetes are classified mainly in three categories: Type 1 diabetes, Type 2 diabetes and gestational diabetes
(Refer Fig. 3) [12].
Body doesn’t
generate sufficient
insulin for glucose
regulation
Diabetes
Type 1 Diabetes Type 2 Diabetes Gestational Diabetes
Insufficient insulin
secretion for blood
glucose regulation
Body is not able to
produce insulin for
glucose regulation
during pregnancy
Symptoms
Always hungry
Unexpected weight loss
Numb or tingling hands/feet
Frequent urination
Sexual disorder
Extreme fatigue
Always thirsty
Complications
Wounds heal slowly
Peripheral neuropath
Cerebrovascular disease
Diabetic Nephropathy
Coronary heart disease
Eye damage
Fig. 3: Different types of diabetes and their symptoms.
For diabetes of type-1, the pancreas does not produce insulin inside the body which is resulted in a
weak immune system. This results in a person who is unable to generate insulin naturally [2], [13]. In
case of type 2 diabetes, the amount of insulin from pancreas is not sufficient to maintain glycemic profile
of the body. Gestational diabetes usually occurs in a pregnant woman at later stage of the delivery. in the
year 2020, total 2 billion adults around the globe suffers from overweight, and 300 million of them are
obese. In addition, a minimum of 155 million children in the world is overweight or obese. It is projected
that the prevalence of hyperglycemia is 8.0% and expected to increase to 10% by 2025 [7]. There has
been concern for diabetic people specially in developing countries due to increase in Type 2 Diabetes
cases rapidly at earlier age which have overweight children even before puberty. Whereas for developed
countries, most of people have high blood glucose at age around 60 years. Most frequently affected
are at middle aged between 35 and 64 in developed countries [6]. In 2019, 69.2 millions population in
India had Type-2 diabetes. Approximately 2.35 million adults have Type-1 diabetes. In general, there
are around 5% adults have been considered for Type-1 diabetic patients while the others 90-95% are of
Type-2 diabetic patients. Type-1 diabetic patient must have insulin to control the blood glucose level.
Type-2 diabetic patients can control their glucose level by following an optimized diet with medication
and a regular physical exercise schedule.
5
B. The Health Crisis due to Diabetes
The diabetes mainly occurs due to unbalanced glucose insulin level of the body where insulin is
demolished and muscles and cells are not able to generate insulin properly [14], [13]. The probability of
death would also increase upto 50% in comparison to non-diabetes case. The control action of the diabetes
would be possible using proper precautionary measure after frequent glucose measurements. Therefore,
there is a real need for smart healthcare solution which would provide instant self measurement of blood
glucose with high accuracy.
Kidney damage (nephropathy)
Cardiovascular disease
Alzheimer's disease
Eye damage (retinopathy)
Skin conditions
Nerve damage (neuropathy)
Foot damage
Hearing impairment
Sexual, &
Bladder Problems
Gum Disease &
Other
Dental Problems
Fig. 4: Diseases in human body due to diabetes
Hyperglycemia is the major issue which has been considered by several health organizations at world-
wide level [15], [16]. There are several attempts which have been used for glucose measurement [17].
There have been substitutional work using various techniques to make the device more familiar with
clinicians and patients [18]. Diabetes is possible in the age group 18 to 80 years usually [19], [20]. The
normal range of glucose is in the range of 70-150 mg/dL and pathophysiological would be from 40
mg/dL to 550 mg/dL [21]. One of the emerging issues is to design the glucose measurement device for
continuous health care monitoring [22]. The devices for monitoring the glucose level are available for
last two decades [23].
C. Glucose Measurement: A Brief History
The glucose meter (aka glucometer) is a portable medical device for predicting the glucose level
concentration in the blood [24], [25]. It may also be a strip based dipped into any substance and
determined the glucose profile. It is a prime device for blood glucose measurement by people with
diabetes mellitus or hypoglycemia. With the objective of glucose monitoring device advancement, the
concept of the biosensor has been proposed earlier in 1962 by Lyons and Clark from Cincinnati. Clark is
known as the “father of biosensors”, and modern-day glucose sensor which is used daily by millions of
diabetics. This glucose biosensor had been composed with an inner oxygen semipermeable membrane, a
thin layer of GOx, an outer dialysis membrane and an oxygen electrode. Enzymes could be gravitated at
6
an electrochemical detector to form an enzyme electrode [26]. However, the main disadvantage of first-
generation glucose biosensors was that there was the requirement of high operation potential of hydrogen
peroxide amperometric measurement for high selectivity. The first-generation glucose biosensors were
replaced by mediated glucose biosensors (second-generation glucose sensors). The proposed biosensors
till present scenario represent the advancements in terms of portability of device and precision in
measurement. But, due to some environmental and measurement limitations; these biosensors were not
taken for real-time diagnosis. The history of glucose measurement is shown in Fig. 5 [27].
1962 First glucose biosensor based on enzyme electrode
developed by Clarke and Lyons
1965 First ever glucose measurement strip developed by
Ames
1987 First ever self glucose
measurement strip
by Medisense
1971Ames Reflectance glucometer by
Anton Hubert
1991 First ever Continuous
Glucose Measuring Device
2000 First Ever
Non invasive
Commercial
product
Fig. 5: History of Glucose Measurement.
D. Glucose Measurement Technique
Presently, the glucose monitoring is carried out either laboratory based technique or home based
monitoring. These both approaches are invasive in nature which provides discomfort by blood pricking
and it only helps to measure the glucose measurement at that point of time. It is also not very convenient
for the user to take out blood samples multiple times in a day and many patients are reluctant to opt
such type of solution. Therefore, significant changes of glycemic profile may go unnoticed because of
unanticipated side effects and low compliance from the patients. This could impact on improper insulin
dosage and unknown food ingredient. However, they are reliable solution due to their good sensitivity
and higher accuracy for glucose measurement [28], [29].
The novel approach for glucose measurement has been explored from past several years which is based
on the principle of physical detection than conventional chemical based principle. Such non-invasive based
method does not require the blood sample but uses the interstitial fluid (ISF) for glucose molecule detec-
tion. There are several attempts in the same direction for glucose measurement through sweat, saliva, tears
and skin surface [30]. However, the main challenge is to have precise measurement, good sensitivity and
reliability from such measurement. Such approach could be suitable for Continuous Glucose Measurement
(CGM) and self monitoring purpose. Such CGM techniques would provide the frequent measurement in
a day which would helpful for better glucose control and also for the necessary preventive actions for
7
Fingertip/Earlobe/
Skin between
fingers
Light Detection
through Optical
Sensors and Signal
Processing
Data Acquisition
and Prediction of
Blood Glucose
using Regression
Model
Blood
Glucose
Monitoring
(mg/dl)
Preparation of
Lancet Pricking of the
Blood Contact to strip
for Monitoring
Invasive Approach (Capillary Glucose Measurement)
Non Invasive Approach
Blood Glucose
Monitoring
(mg/dl)
Blood Sample
Collection
Glucose Value
(mg/dl) using
Glucose
Analyzer
Clinical Centrifuge for
Separation of Serum Prepared Serum for Glucose
Measurement
Invasive Approach (Serum Glucose Measurement)
Data Acquisition and Prediction of
Blood Glucose
Sample Preparation in Lab/ Requirement of
Disposable Strips and Lancets
Pricking of the
Blood
Fig. 6: Invasive versus Noninavsive Glucose Measurement.
hyperglycemia and hypoglycemia patients. Such kind of techniques would also support for the dietician
and healthcare provider to prepare proper diet plan according to glucose fluctuation for the patient.
E. The Need for Continuous Glucose Measurement (CGM)
The measurement of glucose could be done through non-invasive, semi (or minimal) invasive and
invasive approach. The frequent measurement may not be possible using invasive method which can
cause trauma. The semi-invasive and non-invasive could be useful for Continuous Glucose Measurement
(CGM) without any pricking of the blood. However, the non-invasive glucose measurement is most
suitable technique which helps to measure the blood glucose painlessly [31].
CGM assist to have proper blood glucose level analysis at each prandial mode. It helps to measure
glucose insulin level after insulin secretion,hysical exercise or subsequent to medication. The frequent
glucose reading also helpful to endocrinologist for providing the proper prescription. It mainly helps for
type 1 diabetic patients to take care of their insulin dosage over the period of time. The proper diet
management could be possible with help of recurrent glucose monitoring and flow diagram of CGM is
shown as Fig. 7 [28], [29]. The CGM is useful for the patients for frequent glucose measurement over
the period of time. This would helpful to identify the average blood glucose value for the last 90 days,
by which glycated haemoglobin (HbA1c) can be determined.
8
CGM
through iGLU To avoid excessive
food intake
To avoid excessive
Insulin secretion
Analysis and prescribed
treatment for
diabetic patient
Glucose
Red Blood Cells
To identify the average
blood Glucose value
Fig. 7: The objectives of continuous glucose monitoring.
III. APP ROAC HE S FO R GLU CO SE -LEV EL MEASUREMENT:ABROA D OVE RVI EW
This Section discusses an overview of various types of glucose-level measurement mechanisms. In
the past, many works has done for the glucose measurement. They can be invasive, non-invasive, or
minimally invasive. A lot of works has been completed based on the non-invasive technique. They are
technically based on optical and non-optical methods. Some of the optical techniques used methods based
on Raman Spectroscopy, NIR spectroscopy, and PPG method. A taxonomy of the different methods is
provided in Fig. 8 [25], [28], [29], [32].
A. Invasive Methods
Many commercial continuous blood glucose measurement devices use cost-effective electrochemical
sensors [33]. They are available to respond quickly for glucose detection in blood [34]. Lancets (for
pricking the blood) is used at the primary stage for blood glucose monitoring for various commercial
devices available in the market [35]. The frequent measurement through the process is so much panic due
to picking the blood sample from the fingertip more than 3-4 times in a day for frequent monitoring[36].
The low invasive biosensor for glucose monitoring has been developed with glucose oxidase that re-
quire around 1mm penetration inside the skin for measurement [37]. The technique of photometric was
attempted to detect glucose with help of small blood volumes [38].
B. Minimally Invasive Methods
The minimally invasive method using prototype sensor was developed to have frequent monitoring of
glucose tissue [39]. The sensor is wearable and is implanted on membrane which contains the immobilized
glucose oxidase. The glucose monitoring through implantable devices were developed [40]. The semi or
minimal invasive method using biosensors designed for diabetes patient [41]. The wearable micro system
explored for frequent measurement of glucose [42]. Similarly, there was an attempt of continuous glucose
9
Blood Glucose
Monitoring System
Invasive Minimally Invasive Non Invasive
In-vivo In-vitro
Photo
acoustic
Spectroscopy
Raman
Spectroscopy Polarimetry
Photoplethysmography
(PPG) Signal
Long Wave
Near-Infrared
(NIR)
Detection
Implanted
Micro System
Glucose Control
System Electrochemical
Biosensor
Implanted
Sensor
Amperometric
Near-Infrared
(NIR)
Spectroscopy
iGLU 1.0
Bio-
impedance
Spectroscopy
Capillary
Glucose
Serum
Glucose
Micro
motor
assisted
Optical
Coherence
Tomography
(OCT)
Capillary
Glucose Serum
Glucose
Near-Infrared
(NIR)
Spectroscopy
iGLU 2.0
Fig. 8: An overview of the Glucose Measurement Options [32], [28], [29], [25].
10
monitoring with help of microfabricated biosensor through transponder chip [43]. The signal coming out
of transponder chip was used for the calibration for semi invasive approach of Dexcom sensor [44]. The
diabetes control explored by glucose sensor with artificial pancreas system [45]. The minimal invasive
approaches have limitations mainly accuracy and may have shorter life span for monitoring.
This is a wearable microsystem for the continuous monitoring of the blood glucose. It’s a minimally
invasive method for the glucose monitoring. The main idea behind this is that it uses micro-actuator
which consists the shape memory alloy (SMA) for the extraction of the blood sample from human skin
[46]. An upgraded version of SMA is used for the implementation of PCB. Because of it’s feasibility
and performance, it can be considered as the first wearable device for the glucose monitoring but it is
large in size which makes it inconvenient.
C. Non-invasive Methods
Non-invasive measurement would mitigate all the previous issues and would provide painless and
accurate solutions [47], [48]. The non-invasive glucose measurement solution for smart healthcare had
developed through portable measurement [31]. A lot of approaches have been introduced for glucose
measurement [49]. The non-invasive measurement are more convenient for continuous glucose mea-
surement in comparison to invasive method and semi invasive [47], [48]. The glucose measurement
with help of optical method has observed more reliable and precise in the literature [50]. The popular
optical methods include non-invasive measurement such as Raman spectroscopy, near infer-red spec-
troscopy,polarimetric,scattering spectroscopy [51], photoacoustic spectroscopy [52] etc. For the develop-
ment of a non-invasive measurement device, it is considered by the researcher that the device would
be much convenient for the user’s perspective [53], [54]. Calibration of the blood glucose to interstitial
glucose dynamics have been considered for the accuracy of continuous glucose monitoring system [55],
[56]. Several calibration algorithms have been developed and implemented for portable setup [57]. There
has been several concious efforts towards the development of the self-monitoring system [58].
Blood in Vessel
NIR LED NIR Detector Voltage Acquisition
through Light Detection
from Blood Vessels
Optical Spectroscopy for
Serum Glucose Measurement
Pricking of the
Blood Contact to strip
for Monitoring
Capillary Glucose
Measurement
Blood Pricking from
Epidermis Layer of Skin
Fig. 9: NIR Spectroscopy Mechanism of Serum Glucose Measurement.
D. Invasive Versus Non-invasive Glucose Measurements: The Trade-Offs
Recent glucose measurement methods for the ever-increasing the diabetic patients over the world
are invasive, time-consuming, painful and a bunch of the disposable items which constantly burden for
the household budget. The non-invasive glucose measurement technique overcomes such limitations, for
which this has become significantly researched era. Although, there is tradeoff between these two methods
which is represented in Fig. 10.
E. Capillary Glucose versus Serum Glucose for Noninvasive Measurement
The serum glucose value is precise which is always close to actual blood glucose measurement with
compare to capillary glucose level. Traditional approaches able to measure capillary glucose instantly
11
Non-invasive Glucose
Measurement
Invasive Glucose
Measurement Detector
LED
Fig. 10: Representation of Tradeoffs between Invasive and Non-invasive Glucose Measurement.
but the serum glucose measurement identification is difficult. It is observed that the glucose level of
capillary is always higher than serum glucose. The accurate measurement of blood glucose would help
for appropriate control actions. Therefore, it is really important to measure the serum glucose than the
capillary glucose which is more reliable for medication. Capillary blood glucose measurement has been
used widely than serum glucose estimation for medication purpose. The serum glucose is not possible for
continuous glucose measurement or frequent measurement for diabetes. The blood glucose is controlled in
much better way if one can measure serum glucose at regular interval. Laboratory analysis of glycosylated
haemoglobin (HbA1c) which provides 6-8 weeks blood glucose measurement is also being done through
the serum blood only. For the non-invasive measurement point of view, serum and capillary glucose are
being measured through the optical spectroscopy. The mechanism of blood glucose measurement is based
on received IR light after absorptions and scattering from glucose molecules which flow in blood vessels.
The methodology is quite similar for both types of glucose measurement except the post-processing
computation models which are necessary for blood glucose estimation.
F. Non-invasive Method for Glucose Level Estimation by Saliva
As the most convenient method to estimate glucose level is via saliva [59] and is used for children and
adults. This saliva has specific type of parts which can be defined as: (1) gland-specific saliva and (2)
whole saliva. The collection of the Gland-specific saliva is done by individual glands like parotid, Sub
mandibular, sublingual, and minor salivary glands. This diagnosis is done by the history of the patient in
terms of associated risk factors, family history, age, sex, duration of diabetes,and any associated illness.
12
Other Glucose measuring methods consist of measurement using photo-metric glucometers requiring very
small sample volumes [60]. Figure 2 represents the flow of the model. The basic approach is based on
the reaction of the chemical test strip that reacts with the blood and changes colour. Measurement is done
by capturing the reflections of the test area and then glucose level is estimated. It requires validation in
large number of patients.
IV. APPROACHES FOR NONINVASIVE GLU CO SE -LEV EL MEASUREMENT
This Section presents detailed discussions of various available approaches for noninvasive glucose-level
monitoring. There have been several efforts for noninvasive glucose measurement using optical techniques
[27], [29], [61], [62]. These techniques are mainly based on various spectroscopy based methods. For
the development of a non-invasive measurement device, it is considered by the researcher that the device
would be much convenient for the users perspective. Fig. 11 presents summary of various types of
noninvasive glucose measurement techniques, whereas their comparative perspectives are presented in
Fig. 12. A qualitative comparative perspective of various noninvasive methods is summarized in Table I.
Non-invasive
Glucose
Measurement
Impedance
Spectroscopy
Thermal
emission
spectroscopy
Photo acoustic
spectroscopy Near Infrared
Spectroscopy
Iontophoresis
Ocular
Spectroscopy
Radio frequency
(RF) technique
Capacitance
spectroscopy
Optical
Coherence
Tomography
Fluorescence
Polarimetry
Raman
Spectroscopy
Fig. 11: Various spectroscopy techniques for noninvasive glucose measurement.
TABLE I: Qualitative comparison of various noninvasive glucose-level monitoring methods.
Technique Advantages Disadvantages
Near Infra-Red
(NIR) The signal intensity is directly pro-
portional to glucose molecule
The glucose detection concept would
work with other interfacing sub-
stance such as plastic or glass
The glucose signal weak compara-
tively so complex machine learning
model is required for interpretation
High scattering level
13
Impedance
Spectroscopy
Glucose readings
vary in different
individuals
Change in position
of inductor will
provide undesired
results of glucose
concentration.
Raman
Spectroscopy
Raman scattering
is a nonlinear or
inelastic
scattering which
occurs when
monochromatic
light interacts
with a certain
sample.
Instability of
laser wavelength,
intensity and
long spectral
acquisition times
are the main
limitations of this
method.
Polarimetry
Because of other
polarization-
rotating
components
present in the
interior chamber
of the eye.
The amount of
rotation is a linear
function of the
path length, the
component
concentration and
the specific
rotation constant
(property of the
component).
Bio-
capacitance
Slight difference
in placing the
sensor at the
same location
might affect the
output of the
sensor.
Effect of
pressure on the
sensor, body
temperature and
sweat on the
skin.
Fig. 12: Comparative Perspective of Various spectroscopy techniques for noninvasive glucose measure-
ment.
Technique Advantages Disadvantages
Mid Infra-Red
(MIR) The glucose molecule absorption
stronger
Low scattering
The light has limited penetration
with tissue
Noise is present in the signal so
water and other non-glucose metabo-
lites would be detected.
Far Infra-Red
(FIR)/Thermal
emission
spectroscopy
Frequent Calibration is not required
Least sensitive towards scattering
The radiation intensity depends on
temprature and substance thickness
Strong absorption with water so it
is difficult to have precise glucose
measurement
Raman
Spectroscopy Less sensitivity towards temperature
and water
High specificity
Requirement of the laser radiation
source hence it can dangerous cell
for CGM
Susceptible towards noise interfer-
ence so low SNR
14
Technique Advantages Disadvantages
Photo acoustic
Simple and compact sensor design
Optical radiation will not harmful for
the tissue
Signal is vulnerable towards acoustic
noise, temperature,motion etc.
It carries some noise from some non-
glucose blood components
Polarimetry
The laser intensity variation will not
change much the glucose prediction
Requirement external laser source
and requires proper alignment with
eye
sensitive for the change in PH and
temperature
Reverse
Iontophoresis Based on simple enzyme based elec-
trode system
Highly accurate as it measure glu-
cose from interstitial fluid
Difficult to have proper calibration
Not so user-friendly approach due to
passing of the current through skin
Fluorescence
Highly sensitive for glucose
molecule detection due to immune
for light scattering
Good sensitivity because of distinc-
tive optical properties
Very much sensitive for local pH
and/or oxygen,
Suffers from foreign body reaction
Bio impedance
spectroscopy Comparatively less extensive
Easy for CGM
Prone towards sweating, motion and
temperature
Require large calibration period
Millimetre and Mi-
crowave sensing Deep penetration depth for precise
glucose measurement
No risk for ionization
Poor selectivity
Very much sensitive for physiolog-
ical parameters such as sweating,
breathing and cardiac activity
Optical Coherence
Tomography High resolution and good SNR
Not vulnerable for blood pressure
and cardiac activity
Glucose value may change as per
skin and motion
Suffers from tissue inhomogeneity
Surface Plasma
Resonance Small glucose molecule can be de-
tected due to high sensitivity
Long calibration process and size is
bulky
Glucose value changes with varia-
tion in temperature,sweat and mo-
tion
15
Technique Advantages Disadvantages
Time of flight and
THz Time domain
Spectroscopy
strong absorption and dispersion for
glucose molecule
Lesser depth resolution and longer
time for measurement
Metabolic Heat
Conformation Uses the concept of well-known
various physiological parameters for
glucose prediction
Sensitive towards variation in tem-
perature and sweat
Electromagnetic
sensing low-cost and can be easily miniatur-
ized
No risk of ionization
Lack of selectivity due to dielec-
tric constant is mainly affected with
other blood components
More sensitive for the slight change
of temperature
Ultrasound
Technology Well established technology with not
much harm to tissue cell
Long penetration below the skin or
tissue
Limited accuracy with ultrasound
only hence mostly used with NIR as
multi-model
costly technology for measurement
and not useful for CGM
Sonophoresis
Favourable technology as there is no
side-effect to skin
Based on well known enzymatic
method
Error prone due to environmental
parameters
A. Near-Infrared (NIR) Spectroscopy
It is well known as Infrared spectroscopy (IR spectroscopy) or vibration spectroscopy where radiation
of infrared type are incident on the matter [63], [64]. Various types of IR spectroscopy is shown in
Fig. 13. In general, IR spectroscopy includes reflection, scattering and absorption spectroscopy [65]. The
wave from IR absorption cause the molecular vibration and generate the spectrum band with wavelength
number in cm1[66].
In this case, the light in the wavelength range of 700nm to 2500nm for Near-infrared region is applied
at the object (may be finger or ear lobe) [68]. The light may interact with blood components and it
may scattered, absorbed and reflected [69], [70]. The intensity of received light varies as per glucose
concentration as per Beer-Lambert law [71], [72] The receiver would help to measure the presence glucose
molecule from the blood vessel [73].
1) Long-Wave versus Short-Wave NIR Spectroscopy: The optical detection is useful approach to have
precise glucose measurement. FIR (Far infra-red) based optical technique help to get the resonance
between OH and CH for first overtone. However, long wave NIR has good performance in vitro testing.
In similar way, the fiber-optic sensor is used along with laser based mid-infrared spectroscopy for vitro
based glucose measurement. The continuous glucose measurement has been achieved with multivariate
calibration model for error analysis [74]. The FIR approach has limitation of shallow penetration in
comparison with short wave NIR. The short NIR would help to detect the glucose molecule more
16
Vibrational
Spectroscopy
NIR
Spectroscopy
(700nm-
2500nm)
Absorbance
Spectroscopy Reflectance
Spectroscopy Scattering
Spectroscopy
MIR
Spectroscopy
(2.5μm-25μm)
FIR
Spectroscopy
(25μm-1mm)
Fig. 13: Classification of vibrational spectroscopy [67].
IR LED Object OPD Filter
Non-
Inverting
Amplifier
Micro-
controller
Statistical
Analysis
Display
1550E Finger/Ear
Lobe
PWM
Circuit
Light to voltage
Converter RC Low
Pass Filter
LM324
PC/Mobile/
LCD
NIR Spectroscopy
ADC
Fig. 14: Block diagram representation of IR spectroscopy.
accurately [75]. The concept of NIR spectroscopy for glucose detection is shown in Fig. 15. The specific
wavelength of NIR spectroscopy has already been applied earlier for precise glucose measurement using
non-invasive measurement [76]. Some specific wavelength such as 940 nm has been considered for
the detection of glucose [77]. The vibration of CH molecule has been observed at 920 nm with NIR
spectroscopy [76]. In some other works, the glucose absorption has been validated for the range 1300 to
1350 nm and stretching of glucose has been identified in NIR region [78], [79]. The presence of glucose
component has been measured at 1300 nm in the work [80].
17
Epidermis Layer
Dermis layer
Subcutaneous Tissues
Near Infrared
(0.7μm-2.5μm)
Short wave
(0.7μm-1.3μm)
Long wave
(1.3μm-2.5μm)
Mid and Far Infrared
(0.7μm-2.5μm)
Fig. 15: Penetration depth various Infrared Signals in Human Skin [25], [32].
2) NIR Spectroscopy Based Methods: A method to estimate the non-invasive blood glucose with NIR
spectroscopy using PPG has been proposed in literature [81]. This method is performed using NIR LED
and photo detector with an optode pair. At NIR wavelengths(935nm, 950nm, 1070nm), PPG signal is
obtained by implementation of analog front end system. The glucose levels has been estimated using
Artificial Neural Network (ANN) running in FPGA. A microcontroller is used, for the painless and
autonomous blood extraction [82]. The ideal system Blood Glucose Measurement (BGM) in which the
microcontroller is used to display the blood glucose and for the transmission of blood glucose. A remote
device is used for the tracking of the insulin pump which is needed for diabetes management. This type
of measurement [83] method uses change in the pressure of the sensitive body part, because it generates
the sound waves. The response of the photo acoustic signals will be stronger when glucose concentration
is higher. In order to improve SNR and for the reduction of noise to transfer the signal to the computer
for further processing,the signal is then amplified. Feature extraction and glucose estimation is estimated
by photo acoustic amplitude. In order to gather the photo acoustic signals, two pulsed laser diodes and
piezoelectric transducer is used. Utilization of the LASER makes the setup costly and bulky.
3) Non-invasive Blood Glucose Measurement Device (iGLU): In this approach, “Intelligent Glucose
Meter (iGLU)” [84] has been utilized for the acquisition of data. This device works on a combination
of NIR spectroscopy and machine learning. This device has been implemented using three channels. It
uses an Internet-of-Medical-Things platform for storage and remote monitoring of data. In the proposed
device, an NIR Spectroscopy is used with multiple short wavelengths [85]. It uses three channels for data
collection. Each channel has its own emitter and detector for optical detection. Then the data collection
processed by a 16 bit ADC with the sampling rate of 128 samples/second. Regression techniques is used
to calibrate and validate the data and analyse the optimized model. The data that is stored on cloud can
18
be used and monitored by the patients and the doctors. Treatment can be given based on the stored data
values. This is a low cost device with more than 90 % accuracy but it does not give real time results.
4) Why NIR is Preferred Over other Noninvasive Approaches?: Glucose measurement has been done
using various non-invasive approaches such as impedance spectroscopy, NIR light spectroscopy, PPG
signal analysis and so on. But, apart from optical detection, other techniques have not be able to provide
the precise measurement. PPG is one of the promising alternative but the PPG signal varies according to
blood concentration [86], [87]. It may not be useful to have precise prediction of the blood glucose. The
saliva and sweat properties vary from one person to another person. Therefore, it could not be reliable
glucose measurement method. The other spectroscopy have been also applied for glucose measurement.
However, they are not able to provide portable, cost effective and accurate prediction of body glucose.The
glucose measurement using optical detection using long NIR wave which is not capable to detect the
glucose molecules beneath the skin as it has shallow penetration [75]. Therefore, small NIR wave has
been considered as potential solution for real-time glucose detection [77], [88].
B. Mid Infrared (MIR) Spectroscopy
The bending and stretching of glucose molecules would be observed very well with Mid Infrared (MIR)
spectroscopy [89]. The depth of skin penetration is very less because it tends to have larger absorption
of water. This technique helps to have ISF glucose value in vivo measurement. There are some attempts
for precise glucose measurement through saliva and palm samples.
C. Blood Glucose Level Measurement using PPG
The change of blood volume with absorption of the light from tissue has been detected with PPG
signal [87]. The change of the blood volume has been measured using pressure pulse with help of light
detector [86]. The change in volume of blood would result as the change of light intensity hence it may
not be occur due to glucose molecule. This may result as inaccurate glucose measurement. The difference
of NIR against PPG has been shown in Fig 16. The intelligent glucose measurement device iGLU is
mainly based on principle of NIR spectroscopy which helps to have precise glucose measurement. There
have been several work for glucose detection based on PPG signal [90]. The data from patient body has
logged to estimate the presence of glucose using PPG. Subsequently, various machine leaning models
have been used for prediction of body glucose value [91]. The different parameters from total 70 subjects
of healthy and diabetes have been considered for the prediction using Auto-Regressive Moving Average
(ARMA) models [92]. There have been also several other smart solutions for glucose estimation using
PPG signal with intelligent algorithms [93], [94], [95].
One of the optical based techniques is Photo-plethysmography (PPG) which is used in advanced health
care. It is non-invasive glucose measurement technique. In NIR spectrum a sensor similar to a pulse
oximeter is used to record the PPG signal [87]. Photo transmitter and receiver is used to build the sensor
which will operate in near infrared region at 920nm. At wavelength 920nm, by measuring changes in the
absorption of light, a PPG signal can be obtained. The veins in the finger grow and contract with every
heartbeat.
A method of measuring blood glucose using pulse oximeter and transmission of the PPG glucose
monitoring system is available [90]. As the glucose concentration increases, there is decrease in the light
absorbance in the blood. The obtained signal is in the form of photo current, and for the filtering of this
signal is then changed into the measurable voltage values. For the processing of filtered signal, lab view
is used to estimate the blood glucose level.
A system using machine learning techniques and PPG system for the measurement of blood glucose
level non-invasively has been prototyped [86]. In this model, a PPG sensor, an activity detector, and a
signal processing module is used to extract the features of PPG waveform. It finds the shape of the PPG
19
waveform and the blood pressure glucose levels, the functional relationship between these two can be
obtained then.
In PPG, the change in light intensity will be varied according to changes in blood volume. PPG signal
analysis is not based on the principle of glucose molecule detection. Hence, the system has limited
accuracy [25], [32]. Fig. 16 illustrates the differences.
LED Detector Logged signal for
features extraction
Blood glucose
estimation
using machine
learning model
after extracting
features sets
from signal
Specific Wavelengths
are not required
PPG Signal Analysis Time and
Frequency
analysis at
frame level
Single pulse
analysis
LED Detector Logged voltage values
after absorption and
reflectance of light from
glucose molecule
Blood Glucose estimation
using proposed and
optimized machine
learning model
Specific Wavelengths
needed for glucose
molecule detection
NIR Spectroscopy
Fig. 16: PPG Versus NIR for Non-invasive Glucose Measurement [25], [32].
D. Impedance Spectroscopy
Impedance spectroscopy (IMPS) refers to the dielectric spectroscopy [96]. The steps of impedance
spectroscopy (IMPS) is shown in Fig. 17. This technique finds the dielectric properties of skin [97].
The current is directed through the skin [98]. Due to directed small current at multiple wavelengths, the
impedance range is obtained [99]. The range lies between 100 Hz to 100 MHz [100], [101]. Change in
glucose concentration will reflect the change in sodium ions and potassium ions concentration [102]. So,
the cell membrane potential difference will be changed [103]. Thus, the dielectric value will be changed
which predicts the glucose value of human body [104].
An enzyme sensor in a flow cell has been explored for glucose measurement in saliva [105]. Polypyrrole
(PPy) supported with copper (Cu) nanoparticles on alkali anodized steel (AS) electrode for glucose
detection in human saliva is available in [106]. The high precision level cannot be possible through these
methods as sweat and saliva properties vary according to person. Hence, this approach is not suitable for
glucose measurement in smart healthcare.
E. Raman Spectroscopy
Due to the interaction of light with a glucose molecule, the polarization of the detected molecule
will change [107]. In this technique, oscillation and rotation of molecules of the solution are possible
through the incident of LASER light [108]. The vibration of the molecule affects the emission of scattered
light [109]. Due to this principle, blood glucose concentration can be predicted as [110]. This technique
provides more accuracy with compared to infra-red spectroscopy technique [111]. There has been several
research based on Raman spectroscopy to have precise glucose measurement. The validation has been
20
Voltage Control
Oscillator
Signal
Conditioning
Circuit
Resonance Circuit
(Operating
Frequency)
Detection
Circuit
Analog to
Digital
Converter
Calibration
and estimated
value
Digital to
Analog
Converter
Monitoring
and Storage
of Data
Electrodes
connected
to skin
Fig. 17: The Steps of Impedance Spectroscopy (IMPS).
also carried out on using vivo testing. Fig. 18 presents basic framework of Raman spectroscopy, whereas
Fig. 19 presents its usage for noninvasive glucose measurement.
LASER
Light Beam
Expander Mirror
Beam Splitter Raman Spectrometer
Data Analyzer
Display
Object
Vacuum System
Fig. 18: Building blocks of Raman spectroscopy.
F. Time of Flight and THz Domain
The blood glucose estimation is adopted though Time of Flight (TOF) measurements for vitro testing
[112]. The short pulse of laser light is inserted in the sample for photon migration measurement. This
photon will experience scattering and absorption phenomenon while traveling from the sample. The
optical analysis of the photons would be useful for precise glucose measurement.
21
LASER Diode Band pass
Filter Spectrograph
Blood
Glucose
Monitoring
Object (Finger
or Ear lobe)
Parabolodal
Mirror
Lens
Notch Filter
Lens
Fig. 19: Noninvasive glucose measurement using Raman spectroscopy.
G. Photo Acoustic Spectroscopy
Photoacoustic spectroscopy refers to the photoacoustic effect for the generation of the acoustic pressure
wave from an object (refer Fig. 20) [113]. In this spectroscopy technique, the absorption of modulated
optical input provides the estimation of blood glucose detection [114]. High intense optical light is
absorbed by an object according to its optical conditions [115]. This process provided excitations of
particular molecules according to its resonant frequency [116]. The absorbed light is considered as heat
which provides rising in localized temperature and thermal expansion of the sample [117]. The expansion
in volume generates pressure in acoustic form [118]. The generated photoacoustic wave can be used
to predict the glucose concentration through specific excited wavelengths which are resonant for the
vibration of glucose molecules [119]. At the specific resonance frequency, the glucose molecule changes
own characteristic. This change is in the acoustic waveform [120]. In previous work, 905 nm wavelength
optical light is used for excitation [121], [122].
H. Capacitance Spectroscopy
In the capacitance spectroscopy technique, inductor stray capacitance varies according to body ca-
pacitance (Fig. 21) [123]. The body capacitance is used to estimate body glucose concentration [124].
Flexible inductor based sensor follows the coupling capacitance principle for body glucose detection.
In this technique, there is not any interaction between the inductive sensor and body skin through the
current [125]. This is the advantage of the impedance spectroscopy technique. The stray capacitance of
the inductive sensor will vary according to body glucose. In this technique, the effect of fat and muscles
will be negligible with respect to body glucose [126].
I. Surface Plasmon Resonance (SPR)
The Surface Plasmon Resonance (SPR) utilizes electron oscillation approach at dielectric and metal
interface for glucose sensing [127]. It detects mainly the change in refractive index before as well as
after the analytes interaction. The optical fiber based SPR has been used for point of care measurement
for glucose due to its portability.
J. Radio Frequency (RF) Technique and Microwave Sensing
In the RF technique, the variation in the s-parameters response reflects the change in blood glucose
[128], [129]. Fig. 22 shows typical steps of this technique. The response is determined through the antenna
22
Pulse Laser
Diode Object PZT LNA ADC
Coherent
Averaging
Clark error
grid Analysis
Display
LS9 Series, 100
Hz TTL ckt Finger/Ear
Lobe
PWM Circuit
(905 nm)
Pressure to voltage
Converter 351A
Best fit
Analysis
PC/Mobile/
LCD
Over 1024
frames using
FPGA
Lead zirconate
titanate
Embedded System
Development
(FPGA)
Fig. 20: Photo acoustic spectroscopy.
Voltage Control
Oscillator
Signal
Conditioning
Circuit
Resonance
Circuit with stray
capacitance
(Operating
Frequency)
Detection
Circuit
(Amplitude
and phase)
Analog to
Digital
Converter
Calibration
and estimated
value
Digital to
Analog
Converter
Monitoring
and Storage
of Data
Electrodes
connected
to skin
Fig. 21: The typical steps of capacitance spectroscopy.
23
or resonator [130], [131]. They follow the changes in dielectric constant value through the transmission
[132]. The change in dielectric constant can be found as the change in resonance frequency spectrum
through the antenna or resonator [133], [134]. The dielectric of blood varies according to blood glucose
concentration. The human finger is an appropriate measurement object but there are many factors that
play a cardinal and dominant role in the accuracy of measurement and repeatability. These are; the skin
thickness, fingerprints, the applied pressure by the fingertip during measurement and positioning of a
finger on the sensor [135].
Ferrite Antenna
based
Implantable Tag
Signal
Demodulator
Circuit
A/D
Converter Temperature
Sensor
Estimated
Blood
Glucose
Post
Processing
Model
Signal
Conditional
Circuit
Control
Circuit
Limiting
Circuit
Fig. 22: Glucose measurement using RF sensing technique.
K. Ocular Spectroscopy
In the Ocular Spectroscopy technique, glucose concentration is measured through the tears. A specific
lens is used to predict the body glucose concentration [136]. A hydrogel wafer is deposited to the lens.
This wafer is prepared by boronic acid with 7 µm thickness. The wafer is deposited on lens and then
optical rays are inserted on the lens. Then reflected light will change its wavelength. Change in wavelength
will refer to a change in glucose concentration in tears.
L. Iontophoresis
In the Iontophoresis or Ionization technique, a small electric current passes through the skin diffusively.
Three electrodes are used for the same [137]. A small potential is applied through the electrodes to
the different behaviour electrodes. During this process, glucose is transferred towards the cathode. The
working electrode can have the bio-sensing function by the generation of current during applied potential
through electrodes. This biosensor determines passively body glucose. The measurement is possible
through wrist frequently [138].
M. Optical Coherence Tomography
The Optical Coherence Tomography technique is based on the principle followed by reflectance
spectroscopy. In this technique, low coherent light is excited through the sample (sample is placed in
24
an interferometer). In an interferometer, a moving mirror is placed in reference arc. A photodetector is
placed on another side and it detects the interferometric signal. This signal contains backscattered and
reflected light. Due to this process, we could get high-quality 2-D images. The glucose concentration
increases with the increment of the refractive index in interstitial fluids. Change in the refractive index
indicates the change in the scattering coefficient [107]. So, the scattering coefficient relates to glucose
concentration indirectly.
N. Polarimetry
The Polarimetry technique is commonly used in a clinical laboratory with more accuracy. The optical
linear polarization-based technique is used for glucose monitoring [139]. This technique is usually based
on the rotation of vector due to thickness, temperature and concentration of blood glucose. Due to the
process of prediction of glucose, the polarized light is transmitted through the medium containing glucose
molecule. Due to high scattering through the skin, the depolarization of beam is possible. To overcome
this drawback, a polarimetric test has been done through the eye. The light passes through the cornea.
This technique is totally unaffected due to rotation of temperature and pH value of blood [140].
Multi-
wavelength
light source
Linear
Polarizer Angle
Detection
Unit
Parabolodal
Mirror
λ/4
Retarder
Beam
Splitter
Path Length
Detection
Unit
Control Unit
and Data
Analysis
Glucose
Concentration
(mg/dl)
Fig. 23: Non-invasive glucose measurement using Polarimetry.
O. Thermal Emission Spectroscopy
The Thermal Emission Spectroscopy based technique is based on the naturally generated IR wave
from the body. The emitted IR waves will vary according to body glucose concentration. The usual
mid-IR emission from tympanic membrane of human body is modulated with tissue emitting. The
selectivity of this technique is same as the absorption spectroscopy. Due to this technique, glucose
25
can be determined through the skin, fingers and earlobe. This technique is highly precise and accurate
for glucose measurement [141]. It could provide the useful solution which is precise and acceptable at
clinical with measurement of thermal emission from tympanic membrane.
P. Ultrasound
The Ultrasound method is based on low frequency components to extract the molecules from skin
similar as reverse iontophoresis method [142]. It is also alike sonophoresis and has larger skin permeability
than reverse iontophoresis. Few or several tens of minutes of ultrasound exposure are required to pull
glucose outward through the skin. There are few attempts for such technology and there is not any
commercial device with such type of technology.
Q. Metabolic Heat Conformation (MHC)
The Metabolic Heat Conformation (MHC) method helps to measure the glucose value with metabolic
heat and oxygen level along various physiological parameters considerations [143]. The mathematical
model for metabolic energy conservation has been modified by several physiological parameters consid-
eration such as pulse rate, oxyhemoglobin saturation, heat metabolic rate and the blood flow volume.
This method has shown good reproducibility and decent accuracy in humans.
R. Fluorescence
The Fluorescence technique is based on the excitation of blood vessels by UV rays at particular
specified frequency ranges [144]. This is followed through the detection of fluorescence at a specified
wavelength. The sensing of glucose using fluorescence through tear has been done by the diffraction of
visible light. At 380 nm, an ultraviolet LASER was taken for excitation through the glucose solution
medium. Fluorescence was estimated which is directly related to glucose concentration. In this technique,
the signal is not affected by variation in light intensity through the environment.
S. Kromoscopy
The Kromoscopy technique uses the response from various spectroscopic of NIR light with four
different detectors over different wavelength [145]. It employs the multi-channel approach with overlapped
band-pass series filters to determine the glucose molecule. In this method, the radiation of IR are imparted
on the sample and this will be divided among four detectors with band-pass filter. Each detector will
detect the light of the similar structure of the tissue. Subsequently, the complex vector analysis has been
utilised to measure the glucose concentration.
T. Electromagnetic Sensing
In the Electromagnetic Sensing method, the variations in blood sample conductivity is observed by
change in blood glucose concentration [146]. The alternation of electric field would be measured by
electromagnetic sensor whenever there will be change in blood glucose concentration. This method utilizes
the dielectric parameter of the blood samples. The frequency range for electromagnetic sensing is in the
range of 2.4 to 2.9 MHz. The glucose molecule has maximum sensitivity at particular optimal frequency
for given temperature of the medium.
26
U. Bioimpedance Spectroscopy and Dielectric Spectroscopy
It is useful to measure the variation of the blood glucose with help of conductivity and permittivity
from red blood cells membrane [147]. The spectrum of bioimpedance spectrum is measured from 0.1
to 100 MHz frequency range. It help to find the resistance with passing through electric current which
is flowing from human biological tissue. The change of plasma glucose would allow the changes in
potassium and sodium to have the change in conductivity of the membrane of the red blood cell. The
multisensor approach is usually incorporated with this spectroscopy in order to measure sweat, moisture,
movement and temperature for precise glucose measurement.
V. Reverse Ionospheresis
The small DC current is passed from anode to cathode on the skin surface to have small interstitial fluid
(ISF). Iontophoresis is employed for ionized molecules penetration at skin surface by such low current
[148]. The electric potential is passed from anode and cathode to electroosmotic flow across the skin.
This would allow to extract the molecules through skin whereas the the molecules of glucose are moved
towards the cathode. The enzyme method helps to sense the concentration of glucose molecules through
oxidation process. the method has very widely accepted and has good potential to measure accurate
glucose value.
W. Sonophoresis
The Sonophoresis technique is based on the cutaneous permittivity of the interstitial fluid (ISF) [149].
It also uses enzyme method for glucose measurement. The low frequency ultrasound wave has been
applied in order to have glucose molcules at the skin surface. The cutaneous permittivity of the ISF is
increased to enable glucose at the epidermis surface. The contraction and expansion occurs in stratum
corneum that subsequently opens the ISF pathway. There has been some attempts with this method for
glucose detection but it has been observed that it could be helpful in drug delivery in stead of glucose
measurement.
X. Occlusion Spectroscopy
The Occlusion spectroscopy based methods depend on the concept of light scattering which is of inverse
proportion of glucose concentration [150]. The flow is ceased for few seconds by applying pressure with
pneumatic cuff. The volume of blood would change due to pulse generated from the pressure excursion.
The light is transmitted through the sample and the variation of the intensity of in a received light defines
the glucose concentration. The momentary blood flow cessation helps to get higher SNR value of the
received signal. Hence, the sensitivity for glucose detection would be increases with good robustness for
accurate glucose measurement.
Y. Skin Suction Bluster Technique
The Skin Suction Bluster technique uses the concept of blister generation through vacuum suction
over limited skin area [151]. The glucose measurement is performed on fluid which is collected from the
blister. It has lower glucose molecules than plasma but it is well enough to have the glucose measurement.
This method has low risk of infection, painless and well-tolerated. It is actually useful to measure HbA1c
value which represents three month average glucose value.
27
Z. Multimodal approach based measurement
A two modal spectroscopy combining IMPS and mNIR spectroscopy is explored for high-level re-
producibility of non-invasive blood glucose measurement [152]. These two techniques are combined to
overcome the limitation of individual employed technique [153]. Impedance spectroscopy based circuit
measures the dielectric constant value of skin or tissue through RLC resonant frequency and impedance to
predict glucose level [154]. To improve the accuracy of NIR spectroscopy, mNIR spectroscopy technique
is used. In this technique, three wavelengths 850 nm, 950 nm and 1300 nm are used [155]. For precise
and accurate measurement, IMPS and mNIR are joined by an ANN (Artificial Neural Network) through
DSP processor [80]. Multiple techniques are used concurrently to reduce noise from the signal [156].
Optimized signal conditioning circuits are used for removing garbage part of the received signal for final
estimated value. Somewhere, optimized differential amplifiers are designed for noise cancellation. These
are useful for biomedical measurement applications [157]. These signal conditioning circuits are used
as post-processing approaches for glucose measurement [158], [159]. This device explored high-level
accuracy in clinical trials. Based on the Clarke error grid analysis, the measured values are in A zone.
This device has USB connectivity, battery charge and alerts for various stages of glucose level.
Multimodal
Spectroscopy IC
Impedance Spectroscopy mNIR Spectroscopy
(850, 950 & 1300nm)
Data Combining
Through ANN
Estimated
Glucose Value
Fig. 24: Multimodal IC based non invasive glucose measurement.
V. PO ST-PROCESSING AND CALIBRATION TECHNIQUES FOR NON-INVASIVE GLUCOSE-LEVEL
MEASUREMENT
This Section presents various post-processing and calibration techniques which are deployed in various
systems or frameworks for noninvasive glucose-level monitoring.
28
TABLE II: Approaches Comparison with Noninvasive Works [25], [32].
Works Spectroscopy Spectra Specific Measurement Linearity
technique wavelength range (%)
Singh, et al. [160] Optical - - 32-516 mg/dl 80
Song, et al. [80] Impedance and Reflectance NIR 850-1300 nm 80-180 mg/dl -
Pai, et al. [161] Photoacoustic NIR 905 nm upto 500 mg/dl -
Dai, et al. [162] Bioimpedance - - - -
Beach, et al. [163] Biosensing - - - -
Ali, et al. [88] Transmittance and Refraction NIR 650 nm upto 450 mg/dl -
Haxha, et al. [77] Transmission NIR 940 nm 70-120 mg/dl 96
Jain, et al. [164] Absorption and Reflectance NIR 940 nm 80-350 mg/dl 90
Jain, et al. (iGLU 1.0)
[32], [28]
Absorption and Reflectance NIR 940 and 1300 nm 80-420 mg/dl 95
Jain et al. (iGLU 2.0)
[29], [25]
Absorption and Reflectance NIR 940 and 1300 nm 80-420 mg/dl 97
TABLE III: Statistical and Parametrical Comparison with Noninvasive Works [25], [32].
Works R MARD AvgE MAD RMSE Samples Used Measurement Device
value (%) (%) (mg/dl) (mg/dl) (100%) model sample cost
Singh, et al. [160] 0.80 - - - - A&B Human Saliva Cheaper
Song, et al. [80] - 8.3 19 - - A&B Human Blood Cheaper
Pai, et al. [161] - 7.01 - 5.23 7.64 A&B in-vitro Blood Costly
Dai, et al. [162] - 5.99 5.58 - - - in-vivo Blood Cheaper
Beach, et al. [163] - - 7.33 - - - in-vitro Solution -
Ali, et al. [88] - 8.0 - - - A&B Human Blood Cheaper
Haxha, et al. [77] 0.96 - - - 33.49 A&B Human Blood Cheaper
Jain, et al. [164] 0.90 5.20 5.14 5.82 7.5 A&B Human Blood Cheaper
Jain, et al. (iGLU 1.0)
[32]
0.95 6.65 7.30 12.67 21.95 A&B Human Blood Cheaper
Jain et al. (iGLU 2.0)
[29]
0.97 4.86 4.88 9.42 13.57 Zone A Human Serum Cheaper
A. Post processing and calibration techniques
Various calibration processes have been applied for a high level of accuracy and noise reduction from
received signal. These post-processing techniques are used to design the model for errorless continuous
monitoring [165], [166].
1) Noise Minimization and Signal Conditioning: The coherent averaging technique has been adapted
to minimize the variance of random noise [167]. The impact of noise is minimized with averaging of N
number of individual samples coming from the continuous frames [168]. Frames in the maximum count
have been chosen for averaging to have SNR improvement [169]. This proposed coherent averaging has
been used frequently through MATLAB and coherent averaged signal acquired. Golay code has been
proposed as calibration of measured data. The filtering or cancellation of unusual measured data has
been achieved through the implementation of Golay code [170], [171], [172].
2) Computation Models for glucose Estimation: The regression model of regularized least square is
proposed by several researchers for measurement [173]. The estimated value is computed from photoa-
coustic signals. These photoacoustic signals are used to calibrate for estimation of glucose concentration
[174]. This can be possible through multi-variable linear regression model [175]. With the objective
of high-level accuracy, a post-processing SVM technique is proposed [176]. Support vector machine is
a better option of correct measurement in glucose monitoring system [177]. Artificial Neural Network
(ANN) has also been proposed for data combining [178]. The measured data from multiple techniques
are combined through the proposed neural network model [179]. This artificial neural network has
29
been implemented in DSP processor [180]. This proposed data interpretation model has been used for
combining and calibrating of data for final estimated glucose concentration [181].
B. Metrics for Model Validation
The calibration method is used to have precise blood glucose estimation for measurements [182].
The obtained glucose concentration values are used to compare with conventionally measured glucose
concentrations [183]. The Clarke error grid analysis has been considered maximum measurement for
analysis which is used to check the performance of any device for accuracy measurement [184]. The
process flow is represented in Fig. 25.
Error Analysis
from Predicted
Glucose
Concentration
Capillary Glucose
Concentration (mg/dl)
Prediction from Calibrated
Machine Learning Models
for Validation
Analysis of
Device
Performance
Serum Glucose
Concentration (mg/dl)
Calibration
through Machine
Learning
Techniques
Dataset Dataset
Error Analysis
from Predicted
Glucose
Concentration
Data Acquisition System
of Non-invasive Glucose
Measurement
Data Acquisition System
of Non-invasive Glucose
Measurement
Fig. 25: Representation of Metrics for model Validation.
C. Clinical Accuracy Evaluations using Clarke error grid analysis
The Clarke Error Grid has been analysed as benchmark tool to examine the clinical precision for
biomedical application. It has prediction of point as well as rate accuracy, and it amends for physiologic
time lags inherent for measurement of body glucose. The exploitation of the Clarke error grid modelling
will significantly make easy the development and refinement of a precise biomedical device. In 1970,
this technique was developed by C.G. Clark to identify the accuracy of the clinical trials which helps to
find the precision of estimated blood glucose with blood glucose value through the conventional method.
A description of the Error Grid Analysis came into view in diabetes care in 1987. The grid is divided
with five different zones mainly as zone A, zone B, zone C, zone D, and zone E. If the values residing in
either zone A or zone B then it signifies satisfactory or accurate prediction of glucose results according
to Beckman analyzer. The zone C values may prompt gratuitous corrections which may lead to a poor
30
outcome. If the values are under zone D which actually defines a hazardous failure to sense. Zone E
reflects the “erroneous treatment” [185].
400
300
200
100
00400300200
100
Zone A-
Clinically Accurate
Zone B-
Benign
Zone C-
Overcorrect
Zone D-
Failure to Detect
Zone E-
Erroneous
IE
uE
ID
uC
IC
IB
uB
uD
Fig. 26: Clarke error grid analysis.
VI. CONSUMER PRO DU CT S FO R GLU CO SE -LEV EL MEASUREMENT
There have been several non-invasive glucometer at market(such as Freestyle Libre sensor, SugarBEAT
from Nemaura medical) which used for proper medication. They would be like skin-patch with daily
disposable feature and adhesive to have the continuous glucose monitoring. Such solutions may not be
consider as completely non-invasive device which would help in frequent glucose measurement. Therefore,
they may not be useful for continuous monitoring.
There are some products as DiaMon Tech, glucowise, glucotrack, glutrac and CNOGA medical device.
Glutrac is smart healthcare device but it has accuracy issues for the blood glucose measurement. It has
higher cost while precision is still not acceptable. The non-invasive stripless device known as Omelon B-2
has been used for the CGM. The fluorescent technique based Glucosense has been made for contonuous
monitoring of the glucose value. The flexible textile-based biosensor has developed from Texas University
to measure the glucose level. All the available device have accuracy issues and considerable higher cost.
A. Wearable versus Non-wearable for Glucose Monitoring
The glucose monitoring have been attempted using non-wearable and wearable solutions in the lit-
erature. Most of the non-wearable approaches are based on photoacoustic spectroscopy and Raman
spectroscopy which are also of invasive type. The implantable devices are of semi-invasive type and
are mainly of biosensors in nature. Sweat patches, Glucowatch and Smart contact lenses are of wearable
devices category. LifePlus has developed non-invasive and wearable device for CGM purpose and it is
under consideration for commercialization. Most of non-invasive device are wearable and helpful for
frequent glucose measurement.
B. Noninvasive Glucose Measurement Consumer Products
There are variety of products such as GlucoTrack®, glucometer from Labiotech [186], and similar
available solutions have accuracy issues and cost is also high. The glucowise is another non-invasive device
31
for continuous glucose measurement from Medical Training Initiative (MTI) . The Raman scattering
spectroscopy based non-invasive solution is also developed by 2M Engineering [187]. These devices
are not much popular because of their cost and precision. Further for the high level of accuracy of
glucose measurement, Glucotrackhas been developed by integrity applications Ltd. [188]. This non-
invasive glucose monitoring device employed three consecutive ultrasonic spectroscopy, thermal emission
and electromagnetic techniques. This device is highly precise and accurate because of a combination of
three techniques [189]. A comparative perspective of various consumer products for noninvasive glucose
measurement has been summarized in Table IV.
TABLE IV: A Comparative perspective of a selected consumer products for noninvasive glucose
measurement.
Company Device Technology Object Summary Snapshot
Cygus
Inc.
(USA)
GlucoWatch
G2
Biographer
Reverse ion-
tophoresis
Wrist
skin
It would be worn as watch is
used with disposable compo-
nent, autosensor which is to be
attached at back of biographer
that contact with the skin to
provide frequent glucose mon-
itoring
CNOGA
(Israel)
Combo
glucometer
Tissue
photography
analysis
Finger On basis of tissue photography
analysis from fingertip capillar-
ies, this device can analyze vari-
ous bio parameters in very short
time
Pendragon
Medical
(Switzer-
land)
Pendra Impedance
Spectroscopy
Wrist
Skin
It helps to measure the glucose
with sodium transport of ery-
throcyte membrane, The change
of fluxes of transmembraneous
sodium occur due to impedance
field which is detected by de-
vice to generate final glucose
value
OrSense
Ltd.
(Israel)
OrSense
NBM-
200G
Occlusion
Spectroscopy
Fingertip
skin
It is based on optical con-
cept on finger which is at-
tached to a ring-shaped sensor
probe. The probe has red/near-
infrared RNIR spectral region
light source as well as detector.
It has pneumatic cuffs which
generates systolic pressure to
produce optical signal for glu-
cose monitoring
32
Company Device Technology Object Summary Snapshot
C8
Medis-
ensors
(USA)
C8 Medis-
ensor Glu-
cose detec-
tor
Raman Spec-
troscopy
Fingertip
skin
This technique is based on
monochromatic light source
passes through skin where
scattered light is detected. The
generated colors from Raman
spectra helps to exact chemical
structure of glucose molecule
Integrity
Appli-
cations
(Israel)
Glucotrack Combination
of Electro-
magnetic,
ultrasonic and
Thermal
Ear lobe
tissue
In this device, three differ-
ent techniques are used concur-
rently to increase the accuracy
and precision
Tech4Life
Enter-
prises
(USA)
Non
invasive
glucometer
Infra red
Spectroscopy
Finger It is helpful for Hyperglycemia
or Pre-Diabetic patients which
allow for regular monitoring of
precise blood glucose measure-
ment at every 30 seconds
MediWise
Ltd.
(United
King-
dom)
Glucowise Radio Wave
Spectroscopy
Forefinger
skin/Earlobe
This non invasive wireless de-
vice can measure glucose con-
centration in very short time.
It is based on electromagnetic
waves of specific frequencies
for blood glucose detection. It
uses a thin-film layer of meta-
material which increases the
penetration for precise glucose
measurement
Nemaura
Medical
(united
King-
dom)
SugarBeat Reverse ion-
tophoresis
Arm,Leg
and
adbomen
This has been proved accu-
rate device, pain-free contin-
uous blood glucose monitor-
ing. SugarBEAT®provides real-
time, needle-free glucose mea-
surement. Generally, it needs
one time finger-prick test for
calibration. One time finger
prick is used when new patch
is required to insert
33
Company Device Technology Object Summary Snapshot
Abott
Ltd.
(USA)
Free Style
Libre
Glucose oxi-
dase method
Fore-arm
skin
It uses enzyme glucose sens-
ing technology for the detec-
tion of glucose levels through
interstitial fluid Glucose oxidase
method is applied through sen-
sor where electrical current pro-
portional to the glucose con-
centration and glucose can be
measured.
C8
Medisen-
sor
Non
invasive
glucose
monitor
Raman Spec-
troscopy
Fore arm
skin
Raman spectroscopy technique
based this device can detect glu-
cose in blood through returning
spectrum from the skin
BODYO Non
invasive
glucometer
Optical Tech-
nology
Finger NA
VII. GLU CO SE LE VE L CONTRO LS AP PROACH ES A ND CONSUMER PRODUCTS
Various models have been developed for diet control using various parameters for glucose-insulin
balance. The parameters are mainly includes net hepatic glucose balance, renal excretion rate, glucose
absorption rate and peripheral glucose utilization for the glucose consumption prediction for the diabetic
patients. These are useful parameters to calculate the glucose level by proper insulin dosage along with
scheduled diet plan. Therefore, the glucose-insulin control model was designed to balance glucose insulin
level in the body for diabetes persons using proper medication.
A. Glucose Controls Approaches
The mathematical models for insulin delivery have been presented to determine the coefficients of
blood regulation. The model has been proposed for insulin secretion with glycemic profile for type 2
diabetic person [190], [191]. The non-linear model is developed using differential equation with delay
model with help of non-diabetic subjects [192]. Most poplar “Uva/Padova Simulator” was also explored
which was approved from FDA to have the proper clinical trials. The parameter are extracted with type
1 diabetic virtual patients [193]. The intravenous test for glucose tolerance with Hovorka maximal model
has explored for non-diabetic subjects [194]. The samples from type 1 diabetic persons were collected to
explain the model with help of time monitoring. The model is proposed mathematically for blood glucose
value prediction in the postprandial mode for type 1 diabetes patients [195], [196]. The mathematical
model for glucose-insulin balance for longer period is explored using two days clinical information
[197]. A algorithm was developed for T1DM patient meal detection for the purpose of frequent glucose
measurement. The work has integrated bolus meal mathematical model for glucose-insulin delivery model
[198]. Diabetic and healthy people were considered to acquire the values for the variable state dimension
algorithm. The diet plan was examined in the absence of meal profile to have the glycemic profile balance,
an intelligent PID controller (iPID) was developed to type 1 diabetic person [199], [200].
B. Glucose Controls Consumer Products
Type-1 diabetic patients aren’t able to produce insulin. Insulin is a hormone that can balance body
sugar (glucose) which is a prime source of energy that obtains from carbohydrates. If anybody has type 1
34
diabetes, it is necessary to be ready for insulin therapy. Insulin may be injected by self-injection, patients
who take multiple injections daily of insulin may also think about use of an insulin pump. An insulin
pump gives short-acting insulin all day long continuously. The insulin pump replaces the requirement of
long-acting insulin. A pump also substitutes the requirement of multiple injections per day along with
continuous insulin infusion and also serves to improve the glucose levels. Various types of insulin pumps
are already available in the market as consumable product mainly as Animas, Medtronic, Roche, Tandem
and Omnipod insulin pump are consumables. These insulin pumps are advanced to each other in terms of
their upgraded features. A comparative perspective of a selected consumer products for glucose control
is presented in Table V.
TABLE V: A comparative perspective of a selected consumer products for glucose control.
Work Technology Object Findings Observation
[86] photoplethy-
-smography
(PPG)
Finger It helps to extract the fea-
tures of PPG signal through
machine learning models to
estimate Systolic and di-
astolic blood pressure and
blood glucose values
machine learning models ap-
plied where random forest tech-
nique has best prediction results
as R2
SB P = 0.91, R2
DBP = 0.89
and R2
BGL = 0.90. CEG has
87.7% observation in Zone A,
10.3 % in Zone B, and 1.9% in
Zone D
[201] mid-infrared
attenuated total
reflection
(ATR)
spectroscopy
and trapezoidal
multi-reflection
ATR prism
oral mucosa
inner lips
Using a multi-reflection
prism brought about higher
sensitivity, and the flat and
wide contact surface of the
prism resulted in higher
measurement reproducibility
& spectra around 1155
cm1for different blood
glucose levels for fasting
and before fasting
the coefficient of determination
R2is 0.75. The standard error is
12 mg/dl, and all the measured
values are in Region A
[202] Optical Coher-
ence Tomogra-
phy
Fingertip It measures the optical ro-
tation angle and depolariza-
tion index of aqueous glu-
cose solutions with low and
high scattering, respectively.
The value of angle increases
while depolarization index
decreases with glucose value
increases
The correlation factor has a
value of R20.9101, the average
deviation is found around 0.027.
35
Work Technology Object Findings Observation
[203] Contactlenses
fluoresence
Tears r the fabrication of a soft,
smart contact lens in which
glucose sensors, wireless
power transfer circuits, and
display pixels to visualize
sensing signals in real time
are fully integrated using
transparent and stretchable
nanostructures
-
[204] transmission
spectroscopy
Sliva After completely absorbing
the sufficient amount of
saliva on the strip, the sam-
ple would reach detection
zone via paper microfluidic
movement and enzymatic re-
action between GOx and
salivary glucose would ini-
tiate a pH change, resulting
in a change in strip color
that was recorded by using
RGB detector on the hand-
held instrument which helps
for glucose detection
The developed biosensor had
a wide detection range of de-
tection between 32- and 516-
mg/dL glucose concentration
while the sensitivity of detec-
tion was 1.0 mg/dL/count at a
limit of detection (LOD) of 32
mg/dL within a response time
of 15 s
[205] impedance
spectroscopy
(IMPS)
and multi-
wavelength
near-infrared
spectroscopy
(mNIRS)
Left
Handand
wrist Hand
IMPS and mNIRS use the
indirect dielectric character-
istics of the surrounding tis-
sue around blood and the
optical scattering character-
istics of glucose itself in
blood, respectively, the pro-
posed IC can remove various
systemic noises to enhance
the glucose level estimation
accuracy
mean absolute relative
differences (mARD) to 8.3%
from 15.0% of the IMPS and
15.0–20.0% of the mNIRS
in the blood glucose level
range of 80–180 mg/dL. From
the Clarke grid error (CGE)
analysis, all of the measurement
results are clinically acceptable
and 90% of total samples can
be used for clinical treatment
36
Work Technology Object Findings Observation
[84] NIR
Spectroscopy
Fingertip short NIR waves with ab-
sorption and reflectance of
light using specific wave-
lengths (940 and 1,300 nm)
has been introduced
The Pearson’s correlation coef-
ficient (R) is 0.953 and MAD is
09.89 which is RMSE 11.56
[206] Microwave De-
tection
earlobe The absorption spectrum of
microwave signal helps to
measure using two antenna.
The sine wave of 500 MHz
is for blood glucose mea-
surement.
It can measure blood glucose
from 0 to 500 mg/dl with step
size of 200 mg/dl used for
the experiment for testing the
resolution. It obtained 0.5226
mean standard deviation while
the minimum value of standard
deviation is 0.04119.
[94] PPG Finger The prediction of blood glu-
cose was with machine-
learning using a smartphone
camera. First the invalid
data was separated from the
valid signals for two blood-
glucose groups. The system
did not require any type of
calibration
The device was able to mea-
sure glucose only 70-130 mg/dl
range. The results show accu-
racy of 98.2% for invalid single-
period classification and and the
overall accuracy is 86.2%.
[46] MEMS Finger It is minimally invasive tech-
nique known as e-Mosquito
which extracts blood sam-
ple with shape memory al-
loy (SMA)-based microactu-
ator. It considered as first
ever wearable device which
performs the automatic situ
blood extraction and per-
forms the glucose analysis.
The method provided linear cor-
relation (R2= 0.9733) between
standard measurements and the
e-Mosquito prototype.
[207] Visible NIR Wrist The paper developed biosen-
sor which helps to exploit
pulsation of arterial blood
volume from the wrist tis-
sue. The visible NIR spec-
troscopy was used for re-
flected optical signal to es-
timate blood glucose.
The correlation coefficient (Rp)
value after averaging all obser-
vation is 0.86, whereas the stan-
dard prediction error is around
6.16 mg/dl.
37
Work Technology Object Findings Observation
[201] mid-infrared
attenuated total
reflection
(ATR)
spectroscopy
inner lip
mucosa
Novel optical fiber probe
was introduced using mul-
tireflection prism with help
of ATR spectroscopy. The
sensitivity increases with the
number of reflections while
measurement reproducibility
was higher due to prism’s
wide and flat and wide con-
tact surface.
VIII. GLU CO SE -LEV EL MEASUREMENT AND CONTROL S - IOMT PERSPECTIVES
The practical and sustainable mechanisms are the prime factors of smart and automated healthcare
system. These are being optimized to support the population migration and quality of life in smart cities
and smart villages [208], [209]. The features of smart healthcare system are continuous monitoring for
critical care, ambient intelligence and quality of service for proper point of care mechanism [210], [211].
The non-invasive and precise glucose measurement is requirement for diabetic person and would also
needed to store the information using IoMT for proper treatment [26]. The traditional method for glucose
measurement has limited capability and is not able to assist the remotely located healthcare provider. The
diabetic person would like to monitor their glycemic profile frequently in a day with support of storing
at cloud server. The smart health care system would allow the point of care treatment for diabetes person
with frequent monitoring.
The internet of Medical Things (IoMT) has allowed to connect the patients with doctors remotely
for rapid treatment and special assistance using smart healthcare [208]. The continuous monitoring of
vital parameters have provided to awareness about the diet plan and routine activity management with
contemporary healthcare consumers devices. With the active support of remote healthcare solution, the
smart healthcare has potential to ameliorate the quality of service at reduced cost. The smart sensors
would capture the patient data continuously and help to store the data on cloud data centre. It is also
useful for the analysing the data and easy exchange of the information through mobile applications to
doctors as well as patients. The healthcare Cyber-Physical System (H-CPS) has been used successfully
to address the various challenges of healthcare sector with intelligent algorithms.
The continuous glucose monitoring would certainly help the diabetic patients to plan their diet for
the purpose of glucose control. The solution should be precise, low cost and easy to operate for rapid
diagnosis [32], [28]. The serum glucose would always consider as accurate than capillary measurement.
Therefore, the rapid serum glucose measurement solution with continuous monitoring is desired for the
smart healthcare. The novel serum glucometer is portable device and is also integrated with IoMT to
store the glucose values continuously at cloud. It would be useful for the healthcare provider to track
the health records of remote located diabetes person. The smart healthcare management of continuous
glucose measurement is defined in Fig. 27.
A detailed example of a closed-loop system that presents glucose-level monitoring and insulin release
to control it is illustrated in Fig. 28 [2]. This IoMT framework can provide a better solution for evaluation
of insulin doses through the closed-loop automated insulin secretion diabetes control. Such an integrated
IoMT framework can be implemented to diagnose and for the treatment of diabetic patients in terms of
controlling their blood glucose level in smart healthcare and be effective in smart village and smart cities
for healthcare with limited medical personnel.
The security and privacy issues of the medical devices are paramount aspect in any IoT network. The
hardware security of wearable device is very crucial because control actions mainly occur in wireless
38
Smart healthcare
For Glycemic
Profile balance
Continuous
Glucose
Measurement
Cloud
Data storage
Analysis of
glucose insulin
Necessary
Preventive
actions
Fig. 27: Blood glucose diagnosis and Control in smart health care system.
media. The security vulnerabilities are defined for glucose measurement device and its control are shown in
Fig. 29. The devices security are important due to connected health system in an insecure and unreliable
IoMT framework [212]. The integrity of useful medical information is also crucial security aspect of
smart healthcare. All patients medical records are stored over the server therefore the security of such
data are also really important. The controlled access with proper authentication is required to have secure
monitoring with proper patient treatment.
IX. SH ORT-C OMINGS OF EXISTING WORKS AND OPE N PROBLEMS
This Section outlines the shortcomings and discusses some open problems of glucose level measure-
ments and control.
A. Limitations of the Existing Approaches and Products
1) Photoacoustic spectroscopy has been implemented for glucose measurement. Real-time testing and
validation have not been done from human blood. The artificial solution was prepared in the
laboratory for glucose measurement. The prototype module with LASER and corresponding detector
is costly and at the same time requires considerable bigger area and does not provide portable
solution. Therefore, it is not much popular solution for continuous glucose monitoring.
2) Raman spectroscopy is a nonlinear scattering which occurs when monochromatic light interacts
with a certain sample. Raman spectroscopy based solution is applicable for a laboratory test and
also occupies the significant larger area. Hence, the system based on this approach will not be
applicable for frequent glucose measurement.
39
Prescribed Schedule
for Diet and Insulin Secretion
Internet
Connectivity
Glucose-Insulin Model
(Artificial Pancreas System)
Sample
for Test
Output for
Prescribed Schedule
Internet Connectivity
and Cloud Storage Diabetologist
Blood Glucose
Level (mg/dl)
Plasma Insulin
Level (mU/L)
Other Glucose
Consumption
Parameters
Blood Glucose
Level (below
70 mg/dl)
Blood Glucose
Level (between
70-150 mg/dl)
Blood Glucose
Level (above
150 mg/dl)
Hypoglycemia
Normal
Glucose
Hyperglycemia
No Need
of Insulin
Secretion
Fig. 28: A closed-loop automated insulin secretion diabetes control system in an IoMT framework [2].
Display of Parameters
Wearable for Noninvasive
Serum Glucose
Monitoring iGLU 2.0
Hospital Doctor
Cloud Storage
Caretaker
Medical Device Security
Integrity of
Channel Data
Access Control
Security/Privacy
of Personal Data
Insulin
Pump
Fig. 29: Our Long-Term Vision of Security-Assured Non-invasive Glucose-Level Measurement and
Control through our Proposed iGLU.
3) The retina based glucose measurement is also one of the alternate non-invasive glucose detection
approach, data has also been collected through retina for glucose measurement. Such technique is
not useful for the glucose measurement all the time.
4) In case of bio-capacitance spectroscopy, the slight difference in placing the sensor at the same
40
location might affect the output of the sensor. Effect of pressure on the sensor, body temperature
and sweat on the skin may also affect the output of the sensor.
5) Glucose detection is performed with the impedance spectroscopy (IMPS) by electrodes connection
to the skin which is affected with skin. The accuracy is always an issue as the saliva and sweat
could change for each individual and that may reflect to the precision of glucose. Therefore, this
technique is not best for reliable glucose measurement in smart healthcare.
6) PPG signal has been used to extract features for blood glucose level prediction. But the PPG may
be precise blood glucose measurement technique where the output value would vary according the
blood volume only. Therefore, the glucose molecule has not been detected precisely in the blood
sample using this technique.
B. The Open Problems in Non-invasive Glucose Measurement
There are lots of challenges for commercialization of non-invasive glucose measurement device. But,
some open problems have been discussed which are prime challenges for precise non-invasive glucose
measurement. These challenges have been represented in Fig. 30. The precise glucose measurement of
hypoglycemic patient and long-time continuous glucose measurement without instantaneous error are the
open problems which are focussed by the researchers recently.
Challenges for
Non-invasive
Glucose
Measurement
Device
Precision in
Glucose
Measurement of
Hypoglycemic
Patients
Overcome the
Environment
and Skin
Constraints for
Precision
Cost-effective
Device with
advanced and
Dynamic
features
Long-time
Continuous
Measurement
without
Instantaneous
Error
Fig. 30: Open Challenges in Noninvasive Glucose-Level Measurement.
The effect of blood pressure, body temperature and humidity have not been considered in the
literature which affect the values of glucose measurement.
The cost effective and portable solution of continuous glucose measurement device has also not been
addressed properly.
The accurate glucose measurement has been also been open challenge for full rage from 40 mg/dl
to 450 mg/dl.
The effective integration of glucometer with internet of medical things for continuously data logging
to the cloud has still not potentially resolved.
The mathematical model for automatic insulin secretion according to measured glucose value has
to be address in better manner with internet framework.
41
The privacy and security issues of insulin and blood glucose measurement system is still not resolved
yet.
The efficient power management mechanism has to be developed for continuous glucose measure-
ment with insulin delivery system.
X. CONCLUSIONS AND FUTURE RESEARCH
The paper presents survey of glucose measurement approaches along with overview of glucose control
mechanism. Many techniques available in literature are only a proof of concept, showing good correlation
between device estimated result and reference value of blood glucose. However, they are neither accurate
nor cost effective solutions and not available for commercial purpose. The optical detection using short
NIR has been potential solution to mitigate the drawbacks of all previous methods. In future, the multi-
model approaches could be considered for precise glucose estimation. The device or prototype model
should be more effective in different zones to support the continuous health monitoring. It should be
implemented as a portable device for real time application with more frequently. This device should be
developed as continuous health monitoring with minimum cost.
The future research for upcoming noninvasive glucose monitoring device is mentioned in Fig. 31. The
device is required to be integrated with advanced IoMT framework. This advanced IoMT framework will
alow to connect the device with all nearest diabetic centers to get best treatment. Unification of glucose-
level measurement and automatic diet quantification can have strong impact on smart healthcare domain
[213]. The durability, portability and user-friendly device is also the future vision in this era. The device
should have the feature of border-line cross indication. Because of this feature, any person will be aware
to take own blood glucose level. A secured device with end to end users control and authentication is also
necessary for future advancement. Physical Unclonable Function (PUF) based security of IoMT-devices
can be effective for IoMT-devices which are intrinsically resource and battery constrained [212], [214].
Unified healthcare Cyber-Physical System (H-CPS) with blockchain based data and device management
can be effective and needs research [215], [216].
Wide Range
Glucose
Measurement
(30- 600 mg/dl)
Wearable and
Automated
Operation based
Device
Device with free
from
Environmental
Constraints
Device with
Advanced IoMT
Framework
Portable,
Durable and
User-friendly
Device
Highly Precise
Device for
World-wide
Diabetic Patients
A Secured
Device with end
to end users
Control
A Low Cost
Device with
Border-line
Cross Indication
Fig. 31: Our Future Vision for Non-invasive Glucose-Level Measurement.
42
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51
ABO UT T HE AU TH OR S
Amit M. Joshi (Member, IEEE) received the Ph.D. degree from the NIT, Surat, India. He is currently an
Assistant Professor in Department of ECE, MNIT, Jaipur. He is an author of 15 peer-reviewed publications.
His current research interests include biomedical signal processing, VLSI DSP Systems and embedded
system design. He is a regular reviewer of 10 journals and 30 conferences. He has advised 06 Ph.D. and
15 Masters thesis.
Prateek Jain (Member, IEEE) earned his B.E. degree in Electronics Engineering from Jiwaji University,
India in 2010 and Master degree from ITM University Gwalior. Currently, he is an Assistant Professor in
SENSE, VIT University, Amaravati (A.P.). His current research interest includes VLSI design, Biomedical
Systems and Instrumentation. He is an author of 14 peer-reviewed publications. He is a regular reviewer
of 12 journals and 10 conferences.
Saraju P. Mohanty (Senior Member, IEEE) received the bachelor’s degree (Honors) in electrical engi-
neering from the Orissa University of Agriculture and Technology, Bhubaneswar, in 1995, the master’s
degree in Systems Science and Automation from the Indian Institute of Science, Bengaluru, in 1999, and
the Ph.D. degree in Computer Science and Engineering from the University of South Florida, Tampa, in
2003. He is a Professor with the University of North Texas. His research is in “Smart Electronic Systems”
which has been funded by National Science Foundations (NSF), Semiconductor Research Corporation
(SRC), U.S. Air Force, IUSSTF, and Mission Innovation. He has authored 350 research articles, 4 books,
and invented 4 granted and 1 pending patents. His Google Scholar h-index is 39 and i10-index is 149 with
6600 citations. He is regarded as a visionary researcher on Smart Cities technology in which his research
deals with security and energy aware, and AI/ML-integrated smart components. He introduced the Secure Digital Camera (SDC)
in 2004 with built-in security features designed using Hardware-Assisted Security (HAS) or Security by Design (SbD) principle.
He is widely credited as the designer for the first digital watermarking chip in 2004 and first the low-power digital watermarking
chip in 2006. He is a recipient of 12 best paper awards, Fulbright Specialist Award in 2020, IEEE Consumer Technology Society
Outstanding Service Award in 2020, the IEEE-CS-TCVLSI Distinguished Leadership Award in 2018, and the PROSE Award for
Best Textbook in Physical Sciences and Mathematics category in 2016. He has delivered 10 keynotes and served on 11 panels
at various International Conferences. He has been serving on the editorial board of several peer-reviewed international journals,
including IEEE Transactions on Consumer Electronics (TCE), and IEEE Transactions on Big Data (TBD). He is the Editor-in-
Chief (EiC) of the IEEE Consumer Electronics Magazine (MCE). He has been serving on the Board of Governors (BoG) of
the IEEE Consumer Technology Society, and has served as the Chair of Technical Committee on Very Large Scale Integration
(TCVLSI), IEEE Computer Society (IEEE-CS) during 2014-2018. He is the founding steering committee chair for the IEEE
International Symposium on Smart Electronic Systems (iSES), steering committee vice-chair of the IEEE-CS Symposium on
VLSI (ISVLSI), and steering committee vice-chair of the OITS International Conference on Information Technology (ICIT). He
has mentored 2 post-doctoral researchers, and supervised 12 Ph.D. dissertations, 26 M.S. theses, and 12 undergraduate projects.
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