# A Survey of Insulin-Dependent Diabetes—Part I: Therapies and Devices

Authors: Daisuke Takahashi; Yang Xiao; Fei Hu; Michael Lewis
Journal: International Journal of Telemedicine and Applications
 (2008)

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## Abstract

This paper surveys diabetes therapies from telemedicine viewpoint. In type 1 diabetes therapies, the exogenous insulin replacement is generally considered as a primary treatment. However, the complete replacement of exogenous insulin is still a challenging issue because of its complexity of modeling the dynamics, which is typically modeled nonlinearly. On the other hand, thanks to the progress of medical devices, currently the diabetes therapies are being automated. These medical devices include automated insulin pumps and blood glucose sensors. Insulin pumps are designed to create artificial insulin perfusion while they largely rely on the blood glucose profile measurements and these measurements are achieved by one or more blood glucose sensors. The blood glucose measurements are also important for the insulin-dependent diabetes therapies. An insulin pump along with sensors establishes a good feedback system providing the appropriate amount of the exogenous insulin on demand. Controlling the amount of exogenous insulin to suppress the blood glucose levels requires complicated computations. This paper mostly explains both type 1 and 2 diabetes and their mechanisms accompanied by descriptions of diabetes therapy and medical devices currently utilized in the therapy


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## Body

## 1. Introduction

Diabetes mellitus is a metabolic disorder
resulting from the permanent lack of insulin production from the pancreas (type
1 diabetes) or the chronic degradation of the functionality of endogenous
insulin (type 2 diabetes), which results in raising the glucose concentration
in blood because without insulin, the cellular system cannot properly convert
carbohydrates such as sugars, starches, or other foods into energy usable by the
body. These factors eventually result in several complications, such as
cardiovascular disease, chronic renal failure, retinal damage, nerve damage,
and microvascular damage [1]. Both types 1 and 2 diabetes are chronic and
currently incurable, seemingly linked to genetics.In addition, diabetes is a condition that disproportionately
affects developed countries. From a report of the World Health Organization
(WHO), currently, around 180 million people suffer from diabetes all over the
world, and it is thought that over 350 million people will suffer from diabetes
by the year 2030. Besides, the number of people died from diabetes was
approximately 1.1 million in 2005, and half of this number is aged under 70
years old [2]. It is also thought that 136 billion dollars are spent annually
in the United States
for 12 million diabetes patients [3, 4].Current treatment for diabetes can include home-administered care
under the guidance of a physician. Intensive treatment can mitigate the effects
of existing conditions as well as reducing the risk of developing advanced
complications, such as those previously listed.Early methods of home care involved using logs and tables,
applying diet and exercise to predetermined doses prescribed by the patient’s
doctor. Modern microcontrollers, sensors, and pumps now allow for the automated
administration of insulin within doctor-prescribed parameters. Further,
technological advances currently permit these devices to be wearable, acting as
anartificial pancreas. The goals of such a product include being safe,
automatic, and nonintrusive. These devices must employ an effective control
scheme that allows the blood glucose (BG) level to be kept within a safe range
of nominal.This paper overviews diabetes therapies and devices from a telemedicine viewpoint. We mostly discuss the insulin-dependent diabetes
therapy or type 1 diabetic therapy although we may occasionally mention the noninsulin-dependent one. It first
briefs both types of diabetes mellitus with respect to the mechanisms of endogenous
insulin deficiency in Section2. In Section 3, we outline a basic procedure of
the therapy and address the difficulties and the goals. In Section 4, we survey
several ways, in which the exogenous insulin is injected, and their effect. In Section 5, we present some
commercially available medical devices particularly for diabetes as well as
those in research. Then Section 6 is spent to briefly explain control theories
used for the diabetes therapy. Due to the limit space and complexity of controlling
the amount of exogenous insulin to suppress the blood glucose levels, control
methods are briefly discussed. Details about the control schemes are included
in another paper [5]. Finally, we conclude our paper in Section 7.


## 2. Diabetes Mellitus

Diabetes has been recognized since about
2000 B.C. However, until the discovery of insulin in 1921, diabetes was properly
treated so that the insulin-dependent diabetic could delay the emergence of the
complications [6, 7]. A characteristic of diabetes mellitus is the high blood
glucose concentration mainly caused by the lack of internal insulin production,
which is the principal hormone and suppresses the rising of the blood glucose
concentration by turning it into a main energy required by the human body [1].
While blood glucose is used as energy to work muscles, the brain, and all other
tissues, excessive concentration of glucose in blood leads to several
complications. Cardiovascular disease, chronic renal failure, retinal damage,
nerve damage, and microvascular damage are known as serious complications
caused by diabetes.According to mechanisms in which insulin deficiency occurs, the
World Health Organization categorizes two types of diabetes mellitus: type 1
and type 2 diabetes [1]. The characteristics of type 1 diabetes are the
permanent lack of insulin production from the pancreas due to the destruction
of the β cells of the Islets of Langerhans. In this kind of diabetes, insulin
replacement is required to compensate its production by the therapy.On the other hand, in type 2 diabetes, the functionality of
internal insulin becomes gradually degraded, and metabolisms that exchange
blood glucose into a main energy work less than that in the normal person.
This condition keeps blood glucose unused and eventually leads
to hyperglycemia, which may cause eye, kidney, and nerve damage [8]. In the
early stage, exercises and controlled regimens can improve, but not cure, this
metabolic disorder. However, leaving type 2 diabetes untreated, hyperglycemia
requires exogenous insulin inputs like the type 1 diabetic therapy.


### 2.1. Blood Glucose and Insulin

From its metabolism, blood glucose or blood sugar derived from a
form of carbohydrate eventually turns into energy required by the human body
and also works the brain and the nervous system. Glucose is typically carried
throughout the human body via
blood vessels as a form of red blood cell and plasma. In the human body, only insulin
and glucagon play a role of regulating blood glucose levels within a very
narrow range by bearing it from blood to the most cells, such as muscles and
adipose tissues, turning it to energy [8, 9].Typically, either excess or shortage of glucose in blood is known
as a metabolic disorder. The condition where the blood glucose is much lower
than expected is called hypoglycemia causing drowsiness, mental malfunctioning,
irritability, and loss of consciousness [8]. To the contrary, the condition
where the blood glucose levels are much higher is called hyperglycemia, and
long-term hyperglycemic conditions eventually result in diabetes [8].As we already mentioned, insulin strictly regulates blood glucose
levels. Insulin is a polypeptide hormone and a production of theβ cells of the
Islets of Langerhans in the pancreas. The main activities of endogenous insulin
are mainly two things: to help the liver yield glycogen to be preserved from
glucose, and to help muscles and adipose tissues intake glucose to be broken
down into energy. However, the lack of insulin in the liver forces glycogen to
turn back to glucose that is ejected into blood vessels. Also, the condition
leads to keep glucose in blood not processed into energy. Thus the lack or the shortage
of the insulin production by the pancreas immediately causes metabolic
disorders, that is, hyperglycemia or high blood glucose concentration, thus
eventually resulting in diabetes [9].


### 2.2. Type 1 Diabetes

In type 1 diabetes, theβ cells in the pancreas are destroyed by
the immune system which should respond to an infection caused by viruses, such
as the Coxsackie virus family or German measles [10]. As a result, the pancreas
stops supplying insulin into blood causing high blood glucose concentration.
Although type 1 diabetes is occasionally called childhood, juvenile, or
insulin-dependent diabetes, it is not a metabolic disorder that emerges only
during a childhood but after growing up to adults [10].When type 1 diabetes is untreated for a long time, it eventually
results in diabetic coma, diabetic ketoacidosis, or death [10]. Diabetic
ketoacidosis comes from a fact that when blood glucose cannot be used in a form
of energy for the body due to the lack of insulin, instead, proteins or fats
are used to be turned into a main energy. This metabolic process involves several
chemical reactions, such as oxidization of the fatty acid resulting into acetyl coenzyme A (CoA), and a sequence
of the citric acid cycle and the respiratory chain where acetyl coenzyme is
eventually turned into energy by an electron transport chain [11–14].
However, the process of these chemical reactions also creates ketones as by-products,
and because of their acidity, ketones turn blood into acid resulting in
acidosis or ketoacidosis.Treatment of type 1 diabetes is to compensate for the loss of
endogenous insulin usually by infusing exogenous insulin into the body. This
artificial insulin supplement suppresses a rise of blood glucose concentration
and delivers blood glucose to the most cells through the body. The insulin
injections are conducted three or four times per day, or alternatively, an
insulin pump is utilized to continuously deliver a little fast-acting insulin
for the basal insulin supply [15]. These treatments of type 1 diabetes are known
as the insulin-dependent diabetes therapy.


### 2.3. Type 2 Diabetes

Type 2 diabetes emerges in conditions of insulin resistance,
insulin deficiency, and hyperglycemia [16]. In insulin resistance, since functions
of internal insulin are largely degraded, it cannot appropriately facilitate
the insulin-glucose metabolism, so regardless of its existence, body cells cannot
take in blood glucose enough for energy supply [17]. Eventually, type 2
diabetes stimulates hyperglycemia, which is a condition where blood glucose
levels keep much higher than expected for a long time, it may cause eye, kidney,
and nerve damage [8]. However, in its initial stages, the symptoms of the
disease are not so serious that they cannot be often realized until they are
brought up to a more critical and chronic situation [17]. Type 2 diabetes is
mainly caused by several irregular lifestyles, such as the lack of exercise,
obesity, or a sedentary lifestyle [16]. Meanwhile, genetic factors also cause
this type of diabetes.Type 2 diabetes is also called noninsulin-dependent, obesity
related, or adult-onset diabetes.Treatment in the earlier phases of type 2 diabetes is
comparatively easier than type 1 diabetes because of the existence of more or
less internal insulin production [17]. The treatment in the initial stages mainly
consists of glycemic control, which keeps blood glucose levels normal to
prevent hyperglycemic stimuli [18], and lifestyle control, which provides
patients with desired meals and exercises from the aspect of the personal
nutrition, and typically supported by a variety of medical staffs [17].
However, as type 2 diabetes grows worse, the antidiabetic drug therapy is
necessary in addition to glycemic and lifestyle controls. Moreover, if these
therapies cannot help managing blood glucose levels, further treatments, such
as insulin therapy, are required besides the oral medication therapy.The reason or origin of type 2 diabetes is still unknown in etiology,
and currently, no one can be cured completely from type 2 diabetes [17].


## 2.1. Blood Glucose and Insulin

From its metabolism, blood glucose or blood sugar derived from a
form of carbohydrate eventually turns into energy required by the human body
and also works the brain and the nervous system. Glucose is typically carried
throughout the human body via
blood vessels as a form of red blood cell and plasma. In the human body, only insulin
and glucagon play a role of regulating blood glucose levels within a very
narrow range by bearing it from blood to the most cells, such as muscles and
adipose tissues, turning it to energy [8, 9].Typically, either excess or shortage of glucose in blood is known
as a metabolic disorder. The condition where the blood glucose is much lower
than expected is called hypoglycemia causing drowsiness, mental malfunctioning,
irritability, and loss of consciousness [8]. To the contrary, the condition
where the blood glucose levels are much higher is called hyperglycemia, and
long-term hyperglycemic conditions eventually result in diabetes [8].As we already mentioned, insulin strictly regulates blood glucose
levels. Insulin is a polypeptide hormone and a production of theβ cells of the
Islets of Langerhans in the pancreas. The main activities of endogenous insulin
are mainly two things: to help the liver yield glycogen to be preserved from
glucose, and to help muscles and adipose tissues intake glucose to be broken
down into energy. However, the lack of insulin in the liver forces glycogen to
turn back to glucose that is ejected into blood vessels. Also, the condition
leads to keep glucose in blood not processed into energy. Thus the lack or the shortage
of the insulin production by the pancreas immediately causes metabolic
disorders, that is, hyperglycemia or high blood glucose concentration, thus
eventually resulting in diabetes [9].


## 2.2. Type 1 Diabetes

In type 1 diabetes, theβ cells in the pancreas are destroyed by
the immune system which should respond to an infection caused by viruses, such
as the Coxsackie virus family or German measles [10]. As a result, the pancreas
stops supplying insulin into blood causing high blood glucose concentration.
Although type 1 diabetes is occasionally called childhood, juvenile, or
insulin-dependent diabetes, it is not a metabolic disorder that emerges only
during a childhood but after growing up to adults [10].When type 1 diabetes is untreated for a long time, it eventually
results in diabetic coma, diabetic ketoacidosis, or death [10]. Diabetic
ketoacidosis comes from a fact that when blood glucose cannot be used in a form
of energy for the body due to the lack of insulin, instead, proteins or fats
are used to be turned into a main energy. This metabolic process involves several
chemical reactions, such as oxidization of the fatty acid resulting into acetyl coenzyme A (CoA), and a sequence
of the citric acid cycle and the respiratory chain where acetyl coenzyme is
eventually turned into energy by an electron transport chain [11–14].
However, the process of these chemical reactions also creates ketones as by-products,
and because of their acidity, ketones turn blood into acid resulting in
acidosis or ketoacidosis.Treatment of type 1 diabetes is to compensate for the loss of
endogenous insulin usually by infusing exogenous insulin into the body. This
artificial insulin supplement suppresses a rise of blood glucose concentration
and delivers blood glucose to the most cells through the body. The insulin
injections are conducted three or four times per day, or alternatively, an
insulin pump is utilized to continuously deliver a little fast-acting insulin
for the basal insulin supply [15]. These treatments of type 1 diabetes are known
as the insulin-dependent diabetes therapy.


## 2.3. Type 2 Diabetes

Type 2 diabetes emerges in conditions of insulin resistance,
insulin deficiency, and hyperglycemia [16]. In insulin resistance, since functions
of internal insulin are largely degraded, it cannot appropriately facilitate
the insulin-glucose metabolism, so regardless of its existence, body cells cannot
take in blood glucose enough for energy supply [17]. Eventually, type 2
diabetes stimulates hyperglycemia, which is a condition where blood glucose
levels keep much higher than expected for a long time, it may cause eye, kidney,
and nerve damage [8]. However, in its initial stages, the symptoms of the
disease are not so serious that they cannot be often realized until they are
brought up to a more critical and chronic situation [17]. Type 2 diabetes is
mainly caused by several irregular lifestyles, such as the lack of exercise,
obesity, or a sedentary lifestyle [16]. Meanwhile, genetic factors also cause
this type of diabetes.Type 2 diabetes is also called noninsulin-dependent, obesity
related, or adult-onset diabetes.Treatment in the earlier phases of type 2 diabetes is
comparatively easier than type 1 diabetes because of the existence of more or
less internal insulin production [17]. The treatment in the initial stages mainly
consists of glycemic control, which keeps blood glucose levels normal to
prevent hyperglycemic stimuli [18], and lifestyle control, which provides
patients with desired meals and exercises from the aspect of the personal
nutrition, and typically supported by a variety of medical staffs [17].
However, as type 2 diabetes grows worse, the antidiabetic drug therapy is
necessary in addition to glycemic and lifestyle controls. Moreover, if these
therapies cannot help managing blood glucose levels, further treatments, such
as insulin therapy, are required besides the oral medication therapy.The reason or origin of type 2 diabetes is still unknown in etiology,
and currently, no one can be cured completely from type 2 diabetes [17].


## 3. Insulin-Dependent Diabetes Therapy

A basic idea of insulin-dependent diabetes therapy is initiated
by a report of the Diabetes Control and Complication Trial, that is, the
well-controlled glucose metabolism manages well or delays the emergence of the
complications of insulin-dependent diabetes [15, 19, 20]. Thus in typical cases
of the insulin therapy, according to blood tests, three or four times of insulin
injections are subcutaneously carried out per day to compensate the lack of
endogenous insulin secretion for type 1 diabetes in order to suppress the rise
of blood glucose levels [10]. Sample blood is typically picked from the tip of
a finger or earlobe, and the amount of blood glucose is checked using a sensor [15]. For example, thanks to
the development of the NPH (neutral protamine hagedorn) insulin, the
combination of the NPH and regular insulin is injected before breakfast.
Usually, the effect of the NPH insulin is very slow and continues for a long
period, which resembles the basal supply of endogenous insulin for a normal
person. Meanwhile, the regular insulin makes up for the bolus supply of
endogenous insulin during a meal intake, so the regular insulin acts immediately
and whose peak is higher than the NPH insulin, shown in Figure 1. Then before
dinner and bedtime, a couple of other regular insulin injections are carried
out according to test results [6].Figure 1
An example of
insulin pump that integrates a blood glucose sensor [21]. Patient’s blood is
sampled from the tip of his/her finger, and from the direct measurements of a
blood glucose sensor, the amount of the short-acting insulin is adjusted and
continuously delivered into the human body.Although the subcutaneous insulin infusion is expected to follow
precisely the complex real hormone secretion, the conventional insulin therapy does
not follow this complex system enough neither temporally nor quantitatively yet.
In fact, the metabolism of a nondiabetes person controls blood glucose levels
in a quite narrow range all the time [6], for example, within the range of 4
to 8 mmol/L [22].Thus one goal of the insulin-dependent diabetes therapy is to
precisely capture the insulin-glucose dynamics of the normal person and design a
system yielding the insulin secretion quantitatively as close to the real
metabolism as possible. However, in practice, many parameters around the
metabolism, such as environmental conditions, stress of patients, behavioral
changes, and duration of tests make a calculation of the actual demand of
exogenous insulin intricate [23]. As a result, designed algorithms and mathematical
representations must be complex and nonlinearly modeled in order to resemble
the real hormone secretion [24].Meanwhile, to support the therapy, short-term in vivo glucose
sensors have been recently integrated into insulin-dependent diabetes
therapeutic system [25]. The in vivo glucose sensors typically are implanted
subcutaneously and send blood glucose profiles as vital signals to exterior
receivers, such as PDAs or laptop PCs, at very short intervals. Since many
samples make modeling a blood glucose curve relatively easy resulting in
enhancing predictions of the future transition of blood glucose concentration [24],
the in vivo sensors are considered to be largely beneficial to a reliable
insulin-dependent diabetes therapy. Currently in collaboration with an insulin
pump, in vivo blood glucose sensors are integrated into closed-loop blood glucose
control systems.Problems of current in vivo blood glucose sensors are, however,
that reliable long-term blood glucose monitoring is still challenging and is
not approved by U.S. Food and Drug Administration (FDA). Currently, only
three-day monitoring is considered to be safe and reliable [24, 26]. In addition,
these blood glucose sensors largely still rely on the discrete measurements
rather than continuous ones [24].Broadly speaking, as types of the insulin therapy, three models
are mainly utilized, for example, open-loop, closed-loop, and partially
closed-loop control models. These models have their own advantages and
disadvantages for their use. Among the three models, the open-loop control and the
partial closed-loop control require physician’s assistance for injecting the exogenous
insulin, whereas in the closed-loop control according to feedbacks from the output of blood
glucose sensors, the amount of the exogenous insulin is determined so that the
system is ideally autonomous and self-organized. Examples of the closed-loop
control schemes are pole-assignment strategy and self-tuning adaptive control, and
examples of the partially closed-loop controls are the automated insulin dosage
advisor (AIDA) and the diabetes advisory system (DIAS) [15].


## 4. Methods of Insulin Injection and Infusion

There are several ways to
inject insulin into the human body, that is, intravenous, subcutaneous, and
intraperitoneal routes. The most direct method is intravenous infusion [15],
while subtler ways can be used for continuous or less painful dispensation,
such as subcutaneous injection. Furthermore, the method of injection as well as
the control method places a number of requirements on the type of insulin
applied to the patient. In either way of the insulin infusion, the objective is
to keep the condition of normoglycemia for the type 1 diabetic like normal
people at all times.


### 4.1. Intravenous Insulin Injection

One way for the exogenous insulin
injection is to utilize an intravenous route. Intravenous infusion works by
injecting drugs directly into a patient’s blood stream through a needle, which
penetrates the skin, and into a vein. Several
advantages of the intravenous insulin injection benefit for insulin-dependent
diabetes therapy. Compared with the other routes, to inject insulin
intravenously delivers insulin more quickly and helps it reach the bloodstream
in the higher ratio. In addition, against the overdose of insulin, utilizing this
route can enhance the sensitivity to hypoglycemia, respond immediately and stop
delivering. Furthermore, this route of insulin injection is considered to be
better suited for improved closed-loop mechanisms [27].However, despite of a lot
of benefits, the intravenous route also includes a couple of shortcomings. For
example, in the intravenous insulin infusion, since the catheter is kept to be
put into the vein, this may cause the blood vessel to be irritated. Also, in a
long time insulin infusion, the catheter may be put away from the vein or it
may be obstructed [27].One experiment showed that
for the type 1 diabetic, a continuous crystalline insulin infusion
intravenously could improve the insulin profile prominently close to the normal
for 30 minutes from the beginning of a meal [6]. To the contrary, the same
experiment reported the anomaly of the glycemic profile where the blood glucose
concentration regained above normal after the initial 15–30 minutes of the
experiment [6].Moreover, to achieve the
normalization of the glycemic and metabolic profile with an ambulatory
insulin-dependent diabetes therapy, delivering insulin in the central venous
route with a continuous open-loop infusion system is feasible [28].


### 4.2. Subcutaneous Insulin Injection

An alternative way to inject
exogenous insulin is the subcutaneous route that is much simpler and less risky
of infection at an injection site than in an intravenous route, although it
presents certain design challenges for blood glucose level control. It can be
used to facilitate continuous, noninterrupted glucose management. Due to its
relatively pain-free application (compared to intravenous infusion), it is much
more agreeable to home monitoring patients who wear artificial pancreas devices
at all times [29]. Therefore, basically insulin injections and infusions are
conducted safely by the diabetic on their own. Most of the clinical experiments
demonstrated that, compared with conventional single injections, to infuse
insulin subcutaneously administrates the glycemic profile better. Also, it was
turned out that by delivering insulin mechanically, long-term subcutaneous
experiments regulated values of hemoglobin A1C for the diabetic [6].However, occasionally
infusing insulin subcutaneously is not sufficient for reversing diabetic complications,
particularly brittle patients, because of its limitations of controlling the
glycemic profile [6].


### 4.3. Intraperitoneal Insulin Injection

Although only a limited
number of experiments were carried out, insulin can be injected in an
intraperoneal route. Early experiments of insulin-dependent diabetes therapy
with the intraperitoneal insulin infusion showed that insulin soaked up from
the peritoneum would appear in the surrounding blood system of the diabetic
with peritoneal dialysis. Meanwhile, it was possible for diabetics to have
daily activities and ambulate as usual. In addition to these benefits, the same
experiments demonstrated no diabetic complications by daily basis catheters replacement
[6, 30].Furthermore, in the
intraperitoneal insulin infusion, insulin is soaked up into the blood system
moderately in the range of subcutaneous insulin injection to intravenous
insulin infusion, while the insulin is delivered from the peritoneum directly
to the liver resulting in the reduction of high concentration of peripheral
insulin [6].On the other hand, despite
of its advantages, in the intraperitoneal insulin infusion, external insulin
delivery systems increase the risk of infection developing peritonitis as well
as tissue degradation at the catheter site [6].


### 4.4. Comparison of Methods

Because it is less invasive
to the body, subcutaneous injection is generally safer for several reasons [15].
Persons with an active lifestyle are put at risk by leaving an embedded needle
protruding from their body, necessary to bridge the fluids gap between their
bodies and their artificial pancreas. Subcutaneous administration greatly
reduces this safety hazard by interfacing no deeper than the skin layers, often
distributed over an area, decreasing the invasiveness of the device [29].
Furthermore, continuous needle-sticking as well as prolonged embedding poses
health risks of infection, clotting, or other sorts of body-triggered rejection
to an invasive foreign device. Because subcutaneous injection is far less
invasive, it is less likely to trigger self-defense mechanisms like this, and
if triggered, they tend to be far less severe.However, subcutaneous
injection is not without its drawbacks. Due to its less invasive nature,
insulin takes far longer to permeate into the body than through direct
intravenous infusion. It has been reported that when using standard insulin for
both injection types, subcutaneous injection can take as much as three times
longer to take effect. This makes implementing an accurate control system quite
challenging due to the time delays.


### 4.5. Insulin Selection

Several options are
available for insulin to be injected, depending upon the situation [15]. Regular
insulin has historically been used to treat diabetes. It can be both
intravenous and subcutaneous injected, depending upon the injection interface
used. When it is subcutaneously injected, its effects take up to three times
longer than if it is intravenously injected, posing a difficult control systems
problem.An insulin preparation by
the name of Lispro was developed to aid in the rapid absorption of the insulin
[15]. It is designed to take immediate effect, and can be fully absorbed into
the body’s system significantly faster than regular insulin. Lispro is designed
to take effect within 15 minutes and peak about an hour after application.
Because of its fast-delivery capabilities, Lispro is the most commonly used
with subcutaneous injection. Subcutaneous injected Lispro has been proven to
take effect within approximately the same time frame as intravenous injected
normal insulin. This enables home monitoring and injection patients to control
their glucose levels to the same levels as with intravenous management, but in
a far less invasive and painful way.An insulin preparation by
the name of NPH has also been developed for the exact opposite purpose of
Lispro [15]. NPH is designed to take effect over a much longer period of time,
lasting up to 24 hours. The purpose of insulin with this property is to provide
the patient with a predictable baseline level of insulin throughout the day,
allowing the control system to focus its efforts on accounting for and
correcting anomalies and disruptions that are encountered, such as meals,
exercise, and sleep.Appropriate injections of a
combination of Lispro and NPH has been proven incredibly effective in
maintaining short and long-term glucose stability within patients using a
continuous monitoring and control device [29]. Lispro is usually used for
fast-acting control to counterbalance blood glucose fluctuations due to meals.
NPH is usually used to provide a constant trickle of insulin in order to
establish a baseline, known as a basal level.


## 4.1. Intravenous Insulin Injection

One way for the exogenous insulin
injection is to utilize an intravenous route. Intravenous infusion works by
injecting drugs directly into a patient’s blood stream through a needle, which
penetrates the skin, and into a vein. Several
advantages of the intravenous insulin injection benefit for insulin-dependent
diabetes therapy. Compared with the other routes, to inject insulin
intravenously delivers insulin more quickly and helps it reach the bloodstream
in the higher ratio. In addition, against the overdose of insulin, utilizing this
route can enhance the sensitivity to hypoglycemia, respond immediately and stop
delivering. Furthermore, this route of insulin injection is considered to be
better suited for improved closed-loop mechanisms [27].However, despite of a lot
of benefits, the intravenous route also includes a couple of shortcomings. For
example, in the intravenous insulin infusion, since the catheter is kept to be
put into the vein, this may cause the blood vessel to be irritated. Also, in a
long time insulin infusion, the catheter may be put away from the vein or it
may be obstructed [27].One experiment showed that
for the type 1 diabetic, a continuous crystalline insulin infusion
intravenously could improve the insulin profile prominently close to the normal
for 30 minutes from the beginning of a meal [6]. To the contrary, the same
experiment reported the anomaly of the glycemic profile where the blood glucose
concentration regained above normal after the initial 15–30 minutes of the
experiment [6].Moreover, to achieve the
normalization of the glycemic and metabolic profile with an ambulatory
insulin-dependent diabetes therapy, delivering insulin in the central venous
route with a continuous open-loop infusion system is feasible [28].


## 4.2. Subcutaneous Insulin Injection

An alternative way to inject
exogenous insulin is the subcutaneous route that is much simpler and less risky
of infection at an injection site than in an intravenous route, although it
presents certain design challenges for blood glucose level control. It can be
used to facilitate continuous, noninterrupted glucose management. Due to its
relatively pain-free application (compared to intravenous infusion), it is much
more agreeable to home monitoring patients who wear artificial pancreas devices
at all times [29]. Therefore, basically insulin injections and infusions are
conducted safely by the diabetic on their own. Most of the clinical experiments
demonstrated that, compared with conventional single injections, to infuse
insulin subcutaneously administrates the glycemic profile better. Also, it was
turned out that by delivering insulin mechanically, long-term subcutaneous
experiments regulated values of hemoglobin A1C for the diabetic [6].However, occasionally
infusing insulin subcutaneously is not sufficient for reversing diabetic complications,
particularly brittle patients, because of its limitations of controlling the
glycemic profile [6].


## 4.3. Intraperitoneal Insulin Injection

Although only a limited
number of experiments were carried out, insulin can be injected in an
intraperoneal route. Early experiments of insulin-dependent diabetes therapy
with the intraperitoneal insulin infusion showed that insulin soaked up from
the peritoneum would appear in the surrounding blood system of the diabetic
with peritoneal dialysis. Meanwhile, it was possible for diabetics to have
daily activities and ambulate as usual. In addition to these benefits, the same
experiments demonstrated no diabetic complications by daily basis catheters replacement
[6, 30].Furthermore, in the
intraperitoneal insulin infusion, insulin is soaked up into the blood system
moderately in the range of subcutaneous insulin injection to intravenous
insulin infusion, while the insulin is delivered from the peritoneum directly
to the liver resulting in the reduction of high concentration of peripheral
insulin [6].On the other hand, despite
of its advantages, in the intraperitoneal insulin infusion, external insulin
delivery systems increase the risk of infection developing peritonitis as well
as tissue degradation at the catheter site [6].


## 4.4. Comparison of Methods

Because it is less invasive
to the body, subcutaneous injection is generally safer for several reasons [15].
Persons with an active lifestyle are put at risk by leaving an embedded needle
protruding from their body, necessary to bridge the fluids gap between their
bodies and their artificial pancreas. Subcutaneous administration greatly
reduces this safety hazard by interfacing no deeper than the skin layers, often
distributed over an area, decreasing the invasiveness of the device [29].
Furthermore, continuous needle-sticking as well as prolonged embedding poses
health risks of infection, clotting, or other sorts of body-triggered rejection
to an invasive foreign device. Because subcutaneous injection is far less
invasive, it is less likely to trigger self-defense mechanisms like this, and
if triggered, they tend to be far less severe.However, subcutaneous
injection is not without its drawbacks. Due to its less invasive nature,
insulin takes far longer to permeate into the body than through direct
intravenous infusion. It has been reported that when using standard insulin for
both injection types, subcutaneous injection can take as much as three times
longer to take effect. This makes implementing an accurate control system quite
challenging due to the time delays.


## 4.5. Insulin Selection

Several options are
available for insulin to be injected, depending upon the situation [15]. Regular
insulin has historically been used to treat diabetes. It can be both
intravenous and subcutaneous injected, depending upon the injection interface
used. When it is subcutaneously injected, its effects take up to three times
longer than if it is intravenously injected, posing a difficult control systems
problem.An insulin preparation by
the name of Lispro was developed to aid in the rapid absorption of the insulin
[15]. It is designed to take immediate effect, and can be fully absorbed into
the body’s system significantly faster than regular insulin. Lispro is designed
to take effect within 15 minutes and peak about an hour after application.
Because of its fast-delivery capabilities, Lispro is the most commonly used
with subcutaneous injection. Subcutaneous injected Lispro has been proven to
take effect within approximately the same time frame as intravenous injected
normal insulin. This enables home monitoring and injection patients to control
their glucose levels to the same levels as with intravenous management, but in
a far less invasive and painful way.An insulin preparation by
the name of NPH has also been developed for the exact opposite purpose of
Lispro [15]. NPH is designed to take effect over a much longer period of time,
lasting up to 24 hours. The purpose of insulin with this property is to provide
the patient with a predictable baseline level of insulin throughout the day,
allowing the control system to focus its efforts on accounting for and
correcting anomalies and disruptions that are encountered, such as meals,
exercise, and sleep.Appropriate injections of a
combination of Lispro and NPH has been proven incredibly effective in
maintaining short and long-term glucose stability within patients using a
continuous monitoring and control device [29]. Lispro is usually used for
fast-acting control to counterbalance blood glucose fluctuations due to meals.
NPH is usually used to provide a constant trickle of insulin in order to
establish a baseline, known as a basal level.


## 5. Devices in Insulin-Dependent Diabetes  Therapy

### 5.1. Insulin Pump

Insulin pumps are used to create an
artificial insulin secretion subcutaneously that can suppress excessive blood
glucose propagation for the type 1 diabetic. In general, it continuously
delivers a basal rate of exogenous insulin automatically and also has
capability of manually adding extra insulin to the basal rate for the intensive
insulin secretion by a continuous subcutaneous insulin infusion (CSII) technique
[31]. Most of the insulin pumps consist of a small processing module with a
display, a disposable insulin reservoir, and an insulin syringe, and are
powered by batteries, illustrated in Figures 2 and 3. The amount of insulin
supply is externally controllable depending on blood glucose measurements.Figure 2
An image of an insulin pump. This image also includes a blood
glucose sensor. In the general use, an insulin pump continuously infuses a
little amount of the short-acting exogenous insulin via an attached needle as a
basal dosage. It is also able to add extra exogenous insulin for intensive
care, for example, meal time. Insulin pumps have a lot of advantages compared
with the insulin shots.Figure 3
Another example of
insulin pumps of Medtronic. A processing module has a small display that shows
a current rate of an exogenous insulin infusion. It also has several control
buttons just below the display. Two of these buttons are used to manage a
current insulin infusion rate.In the use of an insulin pump, after finishing setting-up, a
patient inserts a cannula into his/her abdomen as seen in Figure2. Upon
determining an insulin infusion rate, it starts delivering exogenous insulin
continuously in 24 hours per day and 7 days a week, that is, a basal dose [32].
During meal time, when more amount of the insulin dosage is required because of
carbohydrate intakes, the insulin pump enhances its insulin supply to adjust high
blood glucose concentrations, which is called a bolus dose so that this
artificial insulin metabolism should occur after a real physiological
metabolism in the normal human body.In case of the insulin injection using a syringe, since the
insulin dosage is performed three or four times a day, each shot is devised in such
a way that the insulin dosage can keep its effect constantly as long as
possible. In general, using a delayed action insulin or slow-acting insulin helps
a basal supply of exogenous insulin. A difficulty of the insulin injection,
however, results from using this slow-acting insulin. Although the duration of the
effect is achieved longer than other types of insulin, it also takes a longer
time to start taking effect as illustrated in Figure1. This disadvantage largely
prevents effective predictions of a future blood glucose profile. In this
connection, its variance eventually grows up to 52% [31]. Moreover, the insulin
injection with insulin shots inevitably restricts a patient’s life style, for
example, the hour of rising and meals.Meanwhile, in case of insulin pumps, an accompanying insulin
cannula is put into the human body continuously supplying a little amount of theshort-acting insulin even in bedtime.
Although the duration of the effect of insulin is very low, the short-acting
insulin acts faster than the slow-acting insulin. Therefore, a little amount of
a continuous dose of insulin can make predictions of blood glucose
concentration comparatively easy and its variance is not more than 3% [31].Currently, one of the most promising pump technologies is a
piezoelectric fluid device [29]. Piezoelectric pumps operate by applying
voltage to a thin lead zirconate titanate (PZT) film. This distorts the film,
causing it to pump fluid through an adjoined silicon nitride membrane, shown in
Figure 4.Figure 4
Piezoelectric pump and micro-needle device.The displacement volume of an unloaded pump can be described as(1)ΔV=3r4(5+2μ)(1−μ)d13U4h2(3+2μ),(2)K=3r4(5+2μ)(1−μ)d134h2(3+2μ),(3)ΔV=KΔU,(4)Q=KfΔU,
where r is the radius of the membrane in μm, h is the thickness of the membrane in μm, μ is the Poisson ratio, ΔU is the peak-to-peak voltage applied to the
pump every period, d13 is the piezoelectric coefficient, and f is
the frequency at which voltage is applied to the pump. K represents the pump
coefficient described by (1). Q is the flow rate of the pump.Note thatΔV is
linearly proportional to ΔU.
Likewise, Q is also linear for a fixed f or a fixed ΔU. This permits very simple and intuitive
control of the pump by the controller, allowing it to control the flow rate
through a variable amplitude signal or a variable frequency signal, depending
upon system requirements and the resources available.Pump reliability is an incredibly crucial factor when considering
a blood glucose management system. Pump, sensor, or control failure can lead to
incorrect dosages or even a failure to inject. Due to its mechanical nature,
pump failure is often the most likely cause of malfunction. This can results
from o-ring leaks, air bubbles, bleeding, infection, and clogs. These
conditions can easily result in hyperglycemia or hypoglycemia and must be
monitored for.We compare five types of popular insulin pumps in Table1.Table 1
Specification comparison of commercial insulin pumps.
CompanyAnimasDeltecDisetronicMiniMedInsuletModelIR-1250 [11]Cozmo [12]Spirit [13]Paradigm522/722 [14]OmniPod [33]Dimensions79× 51 × 1980× 47 × 2480× 56 × 20522: 51× 79 × 20 722: 51 × 79 × 20Pod: 41× 61 × 18 Pda: 66 × 110 × 26Screen size992 sq mm870 sq mmUnavailable774 sq mm1,848 sq mm on PDA controllerBasal deliveryEvery 3 minutesEvery 3 minutesEvery 3 minutesVariesInformation unavailableBasal temperatureInitially −90% to +200%, varies for
every half an hourVaries from 0% to 200% with an
increment of 5% for every half an hourVaries from 0% to 200% with an
increment of 10% for every half an hour+/−0.1 increment as single basal
rate for 0.5 to 24 hoursInformation unavailableCarb and correction factorsManual entry and assist from EZ managerManual carbohydrate, BG from
attached CoZ monitorManual carbohydrate, BG from Accu-check
BG monitorManual carbohydrate, BG from BD
meter or manual entryInformation unavailableBatteryAA lithium× 1AAA× 1AA× 1 Alkaline or RechargeableAAAAAA× 2MotorDCDCDCDCStepperMemoryNonvolatile: 600 bolus, 270 basal,
120 daily totals, 30 alarms, and 60 primesNonvolatile: 90 days of basals,
carbohydrates, boluses, correction boluses, and alarmsNonvolatile: 90 days history recall
of last 30 boluses, alerts, daily insulin totals, and temporary basal rate
increase4000 events volatile: 24 boluses,
and 7 days totals90 days of dataExtra featuresClip-on covers, personalized
carbohydrate, and correction factors, tracks residual bolus insulinCarbohydrate and correction factors,
tracks residual bolus insulin, detailed records of pump, and daily bolus
total correctionAvailability of different types of
user menus, icon and menu driven programming, backlight display, and reversible
display screenExtended bolus, auto offIntegrated free style meter, 1000
common foods in PDATable 2
Specification comparison of commercial blood glucose sensors.
FeaturesAbbott freestyle navigator [39]MiniMed paradigm real-time system [40]MiniMed guardian real-time system [41]DexCom [42]AccuracyVariesConsensus error grid: 98.9%A+B mard(mean) −19.7% (median) −15.5%Consensus error grid: 98.9%A+B mard(mean) −19.7% (median) −15.5%Consensus error grid: 95.4%A+B mard(mean) −49% (median) −15.9%Startup initiation   time10 hours2 hours2 hours2 hoursSensor life5-day wear indicationAbove 72 hoursAbove 72 hoursAbove 72 hoursCalibration   methodRequires calibration at
10, 12, 24, and 72 hours after the insertion of the sensorAlarms when calibration value is not entered on time.
First and second calibration should be done for 2 and 6 hours after
insertionAlarms when calibration
value is not entered on time. First and second calibration should be done for
2 and 6 hours after insertionFirst calibration after 30
minutes and then for every 12 hours. Manual calibration is not possibleFrequency of   displayEvery 1 minuteEvery 5 minutesEvery 5 minutesEvery 5 minutesTransmitter   memory—Yes, the transmitter stores missed data for up to 40
minutesYes, the transmitter stores
missed data for up to 40 minutesNo, transmission lost is
data lostRange of monitor   to transmitter10 feet6 feet6 feet5 feetMonitor batteriesUses 2 AAA batteries with
replacement for every three monthsNo separate monitor required. Uses insulin pumpUses 2 AAA Batteries.
Indication is set for chance of batteryUses rechargeable batteriesMonitor size3“× 2.5”Separate monitor is not available. Uses insulin pump
for display3“× 2.7”3“× 2.5”Alarms on user-set low and high   thresholdsApplicableApplicableApplicableApplicable


### 5.2. Blood Glucose Sensor

In consideration of easy predictions of
blood glucose profile, recently, utilization of both an insulin pump and a
blood glucose sensor is very important for the intensive insulin-dependent diabetes
therapy. In general, when the system has a capability of the continuous glucose
measurement, and with this measurement, a rate of exogenous insulin dosage is
automatically or manually adjusted,
and the system is called a closed-loop control system. In this system, a
glucose sensor may be implanted in the human body as shown in Figure5 [15]. On the other hand, when the system
still counts on periodical glucose measurements, the system is called a partially
closed-loop control system. Generally, this latter system utilizes very complex
nonlinear calculations or mathematical modeling to pursue its accuracy from few
glucose measurements. Besides, insulin
dosage plan is designed by a physician with an expert system that performs comparisons
between the generated predictions and model cases.Figure 5
An image shows a miniature size of in vivo
blood glucose sensor that is being developed [15]. It is currently proven by FDA
that in vivo blood glucose sensors are only safe and reliable in a short period
of time (e.g., three days). Thus after the period, they are required to be
replaced by a new one regularly to keep their accuracy.


#### 5.2.1. Fingersticks

There are many kinds of blood glucose sensors to be exploited.
One of them, fingerstick meter readings, measures blood glucose profiles
directly from blood samples taken out of the tip of a finger. This is invasive
and can be painful. Additionally, measurements of this sort are only taken a
few times per day due to the conscious effort required to perform them [34].In testing a patient blood sample, for example [35], some products
require only 0.3 micro liters of the blood sample, but required samplings are
at least 4 times per day [36]. Besides, this kind of sensor is also integrated
into an insulin pump enhancing portability of the system as well as eliminating
a requirement of the manual input of data into the insulin pump, shown in Figure 6 [35]. A drawback of the sensor is that since it invasively samples blood from
a finger or earlobe, it is almost impossible to take samples continuously in order to enhance the measurements. Therefore,
increasingly, different types of sensors are being developed and used, and they
provide a wealth of benefits compared to finger sticks.Figure 6
An image shows a fingerstick meter
reading. In the use of the sensor, first
off, cut the tip of a finger or earlobe bleeding. Then put the blood on a blood
glucose sensor, which is a protuberance at the bottom of the module. The result
is shown on the display in the middle-top of the module.


#### 5.2.2. Implantable Sensors

In addition to the fingerstick meter readings, implantable
glucose sensors are available with some limitations. One type of these
implantable sensors is needle-type sensors [24]. These needle-type sensors are
intravenously or subcutaneously inserted into the body. Intravenous systems
monitor blood glucose levels by drawing blood through a vascularly embedded
needle [15]. This has the advantage of up to date, real-time BG levels, but at
the expensive of being invasive and painful. Additionally, there are long term
effects associated with prolonged vascular invasion, making it a suboptimal
solution for continuous long-term home monitoring.Subcutaneous glucose sensors are small electrode devices that can
be inserted into the skin in the fatty tissues. This includes collecting a
blood sample from the dermis layer of the skin [24], which is located about a
tenth of a millimeter into the surface of the body [2]. When the sensors are
placed correctly, current proportional to the blood glucose level can be
detected and measured. For example, a probe of a subcutaneous sensor is made of
an amperometric cell covered by a thin membrane. With this sensor, only needle
part is inserted subcutaneously into the body while a processor module stays
outside. Due to its shallow position, subcutaneous monitoring can be
significantly less painful than finger sticking. The greatest boon of
subcutaneous monitoring, however, is that it can be performed continuously in a
wearable fashion. This quality enables new types of control techniques to be
exploited. The finer the measuring time increment is, the more accurate control
methods will be. Continuously glucose monitoring permits real-time signal
filtering in attempts to closely regulate changes in glucose due to various
factors such as meals, exercise, or sleep patterns.There are several methods for administering subcutaneous
monitoring, including dialysis and open-flow microperfusion. Currently, the
most advanced method of subcutaneous monitoring is considered to be
microperfusion [24]. Microperfusion entails diffusing interstitial fluids from
the dermis into a double lumen catheter where it can be monitored by an
external sensor without actually drawing blood.Also, another type of in vivo sensor is a small piece of module
which is completely implanted into a segment of the body of the diabetic. Since
these glucose sensors are implanted into the human body, continuous measurement
of blood glucose levels will be possible. The authors in [26] demonstrated that
samplings were conducted every 5 minutes. The sampled blood glucose profiles are wirelessly transmitted to external
receivers that could be a PDA or
some other small devices looking like a list-watch.
According to the transferred vital data,
it is preferable to automatically reconfigure a current insulin delivery rate,
but some systems still require the users to manually reconfigure the delivery
rate. Although, if realized,
the continuously blood glucose monitoring must largely benefit for the insulin therapy, there are many difficulties to implant blood
sensors subcutaneously in a long
period of time because of physiological reactions that deteriorate the sensors
and limit them working sufficiently up to 3 days [21, 24, 37]. For example, MiniMed
CGSM System Gold is currently approved
by U.S. Food and Drug Administration (FDA) for 3-day use [24, 26].


#### 5.2.3. GlucoWatch

Furthermore, noninvasive blood glucose sensors also exist. Dielectric spectroscopy
(DS) is a noninvasive, extracorporeal approach to continuous blood glucose
monitoring [2, 24]. DS involves analyzing the electrolyte balance across cells,
and comparing those results to known behaviors for differing BG concentrations.
One implementation of DS blood glucose monitoring entails coupling an open
resonant circuit to the skin. This acts as an RCL sensor (R refers to a general
organic molecule and CL refers to chlorine), comparing measurement results to
derived system models in order to deduct the BG level of the patient.GlucoWatch is a new glucose
monitor from Cygnus Corp., Ill, USA. The monitor straps to the wrist of the
patient and uses a patented electrochemical sensor to measure glucose levels in
the patient. The GlucoWatch works both continuously and noninvasively,
permitting closed loop blood glucose level control. GlucoWatch displays the
most recent blood glucose levels of the patient, updating every 20 minutes, and
will sound an alarm if the blood sugar level goes above or below predetermined
thresholds. The device stores the previous 4,000 readings that can be offloaded
for use by a physician. This permits accurate monitoring of long-term insulin
dosage regiments and their results.The GlucoWatch has also
recently won FDA approval and is offered for sale in the United States and the UK. The device is actually based
upon technology that is almost 100 years old. It takes advantage of the
observation that an electric current can selectively transport chemicals
through human skin. This transport phenomenon, callediontophoresis, has
historically been seen as a one-way street, a way to get chemicals into the
body. Cygnus scientists and engineers saw an untapped opportunity, creating a
device that reverses iontophoresis to get the glucose out. “A lot of
substances can be measured through reverse iontophoresis, but we felt there was
a great unmet need for glucose monitoring,” says Dr. Russell Potts, a
biochemist and Cygnus vice president of research [38].The watch applies a biosensor, called the Autosensor, against the skin that measures BG levels,
producing a current proportional to the BG level. A 20-minute analysis cycle
starts as the sensor silver-silver chloride iontophoresis electrode applies a 300-microamp
current to the skin. For the next three minutes, positive and negative ions
travel through the patient skin to the GlucoWatch side-by-side collection
discs, which serve as an anode and cathode during glucose extraction. This ion
migration acts as a glucose transport, depositing it at the cathode to be
measured. The onboard microcontroller then interprets the glucose level into a
standard unit of mm/dl.The DirecNet group conducted
a 6-month randomized trial [4] to measure the effects of the GlucoWatch
continuous sensor on blood glucose control, hypoglycemia, and quality of life
as compared to standard care. At the end of six months, there was no measurable
difference in blood glucose control between the experimental and control
groups, as measured by A1C and mean glucose using the Medtronic retrospective
CGMS device. The results also showed that the use of the device had no positive
or negative psychological impact on the subjects in the experimental group.
These results were puzzling until the usage data was reviewed, which tracked
the number of times per week subjects actually used the device. During the
first month, 64% of subjects used the device at least twice per week (2.1±0.8). However, by the third month, average use was only 1.6±0.7 times per
week, and 7 of the 99 subjects had discontinued use altogether. By the sixth
month, the average use was 1.5±0.6 times per week, and 26 of the original 99
subjects had discontinued use. In summary, differences in clinical outcome
failed to materialize because an increasing number of subjects stopped using
the device. Data gathered from the questionnaires revealed that families felt
the information gained from the device was not worth the discomfort and
adhesive problems encountered with its use.The current version of
GlucoWatch, called GlucoWatch G2 Biographer, is shown in Figure7 [1]. As
already mentioned, a list-watch shaped blood glucose sensor utilizes a quite
low electric current to draw blood glucose penetrable through the skin [1]. This
collected glucose is aggregated into a sensing part of the device integrating
an electrode that is used for measuring blood glucose levels. Every measurement
is saved in memory, and from efficiently sampled data, the blood glucose level
transitions and patterns can be computed. In case of GlucoWatch G2 Biographer,
a blood glucose reading period is adjustable in the range of 10 minutes to 13
hours [1]. Although the GlucoWatch already won FDA approval, the noninvasive
blood glucose sensors are still supplemental use only rather than used as the main
measurements, such as fingerstick blood glucose sensors [1]. Therefore, in
case intensive measurements that pursue more accurate vital data are required,
noninvasive blood glucose sensors are used supplemental to the conventional
testing results. From the results, the best decisions are made by a physician.Figure 7
An image shows a list-watch type noninvasive
blood glucose measurement [1]. The
sensor can avoid damaging the tip of a finger or earlobe to sample blood in a
noninvasive way. Therefore, it basically utilizes a quite low electric current
to draw blood glucose penetrable through the skin. This sampled glucose is
aggregated into a sensing part of the device integrating an electrode that is
used for measuring blood glucose levels.


#### 5.2.4. Commercial Sensors

Here
we use a table as follows to compare between four typical commercial glucose
sensors (Abbott [39], MiniMed Paradigm [40], MiniMed Guardian, [41] and DexCom
[42]) from the following aspects: (1) accuracy of measurements, (2) start-up
time, (3) sensor lifetime (with batteries), (4) how they calibrate values, (5)
how frequently they display the data, (6) memory size to store the data, (7)
transmission distance (from the sensor to a monitor), (8) batteries, (9)
monitor size, and (10) alarm system.


### 5.3. Subcutaneous Devices

For the sake of the safety, currently,
most of the continuous blood glucose sensors being developed are designed to be
put into subcutaneous tissues. Several methods for subcutaneous injection have
been proposed and implemented in order to take advantage of the benefits of
subcutaneous injection [15]. Manual injection systems typically include a
subcutaneous needle or injection pen, which are applied according to a
physician prescribed schedule. Continuous control systems generally deal with
its time-to-act shortfalls through appropriate algorithms and choice of
insulin.


#### 5.3.1. Open-Flow Microperfusion (OFM)

In the open-flow microperfusion (OFM), in order to capture the blood glucose
levels subcutaneously, a needle-like double-lumen catheter is inserted into the
adipose tissue [24]. Firstly, it is supported by a steel mandril, but eventually
this steel mandril is switched by the inner cannula. In the double-lumen
catheter, a perfusion fluid is filled in the annular space between the inner
cannula and the outer catheter. Because of partial equilibration between the
interstitial fluid and the perfusate, aspiration occurs. Thus the glucose
sensor outside the body can capture glucose from the aspirated fluid.In this method, since the
implantable part of sensor is just like a needle for the subcutaneous insulin
injection, it is comparatively easy for patients to insert the sensor.Compared to actual clinical practices, where blood samples are
picked from intravenous injections directly measuring current blood glucose
profiles, the subcutaneous monitoring has different results from those from the
capillary monitoring due to the first-order lag [43]. Therefore, in the
subcutaneous monitoring, it is required to approximate actual blood glucose
profiles from subcutaneously captured data by finding a relation between blood
and subcutaneous glucose profiles. A capillary and interstitial compartment
model is shown in Figure 8.Figure 8
A capillary and interstitial
compartmental model [43, 44]. glucose uptake, and diffusions between capillary
and interstitial tissues are represented as arrows.To find a mathematical relation between the blood and
subcutaneous glucose profiles, [43] utilizes a first-order lag to describe the
subcutaneous glucose dynamics in terms of the blood CB and subcutaneous glucose profiles
CS as follows:(5)dCsdt=−(k02+k12)Cs+k21V1V2CB,
where k02 is an uptake rate of glucose in the subcutaneous tissues, k12
and k21 are diffusion rates
between the blood and subcutaneous compartments, and V1 and V2
represent the volumes of both blood and subcutaneous tissues, respectively.The same first-order model for the subcutaneous glucose dynamics
model is derived in the paper [45], which showed that an actual value of k12
is within the range of
0.04 to 0.11 min−1. Also, [45] figured out from rat studies that a
value of k02 is 0. Moreover,
a first-order model can be written as(6)dydt=ay+bu=−1τy+kτu,
where u and y are the input and output
perturbations, respectively, and k and τ are the gain and time
constants. Thus comparing this standard form to an equation derived by [43, 45], k and τ are solved as follows:(7)k=k12k02+k12,τ=1k02+k12.In [43], by setting k and τ to 1 and 12 minutes,
respectively, a simple simulation model is generated with the reduction of
blood glucose from 200 to 100 mg/dl and a first-order decay time is 75 minutes.
Subcutaneous measurement has a noise with a standard deviation of 1 mg/dl.


#### 5.3.2. Microneedle Array

One subcutaneous device to be proposed is microneedles made out
of silicon [29]. Microneedles for insulin injection are designed to penetrate
through several layers of skin: the stratus corneum layer, the epidermis layer,
and part of the dermis layer. This method of injection punctures through far
fewer nerve cells than classic intravenous injection, while still having access
to the dermis layer, which is rich in blood vessels. This results in a far less
invasive and painful injection experience for the patient.An expansion upon this idea has been to fabricate an array of
microneedles. This provides many benefits, with few disadvantages. The more
microneedles used, the smaller in diameter each needle needs to be in order to
facilitate a load-free flow of insulin into the body. Shrinking the size of the
needles translates into an even less painful experience, while maintaining the
same operational insulin flow rate. Additionally, an array of needles provides
redundancy to the injection system, safeguarding against reduced flow due to
channel blocking or clotting. Flow rate,Q, can be found as follows, given n needles, pressure change ΔP,
needle length L, needle radius r, and fluid viscosity μ, where
the relationship of R and r can be found in Figure 9:(8)R=8μLπr4,Q=nΔPR,Q=nΔP(πr48μL).Figure 9
Microneedle
honeycomb formation.Note that the flow rate is linearly proportional to the number of
microneedles, given a fixed radius. Unfortunately, the flow also decreases by
an order of 4 as radius is reduced.Replacing a single large needle with a honeycomb formation of 7
tightly packed microneedles (each one-third of the diameter of the original needle)
produces a flow of only 8.6% of the original flow for the same surface area.
This observation makes evident the fact that due to the high-order impact of
needle radius, the skin area required for a microneedle array increases
exponentially as the size of the needles are reduced. In practice, the flow
rate required is actually quite low, however, making this exponentially
increasing contact area functionally negligible to the end user, due to its
still relatively small size. As far as the patient is concerned, the increase
in skin surface required is well worth the significantly reduced invasiveness
and pain of the device.


## 5.1. Insulin Pump

Insulin pumps are used to create an
artificial insulin secretion subcutaneously that can suppress excessive blood
glucose propagation for the type 1 diabetic. In general, it continuously
delivers a basal rate of exogenous insulin automatically and also has
capability of manually adding extra insulin to the basal rate for the intensive
insulin secretion by a continuous subcutaneous insulin infusion (CSII) technique
[31]. Most of the insulin pumps consist of a small processing module with a
display, a disposable insulin reservoir, and an insulin syringe, and are
powered by batteries, illustrated in Figures 2 and 3. The amount of insulin
supply is externally controllable depending on blood glucose measurements.Figure 2
An image of an insulin pump. This image also includes a blood
glucose sensor. In the general use, an insulin pump continuously infuses a
little amount of the short-acting exogenous insulin via an attached needle as a
basal dosage. It is also able to add extra exogenous insulin for intensive
care, for example, meal time. Insulin pumps have a lot of advantages compared
with the insulin shots.Figure 3
Another example of
insulin pumps of Medtronic. A processing module has a small display that shows
a current rate of an exogenous insulin infusion. It also has several control
buttons just below the display. Two of these buttons are used to manage a
current insulin infusion rate.In the use of an insulin pump, after finishing setting-up, a
patient inserts a cannula into his/her abdomen as seen in Figure2. Upon
determining an insulin infusion rate, it starts delivering exogenous insulin
continuously in 24 hours per day and 7 days a week, that is, a basal dose [32].
During meal time, when more amount of the insulin dosage is required because of
carbohydrate intakes, the insulin pump enhances its insulin supply to adjust high
blood glucose concentrations, which is called a bolus dose so that this
artificial insulin metabolism should occur after a real physiological
metabolism in the normal human body.In case of the insulin injection using a syringe, since the
insulin dosage is performed three or four times a day, each shot is devised in such
a way that the insulin dosage can keep its effect constantly as long as
possible. In general, using a delayed action insulin or slow-acting insulin helps
a basal supply of exogenous insulin. A difficulty of the insulin injection,
however, results from using this slow-acting insulin. Although the duration of the
effect is achieved longer than other types of insulin, it also takes a longer
time to start taking effect as illustrated in Figure1. This disadvantage largely
prevents effective predictions of a future blood glucose profile. In this
connection, its variance eventually grows up to 52% [31]. Moreover, the insulin
injection with insulin shots inevitably restricts a patient’s life style, for
example, the hour of rising and meals.Meanwhile, in case of insulin pumps, an accompanying insulin
cannula is put into the human body continuously supplying a little amount of theshort-acting insulin even in bedtime.
Although the duration of the effect of insulin is very low, the short-acting
insulin acts faster than the slow-acting insulin. Therefore, a little amount of
a continuous dose of insulin can make predictions of blood glucose
concentration comparatively easy and its variance is not more than 3% [31].Currently, one of the most promising pump technologies is a
piezoelectric fluid device [29]. Piezoelectric pumps operate by applying
voltage to a thin lead zirconate titanate (PZT) film. This distorts the film,
causing it to pump fluid through an adjoined silicon nitride membrane, shown in
Figure 4.Figure 4
Piezoelectric pump and micro-needle device.The displacement volume of an unloaded pump can be described as(1)ΔV=3r4(5+2μ)(1−μ)d13U4h2(3+2μ),(2)K=3r4(5+2μ)(1−μ)d134h2(3+2μ),(3)ΔV=KΔU,(4)Q=KfΔU,
where r is the radius of the membrane in μm, h is the thickness of the membrane in μm, μ is the Poisson ratio, ΔU is the peak-to-peak voltage applied to the
pump every period, d13 is the piezoelectric coefficient, and f is
the frequency at which voltage is applied to the pump. K represents the pump
coefficient described by (1). Q is the flow rate of the pump.Note thatΔV is
linearly proportional to ΔU.
Likewise, Q is also linear for a fixed f or a fixed ΔU. This permits very simple and intuitive
control of the pump by the controller, allowing it to control the flow rate
through a variable amplitude signal or a variable frequency signal, depending
upon system requirements and the resources available.Pump reliability is an incredibly crucial factor when considering
a blood glucose management system. Pump, sensor, or control failure can lead to
incorrect dosages or even a failure to inject. Due to its mechanical nature,
pump failure is often the most likely cause of malfunction. This can results
from o-ring leaks, air bubbles, bleeding, infection, and clogs. These
conditions can easily result in hyperglycemia or hypoglycemia and must be
monitored for.We compare five types of popular insulin pumps in Table1.Table 1
Specification comparison of commercial insulin pumps.
CompanyAnimasDeltecDisetronicMiniMedInsuletModelIR-1250 [11]Cozmo [12]Spirit [13]Paradigm522/722 [14]OmniPod [33]Dimensions79× 51 × 1980× 47 × 2480× 56 × 20522: 51× 79 × 20 722: 51 × 79 × 20Pod: 41× 61 × 18 Pda: 66 × 110 × 26Screen size992 sq mm870 sq mmUnavailable774 sq mm1,848 sq mm on PDA controllerBasal deliveryEvery 3 minutesEvery 3 minutesEvery 3 minutesVariesInformation unavailableBasal temperatureInitially −90% to +200%, varies for
every half an hourVaries from 0% to 200% with an
increment of 5% for every half an hourVaries from 0% to 200% with an
increment of 10% for every half an hour+/−0.1 increment as single basal
rate for 0.5 to 24 hoursInformation unavailableCarb and correction factorsManual entry and assist from EZ managerManual carbohydrate, BG from
attached CoZ monitorManual carbohydrate, BG from Accu-check
BG monitorManual carbohydrate, BG from BD
meter or manual entryInformation unavailableBatteryAA lithium× 1AAA× 1AA× 1 Alkaline or RechargeableAAAAAA× 2MotorDCDCDCDCStepperMemoryNonvolatile: 600 bolus, 270 basal,
120 daily totals, 30 alarms, and 60 primesNonvolatile: 90 days of basals,
carbohydrates, boluses, correction boluses, and alarmsNonvolatile: 90 days history recall
of last 30 boluses, alerts, daily insulin totals, and temporary basal rate
increase4000 events volatile: 24 boluses,
and 7 days totals90 days of dataExtra featuresClip-on covers, personalized
carbohydrate, and correction factors, tracks residual bolus insulinCarbohydrate and correction factors,
tracks residual bolus insulin, detailed records of pump, and daily bolus
total correctionAvailability of different types of
user menus, icon and menu driven programming, backlight display, and reversible
display screenExtended bolus, auto offIntegrated free style meter, 1000
common foods in PDATable 2
Specification comparison of commercial blood glucose sensors.
FeaturesAbbott freestyle navigator [39]MiniMed paradigm real-time system [40]MiniMed guardian real-time system [41]DexCom [42]AccuracyVariesConsensus error grid: 98.9%A+B mard(mean) −19.7% (median) −15.5%Consensus error grid: 98.9%A+B mard(mean) −19.7% (median) −15.5%Consensus error grid: 95.4%A+B mard(mean) −49% (median) −15.9%Startup initiation   time10 hours2 hours2 hours2 hoursSensor life5-day wear indicationAbove 72 hoursAbove 72 hoursAbove 72 hoursCalibration   methodRequires calibration at
10, 12, 24, and 72 hours after the insertion of the sensorAlarms when calibration value is not entered on time.
First and second calibration should be done for 2 and 6 hours after
insertionAlarms when calibration
value is not entered on time. First and second calibration should be done for
2 and 6 hours after insertionFirst calibration after 30
minutes and then for every 12 hours. Manual calibration is not possibleFrequency of   displayEvery 1 minuteEvery 5 minutesEvery 5 minutesEvery 5 minutesTransmitter   memory—Yes, the transmitter stores missed data for up to 40
minutesYes, the transmitter stores
missed data for up to 40 minutesNo, transmission lost is
data lostRange of monitor   to transmitter10 feet6 feet6 feet5 feetMonitor batteriesUses 2 AAA batteries with
replacement for every three monthsNo separate monitor required. Uses insulin pumpUses 2 AAA Batteries.
Indication is set for chance of batteryUses rechargeable batteriesMonitor size3“× 2.5”Separate monitor is not available. Uses insulin pump
for display3“× 2.7”3“× 2.5”Alarms on user-set low and high   thresholdsApplicableApplicableApplicableApplicable


## 5.2. Blood Glucose Sensor

In consideration of easy predictions of
blood glucose profile, recently, utilization of both an insulin pump and a
blood glucose sensor is very important for the intensive insulin-dependent diabetes
therapy. In general, when the system has a capability of the continuous glucose
measurement, and with this measurement, a rate of exogenous insulin dosage is
automatically or manually adjusted,
and the system is called a closed-loop control system. In this system, a
glucose sensor may be implanted in the human body as shown in Figure5 [15]. On the other hand, when the system
still counts on periodical glucose measurements, the system is called a partially
closed-loop control system. Generally, this latter system utilizes very complex
nonlinear calculations or mathematical modeling to pursue its accuracy from few
glucose measurements. Besides, insulin
dosage plan is designed by a physician with an expert system that performs comparisons
between the generated predictions and model cases.Figure 5
An image shows a miniature size of in vivo
blood glucose sensor that is being developed [15]. It is currently proven by FDA
that in vivo blood glucose sensors are only safe and reliable in a short period
of time (e.g., three days). Thus after the period, they are required to be
replaced by a new one regularly to keep their accuracy.


### 5.2.1. Fingersticks

There are many kinds of blood glucose sensors to be exploited.
One of them, fingerstick meter readings, measures blood glucose profiles
directly from blood samples taken out of the tip of a finger. This is invasive
and can be painful. Additionally, measurements of this sort are only taken a
few times per day due to the conscious effort required to perform them [34].In testing a patient blood sample, for example [35], some products
require only 0.3 micro liters of the blood sample, but required samplings are
at least 4 times per day [36]. Besides, this kind of sensor is also integrated
into an insulin pump enhancing portability of the system as well as eliminating
a requirement of the manual input of data into the insulin pump, shown in Figure 6 [35]. A drawback of the sensor is that since it invasively samples blood from
a finger or earlobe, it is almost impossible to take samples continuously in order to enhance the measurements. Therefore,
increasingly, different types of sensors are being developed and used, and they
provide a wealth of benefits compared to finger sticks.Figure 6
An image shows a fingerstick meter
reading. In the use of the sensor, first
off, cut the tip of a finger or earlobe bleeding. Then put the blood on a blood
glucose sensor, which is a protuberance at the bottom of the module. The result
is shown on the display in the middle-top of the module.


### 5.2.2. Implantable Sensors

In addition to the fingerstick meter readings, implantable
glucose sensors are available with some limitations. One type of these
implantable sensors is needle-type sensors [24]. These needle-type sensors are
intravenously or subcutaneously inserted into the body. Intravenous systems
monitor blood glucose levels by drawing blood through a vascularly embedded
needle [15]. This has the advantage of up to date, real-time BG levels, but at
the expensive of being invasive and painful. Additionally, there are long term
effects associated with prolonged vascular invasion, making it a suboptimal
solution for continuous long-term home monitoring.Subcutaneous glucose sensors are small electrode devices that can
be inserted into the skin in the fatty tissues. This includes collecting a
blood sample from the dermis layer of the skin [24], which is located about a
tenth of a millimeter into the surface of the body [2]. When the sensors are
placed correctly, current proportional to the blood glucose level can be
detected and measured. For example, a probe of a subcutaneous sensor is made of
an amperometric cell covered by a thin membrane. With this sensor, only needle
part is inserted subcutaneously into the body while a processor module stays
outside. Due to its shallow position, subcutaneous monitoring can be
significantly less painful than finger sticking. The greatest boon of
subcutaneous monitoring, however, is that it can be performed continuously in a
wearable fashion. This quality enables new types of control techniques to be
exploited. The finer the measuring time increment is, the more accurate control
methods will be. Continuously glucose monitoring permits real-time signal
filtering in attempts to closely regulate changes in glucose due to various
factors such as meals, exercise, or sleep patterns.There are several methods for administering subcutaneous
monitoring, including dialysis and open-flow microperfusion. Currently, the
most advanced method of subcutaneous monitoring is considered to be
microperfusion [24]. Microperfusion entails diffusing interstitial fluids from
the dermis into a double lumen catheter where it can be monitored by an
external sensor without actually drawing blood.Also, another type of in vivo sensor is a small piece of module
which is completely implanted into a segment of the body of the diabetic. Since
these glucose sensors are implanted into the human body, continuous measurement
of blood glucose levels will be possible. The authors in [26] demonstrated that
samplings were conducted every 5 minutes. The sampled blood glucose profiles are wirelessly transmitted to external
receivers that could be a PDA or
some other small devices looking like a list-watch.
According to the transferred vital data,
it is preferable to automatically reconfigure a current insulin delivery rate,
but some systems still require the users to manually reconfigure the delivery
rate. Although, if realized,
the continuously blood glucose monitoring must largely benefit for the insulin therapy, there are many difficulties to implant blood
sensors subcutaneously in a long
period of time because of physiological reactions that deteriorate the sensors
and limit them working sufficiently up to 3 days [21, 24, 37]. For example, MiniMed
CGSM System Gold is currently approved
by U.S. Food and Drug Administration (FDA) for 3-day use [24, 26].


### 5.2.3. GlucoWatch

Furthermore, noninvasive blood glucose sensors also exist. Dielectric spectroscopy
(DS) is a noninvasive, extracorporeal approach to continuous blood glucose
monitoring [2, 24]. DS involves analyzing the electrolyte balance across cells,
and comparing those results to known behaviors for differing BG concentrations.
One implementation of DS blood glucose monitoring entails coupling an open
resonant circuit to the skin. This acts as an RCL sensor (R refers to a general
organic molecule and CL refers to chlorine), comparing measurement results to
derived system models in order to deduct the BG level of the patient.GlucoWatch is a new glucose
monitor from Cygnus Corp., Ill, USA. The monitor straps to the wrist of the
patient and uses a patented electrochemical sensor to measure glucose levels in
the patient. The GlucoWatch works both continuously and noninvasively,
permitting closed loop blood glucose level control. GlucoWatch displays the
most recent blood glucose levels of the patient, updating every 20 minutes, and
will sound an alarm if the blood sugar level goes above or below predetermined
thresholds. The device stores the previous 4,000 readings that can be offloaded
for use by a physician. This permits accurate monitoring of long-term insulin
dosage regiments and their results.The GlucoWatch has also
recently won FDA approval and is offered for sale in the United States and the UK. The device is actually based
upon technology that is almost 100 years old. It takes advantage of the
observation that an electric current can selectively transport chemicals
through human skin. This transport phenomenon, callediontophoresis, has
historically been seen as a one-way street, a way to get chemicals into the
body. Cygnus scientists and engineers saw an untapped opportunity, creating a
device that reverses iontophoresis to get the glucose out. “A lot of
substances can be measured through reverse iontophoresis, but we felt there was
a great unmet need for glucose monitoring,” says Dr. Russell Potts, a
biochemist and Cygnus vice president of research [38].The watch applies a biosensor, called the Autosensor, against the skin that measures BG levels,
producing a current proportional to the BG level. A 20-minute analysis cycle
starts as the sensor silver-silver chloride iontophoresis electrode applies a 300-microamp
current to the skin. For the next three minutes, positive and negative ions
travel through the patient skin to the GlucoWatch side-by-side collection
discs, which serve as an anode and cathode during glucose extraction. This ion
migration acts as a glucose transport, depositing it at the cathode to be
measured. The onboard microcontroller then interprets the glucose level into a
standard unit of mm/dl.The DirecNet group conducted
a 6-month randomized trial [4] to measure the effects of the GlucoWatch
continuous sensor on blood glucose control, hypoglycemia, and quality of life
as compared to standard care. At the end of six months, there was no measurable
difference in blood glucose control between the experimental and control
groups, as measured by A1C and mean glucose using the Medtronic retrospective
CGMS device. The results also showed that the use of the device had no positive
or negative psychological impact on the subjects in the experimental group.
These results were puzzling until the usage data was reviewed, which tracked
the number of times per week subjects actually used the device. During the
first month, 64% of subjects used the device at least twice per week (2.1±0.8). However, by the third month, average use was only 1.6±0.7 times per
week, and 7 of the 99 subjects had discontinued use altogether. By the sixth
month, the average use was 1.5±0.6 times per week, and 26 of the original 99
subjects had discontinued use. In summary, differences in clinical outcome
failed to materialize because an increasing number of subjects stopped using
the device. Data gathered from the questionnaires revealed that families felt
the information gained from the device was not worth the discomfort and
adhesive problems encountered with its use.The current version of
GlucoWatch, called GlucoWatch G2 Biographer, is shown in Figure7 [1]. As
already mentioned, a list-watch shaped blood glucose sensor utilizes a quite
low electric current to draw blood glucose penetrable through the skin [1]. This
collected glucose is aggregated into a sensing part of the device integrating
an electrode that is used for measuring blood glucose levels. Every measurement
is saved in memory, and from efficiently sampled data, the blood glucose level
transitions and patterns can be computed. In case of GlucoWatch G2 Biographer,
a blood glucose reading period is adjustable in the range of 10 minutes to 13
hours [1]. Although the GlucoWatch already won FDA approval, the noninvasive
blood glucose sensors are still supplemental use only rather than used as the main
measurements, such as fingerstick blood glucose sensors [1]. Therefore, in
case intensive measurements that pursue more accurate vital data are required,
noninvasive blood glucose sensors are used supplemental to the conventional
testing results. From the results, the best decisions are made by a physician.Figure 7
An image shows a list-watch type noninvasive
blood glucose measurement [1]. The
sensor can avoid damaging the tip of a finger or earlobe to sample blood in a
noninvasive way. Therefore, it basically utilizes a quite low electric current
to draw blood glucose penetrable through the skin. This sampled glucose is
aggregated into a sensing part of the device integrating an electrode that is
used for measuring blood glucose levels.


### 5.2.4. Commercial Sensors

Here
we use a table as follows to compare between four typical commercial glucose
sensors (Abbott [39], MiniMed Paradigm [40], MiniMed Guardian, [41] and DexCom
[42]) from the following aspects: (1) accuracy of measurements, (2) start-up
time, (3) sensor lifetime (with batteries), (4) how they calibrate values, (5)
how frequently they display the data, (6) memory size to store the data, (7)
transmission distance (from the sensor to a monitor), (8) batteries, (9)
monitor size, and (10) alarm system.


## 5.2.1. Fingersticks

There are many kinds of blood glucose sensors to be exploited.
One of them, fingerstick meter readings, measures blood glucose profiles
directly from blood samples taken out of the tip of a finger. This is invasive
and can be painful. Additionally, measurements of this sort are only taken a
few times per day due to the conscious effort required to perform them [34].In testing a patient blood sample, for example [35], some products
require only 0.3 micro liters of the blood sample, but required samplings are
at least 4 times per day [36]. Besides, this kind of sensor is also integrated
into an insulin pump enhancing portability of the system as well as eliminating
a requirement of the manual input of data into the insulin pump, shown in Figure 6 [35]. A drawback of the sensor is that since it invasively samples blood from
a finger or earlobe, it is almost impossible to take samples continuously in order to enhance the measurements. Therefore,
increasingly, different types of sensors are being developed and used, and they
provide a wealth of benefits compared to finger sticks.Figure 6
An image shows a fingerstick meter
reading. In the use of the sensor, first
off, cut the tip of a finger or earlobe bleeding. Then put the blood on a blood
glucose sensor, which is a protuberance at the bottom of the module. The result
is shown on the display in the middle-top of the module.


## 5.2.2. Implantable Sensors

In addition to the fingerstick meter readings, implantable
glucose sensors are available with some limitations. One type of these
implantable sensors is needle-type sensors [24]. These needle-type sensors are
intravenously or subcutaneously inserted into the body. Intravenous systems
monitor blood glucose levels by drawing blood through a vascularly embedded
needle [15]. This has the advantage of up to date, real-time BG levels, but at
the expensive of being invasive and painful. Additionally, there are long term
effects associated with prolonged vascular invasion, making it a suboptimal
solution for continuous long-term home monitoring.Subcutaneous glucose sensors are small electrode devices that can
be inserted into the skin in the fatty tissues. This includes collecting a
blood sample from the dermis layer of the skin [24], which is located about a
tenth of a millimeter into the surface of the body [2]. When the sensors are
placed correctly, current proportional to the blood glucose level can be
detected and measured. For example, a probe of a subcutaneous sensor is made of
an amperometric cell covered by a thin membrane. With this sensor, only needle
part is inserted subcutaneously into the body while a processor module stays
outside. Due to its shallow position, subcutaneous monitoring can be
significantly less painful than finger sticking. The greatest boon of
subcutaneous monitoring, however, is that it can be performed continuously in a
wearable fashion. This quality enables new types of control techniques to be
exploited. The finer the measuring time increment is, the more accurate control
methods will be. Continuously glucose monitoring permits real-time signal
filtering in attempts to closely regulate changes in glucose due to various
factors such as meals, exercise, or sleep patterns.There are several methods for administering subcutaneous
monitoring, including dialysis and open-flow microperfusion. Currently, the
most advanced method of subcutaneous monitoring is considered to be
microperfusion [24]. Microperfusion entails diffusing interstitial fluids from
the dermis into a double lumen catheter where it can be monitored by an
external sensor without actually drawing blood.Also, another type of in vivo sensor is a small piece of module
which is completely implanted into a segment of the body of the diabetic. Since
these glucose sensors are implanted into the human body, continuous measurement
of blood glucose levels will be possible. The authors in [26] demonstrated that
samplings were conducted every 5 minutes. The sampled blood glucose profiles are wirelessly transmitted to external
receivers that could be a PDA or
some other small devices looking like a list-watch.
According to the transferred vital data,
it is preferable to automatically reconfigure a current insulin delivery rate,
but some systems still require the users to manually reconfigure the delivery
rate. Although, if realized,
the continuously blood glucose monitoring must largely benefit for the insulin therapy, there are many difficulties to implant blood
sensors subcutaneously in a long
period of time because of physiological reactions that deteriorate the sensors
and limit them working sufficiently up to 3 days [21, 24, 37]. For example, MiniMed
CGSM System Gold is currently approved
by U.S. Food and Drug Administration (FDA) for 3-day use [24, 26].


## 5.2.3. GlucoWatch

Furthermore, noninvasive blood glucose sensors also exist. Dielectric spectroscopy
(DS) is a noninvasive, extracorporeal approach to continuous blood glucose
monitoring [2, 24]. DS involves analyzing the electrolyte balance across cells,
and comparing those results to known behaviors for differing BG concentrations.
One implementation of DS blood glucose monitoring entails coupling an open
resonant circuit to the skin. This acts as an RCL sensor (R refers to a general
organic molecule and CL refers to chlorine), comparing measurement results to
derived system models in order to deduct the BG level of the patient.GlucoWatch is a new glucose
monitor from Cygnus Corp., Ill, USA. The monitor straps to the wrist of the
patient and uses a patented electrochemical sensor to measure glucose levels in
the patient. The GlucoWatch works both continuously and noninvasively,
permitting closed loop blood glucose level control. GlucoWatch displays the
most recent blood glucose levels of the patient, updating every 20 minutes, and
will sound an alarm if the blood sugar level goes above or below predetermined
thresholds. The device stores the previous 4,000 readings that can be offloaded
for use by a physician. This permits accurate monitoring of long-term insulin
dosage regiments and their results.The GlucoWatch has also
recently won FDA approval and is offered for sale in the United States and the UK. The device is actually based
upon technology that is almost 100 years old. It takes advantage of the
observation that an electric current can selectively transport chemicals
through human skin. This transport phenomenon, callediontophoresis, has
historically been seen as a one-way street, a way to get chemicals into the
body. Cygnus scientists and engineers saw an untapped opportunity, creating a
device that reverses iontophoresis to get the glucose out. “A lot of
substances can be measured through reverse iontophoresis, but we felt there was
a great unmet need for glucose monitoring,” says Dr. Russell Potts, a
biochemist and Cygnus vice president of research [38].The watch applies a biosensor, called the Autosensor, against the skin that measures BG levels,
producing a current proportional to the BG level. A 20-minute analysis cycle
starts as the sensor silver-silver chloride iontophoresis electrode applies a 300-microamp
current to the skin. For the next three minutes, positive and negative ions
travel through the patient skin to the GlucoWatch side-by-side collection
discs, which serve as an anode and cathode during glucose extraction. This ion
migration acts as a glucose transport, depositing it at the cathode to be
measured. The onboard microcontroller then interprets the glucose level into a
standard unit of mm/dl.The DirecNet group conducted
a 6-month randomized trial [4] to measure the effects of the GlucoWatch
continuous sensor on blood glucose control, hypoglycemia, and quality of life
as compared to standard care. At the end of six months, there was no measurable
difference in blood glucose control between the experimental and control
groups, as measured by A1C and mean glucose using the Medtronic retrospective
CGMS device. The results also showed that the use of the device had no positive
or negative psychological impact on the subjects in the experimental group.
These results were puzzling until the usage data was reviewed, which tracked
the number of times per week subjects actually used the device. During the
first month, 64% of subjects used the device at least twice per week (2.1±0.8). However, by the third month, average use was only 1.6±0.7 times per
week, and 7 of the 99 subjects had discontinued use altogether. By the sixth
month, the average use was 1.5±0.6 times per week, and 26 of the original 99
subjects had discontinued use. In summary, differences in clinical outcome
failed to materialize because an increasing number of subjects stopped using
the device. Data gathered from the questionnaires revealed that families felt
the information gained from the device was not worth the discomfort and
adhesive problems encountered with its use.The current version of
GlucoWatch, called GlucoWatch G2 Biographer, is shown in Figure7 [1]. As
already mentioned, a list-watch shaped blood glucose sensor utilizes a quite
low electric current to draw blood glucose penetrable through the skin [1]. This
collected glucose is aggregated into a sensing part of the device integrating
an electrode that is used for measuring blood glucose levels. Every measurement
is saved in memory, and from efficiently sampled data, the blood glucose level
transitions and patterns can be computed. In case of GlucoWatch G2 Biographer,
a blood glucose reading period is adjustable in the range of 10 minutes to 13
hours [1]. Although the GlucoWatch already won FDA approval, the noninvasive
blood glucose sensors are still supplemental use only rather than used as the main
measurements, such as fingerstick blood glucose sensors [1]. Therefore, in
case intensive measurements that pursue more accurate vital data are required,
noninvasive blood glucose sensors are used supplemental to the conventional
testing results. From the results, the best decisions are made by a physician.Figure 7
An image shows a list-watch type noninvasive
blood glucose measurement [1]. The
sensor can avoid damaging the tip of a finger or earlobe to sample blood in a
noninvasive way. Therefore, it basically utilizes a quite low electric current
to draw blood glucose penetrable through the skin. This sampled glucose is
aggregated into a sensing part of the device integrating an electrode that is
used for measuring blood glucose levels.


## 5.2.4. Commercial Sensors

Here
we use a table as follows to compare between four typical commercial glucose
sensors (Abbott [39], MiniMed Paradigm [40], MiniMed Guardian, [41] and DexCom
[42]) from the following aspects: (1) accuracy of measurements, (2) start-up
time, (3) sensor lifetime (with batteries), (4) how they calibrate values, (5)
how frequently they display the data, (6) memory size to store the data, (7)
transmission distance (from the sensor to a monitor), (8) batteries, (9)
monitor size, and (10) alarm system.


## 5.3. Subcutaneous Devices

For the sake of the safety, currently,
most of the continuous blood glucose sensors being developed are designed to be
put into subcutaneous tissues. Several methods for subcutaneous injection have
been proposed and implemented in order to take advantage of the benefits of
subcutaneous injection [15]. Manual injection systems typically include a
subcutaneous needle or injection pen, which are applied according to a
physician prescribed schedule. Continuous control systems generally deal with
its time-to-act shortfalls through appropriate algorithms and choice of
insulin.


### 5.3.1. Open-Flow Microperfusion (OFM)

In the open-flow microperfusion (OFM), in order to capture the blood glucose
levels subcutaneously, a needle-like double-lumen catheter is inserted into the
adipose tissue [24]. Firstly, it is supported by a steel mandril, but eventually
this steel mandril is switched by the inner cannula. In the double-lumen
catheter, a perfusion fluid is filled in the annular space between the inner
cannula and the outer catheter. Because of partial equilibration between the
interstitial fluid and the perfusate, aspiration occurs. Thus the glucose
sensor outside the body can capture glucose from the aspirated fluid.In this method, since the
implantable part of sensor is just like a needle for the subcutaneous insulin
injection, it is comparatively easy for patients to insert the sensor.Compared to actual clinical practices, where blood samples are
picked from intravenous injections directly measuring current blood glucose
profiles, the subcutaneous monitoring has different results from those from the
capillary monitoring due to the first-order lag [43]. Therefore, in the
subcutaneous monitoring, it is required to approximate actual blood glucose
profiles from subcutaneously captured data by finding a relation between blood
and subcutaneous glucose profiles. A capillary and interstitial compartment
model is shown in Figure 8.Figure 8
A capillary and interstitial
compartmental model [43, 44]. glucose uptake, and diffusions between capillary
and interstitial tissues are represented as arrows.To find a mathematical relation between the blood and
subcutaneous glucose profiles, [43] utilizes a first-order lag to describe the
subcutaneous glucose dynamics in terms of the blood CB and subcutaneous glucose profiles
CS as follows:(5)dCsdt=−(k02+k12)Cs+k21V1V2CB,
where k02 is an uptake rate of glucose in the subcutaneous tissues, k12
and k21 are diffusion rates
between the blood and subcutaneous compartments, and V1 and V2
represent the volumes of both blood and subcutaneous tissues, respectively.The same first-order model for the subcutaneous glucose dynamics
model is derived in the paper [45], which showed that an actual value of k12
is within the range of
0.04 to 0.11 min−1. Also, [45] figured out from rat studies that a
value of k02 is 0. Moreover,
a first-order model can be written as(6)dydt=ay+bu=−1τy+kτu,
where u and y are the input and output
perturbations, respectively, and k and τ are the gain and time
constants. Thus comparing this standard form to an equation derived by [43, 45], k and τ are solved as follows:(7)k=k12k02+k12,τ=1k02+k12.In [43], by setting k and τ to 1 and 12 minutes,
respectively, a simple simulation model is generated with the reduction of
blood glucose from 200 to 100 mg/dl and a first-order decay time is 75 minutes.
Subcutaneous measurement has a noise with a standard deviation of 1 mg/dl.


### 5.3.2. Microneedle Array

One subcutaneous device to be proposed is microneedles made out
of silicon [29]. Microneedles for insulin injection are designed to penetrate
through several layers of skin: the stratus corneum layer, the epidermis layer,
and part of the dermis layer. This method of injection punctures through far
fewer nerve cells than classic intravenous injection, while still having access
to the dermis layer, which is rich in blood vessels. This results in a far less
invasive and painful injection experience for the patient.An expansion upon this idea has been to fabricate an array of
microneedles. This provides many benefits, with few disadvantages. The more
microneedles used, the smaller in diameter each needle needs to be in order to
facilitate a load-free flow of insulin into the body. Shrinking the size of the
needles translates into an even less painful experience, while maintaining the
same operational insulin flow rate. Additionally, an array of needles provides
redundancy to the injection system, safeguarding against reduced flow due to
channel blocking or clotting. Flow rate,Q, can be found as follows, given n needles, pressure change ΔP,
needle length L, needle radius r, and fluid viscosity μ, where
the relationship of R and r can be found in Figure 9:(8)R=8μLπr4,Q=nΔPR,Q=nΔP(πr48μL).Figure 9
Microneedle
honeycomb formation.Note that the flow rate is linearly proportional to the number of
microneedles, given a fixed radius. Unfortunately, the flow also decreases by
an order of 4 as radius is reduced.Replacing a single large needle with a honeycomb formation of 7
tightly packed microneedles (each one-third of the diameter of the original needle)
produces a flow of only 8.6% of the original flow for the same surface area.
This observation makes evident the fact that due to the high-order impact of
needle radius, the skin area required for a microneedle array increases
exponentially as the size of the needles are reduced. In practice, the flow
rate required is actually quite low, however, making this exponentially
increasing contact area functionally negligible to the end user, due to its
still relatively small size. As far as the patient is concerned, the increase
in skin surface required is well worth the significantly reduced invasiveness
and pain of the device.


## 5.3.1. Open-Flow Microperfusion (OFM)

In the open-flow microperfusion (OFM), in order to capture the blood glucose
levels subcutaneously, a needle-like double-lumen catheter is inserted into the
adipose tissue [24]. Firstly, it is supported by a steel mandril, but eventually
this steel mandril is switched by the inner cannula. In the double-lumen
catheter, a perfusion fluid is filled in the annular space between the inner
cannula and the outer catheter. Because of partial equilibration between the
interstitial fluid and the perfusate, aspiration occurs. Thus the glucose
sensor outside the body can capture glucose from the aspirated fluid.In this method, since the
implantable part of sensor is just like a needle for the subcutaneous insulin
injection, it is comparatively easy for patients to insert the sensor.Compared to actual clinical practices, where blood samples are
picked from intravenous injections directly measuring current blood glucose
profiles, the subcutaneous monitoring has different results from those from the
capillary monitoring due to the first-order lag [43]. Therefore, in the
subcutaneous monitoring, it is required to approximate actual blood glucose
profiles from subcutaneously captured data by finding a relation between blood
and subcutaneous glucose profiles. A capillary and interstitial compartment
model is shown in Figure 8.Figure 8
A capillary and interstitial
compartmental model [43, 44]. glucose uptake, and diffusions between capillary
and interstitial tissues are represented as arrows.To find a mathematical relation between the blood and
subcutaneous glucose profiles, [43] utilizes a first-order lag to describe the
subcutaneous glucose dynamics in terms of the blood CB and subcutaneous glucose profiles
CS as follows:(5)dCsdt=−(k02+k12)Cs+k21V1V2CB,
where k02 is an uptake rate of glucose in the subcutaneous tissues, k12
and k21 are diffusion rates
between the blood and subcutaneous compartments, and V1 and V2
represent the volumes of both blood and subcutaneous tissues, respectively.The same first-order model for the subcutaneous glucose dynamics
model is derived in the paper [45], which showed that an actual value of k12
is within the range of
0.04 to 0.11 min−1. Also, [45] figured out from rat studies that a
value of k02 is 0. Moreover,
a first-order model can be written as(6)dydt=ay+bu=−1τy+kτu,
where u and y are the input and output
perturbations, respectively, and k and τ are the gain and time
constants. Thus comparing this standard form to an equation derived by [43, 45], k and τ are solved as follows:(7)k=k12k02+k12,τ=1k02+k12.In [43], by setting k and τ to 1 and 12 minutes,
respectively, a simple simulation model is generated with the reduction of
blood glucose from 200 to 100 mg/dl and a first-order decay time is 75 minutes.
Subcutaneous measurement has a noise with a standard deviation of 1 mg/dl.


## 5.3.2. Microneedle Array

One subcutaneous device to be proposed is microneedles made out
of silicon [29]. Microneedles for insulin injection are designed to penetrate
through several layers of skin: the stratus corneum layer, the epidermis layer,
and part of the dermis layer. This method of injection punctures through far
fewer nerve cells than classic intravenous injection, while still having access
to the dermis layer, which is rich in blood vessels. This results in a far less
invasive and painful injection experience for the patient.An expansion upon this idea has been to fabricate an array of
microneedles. This provides many benefits, with few disadvantages. The more
microneedles used, the smaller in diameter each needle needs to be in order to
facilitate a load-free flow of insulin into the body. Shrinking the size of the
needles translates into an even less painful experience, while maintaining the
same operational insulin flow rate. Additionally, an array of needles provides
redundancy to the injection system, safeguarding against reduced flow due to
channel blocking or clotting. Flow rate,Q, can be found as follows, given n needles, pressure change ΔP,
needle length L, needle radius r, and fluid viscosity μ, where
the relationship of R and r can be found in Figure 9:(8)R=8μLπr4,Q=nΔPR,Q=nΔP(πr48μL).Figure 9
Microneedle
honeycomb formation.Note that the flow rate is linearly proportional to the number of
microneedles, given a fixed radius. Unfortunately, the flow also decreases by
an order of 4 as radius is reduced.Replacing a single large needle with a honeycomb formation of 7
tightly packed microneedles (each one-third of the diameter of the original needle)
produces a flow of only 8.6% of the original flow for the same surface area.
This observation makes evident the fact that due to the high-order impact of
needle radius, the skin area required for a microneedle array increases
exponentially as the size of the needles are reduced. In practice, the flow
rate required is actually quite low, however, making this exponentially
increasing contact area functionally negligible to the end user, due to its
still relatively small size. As far as the patient is concerned, the increase
in skin surface required is well worth the significantly reduced invasiveness
and pain of the device.


## 6. Controlling Blood Glucose Profiles

By deploying devices described in the previous section as well as
understanding the mechanism of the insulin-glucose dynamics, blood glucose
profiles can be controlled systematically. However, in general, not only the
insulin-glucose dynamics but also any other human metabolism are so complicated
that they can be hardly quantified. Therefore, arguably, the most complex
component of blood glucose management is the control domain. There are several
classes of solutions to this problem, ranging in complexity, prerequisite
knowledge, and feedback.To do this, researchers first empirically or with the fundamental
methods derive a couple of mathematical equations about the insulin-glucose
dynamics [46, 47]. While the empirical methods largely depend on the
input-output data from experiments, the fundamental methods basically derive
them from the knowledge about the human internal functions which are already
familiar enough. After constructing a mathematical model of the insulin-glucose
dynamics, an insulin-dependent diabetes therapy is designed. The goal of the
therapy is to mitigate the excessive glucose production by artificially
secreting exogenous insulin systematically. The insulin secretion must follow
the actual metabolic functionality.The control methods are broadly categorized in three categories:
open-loop control, closed-loop control, and partial closed-loop control methods
[15]. This section briefly explains these three control methods with
applications. More detailed explanations can be found in our survey on control
methods in [5].


### 6.1. Open-Loop Control

Open-loop
control methods are occasionally called theprogrammed insulin infusion
system. One type of this method is one that was developed by Case Western
Reserve University, and this system is considered to be one of the most intelligent
programmed insulin infusion products that deal with the noninsulin-dependent
diabetics. The idea is that from an analysis of the insulin curve in the nondiabetic,
it was turned out that the curve approximately traces a combination of a double
exponential curve and a basal insulin infusion [48]. According to this
mathematical model, an intravenous insulin delivery system was designed such that
it followed the real pancreas functionality of the nondiabetic. The system
utilized a portable cart containing the control system, the insulin pump, power
supplies, and insulin reservoir so that the patient could move around with the
devices. The insulin pump delivers low-concentration insulin and updates the
insulin delivery rate every 30 seconds. Because of its simplicity, the system
can be set up and operated by nurses [48].


### 6.2. Closed-Loop Control

At first, a flow of the closed-loop control scheme is shown in
Figure10. The closed-loop system
completes its operating cycle within the system and no external interaction to diabetic patients is
required [15, 24]. In other words, the closed-loop control uses the feedback from
the output. Typically, the closed-loop system for type 1 diabetes therapy utilizes the glucose sensor and schematically consists
of three phases: blood glucose measurements, insulin demand calculation, and
insulin injection. The closed-loop system repeats this sequence.Figure 10
A control flow of
closed-loop control models [15]. Entire loop of the control is closed from
outside by utilizing an insulin pump and in vivo blood glucose sensors. Both
insulin injections and glucose measurements are carried out subcutaneously.Several papers already proposed applications and mathematical
models to suffice this model. Such applications include the pole-assignment
strategy, self-tuning adaptive control, model predictive control, and neural
predictive control.In short, the pole-assignment strategy calculates the insulin
injection rate (IIR) according to the current blood glucose levels plus trends
of the blood glucose levels as well as the pharmacokinetics of insulin infusion.
Although the calculation is very simple, the pole-assignment strategy is time consuming
because of repeatedly evaluating the model parameters only from the current
measurements. On the other hand, the self-tuning adaptive control utilizes a
recursive computation of the model parameters to generate the IIR faster than
the pole-assignment strategy [15].


### 6.3. Partially Closed-Loop Control

A flow of the partially closed-loop
control is shown in Figure11. Like the closed-loop control models, the
partially closed-loop control utilizes the external devices, such as insulin
pumps and blood glucose sensors. The major difference between the closed-loop
and partial closed-loop control methods is that the closed-loop control only
depends on the feedback from the output, while the partial closed-loop relies
on the physician assessment of the condition as well.Figure 11
A control flow of partially closed-loop
insulin therapy models from [15]. In general, in this case, insulin dosages are
supported by an expert system that generates an optimal insulin dosage from a
comparison between a model case and a prediction of a future blood glucose
transition.Thus in a partially closed-loop control of the insulin dependent
diabetes therapy, measurements are conducted three to seven times per day, and
insulin injections are also performed three to four times under the supervision
of a physician. These decisions, for example, the number and type of insulin
injections and insulin dosage [15], are made according to model-based or
algorithmic-based decision support systems, such as DIAS, AIDA, and T-IDDM [15].
Insulin injections are usually performed by using the subcutaneous (SC) route
due to its management and safety.For example, unlike the pole-assignment strategy or the
self-tuning adaptive control in the closed-loop control scheme, AIDA simulates
the effect of the exogenous insulin injections and virtually models insulin-glucose
dynamics based on their physiological rules around metabolism of a single
glucose compartment rather than determining the IIR [15, 43, 44]. According to
the virtually modeled insulin-glucose dynamics, a physician determines the
appropriate exogenous insulin injection. Likewise, DIAS is a nonlinear model of the blood
glucose-insulin system based upon real-life parameters versus, simply, the
blood glucose measurements [49]. It incorporates qualitative and quantitative inputs
from the user, including the blood glucose levels, meals, and past insulin
injections.In addition to DIAS, AIDA, and T-IDDM, the Bergman model and physician
prescribed regiment are also categorized in the partially closed-loop control
models [5].


## 6.1. Open-Loop Control

Open-loop
control methods are occasionally called theprogrammed insulin infusion
system. One type of this method is one that was developed by Case Western
Reserve University, and this system is considered to be one of the most intelligent
programmed insulin infusion products that deal with the noninsulin-dependent
diabetics. The idea is that from an analysis of the insulin curve in the nondiabetic,
it was turned out that the curve approximately traces a combination of a double
exponential curve and a basal insulin infusion [48]. According to this
mathematical model, an intravenous insulin delivery system was designed such that
it followed the real pancreas functionality of the nondiabetic. The system
utilized a portable cart containing the control system, the insulin pump, power
supplies, and insulin reservoir so that the patient could move around with the
devices. The insulin pump delivers low-concentration insulin and updates the
insulin delivery rate every 30 seconds. Because of its simplicity, the system
can be set up and operated by nurses [48].


## 6.2. Closed-Loop Control

At first, a flow of the closed-loop control scheme is shown in
Figure10. The closed-loop system
completes its operating cycle within the system and no external interaction to diabetic patients is
required [15, 24]. In other words, the closed-loop control uses the feedback from
the output. Typically, the closed-loop system for type 1 diabetes therapy utilizes the glucose sensor and schematically consists
of three phases: blood glucose measurements, insulin demand calculation, and
insulin injection. The closed-loop system repeats this sequence.Figure 10
A control flow of
closed-loop control models [15]. Entire loop of the control is closed from
outside by utilizing an insulin pump and in vivo blood glucose sensors. Both
insulin injections and glucose measurements are carried out subcutaneously.Several papers already proposed applications and mathematical
models to suffice this model. Such applications include the pole-assignment
strategy, self-tuning adaptive control, model predictive control, and neural
predictive control.In short, the pole-assignment strategy calculates the insulin
injection rate (IIR) according to the current blood glucose levels plus trends
of the blood glucose levels as well as the pharmacokinetics of insulin infusion.
Although the calculation is very simple, the pole-assignment strategy is time consuming
because of repeatedly evaluating the model parameters only from the current
measurements. On the other hand, the self-tuning adaptive control utilizes a
recursive computation of the model parameters to generate the IIR faster than
the pole-assignment strategy [15].


## 6.3. Partially Closed-Loop Control

A flow of the partially closed-loop
control is shown in Figure11. Like the closed-loop control models, the
partially closed-loop control utilizes the external devices, such as insulin
pumps and blood glucose sensors. The major difference between the closed-loop
and partial closed-loop control methods is that the closed-loop control only
depends on the feedback from the output, while the partial closed-loop relies
on the physician assessment of the condition as well.Figure 11
A control flow of partially closed-loop
insulin therapy models from [15]. In general, in this case, insulin dosages are
supported by an expert system that generates an optimal insulin dosage from a
comparison between a model case and a prediction of a future blood glucose
transition.Thus in a partially closed-loop control of the insulin dependent
diabetes therapy, measurements are conducted three to seven times per day, and
insulin injections are also performed three to four times under the supervision
of a physician. These decisions, for example, the number and type of insulin
injections and insulin dosage [15], are made according to model-based or
algorithmic-based decision support systems, such as DIAS, AIDA, and T-IDDM [15].
Insulin injections are usually performed by using the subcutaneous (SC) route
due to its management and safety.For example, unlike the pole-assignment strategy or the
self-tuning adaptive control in the closed-loop control scheme, AIDA simulates
the effect of the exogenous insulin injections and virtually models insulin-glucose
dynamics based on their physiological rules around metabolism of a single
glucose compartment rather than determining the IIR [15, 43, 44]. According to
the virtually modeled insulin-glucose dynamics, a physician determines the
appropriate exogenous insulin injection. Likewise, DIAS is a nonlinear model of the blood
glucose-insulin system based upon real-life parameters versus, simply, the
blood glucose measurements [49]. It incorporates qualitative and quantitative inputs
from the user, including the blood glucose levels, meals, and past insulin
injections.In addition to DIAS, AIDA, and T-IDDM, the Bergman model and physician
prescribed regiment are also categorized in the partially closed-loop control
models [5].


## 7. Conclusion

It is evident that reliable
solutions to diabetes management are highly sought after and researched. The
health benefits associated with intensive diabetes treatment can save untold
lives and make life far more comfortable for many others. Additionally, with
the number of diabetes sufferers increasing annually, and the disease already
costing well over $100 million per year in health care expenses, it is a very
lucrative market. Effective solutions can help mitigate and control the effects
and tolls of diabetes in terms of both health and economic impact.Personalartificial pancreas devices are coming into greater use, spurred on by improvements in
technology and an increasing demand. Appropriate technologies must be developed
and exploited in order to improve upon today’s methods. Increased
miniaturization of sensors, pump, and controls continuously improve the
portability of personal continuous control devices, thereby increasing their
ubiquity among insulin-dependent diabetes patients.This paper summarizes
diabetes and its therapies. Currently, diabetes is considered not to be cured
by any medical treatment. However, since the Diabetes Control and
Complication Trial demonstrated that, by well-controlling, the glucose
metabolism for the diabetic, especially type 1 diabetes patients, expected
emergence of complications can be delayed or protected, several techniques to
replace exogenous insulin to the lack of endogenous insulin in order to
suppress the rise of the amount of glucose in blood are developed, that is, the
insulin-dependent diabetes therapy.Besides, to support the insulin therapy, several medical devices
concerning diabetes are being developed. Examples of these devices are insulin
pumps and blood glucose sensors. In this paper, a couple of examples of insulin
pumps and blood glucose sensors are presented. Especially, in blood glucose
sensors, three types of them are briefed: the fingerstick meter reading, in vivo,
and the noninvasive blood glucose
measurement, and each of them has its advantages and disadvantages. For
example, although, if they are available, in a long time period, the in vivo
blood glucose sensors largely benefit for modeling the blood glucose
transitions and consequently benefit for the insulin therapy, they are only
approved for a short time use currently, for example, only a 3-day use is
approved by U.S. Food and Drug Administration (FDA). The insulin therapy
using the in vivo sensors and insulin pumps are usually called the closed-loop
control.In conclusion, in the near
future, several research intentions will be considered. The first is the early
development of long-term available in vivo blood glucose sensors. There is no
explanation about this direction because it is believed that the emergence of
long-term in vivo sensors should enhance the blood glucose measurement and
consequently ease the predictions and plans for the insulin therapies to avoid
both hyper- and hypoglycemia. The second is the development of a more accurate
but simpler mathematical model for the insulin-glucose dynamics. This direction
will also enhance the insulin therapy largely in the diabetic treatment by partially
closed-loop control. For more details about the control theory in diabetes,
please refer to our survey paper in control methods [5]. In addition to these
two directions, the paper [15] points out two more directions: one is the
development of decision support systems, and the other is the development of
the noninvasive blood glucose measurement.



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*Source: 639019-2008-01-27.xml*