<s>
Sonophoresis	B-Algorithm
is	O
a	O
method	O
that	O
utilizes	O
ultrasound	B-Application
to	O
enhance	O
the	O
delivery	O
of	O
topical	O
medications	O
through	O
the	O
stratum	O
corneum	O
,	O
to	O
the	O
epidermis	O
and	O
dermis	B-Algorithm
.	O
</s>
<s>
Sonophoresis	B-Algorithm
allows	O
for	O
the	O
enhancement	O
of	O
the	O
permeability	O
of	O
the	O
skin	O
along	O
with	O
other	O
modalities	O
,	O
such	O
as	O
iontophoresis	O
,	O
to	O
deliver	O
drugs	O
with	O
lesser	O
side	O
effects	O
.	O
</s>
<s>
Currently	O
,	O
sonophoresis	B-Algorithm
is	O
used	O
widely	O
in	O
transdermal	O
drug	O
delivery	O
,	O
but	O
has	O
potential	O
applications	O
in	O
other	O
sectors	O
of	O
drug	O
delivery	O
,	O
such	O
as	O
the	O
delivery	O
of	O
drugs	O
to	O
the	O
eye	O
and	O
brain	O
.	O
</s>
<s>
Sonophoresis	B-Algorithm
,	O
also	O
known	O
as	O
phonophoresis	O
,	O
was	O
dated	O
back	O
all	O
the	O
way	O
to	O
the	O
1950s	O
in	O
its	O
first	O
mention	O
in	O
a	O
published	O
report	O
.	O
</s>
<s>
This	O
report	O
showcased	O
that	O
a	O
hydrocodone	O
injection	O
yielded	O
better	O
outcomes	O
for	O
bursitis	O
when	O
combined	O
with	O
an	O
ultrasound	B-Application
massage	O
.	O
</s>
<s>
Following	O
this	O
,	O
a	O
series	O
of	O
publications	O
from	O
several	O
investigators	O
showed	O
the	O
increased	O
therapeutic	O
effect	O
when	O
combining	O
ultrasound	B-Application
with	O
hydrocortisone	O
injections	O
for	O
various	O
other	O
disease	O
states	O
,	O
further	O
demonstrating	O
the	O
novelty	O
of	O
sonophoresis	B-Algorithm
.	O
</s>
<s>
However	O
,	O
while	O
some	O
researchers	O
provided	O
evidence	O
that	O
ultrasound	B-Application
had	O
a	O
positive	O
effect	O
on	O
the	O
transdermal	O
permeation	O
of	O
drugs	O
,	O
others	O
contradicted	O
this	O
information	O
by	O
displaying	O
research	O
that	O
showed	O
no	O
quantitative	O
effect	O
using	O
ultrasound	B-Application
.	O
</s>
<s>
These	O
early	O
studies	O
mainly	O
investigated	O
the	O
combination	O
of	O
therapeutics	O
with	O
high-frequency	O
sonophoresis	B-Algorithm
(	O
HFS	O
)	O
,	O
which	O
can	O
be	O
categorized	O
into	O
frequencies	O
greater	O
than	O
0.7MHz	O
.	O
</s>
<s>
High	O
frequency	O
sonophoresis	B-Algorithm
usually	O
includes	O
a	O
range	O
between	O
0.7	O
–	O
16MHz	O
.	O
</s>
<s>
Cavitational	O
effects	O
are	O
inversely	O
proportional	O
to	O
the	O
frequency	O
of	O
the	O
ultrasound	B-Application
applied	O
,	O
which	O
led	O
to	O
further	O
studies	O
of	O
low-frequency	O
sonophoresis	B-Algorithm
(	O
LFS	O
)	O
for	O
use	O
in	O
transdermal	O
drug	O
delivery	O
due	O
to	O
studies	O
showing	O
greater	O
efficacy	O
in	O
enhancing	O
skin	O
permeability	O
in	O
comparison	O
to	O
HFS	O
.	O
</s>
<s>
Low-frequency	O
sonophoresis	B-Algorithm
usually	O
includes	O
a	O
range	O
between	O
20	O
and	O
100kHz	O
.	O
</s>
<s>
Ultrasonic	O
sonicators	O
generate	O
ultrasound	B-Application
waves	O
,	O
which	O
is	O
a	O
longitudinal	O
compression	O
wave	O
,	O
by	O
converting	O
electrical	O
energy	O
into	O
mechanical	O
energy	O
by	O
deformation	O
of	O
piezoelectric	O
crystals	O
in	O
response	O
to	O
an	O
electric	O
field	O
.	O
</s>
<s>
The	O
ultrasound	B-Application
waves	O
generated	O
from	O
this	O
device	O
allow	O
for	O
penetration	O
through	O
biological	O
tissue	O
by	O
molecular	O
oscillation	O
of	O
the	O
biological	O
tissue	O
they	O
travel	O
through	O
.	O
</s>
<s>
The	O
amplitude	O
of	O
the	O
wave	O
can	O
be	O
modified	O
by	O
manipulating	O
the	O
displacement	O
of	O
the	O
ultrasound	B-Application
horn	O
for	O
each	O
half	O
cycle	O
as	O
they	O
are	O
proportional	O
.	O
</s>
<s>
While	O
increased	O
skin	O
permeability	O
is	O
seen	O
through	O
sonophoresis	B-Algorithm
,	O
the	O
precise	O
mechanisms	O
to	O
describe	O
sonophoresis	B-Algorithm
are	O
yet	O
to	O
be	O
fully	O
discovered	O
.	O
</s>
<s>
However	O
,	O
there	O
are	O
several	O
important	O
mechanisms	O
that	O
have	O
been	O
identified	O
that	O
contribute	O
to	O
the	O
phenomenon	O
of	O
sonophoresis	B-Algorithm
.	O
</s>
<s>
Cavitation	O
is	O
generally	O
determined	O
to	O
be	O
the	O
dominant	O
mechanism	O
that	O
drives	O
sonophoresis	B-Algorithm
.	O
</s>
<s>
The	O
frequency	O
of	O
the	O
ultrasound	B-Application
waves	O
helps	O
determine	O
the	O
bubble	O
parameters	O
,	O
such	O
as	O
size	O
and	O
shape	O
.	O
</s>
<s>
However	O
,	O
while	O
cavitation	O
is	O
considered	O
the	O
primary	O
mechanism	O
for	O
sonophoresis	B-Algorithm
,	O
the	O
gas	O
bubbles	O
that	O
contribute	O
to	O
cavitation	O
are	O
generated	O
by	O
a	O
process	O
termed	O
rectified	O
diffusion	O
.	O
</s>
<s>
An	O
important	O
consideration	O
when	O
transferring	O
energy	O
to	O
a	O
patient	O
would	O
be	O
the	O
thermal	O
energy	O
generated	O
from	O
heating	O
of	O
the	O
biological	O
tissue	O
due	O
to	O
energy	O
losses	O
from	O
the	O
ultrasound	B-Application
waves	O
.	O
</s>
<s>
The	O
enhanced	O
circulation	O
of	O
blood	O
that	O
comes	O
as	O
a	O
result	O
of	O
increased	O
temperature	O
from	O
ultrasound	B-Application
parameters	O
also	O
allows	O
for	O
better	O
diffusion	O
of	O
compounds	O
.	O
</s>
<s>
While	O
the	O
intensity	O
and	O
duty	O
cycle	O
of	O
the	O
ultrasound	B-Application
are	O
directly	O
proportional	O
to	O
the	O
corresponding	O
thermal	O
effects	O
,	O
surprisingly	O
thermal	O
effects	O
are	O
not	O
a	O
considerable	O
mechanism	O
for	O
HFS	O
in	O
ranges	O
from	O
1	O
–	O
2	O
degrees	O
Celsius	O
.	O
</s>
<s>
While	O
sonophoresis	B-Algorithm
alone	O
is	O
able	O
to	O
increase	O
the	O
permeability	O
of	O
skin	O
by	O
several	O
factors	O
depending	O
on	O
the	O
procedure	O
and	O
the	O
drug	O
being	O
delivered	O
,	O
a	O
synergistic	O
combination	O
of	O
sonophoresis	B-Algorithm
with	O
other	O
enhancers	O
,	O
such	O
as	O
iontophoresis	O
and	O
electroporation	O
,	O
has	O
shown	O
greater	O
enhancement	O
as	O
well	O
as	O
increased	O
safety	O
in	O
reduction	O
of	O
individual	O
enhancer	O
parameters	O
.	O
</s>
<s>
Iontophoresis	O
is	O
similar	O
to	O
sonophoresis	B-Algorithm
as	O
it	O
is	O
a	O
method	O
for	O
transdermal	O
drug	O
delivery	O
but	O
does	O
so	O
by	O
applying	O
a	O
voltage	O
gradient	O
across	O
the	O
skin	O
.	O
</s>
<s>
Since	O
there	O
are	O
differences	O
in	O
pathways	O
between	O
iontophoresis	O
and	O
sonophoresis	B-Algorithm
,	O
a	O
combination	O
of	O
these	O
two	O
methods	O
allows	O
for	O
greater	O
enhancement	O
.	O
</s>
<s>
displayed	O
,	O
for	O
the	O
case	O
of	O
heparin	O
,	O
that	O
a	O
combination	O
of	O
iontophoresis	O
and	O
sonophoresis	B-Algorithm
resulted	O
in	O
a	O
56-fold	O
enhancement	O
of	O
heparin	O
flux	O
in	O
comparison	O
to	O
sonophoresis	B-Algorithm
having	O
a	O
3-fold	O
enhancement	O
and	O
iontophoresis	O
having	O
a	O
15-fold	O
enhancement	O
.	O
</s>
<s>
However	O
,	O
in	O
these	O
reports	O
,	O
there	O
is	O
mention	O
that	O
the	O
transdermal	O
enhancement	O
created	O
by	O
the	O
combination	O
was	O
greater	O
than	O
the	O
sum	O
of	O
the	O
individual	O
enhancers	O
,	O
suggesting	O
that	O
electroporation	O
and	O
sonophoresis	B-Algorithm
work	O
together	O
synergistically	O
.	O
</s>
<s>
This	O
is	O
incredible	O
as	O
NSAIDs	O
commonly	O
cause	O
gastrointestinal	O
side	O
effects	O
such	O
as	O
nausea	O
and	O
heartburn	O
,	O
which	O
can	O
all	O
be	O
bypassed	O
by	O
delivering	O
NSAIDs	O
using	O
sonophoresis	B-Algorithm
.	O
</s>
<s>
With	O
20kHz	O
ultrasound	B-Application
waves	O
at	O
an	O
average	O
temporal	O
intensity	O
of	O
2	O
W/cm	O
^2applied	O
every	O
second	O
,	O
the	O
permeability	O
of	O
drugs	O
with	O
varying	O
lipophilicity	O
were	O
investigated	O
,	O
such	O
as	O
atenolol	O
and	O
carteolol	O
,	O
increased	O
by	O
2.6	O
and	O
2.8-fold	O
respectively	O
.	O
</s>
<s>
Topical	O
gene	O
therapy	O
is	O
another	O
area	O
for	O
investigation	O
in	O
combination	O
with	O
sonophoresis	B-Algorithm
.	O
</s>
<s>
Since	O
there	O
exists	O
a	O
need	O
to	O
enhance	O
gene	O
transfer	O
into	O
cells	O
,	O
sonophoresis	B-Algorithm
has	O
the	O
ability	O
to	O
achieve	O
higher	O
transfection	O
rate	O
through	O
acoustic	O
cavitation	O
.	O
</s>
<s>
Currently	O
,	O
research	O
being	O
done	O
on	O
sonophoresis	B-Algorithm
is	O
poorly	O
standardized	O
.	O
</s>
<s>
For	O
example	O
,	O
the	O
emission	O
of	O
ultrasound	B-Application
waves	O
further	O
away	O
from	O
the	O
source	O
results	O
in	O
a	O
greater	O
beam	O
area	O
,	O
which	O
drastically	O
changes	O
the	O
ultrasound	B-Application
energy	O
at	O
the	O
targeted	O
area	O
.	O
</s>
<s>
More	O
challenges	O
surround	O
the	O
cost	O
of	O
the	O
actual	O
ultrasound	B-Application
devices	O
used	O
in	O
sonophoresis	B-Algorithm
in	O
more	O
clinical	O
settings	O
.	O
</s>
<s>
Additionally	O
,	O
as	O
previously	O
mentioned	O
,	O
the	O
precise	O
mechanisms	O
as	O
to	O
how	O
sonophoresis	B-Algorithm
works	O
is	O
currently	O
yet	O
to	O
be	O
discovered	O
.	O
</s>
<s>
Further	O
research	O
into	O
the	O
mechanisms	O
,	O
and	O
the	O
dominant	O
mechanisms	O
,	O
can	O
allow	O
for	O
better	O
optimization	O
of	O
sonophoresis	B-Algorithm
parameters	O
,	O
which	O
will	O
increase	O
the	O
efficacy	O
of	O
treatments	O
.	O
</s>
