The range (20 to100 kHz) or LFU, lower frequencies produce more enhancement,

but it has been recognized in recent years that this enhancement may be localized
to certain areas termed localized transport pathways (LTRs). At higher requencies,
transport is more homogeneous, but as discussed, it will also need more energy. An
optimum frequency seems to be around 60 kHz where a reasonable energy dose
can produce significant enhancement in skin permeability. This is perhaps the
marketed SonoPrep device uses a 55-kHz frequency. Formation of LTRs at low
frequencies became evident when recent studies used colored or fluorescent
permeants or quantum dots and noted the presence of millimeter-size discrete
domains or regions that were highly permeable and may occupy about 5% of the
total skin area exposed to ultrasound. Most (but not all) of the studies that reported
the formation of LTRs were done at a frequency of 20 kHz applied with a 5s:5s
on:off duty cycle at intensities ranging from 2.5 to 7.5 W/cm2 , and these were
reviewed by Kushner et al. Diffusion masked experiments where hydrophobic
silicone high vacuum grease is applied to LTRs or non-LTRs regions have been used
along with measurements of skin electrical resistivity to study the relative
permeability of different regions of the skin. LTRs can be up to 80-fold more
permeable than the non-LTR region of skin treated with LFU, and two to three orders
of magnitude more permeable than untreated skin. Also, the electrical resistivity of
skin treated with LFU may decrease about 170-fold in the non LTR region and over
5000 fold in the LTR region.
Another noncavitational mechanism involved in ultrasound-mediated delivery is
acoustic streaming (different from microstreaming), which is a large- scale
convective motion, but this is generally believed not to be a major factor in
enhancing skin permeability. However, it was reported to be a contributing factor to
sonophoretic transport enhancement. Using mannitol as a model hydrophilic
permeant, it was shown than convection can play important role during low LFU
conditions when using human heat-stripped skin. In contrast, convective flow was
not an important contributor to transport when using full-thickness pig skin.
Thermal effects that accompany sonophoresis may also have a role in enhancing
permeation, especially under condition over than LFU. However, ever for delivery of
mannitol under LFU conditions, it was reported tha the thermal effects accounted
for 25% of the enhancement with the rest attributed to cavitation. Several of these
mechanisms may act in synergy during sonophoresis.