Articles, Blog

Sweat-Based Glucose Sensing and Transdermal Drug Delivery | Dae-Hyeong Kim | TEDxKFAS

August 24, 2019


Translator: Jhohans Beltran
Reviewer: Rhonda Jacobs Hello everyone, my name is Dae-Hyeong Kim
from Seoul National University, and today, I will talk about
sweat-based glucose sensing and transdermal drug delivery. Let me first briefly introduce diabetes. Diabetes is caused by high glucose
concentration in the blood, which is called as hyperglycemia. That high glucose concentration
causes chronic diseases such as cardiovascular diseases,
strokes, numbness, kidney problems. Therefore, it’s very important to decrease
that high-glucose concentration by using appropriate medication
such as insulin or metformin. However, if that medication is too much, then too low glucose concentration, which is called
as hypoglycemia can happen. And this hypoglycemia
can lead to tragic results such as shock or death. Therefore it is very important to prevent both hyperglycemia and hypoglycemia, while maintaining the glucose level
near homeostatic level. And to achieve that goal, patients
typically use blood-based glucose sensing. Patients use a finger pricking method
to collect blood sample, and put that blood sample
on the disposable strip, and insert that disposable strip
into the hardware to electrochemically analyze
the blood sample and estimate the blood’s
glucose concentration. After finding out the blood’s
glucose concentration, the patient can take medication
such as an insulin shot, but as you may expect,
these two procedures are quite painful and stressful. And there are a lot of children
who are suffering from type 1 diabetes and those young patients
have a lot of fear in doing these two procedures. Therefore there is a huge need
to develop a painless, stress-free and accurate
glucose monitoring method, hopefully integrated with
automatic, painless drug delivery system. And we wanted to achieve this goal
by using our wearable device technology. To remove that blood collection procedure,
we focused on sweat. The good news is that sweat
contains glucose, and the sweat glucose concentration
has a quite good correlation with blood glucose concentration. However, there are challenges. The first challenge is insensitivity. The sweat glucose
concentration is much lower, almost 100 times lower
than the blood glucose concentration, which means, we need a very good sensor,
with high sensitivity. And we solved this issue
with nanotechnology. The second challenge is inaccuracy. Most glucose sensors
are using glucose oxidase. So, glucose sensors
approach glucose oxidase, then the glucose molecules
will be converted into gluconic acid and hydrogen peroxide. In turn, electrons will be generated and the glucose sensor
is measuring these generated electrons. So, for example, if the glucose
concentration is high, then high current will flow
in the glucose sensor. If the glucose concentration
in the bloodstream is low, then small current will flow
in the glucose sensor. Very straightforward. But the problem is that
the glucose oxidase on the enzyme, also a very important factor
in glucose sensing, will be affected
by environmental factors such as sweat pH, temperature,
and even humidity. Therefore, to enhance accuracy,
we need a very good glucose sensor as well as a humidity sensor, a pH sensor
and a temperature sensor, hopefully as a form of
an integrated system. The third challenge is in deformability. We need to collect sweat efficiently
and also analyze sweat accurately to estimate the glucose concentration
without an error on soft skin. So, the ideal form of the device
is like a patch. It’s a patch-like device,
can be attached to the skin, efficiently collect sweat,
analyze sweat accurately. That means that we need
novel device technology such as flexible and stretchable
device technology. The last challenge is in fast
but painless drug delivery. We need to deliver drug
to control high glucose concentration, but that should be fast and painless. We want to deliver drug rapidly because blood glucose concentration
can be changed very rapidly, within an hour. It can be increased a lot
or decreased a lot. An insulin shot is a very good method
to deliver insulin rapidly, but it is painful. Instead we may use a transdermal
drug delivery patch. It is painless. However, it is slow. So to solve this issue, we chose
a transdermal drug delivery system integrated with microneedles. And to solve these challenges
and to achieve these goals, we developed a new
integrated patch system. We could achieve high sensitivity
by using nanoparticles. Each nanoparticle has a tiny size; however, if we combine
all surface areas of nanoparticles, then the entire surface area
will be massive, which will maximize the sensitivity
of the glucose sensor. For devolved sensors,
we used graphene. Graphene is ultra thin,
highly conductive, soft, and even stretchy. We can easily make graphene
into various kinds of sensors in an array form, and the integrated sensor array
based on graphene, after attached [to] the skin,
it maintains very good performance, even under wrinkled state. To enhance accuracy, we used
multiple different kinds of sensors. We used, of course, a glucosensor
as well as a pH sensor, a temperature sensor, humidity sensor,
even strain gauge to maximize the accuracy. After figuring out the exact
glucose concentration, we need to control
the high glucose concentration by delivering an appropriate
amount of drug painlessly and rapidly. And to achieve that goal,
we used microneedles, and to control the drug delivery
through microneedles, we used an ultra thin heater
underneath the microneedle patch. The patch system is connected
to a portable electrochemical analyzer, which has an LCD touch interface,
it supplies power to the patch, also it collects data
and wirelessly transfers the data to the user’s smartphone. When the patch is laminated on the skin,
sweat will be generated. At first, there is a warm-up period. At some point, the sweat
begins to be generated and the humidity sensor monitors
the sweat generation process, and when the relative humidity
inside the patch reaches 80%, we begin the measurement
by using other sensors. We measure glucose as well as pH
and temperature simultaneously. It’s because glucose oxidase, an enzyme, can be affected by environmental factors
like sweat pH and temperature. For example, these two graphs show
calibration curves of glucose sensors. As I mentioned, the glucose sensor
is measuring current, so by measuring current
we can estimate glucose concentration. The problem is that
the calibration curve can be changed depending on the sweat pH and temperature. So, only when we measure glucose simultaneously with sweat pH
and temperature, we can enhance the accuracy
of the glucose measurement. We applied this patch system
to a human subject. We monitored glucose concentration change
over a day, from 8 am to 10 pm. In this graph, there are three data sets. The blue data set corresponds
to blood glucose concentration measured by a commercial glucose meter. There are two red data sets which correspond to sweat
glucose concentrations, one measured by
our glucose diabetes patch, the other measured
by commercial glucose assay. And as you can see, these two sweat glucose
concentrations match very well, and more importantly, the changing trend
of blood glucose concentration matches very well with the changing trend
of sweat glucose concentration. For example, after a meal, after breakfast,
after lunch, after dinner, the glucose concentration
rapidly increases as time goes [by], the glucose
concentration slowly decreases. And more recently, we developed a disposable-type,
sweat-based glucose sensing strip. The advantage of this design is that
we can miniaturize the sensor size, which means, we can minimize
the required amount of sweat, which will shorten
the sweat generation time, and will accelerate the overall
measurement process. This movie shows how the wearable patch
and disposable strip work for sweat-based glucose sensing. The patch can be attached on the skin. Typically, we add additional
encapsulation film to prevent unwanted evaporation
of generated sweat. We typically use exercise
to generate the sweat such as cycling, jogging or running. And the humidity sensor monitors
the sweat generation process, and in case of the disposable strip
there is a microfluidic channel, which can uptake the generated sweat
through the microfluidic channel, and miniaturized sensors
will analyze the sweat to estimate glucose concentration,
as well as pH and temperature. After finding out the accurate
glucose concentration, we can control the high
glucose concentration by delivering drugs
and we used microneedles. A microneedle is a kind of needle. So the drug injection
period is very fast. But the scale, the size of a needle
is in a microscale. The height is 700 microns.
The width is only 150 microns. So even after it is attached
to the skin, it is painless. The microneedle is made of
a biodegradable polymer mixed with drugs. So when the microneedles
make contact with biofluids such as interstitial fluids in the skin, then the micro needles
will be dissolved away and the drugs mixed in the microneedle
will be injected into the bloodstream. But to control this drug delivery, we intentionally coated the surface
of the microneedle with a hydrophobic protective
coating layer. So in normal conditions
the needle will not be desorbed; however, if we turn on the heater
underneath the microneedles, because of the thermal actuation
the hydrophobic coating layer can be melted away. Then, the microneedles will be exposed
to the interstitial fluid. When the microneedles have contacted
the interstitial fluid in the skin, then the needles will be dissolved, and the drugs contained
in the microneedles will be rapidly injected
into the bloodstream. We tested this transdermal patch
by using a diabetic mouse. We first shaved the fur, and then attached
the microneedle patch on the belly. When we observed
the skin surface of the belly, we could could observe quite good
pores, micropores, of course, made by the microneedles, and when we turned on
the thermal actuator, because of the thermal actuation, the protective coating layer
could be melted away, then the microneedles will make contact
with interstitial fluid inside the skin, so the needles will be desorbed, and the drugs contained in the needles will be rapidly injected
into the bloodstream. So we could successfully decrease
the blood glucose concentration. So in conclusion, we wanted to help
diabetes patients. Therefore, we developed a painless,
stress-free and autonomic closed-loop glucose management system
by using our wearable device technology. Thank you for your attention. (Applause)

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