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Fig. 20.1 Schematic example of a classic device for ultrasound therapy
A. Scalise et al.
• A source of high-frequency current, which is
conveyed by a coaxial cable to a transducer
circuit.
• A transducer circuit, in which the highfrequency current is applied to a quartz crystal
via a linked electrode.
• A metal front plate that represents the treatment head, which is fused to the quartz
crystal.
Different shapes of the crystal quartz produce
different effects.
Ultrasound consists of inaudible high-
frequency mechanical vibrations created when a
generator produces electrical energy that is converted to acoustic energy through mechanical
deformation of a piezoelectric crystal located
within the transducer [1]. Frequencies that are
audible to the human ear range from 20 Hz to
20 kHz, and ultrasound uses frequencies above
20kHz and up to several gigahertz. Ultrasounds
that are delivered in the therapeutical eld have
frequencies ranging from 0.75 MHz to 3 MHz,
and most machines are set at a frequency of 1 or
either 3MHz [1].
The most important parameters for ultrasound
waves are summarized in Table20.1.
These parameters are related in the following
mathematical equation: V = F × l, where
V=velocity, F=frequency, and l=wavelength.
Table 20.1 Ultrasound parameters
Frequency–F The number of times a particle
experiences a complete
compression/rarefaction cycle in
1s. Typically, 1 or 3MHz
Wavelength–l The distance between two equivalent
points on the waveform in a
particular medium. In an “average
tissue,” the wavelength 1MHz would
be 1.5mm and 3MHz would be
0.5mm
Velocity– V The velocity at which the wave
(disturbance) travels through the
medium. In saline solution, the
velocity of US is approximately
1500m/s compared to 350m/s in the
air (sound waves can travel more
rapidly in a denser medium). The
velocity of US in most tissues is
thought to be similar to that in saline
solution
Anyway, these three variables are not constant
for all types of tissues.
Other important parameters that need to be taken
into consideration for therapeutic purposes are:
• Power/intensity (W/cm2).
• Duty cycle that can be pulsed or continuous.
• Treatment duration.
As previously mentioned, frequency plays a key
role when taking ultrasound into account. Highfrequency ultrasounds have shorter wavelengths
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Fig. 20.2 Illustration of the fundamental difference between pulse and continuous ultrasound waveforms
185
and are absorbed more easily. Therefore, they are
not as penetrating and are used on supercial body
structures and for Doppler vascular assessment.
HIFU is transmitted at a frequency ranging from 20
to 120 kHz. On the other hand, low-frequency
ultrasound penetrates deeper and is used to treat
open wounds; it is generally transmitted at frequencies ranging from 1 to 3MHz and can be administered directly, by application of the applicator head
to the skin, usually with a coupling agent, or indirectly, where the affected area is placed in a constant temperature water bath and the ultrasound
administered through the water. Directly applied
ultrasound is usually applied on the periwound skin
rather than on the wound directly.
Low-intensity ultrasound can be further subdivided into pulsed (LIPUS) and continuous (LICUS)
depending on the duty cycle. Pulsed ultrasound
consists of on/off cycles of ultrasound waves, while
continuous ultrasound consists of continuous
acoustic waves with no on/off cycles (Fig. 20.2).
While many studies regarding the effectiveness of
LIPUS have been conducted, studies regarding
LICUS have produced conicting data, so further
studies are required to fully understand the potential benets of LICUS.Low- intensity pulsed ultrasound (LIPUS) on the other hand has been
demonstrated to be a non-invasive physical stimulus for therapeutical applications [2]. LIPUS has
minimal thermal effects due to its low-intensity and
pulsed output mode while maintaining the transmission of acoustic energy to the target tissue [3].
Another important parameter that we have to
take into consideration when speaking about
ultrasound is the property of the tissue on which
the ultrasound is used. Each tissue has its own
impedance, a value obtained by multiplying the
density of the tissue and the speed at which ultrasound can pass through it. Tissue absorption of
ultrasound is higher in tissues with high protein
content (like bones) and low in those with a
higher water content (like fat and blood). For this
reason, the larger the differences in acoustic
impedance between different tissues, the less the
transmission from one to the other [4].
20.3 Mechanism ofAction
When considering the effects produced by therapeutic ultrasound, we primarily have to distinguish between the thermal and non-thermal
effects [1]. When ultrasound travels through tissues, a percentage of it is absorbed, and this leads
to the generation of heat within the tissue [5]. The
effects attributed to this heating include an
increase in blood ow, reduction in muscle
spasm, increased extensibility of collagen bers,
and a pro-inammatory response. In LIPUS,
there is no risk in having heat excess, because its
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A. Scalise et al.
on/off cycles manage to dissipate the heat
between the pulses.
While historically ultrasound has been used
primarily for its professed thermal effects, it is
suggested that the non-thermal mechanisms play
a central role in producing therapeutic effects,
and these are crucial in the wound healing
process.
The two predominant non-thermal effects are:
• Cavitation.
• Microstreaming.
Cavitation is the production and vibration of
micron-sized bubbles within the tissue uids,
which, as the bubbles move and oscillate, can
cause changes in the cellular activities of the targeted tissues.
Microstreaming is described as the localized
mobilization of uids around and along cellular
membranes produced by the displacement of
small ions and molecules.
Together, cavitation and microstreaming
affect cellular activity and are postulated to facilitate wound healing by:
• Reducing inammation.
• Promoting cellular proliferation, stimulation,
and recruitment.
• Increasing collagen synthesis and tensile
strength.
• Promoting angiogenesis, wound contraction,
and brinolysis.
These phenomena are more frequently
observed at lower frequencies. Cavitation is considered responsible for brinolysis and bioburden decrease, producing an effective debridement
of the wound. Multiple in vitro studies have
reported the antimicrobial effects of LFUS. In
addition, some invivo human and animal studies
and clinical studies have demonstrated that LFUS
destroys bacteria’s cell walls and improves healing rates in recalcitrant wounds.
When transmitted at 22.5, 25, or 35kHz, the
removal of necrotic tissue and reduction in bioburden in the wound bed by LIPU is as effective
as surgical and mechanical debridement and is
less painful, making it an optimal debridement
method. In chronic venous ulcers, microcirculation is inhibited during the inammatory phase,
with increased blood ow observed during stasis.
Recent ndings support the role of ultrasound in
stimulating angiogenesis, collagen formation,
and microcirculation during the wound healing
process.
20.4 Therapeutical Eects
ofUltrasound onChronic
Wounds
Promoting the healing of chronic wounds is
very challenging, and this can be achieved by
correctly debriding non-vital tissues, controlling the inammation, balancing moisture, and
stimulating the epithelialization of the wound
edges. Debridement, which represents the
mechanism through which unhealthy tissue and
bacterial biolms are removed, is considered to
be the main key in obtaining chronic wound
healing [6].
Biolms, also known metaphorically as “cities for microbes,” are a three-dimensional structure comprised of a syntrophic consortium of
microorganisms in which cells stick to each other
and often also to a surface. A biolm is found in
more than half of all chronic wounds, and since
they are highly resistant to antimicrobial agents
and phagocytosis, their management is very
problematic. As a result, by inducing prolonged
elevated levels of protease and reactive oxygen
species, biolms trigger a chronic inammatory
response. This inefcient inammatory process
not only hinders healing of damaged tissue but
also increases exudate, which perpetuates the
vicious cycle (Fig.20.3).
Low-frequency ultrasound has been investigated as an adjunctive tool for chronic wound
debridement, in particular to remove devitalized
tissues through microstreaming and cavitational
effects [7]. More specically, ultrasound selectively emulsies dead and dying tissues with
micro-sized gas bubbles, stimulating the mem-
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Fig. 20.3 Chronic wound pathophysiology: chronic inammation is induced by bacterial contamination and
subsequent biolm creation
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branes of surrounding healthy cells, and rendering
bacteria more susceptible to antibiotic treatment [8,
9]. As a result, low-frequency ultrasound is thought
to both debride the wound and promote healing by
upregulating cellular activity, promoting growth
factors and protein synthesis, promoting brinolysis, and disrupting the biolm [10–12].
The effects of ultrasound therapy on difcult
wounds are widely described. Despite the clinical
evidence, the mechanisms of action underlying
wound healing are not fully understood. In addition, up to date there is still no standardization of
the therapy because it varies depending on the
type of ulcer (arterial, venous, diabetic, and pressure sores), location of the wound, and setting of
the device used.
In literature, only a few studies go beyond clinical measures of wound healing, investigating the
underlying biological and molecular mechanisms
produced by ultrasound therapy. Escandon et al.
studied the effects of low-frequency ultrasound on
10 patients presenting venous leg ulcers, treated
with a noncontact device three times a week over a
4-week period [13]. The authors observed a signicant reduction in wound size and in the pain
correlated with the ulcers. Moreover, they reported
decreased values of tumor necrosis factor-α, interleukins 1, 6, 8, and 11, and vascular endothelial
growth factor compared to baseline values. In conclusion, a signicant correlation between reduced
wound size and decreased inammatory cytokine
expression was found.
Samuels etal. also reported increased wound
healing, in particular increased cellular proliferation with ultrasound therapy, invitro [14]. These
authors also observed a reduction in cytokines,
matrix metalloproteinase, growth factors, and
macrophages with the treatment.
When speaking about the effects of lowintensity ultrasound therapy, we have to distinguish between two different devices: a contact
device, which is used in contact with the wound
surface, and a noncontact device.
The therapeutical effects of LIPU on
chronic wounds are described more in detail
as follows:
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• Exudate andSlough
• The effect of ultrasound treatment on wound
exudate and brin slough was noted by several
authors.
• Both the contact system and the noncontact
device were proven to decrease signicantly
the amount of exudate and slough on wound
surfaces, therefore producing an improvement
in the wound conditions [15–17]. With both
techniques, it was also noted a signicant
decrease in erythematous and edematous skin,
undermining, tunneling, and odor and a
decrease in clinical evidence of infection.
• Wound Closure.
• It is proven that ultrasound debridement with
noncontact therapy affects wound size and rate of
closure. In a nonrandomized, baseline-controlled
clinical case series, patients showed signicant
reduction in wound size and a greater rate of closure with ultrasound therapy [18]. Two large
meta-analyses also suggest that ultrasound has a
positive impact on wound size [16, 19]. Also,
Driver et al. [20] suggest an important wound
area reduction over an average period of treatment of 7weeks, with an average time to heal of
9.2weeks. Ennis etal. demonstrated that 69% of
wounds that were taken into account in their
study were healed using ultrasound as a standalone device or in combination with moist wound
care, with signicant reduction in wound volume
and shorter healing time [21].
• Pain.
• Ultrasound therapy, compared to sharp and
mechanical debridement techniques, is considered to be painless [22]. In a study considering 15 patients with ulcers, the treatment
with a noncontact device was found to reduce
patients’ pain [23]. Driver et al. [20] also
found an average reduction of 79% in subjective pain score in patients receiving ultrasound
therapy. In a study by Cole et al., patients
reported a decrease of almost three points on
the subjective pain score following ultrasound
treatment [22].
• Effect onBiolm
• It is well known that biolms in chronic wounds
are important factors limiting the healing.
Ultrasound is thought to disperse biolms
in vitro [24], but techniques to monitor these
effects invivo are limited. In one study that did
assess total viable counts derived from tissue
biopsy, there was no signicant reduction in
bacterial count over the treatment period [13].
However, it is widely recognized that culturebased techniques signicantly underestimate
the bioburden in clinical samples [25]. This is
true in particular for wound swabs that have a
limited role in wound care. We hypothesize that
ultrasound may be having an effect on species
of bacteria not readily cultured under laboratory
conditions. Moreover, dispersal of the biolm
(without affecting bacterial viability) is a recognized therapeutical strategy. Once the biolm is
dispersed, bacteria become more sensitive to
antibiotics and vulnerable to immune
clearance.
20.5 Ultrasound Application
inRelation toDierent
Wound Healing Phases
The process of wound healing is a complex series
of chemically mediated events that lead to the
production of scar tissue, which is constituted by
an effective material to restore the continuity of
the damaged tissue. The entire process can be
divided into different phases each one with a different duration:
• Inammatory phase (2–4days).
• Proliferative phase (10–20).
• Maturation or remodeling phase (3–12months).
The application of ultrasound produces different effects in relation to the different phases of
the wound healing process.
20.5.1 Inammatory Phase
After the initial clotting response begins, the
acute inammatory response. In this phase, there
is vasodilation and invasion of white blood cells
to the affected area. When applied during the
inammatory phase, US has a stimulating effect
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189
on mast cells, platelets, white cells with phagocytic roles, and macrophages [5, 26–28]. It is
well known that the application of ultrasound
induces the degranulation of mast cells, causing
the release of arachidonic acid, which is a precursor for the synthesis of prostaglandins and leukotrienes, which act as inammatory mediators
[29–31]. this means that the overall role of ultrasound in this phase is pro-inammatory rather
than anti- inammatory. The benet of this mode
of action is not to “increase” the inammatory
response itself (though it could be a possible outcome if applied with too great intensity during
this stage) [32], but rather to act as an inammatory optimizer [5].
In order to have an effective tissue repair, it is
essential to have an efcient inammatory
response, and the more efciently the process can
complete, the more effectively the tissue can
progress to the next phase. US is effective at promoting the normality of the inammatory events
and as such has a therapeutic value in promoting
the overall repair events [5, 27]. Another important fact is that the inammatory chemically
mediated events are associated with stimulation
of the proliferative phase, and hence, the promotion of the inammatory phase also acts as a promoter of the proliferative phase.
Applied correctly, with appropriate treatment
dose and optimal treatment parameters (intensity,
pulsing, and time), the benet of US is to generate an efcient and fast repair phase and has a
promotional effect on the whole healing cascade.
For tissues in which there is an inammatory
reaction, but in which there is no repair to be
achieved, the benet of ultrasound is to promote
the normal resolution of the inammatory events.
20.5.2 Proliferative Phase
The proliferative phase represents the phase in
which the scar is produced. Also, during this
phase, US has a stimulative effect, in particular on
broblasts, endothelial cells, and myobroblasts
[5, 28–30, 33–35]. These cells are normally active
during scar production; therefore, US is pro-proliferative in the same way that it is pro- inammatory:
It does not change the normal proliferative phase,
but maximizes its efciency. Harvey et al. [36]
among several other research groups have demonstrated that low-dose pulsed ultrasound increases
protein synthesis and collagen synthesis and
enhances broplasia [37, 38]. It is thought that
ultrasound may cause an early development of
myobroblasts and this causes an accelerated process of wound contraction. When applied within
72h following an injury low- intensity ultrasound
can promote wound contraction, which should
result in a smaller scar. Moreover, the application
of ultrasound to the periwound area stimulates the
release of growth factors needed to regenerate epithelial cells, further protecting the body from
infection and reinstating skin integrity.
20.5.3 Maturation or Remodeling
The response to ultrasound in this stage is dependent on if therapy was initiated in the inammatory phase. Application of thermal ultrasound
during this phase affects the collagen extensibility and enzyme activity and therefore also
improves tensile strength of the healing tissue.
During the remodeling phase of repair, the
scar produced in the initial stages is rened such
that it adopts functional characteristics of the tissue that it is repairing. This is achieved by a number of processes, but mainly related to the
orientation of the collagen bers in the developing scar and also to the change in collagen type,
from predominantly type III collagen to a more
dominant type I collagen. The remodeling process is an essential component of quality repair,
and researchers have demonstrated that it can last
for a year or more [30].
The application of therapeutic ultrasound can
inuence the remodeling of the scar tissue in that
it appears to be capable of enhancing the appropriate orientation of the newly formed collagen
bers and also to the collagen prole change
from mainly type III to a more dominant type I
construction, thus increasing tensile strength and
enhancing scar mobility [30]. Ultrasound applied
to tissues enhances the functional capacity of the
scar tissues [30, 39].
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20.6 Treatment Protocols
Although ultrasounds are widely used in the
treatment of difcult wounds, there are currently
no standard protocols, and the scientic community is divided on this issue. It is generally the
clinician who customizes the program to be used
based on various parameters. Among those is
necessary to take into consideration the type of
lesions, the extension of the target area (which
could be larger than the wound), the depth of the
lesion, the level of contamination, and the sensibility of the patient (Figs.20.4 and 20.5).
In general, there are parameters and references that are used as a guide to create a treatment program that will later be modied
according to the patients’ needs (e.g., suggested
frequencies for dermal wounds are 3Mhz, while
those for deep lacerations or periwound skin are
1Mhz).
Another aspect to consider is the contraindica-
tions and precautions that must be taken:
• Contraindicated over eyes, genital areas,
abdominal area, and exposed neural tissue.
• Should be avoided in cases of thromboembolic diseases.
• Avoided in patients with pacemakers.
• Precautions should be taken with sensory
impairments.
• Ultrasound should be terminated if there is
increased pain.
The following Table 20.2 summarizes the
parameters recommended for the various ultrasound applications.
Fig. 20.4 Pre- and post-treatment with LIPU of a chronic wound of the leg. The slough covering the bottom of the
wound has been cleared away and the wound bed appears adequately bloodied after treatment
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Fig. 20.5 Pre- and
post-treatment with
LIPU of a chronic
wound at the level of the
posterior lodge of the
leg
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Table 20.2 Ultrasound applications and relative parameters recommended
Duration of the
Target area Frequency/mode
Periwound
tissue
Wound
tissue
Chronic
wounds
• 1MHz, continuous mode with intensity at
1–1.5W/cm squared
• The ultrasound head should be 1.5 or two times
the size of the area to be treated. Aqueous
medium is applied to the transducer and is
moved in a slow circular motion around the
treated area
• 20% duty cycle, 3MHz with intensity at
0.3–0.5W/cm squared;
• The ultrasound head should be 1.5 or 2 times
the size of the treated area. If the area is large,
treatment can be completed in sections with
1–2min per zone. Ultrasound medium is applied
to the transducer and in contact with the
hydrogel sheet
• 1Mhz, 0.5W/cm squared at 20% duty cycle
applied to periwound area
• The ultrasound head should be 1.5 or 2 times
the size of the area to be treated. Aqueous
medium is applied to the transducer and is
moved in a slow circular motion around the
treated area
treatment/times a week Purpose
• 2–3min complete
per zone
• 3 times per week
• Acute wounds can be
treated 1–2 times per
day and then
continued 2–3 times
per week
• 2–3min completes
per zone
• Three times per
week
To produce a thermal
effect for vasodilation
and increased tissue
oxygen levels
To stimulate protein
synthesis and increase
cell proliferation
To restart inammatory
phase
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