Biomedical Engineering Reference
In-Depth Information
Ultrasound was primarily developed for military applications for detecting
submarines in World War I. In the late 1940s, several enthusiasts recognized the
potential of this technique in medical imaging. among them was a radiologist
D. Howry. In his basement in Denver, Howry, later together with the nephrologist
J. Holmes, built his first ultrasound scanner to image soft tissue [65]. The principle
of imaging was based on the reflection of an ultrasound signal generated by a piezo-
electric transducer at some fundamental frequency. This ultrasound signal travels
through the biological tissue, gets reflected off a structure, and travels back to the
transducer to produce an image. after a decade of development, the technique under-
went significant modifications, and by the mid-1960s, the first commercial system,
vidoson® by Siemens, Inc., for ultrasound imaging was released.
However, due to poor reflection of signal against biological tissue, measured
signal intensity was low, producing images of poor quality. By serendipity, raymond
gramiak, a radiologist at the University of rochester, while examining a patient for
cardiac output with indocyanine green—a standard method at that time—observed
an intense contrast improvement at the site of injection [66]. In the following paper,
the authors identified a small amount of foam formed upon dissolution of Icg with
water responsible for the intracardiac contrast effect produced by Icg. “It is our
belief that the contrast effect represents the ultrasonic detection of miniature bubbles
within the heart produced by gaseous cavitation, which occurs when the contrast
agent is injected rapidly, or by miniature bubbles injected in the foam of indocya-
nine-green solutions [67].” This discovery paved the way to an era of numerous
designs of micro- and, later, nanobubbles in the following decades that are covered
in many reviews and topics [68-70].
The clinical use of early contrast agents that were made on site by agitation of
saline solutions filled with air were unsuccessful due to the low stability of air-filled
microbubbles and rapid disappearance of the contrast signal
in vivo
. The early agents
also suffered from large and heterogeneous sizes and low permeability through the
pulmonary system. Subsequent efforts showed that the stability of the microbubbles
could be enhanced via a sonication technique instead of agitation and could be further
improved by stabilizing agents such as sorbitol and dextrose [71]. among the new
techniques, a patent filed by feinstein in 1985 [72] introduced a new class of stabi-
lized microbubbles. These microbubbles were formed by sonication of an albumin
solution that led to the formation of a protective coating of serum albumin on the
surface of the bubbles [68] (fig. 1.11). This discovery headed to the development of
the first generation of the commercial contrast agent albunex® (Mallinckrodt, Inc.)
with a thin layer of cross-linked albumin (<15nm) around an air bubble. The
advantage of this contrast agent was that albunex could be purchased in a standard-
ized prepackaged form, minimizing handling complications and errors with dosage.
Despite the presence of protective layers, the microbubbles were still suffering
from short lifetimes in circulation. Due to their relatively large size, they were unable
to cross the lung barrier, thus limiting the imaging to the right side of the heart.
addressing these problems, the second-generation contrast agents were filled with a
heavy gas such as perfluoropropane. The use of the high-density gas as a filling
material was a breakthrough since it drastically reduced the diffusion of the gas from
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