Nearly pain-free microneedle patch can test for antibodies and more in the fluid between cells
Washington University in St. Louis
They
hurt. Veins can burst, or even roll -- like they're trying to avoid the needle,
too.
Oftentimes,
doctors use blood samples to check for biomarkers of disease: antibodies that
signal a viral or bacterial infection, such as SARS-CoV-2, the virus responsible
for COVID-19; or cytokines indicative of inflammation seen in conditions such
as rheumatoid arthritis and sepsis.
These
biomarkers aren't just in blood, though. They can also be found in the dense
liquid medium that surrounds our cells, but in a low abundance that makes it
difficult to be detected.
Until
now.
Engineers at the McKelvey School of Engineering at Washington University in St. Louis have developed a microneedle patch that can be applied to the skin, capture a biomarker of interest and, thanks to its unprecedented sensitivity, allow clinicians to detect its presence.
The
technology is low cost, easy for a clinician or patients themselves to use, and
could eliminate the need for a trip to the hospital just for a blood draw.
The
research, from the lab of Srikanth Singamaneni, the Lilyan & E. Lisle
Hughes Professor in the Department of Mechanical Engineering & Material
Sciences, was published online Jan. 22 in the journal Nature Biomedical
Engineering.
In
addition to the low cost and ease of use, these microneedle patches have
another advantage over blood draws, perhaps the most important feature for
some: "They are entirely pain-free," Singamaneni said.
Finding
a biomarker using these microneedle patches is similar to blood testing. But
instead of using a solution to find and quantify the biomarker in blood, the
microneedles directly capture it from the liquid that surrounds our cells in
skin, which is called dermal interstitial fluid (ISF). Once the biomarkers have
been captured, they're detected in the same way -- using fluorescence to
indicate their presence and quantity.
ISF
is a rich source of biomolecules, densely packed with everything from
neurotransmitters to cellular waste. However, to analyze biomarkers in ISF,
conventional method generally requires extraction of ISF from skin. This method
is difficult and usually the amount of ISF that can be obtained is not
sufficient for analysis. That has been a major hurdle for developing
microneedle-based biosensing technology.
Another method involves direct capture of the biomarker in ISF without having to extract ISF. Like showing up to a packed concert and trying to make your way up front, the biomarker has to maneuver through a crowded, dynamic soup of ISF before reaching the microneedle in the skin tissue.
Under such conditions,
being able to capture enough of the biomarker to see using the traditional
assay isn't easy.
But
the team has a secret weapon of sorts: "plasmonic-fluors," an
ultrabright fluorescence nanolabel. Compared with traditional fluorescent
labels, when an assay was done on microneedle patch using plasmonic-fluor, the
signal of target protein biomarkers shined about 1,400 times as bright and
become detectable even when they are present at low concentrations.
"Previously,
concentrations of a biomarker had to be on the order of a few micrograms per
milliliter of fluid," Zheyu (Ryan) Wang, a graduate student in the
Singamaneni lab and one of the lead authors of the paper, said. That's far
beyond the real-world physiological range. But using plasmonic-fluor, the
research team was able to detect biomarkers on the order of picograms per
milliliter.
"That's
orders of magnitude more sensitive," Ryan said.
These
patches have a host of qualities that can make a real impact on medicine,
patient care and research.
They
would allow providers to monitor biomarkers over time, particularly important
when it comes to understanding how immunity plays out in new diseases.
For
example, researchers working on COVID-19 vaccines need to know if people are producing
the right antibodies and for how long. "Let's put a patch on,"
Singamaneni said, "and let's see whether the person has antibodies against
COVID-19 and at what level."
Or, in an emergency, "When someone complains of chest pain and they are being taken to the hospital in an ambulance, we're hoping right then and there, the patch can be applied," Jingyi Luan, a student who recently graduated from the Singamaneni lab and one of the lead authors of the paper, said.
Instead of
having to get to the hospital and have blood drawn, EMTs could use a
microneedle patch to test for troponin, the biomarker that indicates myocardial
infarction.
For
people with chronic conditions that require regular monitoring, microneedle
patches could eliminate unnecessary trips to the hospital, saving money, time
and discomfort -- a lot of discomfort.
The
patches are almost pain-free. "They go about 400 microns deep into the
dermal tissue," Singamaneni said. "They don't even touch sensory
nerves."
In
the lab, using this technology could limit the number of animals needed for
research. Sometimes research necessitates a lot of measurements in succession
to capture the ebb and flow of biomarkers -- for example, to monitor the
progression of sepsis. Sometimes, that means lot of small animals.
"We
could significantly lower the number of animals required for such
studies," Singamaneni said.
The
implications are vast -- and Singamaneni's lab wants to make sure they are all
explored.
There
is a lot of work to do, he said: "We'll have to determine clinical
cutoffs," that is, the range of biomarker in ISF that corresponds to a
normal vs. abnormal level. "We'll have to determine what levels of
biomarker are normal, what levels are pathological." And his research
group is working on delivery methods for long distances and harsh conditions,
providing options for improving rural healthcare.
"But
we don't have to do all of this ourselves," Singamaneni said. Instead, the
technology will be available to experts in different areas of medicine.
"We
have created a platform technology that anyone can use," he said.
"And they can use it to find their own biomarker of interest."
We
don't have to do all of this ourselves
Singamaneni
and Erica L. Scheller, assistant professor of Medicine in the Division of Bone
and Mineral Disease at the School of Medicine, worked together to investigate
the concentration of biomarkers in local tissues.
Current
approaches for such evaluation require the isolation of local tissues and do
not allow successive and continuous inspection. Singamaneni and Scheller are
developing a better platform to achieve long term monitoring of local biomarker
concentration.
Working
together
Srikanth
Singamaneni, the Lilyan E. Lisle Hughes Professor in the Department of
Mechanical Engineering & Materials Science, and Jai S. Rudra, assistant
professor in the Department of Biomedical Engineering, worked together to look
at cocaine vaccines, which work by blocking cocaine's ability to enter the
brain.
Current
candidates for such a vaccine don't confer long-lasting results; they require
frequent boosting. Singamaneni and Rudra wanted a better way to determine when
the effects of the vaccine had waned. "We've shown that we can use the
patches to understand whether a person is still producing the necessary
antibodies," Singamaneni said. "No blood draw necessary."
