Low frequency ultrasound accelerates healing of venous ulcers
5 August 2013
Researchers at Drexel University have developed a small
electronic patch that delivers low-frequency, low-intensity
ultrasound to wounds to stimulate healing.
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. In
contrast, patients who didn’t receive ultrasound treatment had an
average increase in wound size during the same time period.
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.
An ultrasound patch that delivers
ultrasound directly to wounds
Venous ulcers account for 80% of all chronic wounds found on
lower extremities and affect approximately 500,000 US patients
annually, a number that’s expected to increase as obesity rates
climb. It’s estimated that treatment for venous ulcers costs the US
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 Dr
Michael Weingarten, 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.”
“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 Dr Peter A Lewin, 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.
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% increase in cell
metabolism and a 40% increase in cell proliferation compared with
control cells 24 hours after receiving 20 kHz ultrasound for 15
Lewin and colleagues said one of the greatest challenges of the
study was designing and creating their battery-powered ultrasound
“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. 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
“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, PhD, 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.”
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,”
A major contributor to this study was Dr. Elisabeth Papazoglou of
the School of Biomedical Engineering, Drexel, who recently passed