Mid-Infrared Spectroscopy for

Noninvasive Blood Glucose Monitoring

David C. Klonoff, MD
Department of Medicine
University of California at San Francisco San Francisco, California
and
James Braig, Bernhard Sterling Ph.D., Charles Kramer Ph.D., Daniel Goldberger and Rick Trebino Ph.D.
OptiScan Biomedical Corporation
Alameda, California

Optimal management of diabetes requires stabbing the finger with a needle up to four times daily to obtain a drop
of blood for glucose measurement. Such invasive testing could be replaced by noninvasive, nearly noninvasive, or
minimally invasive technologies. These new technologies will reduce or eliminate the skin trauma, pain, and blood
waste associated with current glucose monitoring technology

Noninvasive blood glucose monitoring involves either radiation or fluid extraction 1. The most promising radiation
technologies are: 1) mid-infrared radiation (Mid-IR) spectroscopy; 2) near-infrared radiation (Near-IR) spectroscopy;
3) radio wave impedance; and 4) optical rotation of polarized light. All of these technologies except Mid-IR
spectroscopy involve application of an external energy source to the body. The interaction between applied radiation
(or thermal emissions in the case of Mid-IR spectroscopy) and glucose in the blood is measured and converted into a
blood glucose concentration.

Fluid extraction from skin, also known as reverse iontophoresis, utilizes an electrical current applied to the skin. The
current pulls out salt, which carries water, which in turn carries glucose. The glucose concentration of this extracted
fluid is measured and is proportionate to that of blood.

Nearly noninvasive blood glucose monitoring involves transcutaneous harvesting and measurement of interstitial
fluid which is the fluid surrounding every cell of the body. The most promising technologies for disrupting the skin
barrier to obtain interstitial fluid include: 1) dissolution with chemicals; 2) microporation with a laser; 3) penetration
with a thin needle; and 4) suction with a pump.

Minimally invasive blood glucose monitoring involves insertion of an indwelling glucose monitor under the skin to
measure the interstitial fluid glucose concentration. Such a monitor typically utilizes a sensor containing the enzyme
glucose oxidase. This enzyme oxidizes glucose and employs oxygen as an electron acceptor. The reaction liberates
H2O2 which is detected by measuring its oxidation current on platinum electrodes 2.

Interstitial fluid glucose concentrations were recently shown to be equal to simultaneously measured fixed or
fluctuating blood glucose concentrations3. Such studies helped validate radiation technologies for noninvasive blood
glucose monitoring. These technologies might measure glucose in blood as well as interstitial fluid. If these two
compartments rapidly equilibrate, then they can be measured with the same method.

Mid-IR spectroscopy is an attractive technology for blood glucose monitoring because it is noninvasive, specific,
rapid, and potentially inexpensive. The remainder of this article discusses that methodology.
In the mid-IR, glucose absorbs strongly with minimal interference from other absorbing species, but sources are not
ideal and water absorbs very strongly. The OptiScan noninvasive glucose meter takes advantage of the realization
that the human body is an excellent blackbody emitter of mid-IR light at precisely the right spectral region, so the
necessary radiation is therefore already present inside the body near enough to the surface (within 10s of microns)
that its emission spectrum may be used to measure glucose.

Unfortunately, the nature of blackbody radiation is such that, if the glucose to be measured is at the same
temperature as the tissue that emitted the blackbody radiation, then the glucose will be effectively transparent, and
no glucose spectrum will be observed in the emitted light due to the balance of absorption, spontaneous emission,
and stimulated emission at equilibrium. Fortunately, this problem can be solved by introducing a temperature
gradiente.g., cooling the surfacewhere the cooler glucose will absorb more than it will emit. This yields a
reasonable glucose absorption spectrum superimposed on the usual smooth blackbody emission spectrum.

An approximate analytical mathematical model yields the predicted emission spectrum and signal-to-background
ratio (S/B) that will be observed by OptiScans glucose monitor. It begins with the simple equation of radiation
transfer, which simply says that the change in intensity is that due to spontaneous emission plus that due to
stimulated emission minus that due to absorption4.

The model assumes that the tissue surface is then cooled to T below the interior tissue temperature, T. Call g the
optical depth due to glucose over the temperature-gradient region and the total optical depth due to everything else
over this region (mainly water). The signal-to-background ratio, that is, the ratio of glucose signal toother light that
will emerge from the chilled tissue can be shown to be:

where is the frequency of observation, " is Plancks constant over 2, and k is Boltzmans constant.

The relevant numbers in the above equation for glucose in water are:
"~3, TT=0.05 (corresponding to T~ 15 C and T ~ 300 K), g/ ~ 0.01 (corresponding to a water
concentration of ~ 1 g/cm3, a glucose concentration of ~ 100 mg/dl ~ .001 g/cm3, and, at a wavelength of 9.7 m,
absorption cross-sections of ~ 2 10-18 cm2 and 2 10-20 cm2 for glucose and water, respectively), and ~ 10
(corresponding to a water absorption 1/e depth of 15 m and a gradient region ~ 150 m long).

As a result, S/B ~ 10-4, which is

not unreasonable in view of the
capabilities of available
spectrometers and detectors.
Also, tissue is, of course, not
entirely water, and skin has
even less water. These factors
actually act to improve the S/B
over that calculated because
absorption in human subjects
is actually less. On the other
hand, humans have complex
variations that reduce
instrument reliability.

Figure 1 shows a composite

graph of clinical results taken
from four volunteer Type 1 diabetic subjects measured on two functionally identical non-invasive prototype
instruments. The data was collected during modified glucose tolerance tests. Two tests were conducted in October,
1997 at the companys clinical laboratory and two other tests were conducted in January, 1998 in an ongoing clinical
study at UCSF. The overall standard error is 24.7 mg/dL and the R2 is 0.94. The data was post-processed using an
individual linear calibration curve for each subject. The reference instrument was a YSI laboratory glucose analyzer
for the two UCSF subjects and an Accu-Chek home blood glucose monitor for the two company subjects.

In conclusion, we believe our data supports the hypothesis that mid-infrared radiation spectroscopy is a viable
method for non-invasively measuring human blood glucose concentrations.

References
1 Klonoff, DC, Noninvasive blood glucose monitoring. Diabetes Care, 1997:20:433-437.

2 Zhang, Z., Liu, H., and Deng, J., A glucose biosensor based on immobilization of glucose oxidase in
electropolymerized o-aminophenol film on platinized glassy carbon electrode, Analytical Chemistry 1996; 68:1632-
1638.

3 Bantle, JP and Thomas, W., Glucose measurement in patients with diabetes mellitus with dermal interstitial fluid.
Journal of Laboratory and Clinical Medicine 1997; 130:436-441.

4 Gaussorgues, G. Infrared Thermography (Chapman and Hall, London, 1994) p. 53

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