Page 193 - Bio Engineering Approaches to Cancer Diagnosis and Treatment

192 CHAPTER 8 Ultrasound applications in cancer therapy

microbubbles (also as drug carriers) at a selected point of treatment in the circu-
lation. Also, microbubble contrast agents are improved the therapeutic efficacy of
biologically activated molecules [34]. In general, the enhancement of the concentra-
tion of therapeutic biomolecules in the vascular compartment and increased thera-
peutic agent delivery by extravasation through blood vessels are some mechanisms
of this method. Molecules of the therapeutic agent can be incorporated within the
bubble shell or loaded into the interior of microbubbles and released in the vas-
cular compartment through ultrasound-induced microbubble disruption [35]. The
main advantage of the ultrasound-microbubble based delivery of therapeutic agents
over other drug carriers such as nanoparticles or liposomes, is the external control
of the ultrasound that used to target the microbubble. The dose of agent to normal
tissue is decreased due to a consequent minimization of unwanted drug effects away
from the treatment site. The cavitation mechanism is also being exploited to cre-
ate a new tissue-ablation method known as histotripsy [36]. In histotripsy very high
amplitude ultrasound pulses typically of less than 50 µs duration at 750 kHz create
a cavitation microbubble cloud to homogenize targeted tissue such as tumors with
little heating [37]. Longer HIFU pulses (t > 3 ms at 2 MHz) of very high intensity
can disrupt tissue by induce rapid heating and generate cavitation and boiling with
vapor bubbles [38]. Determining the energy deposited by ultrasound with cavitation
as well as the problems of dosimetry and control are challenging. Three important
parameters are; understand the medium (including cavitation nuclei), understand the
sound field and know when a cavitation effect happens. Passive detection methods,
measuring broadband acoustic noise from bubble collapses for monitoring cavitation
activity can be deployed and research has indicated useful dosimetric parameters
respect to bioeffects [39]. As new cavitation-based treatments are developed, new
instrumentation will be needed to reach optimum patient safety. Direct sonothrom-
bolysis using external, typically low-frequency ultrasound has been tested for treat-
ment of thrombotic disease, such as stroke [40]. This new strategy shows promise,
but also has shown a potential for deleterious side effects. For example, increased
brain hemorrhage was found in a clinical trial for treatment with 300 kHz ultrasound
plus tissue plasminogen activator relative to treatment with tissue plasminogen acti-
vator alone. Recent work suggests that microbubbles enhance thrombolysis and may
be of value in improving stroke therapy [41]. As an example, the transcranial pulsed
2
ultrasound (0.25–0.5 MHz), at relatively low levels (I = 26–163 mW/cm ), is used
to produce cortical and hippocampal stimulation in mice [42]. Since measured tem-
perature gradients were <0.01°C, nonthermal mechanisms for the neuronal effects
were hypothesized.

8.2.3 Effects of ultrasonic waves on tissues and blood
The ultrasound waves have different effects on the body. Some can only be justi-
fied by linear wave equations. But to explain the cause of some others, one should
refer to nonlinear wave relations. Generally, thermal effect, mechanical stress, and
bubble stresses are predictable with linear equations. However, in order to provide