Development of Wearable Semi-invasive Blood Sampling Devices for Continuous Glucose Monitoring: A Survey

doi:10.4236/eng.2013.55B009

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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

Email: *[email protected]

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

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.

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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