Electrochemical glucose biosensors - Electrochemical Sensors, Biosensors and Their Biomedical Applications - page 64

3.6 CONTINUOUS REAL-TIME IN-VIVO MONITORING

Although self-testing is considered a major advance in glucose monitoring it is limited
by the number of tests per day. The inconvenience associated with standard fi nger-stick
sampling deters patients from frequent monitoring. Such testing neglects night-time
variations and may result in poor approximation of blood glucose variations. Tighter
glycemic control, through more frequent measurements or continuous monitoring, is
desired for detecting sharp changes in the glucose level and triggering proper alarm
in cases of hypo- and hyperglycemia, essential for making valid therapeutic decisions
[34, 35]. Glucose biosensors are thus key components of closed-loop glycemic control
systems. A wide range of possible in-vivo glucose biosensors has thus been studied
for maintaining glucose levels close to normal. The fi rst application of such devices
for in-vivo glucose monitoring was demonstrated fi rst by Shichiri et al. in 1982 [36].
His needle-type glucose sensor relied on a platinum anode held at

0.6 V (vs silver
cathode) for monitoring the enzymatically produced hydrogen peroxide. The enzyme
(glucose oxidase) entrapment was accomplished in connection with a cellulose-diac-
etate/heparin/polyurethane coating. Continuous ex-vivo monitoring of blood glucose
was proposed already in 1974 [37]. The majority of glucose sensors used for in-vivo
applications are based on the GOx-catalyzed oxidation of glucose by oxygen.

3.6.1 Requirements
The major requirements of clinically accurate in-vivo glucose sensors have been dis-
cussed in various review articles [1, 34, 35]. These include proper attention to the issues
of biocompatibility (rejection of the sensor by the body), miniaturization, long-term sta-
bility of the enzyme and transducer, oxygen defi cit, short stabilization times, in-vivo cal-
ibration, baseline drift, safety, and convenience. The sensor must be of a size and shape
that can be easily implanted and cause minimal discomfort. Under biocompatibility one
must consider the effect of the sensor upon the in-vivo environment as well as the envi-
ronmental effect upon the sensor performance. Problems with biocompatibility have
proved to be the major barriers to the development of reliable implantable devices. Most
glucose biosensors lack the biocompatibility necessary for a reliable prolonged opera-
tion in whole blood. Alternative sensing sites, particularly the subcutaneous tissue, have
thus received growing attention. While the above issues represent a major challenge,
signifi cant progress has been made towards the continuous monitoring of glucose.

3.6.2 Subcutaneous monitoring
Most of the recent attention has been given to the development of subcutaneously
implantable needle-type electrodes [14, 15, 34, 38]. Such devices track blood glucose
levels by measuring the glucose concentration in the interstitial fl uid of the subcutaneous
tissue (assuming the ratio of the blood/tissue levels is constant). Subcutaneously implant-
able devices are commonly designed to operate for a few days and be replaced by the
patient. Success in this direction has reached the level of short-term human implantation;