Engineering, 2013, 5, 42-46
doi:10.4236/eng.2013.55B009 Published Online May 2013 (http://www.scirp.org/journal/eng)
Development of Wearable Semi-invasive Blood Sampling
Devices for Continuous Glucose Monitoring: A Survey
Gang Wang*, Martin P. Mintchev
Centre for Bioengineering, University of Calgary, Calgary, Canada
Received 2013
ABSTRACT
Semi-invasive blood sampling devices mimic the way female mosquitoes extract blood from a host. They generally
consist of a microneedle, a microactuator for needle insertion, a blood extraction mechanism and a blood glucose sensor.
These devices have great potential to overcome the major disadvantages of several current blood glucose monitoring
methods. Over last two decades, extensive research has been made in all of these related fields. More recently, several
wearable devices for semi-invasive blood sampling have been developed. This review aims at summarizing the current
state-of-the-art development and utilization of such wearable devices for continuous monitoring of blood glucose levels,
with a special attention on design considerations, fabrication technologies and testing methods.
Keywords: Continuous Blood Glucose Monitoring; Semi-invasive Blood Sampling; Mosquito; Bio-mimetics;
BioMEMS; Wearable Devices
1. Introduction
1.1. Impact of Diabetes Mellitus
Diabetes Mellitus is a systemic disorder that results in
elevated blood glucose levels due to insulin deficiency in
the body and subsequently leads to many secondary com-
plications [1]. More than 180 million people suffer from
diabetes worldwide. This figure is expected to almost
double by the year 2030 [1]. Both type 1 and type 2 dia-
betes mellitus (T1DM andT2DM, respectively) require
long-term treatment, the goal of which is to achieve op-
timal glucose monitoring and control with the long-term
aim of decreasing the risk of vascular complications
while minimizing daily glycemic variations [2].
1.2. Evolution of Glucose Monitoring Devices
Glucose monitoring devices can be classified according
to the level of invasiveness, the type of target biofluid, i.e.
blood or interstitial fluid (ISF) and the sensing technique
[3].
Standard diabetic monitoring relies on finger-prick
testing by a miniature device [4]. Though highly accurate
in detecting blood glucose levels, finger-prick testing is
painful and inconvenient. Therefore, patients, especially
those in their youth and at active maturity, are often un-
able to adhere to the test schedule. As a result, irregular
measurements limit the applicability of the finger-prick
test and disturbes the management of diabetes [4].
Continuous glucose monitoring (CGM), introduced in
1960s, is a concept which measures glucose levels in the
interstitial fluid (ISF). CGM is less invasive than the fin-
ger-prick test. However, its accuracy is dependent on the
equilibrium of glucose levels between ISF and blood.
The balance between the two glucose levels further ac-
counts for a time delay in the measurement [4] and re-
quires frequent recalibration using finger-pricking test
[5].
Retrospective continuous glucose monitoring (retro-
spective CGM) device can be subcutaneously inserted
and record ISF glucose level but only for 3 - 7 days [4].
Clinicians rely on retrospective CGM to understand the
glucose level trend within this short period and guide the
diabetes management [3].
Wearable devices featuring real-time continuous glu-
cose monitoring (rt-CGM) emerge on the market [5].
These devices apply low electric current to extract glu-
cose from ISF through the skin and therefore minimize
the pain and invasiveness, which make them popular
among diabetes patients. However, the techniqueisbeset
by old problems inherited from the indirect ISF glucose
monitoring. In other word, the term “real-time” is some-
what of a misnomer. Also, rt-CGM does not fully replace
conventional blood sampling as it also requires calibra-
tion by using a finger-prick test per use. The price of
achieving lower invasiveness is the decrease in meas-
urement accuracy: especially the false positive rate in-
*Corresponding author.

G. WANG, M. P. MINTCHEV 43
creases significantly due tosweat, to temperature changes,
to electrostatic noise sources, etc. [5].
There is an obvious need for wearable semi-invasive
blood sampling devices which would be able to auto-
matically obtain and analyze a series of static blood sam-
ples over an extended period of time with minimal pain
and limited user intervention. This can be achieved by
inserting a hypodermic needle to a level where capillaries
are abundant but nerve endings are rare [6]. In this sur-
vey, the contemporary technologies of semi-invasive
blood sampling devices will be reviewed, with a focus on
the types of needle used, actuation mechanisms and glu-
cose sensing methods.
2. Components of Semi-invasive
BloodSampling Devices
2.1. Anatomy of Human Skin
On average the skin of an adult has a thickness of roughly 2
mm [7]. The outermost layer of the skin is the stratum
corneum which is a thin but very dense and resistive
compound of dead cells. The thickness of stratum corneum
varies among different skin sites, ranging from
for the forearm and 173.0
for the palm [8]. Situated below is the epidermis which
protects against the rays of the sun and has a thickness of
30 to 130 μm. The dermis, which is located under the
epidermis and ranges 800 - 1500 μm in thickness, holds
abundant blood vessels, hair follicles, sweat glands and
few nerve endings [2]. Lastly, the subcutaneous tissue is
a fatty layer located below the dermis and connects to
internal organs. It is usually about 1.2 mm deep [2].
23.64.33 μm36.96 μm
In order to successfully acquire blood sample, a needle
has to penetrate the resistive stratum corneum and reach
the dermis layer which contains capillaries. An analogy
of this process in nature is blood extraction by female
mosquito’s proboscis.
2.2. Blood Extraction Mechanism of a Mosquito
The micro-scaled structure of the proboscis has been
previously described by several biologists using an elec-
tron microscope [9,10]. It mainly consists of a large lip
called the labium, which serves as the floor of all other
components of the proboscis. At the tip of the labium,
itends in two pieces of lobes called the labella. The la-
bium forms a deep housing for a stylet-shaped labrum.
The labrum is a hollow tube through which the blood is
drawn.At the side of the labrum are two larger needle-
like maxillae with fine saw-toothed tips. Their oscillation
can facilitate the penetration of the labrum.
A recent study by Ramasubramanian et al. [11] uses
high-speed video imaging to observe the skin penetration
process. Axial pushing and retraction of labium at a fre-
quency of about 15 Hz was observed during the early
penetration stage. They compared their experiment with
another electrical impedance measurement of mosquito
biting [12] and confirmed that such vibration facilitates
the penetration. Another group [13] further studied the
movement of mosquito proboscis in transparent thin
skins of laboratory rats and found out that the labium and
two maxillas advanced into the skin alternatively at the
same frequency. After the penetration process, a mos-
quito relies on not only the passive capillary pressure but
also on a two-pump system in its head to suck a large
portion of blood, the weight of which can reach nearly 3
times of its own weight within one minute [12,14].
These findings clearly indicate that the mosquito pro-
boscis is a piece of sophisticated biological actuation
mechanism made of components with highly specialized
functions, rather than just a hypodermic needle as previ-
ously described. The anatomy of a mosquito’s proboscis
and the various functions of its components have, in dif-
ferent aspects, inspired the development of semi-invasive
blood sampling devices, which generally consist of hy-
podermic needles, needle insertion actuators, blood sam-
pling mechanisms and electrochemical glucose sensing
methods.
2.3. Needle Design
Hypodermic needlesand microneedles are both widely
used in the development of semi-invasive blood sampling
devices. Hypodermic needles generally refer to those
stainless-steel made needles that are conventionally used
with syringes to inject drugs into a body or extract fluid
from it. The outer diameter of hypodermic needles is
indicated by needle gauge (G), which is usually ranged
from 7G (4.572 mm) to 33G (0.2096 mm) [15]. Micron-
eedles, which were first introduced in 1970s [16], refer to
those smaller needles, the diameter and length of which
are in micrometers. Microneedles can be made of different
materials, including silicon, polymer, metals and glass,
etc. In terms of mass production, silicon microneedles
can be classified based on how they are manufactured.
The “in-plane” needles are createdparallel to the sub-
strate surface. “out-of-plane” needles are fabricated ver-
tical to the substrate surface [8,17]. In-plane needles can
be made relatively long and penetrate deeper below skin.
Therefore, they are suitable for applications such as
blood extraction [13]. The length of “out-of-plane” nee-
dles is limited during production process. Therefore, ex-
tensive research has been made on their applications in
ISF extraction and therapeutic drug delivery in dermis
layer. For metallic microneedles, special fabrication
techniques are employed. For example, the RF magne-
tron sputtering, a method that had been used for rapid
deposition of thin films, was appliedto coat titanium par-

G. WANG, M. P. MINTCHEV
44
ticles on a rotating copper wire. Finally, the core copper
wire can be removed by an etching process so that the
hollow cavity is formed in the needle [18].
Before starting any device development, the choice of
an appropriate needle has to be made after comparing a
number of mechanical properties of the needles, such as
the Young’s modulus, hardness, skin insertion force,
fracture force, etc., to minimize insertion effort and
maximize the safety margin [8].
2.4. Microactuator for Needle Insertion
The actuation mechanism for the needle insertion is im-
portant in the design of any blood sampling device.
There are several actuation mechanisms that are relevant
to the development of microactuators: piezoelectric,
electrostatic, thermal and shape memory effect [19].
Maximum stroke and the insertion force are the two
primary design factors. In order to successfully acquire
blood, the actuator must be capable to move the needle to
a depth about 150 ~ 1000 μm below the skin, where cap-
illary vessels are abundant. To test the maximum stroke
of an actuator at in-vitro experiment stage, one-dimen-
sional or two-dimensional laser displacement sensor is
usually used [20]. To observe the penetration characteris-
tics beneath the skin during in vivo or human model test,
various real-time monitoring methods have been em-
ployed, including optical coherence tomography, infrared
spectroscopy and electrical impedance spectroscopy, etc.
[21]. Among them, optical coherence tomography (OCT)
is the most often used technique. OCT is a non-invasive
imaging method which is capable of achieving an imag-
ing depth of 2 mm below the skin. Its concept is similar
to ultrasonic imaging: mapping is obtained by reprocess-
ing the dynamic change of reflected light rays rather than
ultrasound waves [22]. Due to the difference in geometry,
materials and sharpness of the needle tip, the required
force for skin penetration by different types of needles
vary in a wide range. The actuation force can be tested
by load cells, the force applied on which can be linearly
converted to an output voltage by piezoresistive effect
[20,23].Synchronization of the force and stroke monitor-
ing can provide useful information such as the skin pene-
tration force and event time.
The “electronic Mosquito” skin-patch blood sampling
system was introduced in 2005 [6]. In its macro-size pro-
totype, it utilizes a pair of piezoelectric actuators which
can exerta force of nearly 100 gf and a maximum stroke
of 1.25 mm [24]. An upgraded version of this system
further incorporates an impedance sensor for the pres-
ence of a blood sample to form a closed-loop control of
the actuator. It successfully extracted a blood sample of
10 µL in a chicken model test [25]. However, the force
and stroke dropped proportionally to the scale of minia-
turization and the development of this system is still
during midway to a practically applicable level. Another
group from Japan reported a blood extraction system
which utilized an SMA actuator to insert a titanium-made
microneedle [26]. Having a high power/size ratio, this
SMA actuator is able to reach a maximum output force
of 80gf and stroke of 3mm on a skin simulation model
[18]. However, no report of in-vivo testing has been
available so far.
Challenges to the microactuator design include the
output force, the stroke as well as the price, the scalabil-
ity and the input power consumption rate. Other not less
important considerations in the device design include
biocompatibility and temperature dependence. The selec-
tion of actuation mechanism for wearable blood sampling
effect is further restricted by limited power supply and
space.
2.5. Blood Extraction Mechanism
Two types of passive blood extraction mechanisms by a
female mosquito were observed: pool feeding, where the
mosquito creates a hemorrhage and feeds slowly via cap-
illary action, and capillary feeding, wherein the mosquito
taps into a capillary vessel and the feeding process is
much faster, as the blood is driven under capillary blood
pressure [14]. As described before [6], the “electronic
Mosquito” system relies on these natural pressure gradi-
ents to extract blood. Several other groups tried to mimic
the active pumping system in the mosquito’s head to ac-
celerate the extraction process. In [18], the authors in-
troduced a pumping unit next to the proximal end of the
microneedle using a bimorph PZT piezoelectric actuator.
Powered by AC voltage @ 25 kHz, the piezoelectric ac-
tuator deflects and creates a pressure drop in the needle
cavity, sucking blood at a rate of 2 µl/min. In [26], an
electrolyte-controlled blood extraction mechanism was
reported. It has beenclaimed its extraction speed reaches
5µl/s. However, the paper lacks details of its experimen-
tal setup and protocol. In [27], a vacuum-driven blood
extraction system was implemented for an automated
finger-prick test. It succeeded in extracting 12.7 μl of
human blood within 2 seconds. However it is question-
able that whether this mechanism can be transferred to a
wearable device due to its bulky size.
2.6. Glucose Sensor
Compared to the other design aspects of wearable semi-
invasive blood sampling devices discussed above, glu-
cose sensing technology is a field that has been the most
intensively studied for several decades [3,28-30].
Electrochemical glucose sensing methods from whole
blood remain the most reliable approach for accurate
glucose level testing [28]. The measurements by the

G. WANG, M. P. MINTCHEV 45
same electrochemical sensors from ISF may have dis-
crepancies due to the dynamic imbalance of glucose level.
Non-invasive approaches, which mainly rely on optical
detection and analysis, have not presented any reliable
results for continuous glucose monitoring, in spite of the
extensive efforts that have been made [28].
The glucose sensing mechanism of a control meter for
home testing of blood glucose can be directly connected
to a wearable semi-invasive blood sampling device. The
concept of this type of sensors relies on a chrono-am-
perometric operation in connection with an incubation
step [3]. The challenge left for its application in wearable
devices is the device miniaturization.
The advance of microfabrication techniques now al-
lows the development of needle-shape glucose sensors.
The underlying concept is a combination of microdialysis
and enzymatic amperometric glucose measurement. The
needle is made hollow and filled with isotonic fluids.
Once being inserted into body, blood glucose molecules
can diffuse into the needle and be transferred to the elec-
trode in the needle [30]. Glucose measurement can be
made on-site and in-situ rather than on the blood sample
transferred from the patient’s body to the device.
3. Discussion and Conclusions
The use of wearable semi-invasive blood sampling de-
vices shows great potential, overcoming the discontinu-
ance of finger-prick test and the inaccuracy of optical and
ISF tests. It aims at reducing pain and inconvenience
experienced by diabetes patients and increasing the
number of blood glucose tests per day thus at improving
the health of diabetic patients. It further opens the possi-
bility to connect with a wearable insulin pump device in
order to form a closed-loop blood glucose control, or an
external electronically-controlled artificial pancreas.
As discussed above, several attempts were already
made by different groups to develop a practical product.
However, to this day, no commercialized products have
entered the market. The main challenges are (a) the de-
vice miniaturization and (b) integration. Safety issues
like bleeding, infection and skin recovery may also
hamper the implementability and marketability, the ap-
proval process from regulatory agencies and final com-
mercialization. Despite the recent great efforts to solve
the existing problems, research on novel materials and
microfabrication technologies is also needed.
4. Acknowledgements
This study was sponsored in part by the National Sci-
ences and Engineering Research Council of Canada.
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