daughter of a Livermore physicist was diagnosed with diabetes in
1994, her doctor at Stanford Childrens Hospital, Dr. Darrell
Wilson, happened to be familiar with the Laboratory. Wilsons
father-in-law was Carl Haussmann, one of the Laboratorys founders
(see S&TR, January/February
2000), so over the years, he had heard about the unique technological
capabilities of the Laboratory. He suggested that Livermore might
be able to do something for the sufferers of diabetes.
It was a chance remark, one
that might have gone nowhere. But the physicist, Tom Peyser of the
Defense and Nuclear Technologies Directorate, saw that he could
tap into Livermores growing capability in medical technologies,
a field that combines expertise in chemistry, physics, optics, electronics,
and microfabrication. He and fellow physicist Steve Lane took up
Dr. Wilsons challenge and began a systematic examination of
the technology necessary for continuous monitoring of blood sugar
in diabetics. Many private companies already were working on this
problem, but Peyser and Lane thought that the Laboratory was uniquely
situated to tackle the problem using optical technologies. They
also realized that spinoffs from their work on glucose sensors might
benefit other Laboratory missions, such as programs for detecting
hostile chemical and biological agents.
Work on the glucose sensor
began in 1995 when the Livermore project team linked up with MiniMed,
Inc., of Northridge, California, to develop an optochemical glucose
sensor. The project has received grants from the Laboratory Directed
Research and Development Program and subsequently been funded by
the National Institutes of Health and the Department of Commerces
Advanced Technology Program.
MiniMed is the largest supplier
of insulin pumps, small pager-size programmable medical devices
that administer insulin to diabetics in place of multiple daily
injections. Someday, the LivermoreMiniMed sensor may be combined
with a MiniMed insulin pump to create an artificial pancreas, which
could change the lives of millions of diabetics.
Diabetes is a metabolic disease
in which the body does not produce or use insulin properly. Insulin
is a hormone secreted by the pancreas that allows glucose, the energy
source for the cells in our body, to enter the cells. Careful stabilization
of glucose levels is crucial for diabetics to avoid a host of complications.
Long-term high glucose levels, or hyperglycemia, may lead to heart
disease, hypertension, blindness, stroke, kidney failure, and amputations.
In fact, complications from diabetes are the leading cause of blindness,
kidney failure, and amputations in the U.S. Hypoglycemia, or low
glucose levels, can lead to unconsciousness and death. The direct
and indirect costs of diabetes to the U.S. health care system exceed
$100 billion annually.
Diabetic patients must test
their blood sugar daily. Some patients have to test themselves up
to eight or more times a day. They prick a finger to draw blood
for reading by a handheld blood glucose meter, and then they inject
the necessary amount of insulin determined by the meter reading.
Because of the pain and inconvenience of the testing, many patients
do not monitor their glucose as often as they should. Whats
more, even if they do test themselves regularly, current technologies
make it virtually impossible to test often enough to maintain reasonably
stable glucose levels. The new sensor that Livermore and MiniMed
are developing can be implanted under the skin without surgery and
is expected to last for a year before replacement. Were
still in the early developmental stages with the sensor, says
Lane, associate program leader for Livermores Medical Technology
Program. It will probably be several years before it hits
Livermores work on
this project has not gone unnoticed. At a White House ceremony in
January, the Department of Energy awarded one of five Bright Light
Awards to the Livermore team for consumer-oriented innovation. In
May, the Federal Laboratory Consortium honored Livermore with an
Excellence in Technology Transfer Award for transferring the glucose
monitoring technology to a private-sector company.
glucose levels for nondiabetic and insulin-dependent diabetic
subjects. Even with regular insulin injections, diabetics using
current treatment methods are unable to mimic normal control
of glucose levels.
Tells the Story
The new device
is a small disk with a fluorescent chemical sensor that consists
of engineered molecules embedded within a polymer. In the absence
of glucose, the sensors molecules have a low level of fluorescence.
The presence of glucose alters the molecules electron configuration
so they become much more fluorescent and emit light of a specific
color. If developmental work on the device goes as planned, a small
handheld instrument will shine light on the skin, and a small detector
will measure the resulting fluorescence. The intensity, or brightness,
of this emitted fluorescence will allow the bodys glucose
level to be determined. A more intense light emission corresponds
to a higher glucose level.
alternative approach is also being developed in which the fluorescent
lifetimes of the molecules are measured by the instrument. Sensor
molecules bound to glucose have longer fluorescent lifetimes than
molecules that are not bound. The average lifetime can therefore
be used to determine the glucose level. This method is much more
tolerant to instrument and other errors. Even something as mundane
as moving the place where a patient wears a watch can change the
detectors readings using the first method.
first step in developing the sensor was to demonstrate that it was
possible to receive a signal from a fluorescent sample placed under
the skin. A beam from a light-emitting diode was passed through
a fiber-optic line to the surface of the skin, through the skin
to the fluorescent-doped plastic, and back out of a fiber-optic
line to a spectrometer that measured the intensity of the fluorescence.
This demonstrated that transdermal fluorescent signaling was possible.
But it also pointed out that only long-wavelength light can easily
pass through skin and other tissue (as demonstrated when only red
light from a white flashlight beam shines through the hand).
Lane takes a glucose-sensitive fluorescent polymer out of a
glass vial for observation.
Right Fluorescence Molecules
earlier work by a Japanese group, several Livermore chemists led
by Joe Satcher, working with researchers from MiniMed, designed
switchable anthracene boronate (AB) molecules, or fluorophores.
The AB molecules are weak fluorescers when not bound to glucose
but become bright when they are. Next, Livermore developed linkers
that could be synthetically attached to the AB molecules so that
the molecules could, in turn, be attached to a biocompatible polymer
substrate. Finally, the team screened a large number of candidate
polymers to hold the AB fluorophores. They found a pHEMA (polyhydroxyethyl
methacrylate) blend, a material similar to that used for contact
lenses. This material is strong and sufficiently permeable to allow
glucose to enter, does not irritate the skin, and allows the AB
molecules to function properly even when they are covalently bonded
to the polymer.
the West Los Angeles Veterans Administration Hospital, Livermore
and MiniMed first demonstrated the glucose-sensitive fluorescent
implant in the ear of an anesthetized rat. The fluorescence signal
closely tracked a separate independent measurement of the rats
glucose levels as the animals blood sugar was raised and lowered
over a 2- to 3-hour period. In these tests, the implant remained
operational for two weeks, the duration of the experiment.
Challenges remain to fully
developing the sensor. The biggest hurdle right now,
says Lane, is engineering a fluorophor with a wavelength that
is long enough to be reliably detected through the skin.
The AB molecule absorbs light
at 380 nanometers and emits fluorescent light at 420 nanometers.
Recently, new glucose-sensitive fluorescent compounds have been
synthesized and tested at Livermore and MiniMed that absorb red
light at 620 nanometers and emit at 670 nanometers. If these
molecules can be made to mimic the other properties of AB, our job
will be nearly complete, adds Lane.
The team has also developed
an alternate method that has been tested on rats. In this version,
a sensor membrane was fixed onto the end of an optical fiber and
then inserted under the skin of the animal where it remained for
many hours. Light at one wavelength was sent down the optical fiber
from outside the animals body. The sensor gave off fluorescence
of an intensity duration that depended on the concentration of glucose
in the surrounding tissue. The fluorescent light emitted by the
sensor was at a different wavelength than the incoming light; it
traveled back up the optical fiber where it was measured by a detector
outside the body. The glucose levels in the tissue could then be
read via the fiber-optic cable rather than via light transmitted
directly through the skin. In this case, long-wavelength fluorescence
is not necessary.
As they continue to pursue
the transdermal sensor, Livermore and MiniMed are also furthering
the development of the fiber-optic version, which would be implanted
under the skin using a needle. A similar electrochemical glucose
sensor already marketed by MiniMed is implanted the same way.
Livermore may be able to
exploit the research on fluorescent molecules in its effort to develop
sensors to detect biological agents of terrorism as well as for
a range of other biomedical applications. Knowledge gained in the
process of developing the glucose sensor may lead to methods for
detecting small amounts of a deadly toxin or pathogen.
schematic of the fiber-optic version of the optochemical glucose
sensor that was used in the first animal trials. The transducer
membrane consists of the anthracene boronate molecule chemically
immobilized into a biocompatible, glucose-permeable polymer.
Search for a Solution
Livermore and MiniMed are
not the only ones trying to achieve a reliable glucose sensor for
diabetes patients. For 30 years, researchers have been trying to
solve the puzzle of long-term glucose sensing. Lane estimates that
work is under way in at least 100 public- and private-sector laboratories
worldwide to produce a continuously operating glucose sensor. With
millions of sufferers and billions of dollars spent annually to
treat the disease, a solution to this problem is urgently needed.
says, We have a long way to go before making a product, but
we have taken the first steps and have measured glucose in animals
using this fluorescent technique. Were at a point similar
to that of the Wright brothers flying their first airplane a few
hundred feet. Weve established that fluorescent glucose sensors
are feasible. The Livermore team is hoping that progress on
the long-wavelength compound and on the polymer work will allow
resumption of animal tests in the near future. When those tests
are completed, MiniMed will likely begin the next phase of research
and development, namely, rigorously conducted clinical trials supervised
by the Food and Drug Administration. It is a lengthy and costly
process, but if Livermore and MiniMed succeed in combining their
glucose sensor with an insulin pump, diabetes patients everywhere
diabetes, glucose sensor.
information contact Stephen M. Lane (925) 422-5335 (firstname.lastname@example.org)
or Tom Peyser (925) 423-6454 (email@example.com).