NIH-funded study finds new technique could
significantly accelerate tissue repair, reduce costs
for chronic wound management.
In a small clinical study, researchers administered
a new method for treating chronic wounds using a
novel ultrasound applicator that can be worn like a
band-aid. The applicator delivers low-frequency,
low-intensity ultrasound directly to wounds, and was
found to significantly accelerate healing in five
patients with venous ulcers. Venous ulcers are
caused when valves in the veins malfunction, causing
blood to pool in the leg instead of returning to the
heart. This pooling, called venous stasis, can cause
proteins and cells in the vein to leak into the
surrounding tissue leading to inflammation and
formation of an ulcer.
The technology was developed by researchers at
Drexel University, Philadelphia, with funding from
the National Institute of Biomedical Imaging and
Bioengineering (NIBIB), part of the National
Institutes of Health.
Venous ulcers account for 80 percent of all chronic
wounds found on lower extremities and affect
approximately 500,000 U.S. patients annually, a
number that’s expected to increase as obesity rates
climb. It’s estimated that treatment for venous
ulcers costs the U.S. healthcare system over $1
billion dollars per year.
Standard treatment for venous ulcers involves
controlling swelling, taking care of the wound by
keeping it moist, preventing infection, and
compression therapy — a technique in which patients
wear elastic socks that squeeze the leg to prevent
blood from flowing backwards. Despite these measures,
wounds often take months and occasionally years to
heal.
“Right now, we rely mostly on passive treatments,”
said Michael Weingarten, M.D., chief of vascular
surgery at Drexel Medicine and a researcher in the
study. “With the exception of expensive skin
grafting surgeries, there are very few technologies
that actively stimulate healing of these ulcers.”
In an article to be published in the Journal of the
Acoustical Society of America, the Drexel
researchers report that patients who received
low-frequency, low-intensity ultrasound treatment
during their weekly check-up (in addition to
standard compression therapy), showed a net
reduction in wound size after just four weeks (Fig.
3a,3b). In contrast, patients who didn’t receive
ultrasound treatment had an average increase in
wound size during the same time period (Fig. 2a,2b).
“There have been studies on the therapeutic benefits
of ultrasound for wound healing, but most of the
previous research was performed at much higher
frequencies, around 1-3 megahertz (MHz),” said Peter
A. Lewin, Ph.D., Richard B. Beard Professor of
Biomedical Engineering at Drexel, and the primary
investigator on this project. “We had an idea that
if we went down to the range of 20 to 100 kilohertz
(kHz), which is at least an order of magnitude lower,
we might see more profound changes; that’s exactly
what happened.”
In order to determine the optimal ultrasound
frequency as well as treatment duration, the
researchers treated patients with either 15 minutes
of 20 kHz ultrasound, 45 minutes of 20 kHz
ultrasound, 15 minutes of 100 kHz ultrasound, or 15
minutes of a sham (placebo) ultrasound.
The group receiving 15 minutes of 20 kHz ultrasound
showed the greatest improvement, with all five
patients experiencing complete healing by the fourth
treatment.
“We were surprised that the group receiving 45
minutes of treatment didn’t achieve the same
benefits as the 15 minute group, but sometimes we
learn that more is not always better,” said Joshua
Samuels, a Ph.D. candidate and lead author of the
study. “There may be a dosing effect.”
The team’s clinical findings were corroborated by
their in vitro studies in which mouse fibroblasts —
cells that play an active role in wound healing —
experienced on average a 32 percent increase in cell
metabolism and a 40 percent increase in cell
proliferation compared with control cells 24 hours
after receiving 20 kHz ultrasound for 15 minutes.
Lewin and colleagues said one of the greatest
challenges of the study was designing and creating
their battery-powered ultrasound patch.
“Most ultrasound transducers require a large
apparatus and need to be plugged into the wall. We
wanted this to be fully wearable as well as portable,
so we needed to make it battery-powered. To achieve
that, we had had to design a transducer that could
produce medically relevant energy levels using
minimum voltage,” said Lewin.
Their resulting ultrasound patch weighs just 100
grams — the equivalent of a king sized candy bar —
and is connected to two lithium ion batteries which
are fully rechargeable. Lewin says the design gives
patients the option of using the transducer in a
home environment, while still wearing their
compression socks. It also prevents the need for a
doctor’s visit, which can be a difficult task for
patients with chronic wounds.
“The wound healing technology described in this
study is a particularly exciting ultrasound therapy
application that holds great promise for future
treatment of chronic wound patients,” said Hector
Lopez, Ph.D., NIBIB program director for Diagnostic
and Therapeutic Ultrasound. “This is an excellent
example of how NIBIB brings together the physical
and life sciences to produce new technology that
improves health.”
Lopez concluded by saying that before the new
treatment would make it to a clinic, studies with
larger numbers of patients are needed to confirm
that the technology is both effective and safe to
use.
In the future, Lewin and Weingarten anticipate that
patients with other types of chronic wounds such as
diabetic or pressure ulcers may also benefit from
therapeutic ultrasound. Because the ideal treatment
frequency, duration, and intensity may be unique for
each type of wound, Lewin and his colleagues have
developed and are currently testing a diagnostic
monitoring component of their ultrasound patch,
which would help physicians optimize treatment for
each patient.
This monitoring component — developed with the help
of Leonid Zubkov, D.Sc. of The School of Biomedical
Engineering, Science and Health Systems, Drexel —
uses near infrared spectroscopy (NIRS) to
non-invasively assess changes in the wound bed that
can reveal whether a treatment is working in its
earliest stages, when healing is difficult to detect
with the naked eye.
“By monitoring subtle changes in tissue response as
we deliver the ultrasound and immediately after, we
can optimize the treatment for each patient,” said
Lewin. “Our goal is to develop a device that can be
used on many different types of wounds for as long
as needed without causing side effects. Once we have
this universal applicator, we can use the near
infrared spectroscopy to help customize the
treatment to individual patients.”
A trial to test the NIRS component involving twenty
patients is currently under way.
The team is also hoping to learn more about why low
frequency ultrasound promotes healing by expanding
their in vitro studies. They are currently examining
the effects of low-frequency ultrasound on
macrophages — immune cells that play a critical role
in wound healing — and on collagen production.
“In wound healing, there is the inflammation phase,
the proliferation phase, and the remodeling phase.
We’re looking at the primary cell participants at
each phase and examining the effects of ultrasound
on each of these individually and then collectively,”
said Samuels.
A major contributor to this study was Dr. Elisabeth
Papazoglou of the School of Biomedical Engineering,
Drexel, who recently passed away.
For more information
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