Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2000-06-07
2003-02-04
Lateef, Marvin M. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
Reexamination Certificate
active
06514209
ABSTRACT:
BACKGROUND OF THE INVENTION
Conventional diagnostic ultrasound techniques such as B-mode imaging are usually based on processing ultrasonic waves at their fundamental frequency (f
0
). Using these ultrasound techniques, one can non-invasively and safely generate real-time images and Doppler data. However, the received signals are at times weak in contrast.
Until recently, ultrasonography lacked substances to be administered to patients to improve or increase the diagnostic yield. However, some contrast agents, most of which consist of gas microbubbles, have been introduced for use in ultrasound imaging. Gas microbubbles act as echo-enhancers by a similar mechanism to that for determining echoscattering in other cases of diagnostic ultrasound. Specifically, the backscattering echo intensity is proportional to the change in acoustic impedance between the blood and the gas making the bubbles. The difference in acoustic impedance at this interface is very high. In fact, all of the incident sound is reflected. However, the acoustic wave reflection is still insufficient to determine a strong enhancement since the microbubbles are very small and sparse within the circulation. Further, reflectivity is proportional to the fourth power of a particle's diameter and directly proportional to the concentration of the particles themselves (Calliada et al.
Eur. J. Radiol
. 1998 27(2):S157-60).
Microbubbles reached by an ultrasound signal resonate with a specific resonance frequency depending on the microbubble diameter. However, the fundamental resonance frequency is not the only frequency the bubble radiates. Multiple frequencies of the fundamental one are also emitted. These harmonic frequencies have decreasing intensity. However, the second frequency, known as the second harmonic, has been extensively used for diagnostic purposes. For example, it has been demonstrated that at very low pressures of approximately 20 kPa, there is a 17.5 to 26 dB enhancement in the second harmonic signals from ALBUNEX™, a contrast agent consisting of microspheres of human serum albumin suspended in a 5% solution of the same developed by Molecular Biosystems, San Diego, Calif. USA (Schrope, A. B., Newhouse, L. V.
Ultrasound Med. Biol
. 1993 9(7):567-579). Second harmonic imaging also permits imaging of extremely small vessels which can be missed with conventional methods (Calliada et al.
Eur. J. Radiol
. 1998 27(2):S157-60). Accordingly, second harmonics have been suggested as a route to exploit the diagnostic benefits of contrast imaging (Burns et al.
Radiology
1992 182(P):142; Goldberg, B. B.
Ultrasound Contrast Agents
Martin Dunitz Ltd, London, 1997; de Jong et al.
Ultrasonics
1994 32(6):447-453).
Apart from emitting widely known 2
nd
harmonics and other higher harmonics, bubbles also emit subharmonics and ultraharmonics. Subharmonic detection of resonating microbubbles has been described (Lotsberg et al. 1996 99(3):1366-1369; Leighton, T. G.; The Acoustic Bubble Academic press, San Diego, 1994, p 413-424; Forsberg, F. and Shi, T. W. New Aspects of Harmonic and Subharmonic Imaging. Proc. Symp. The Leading Edge in Diagnostic Ultrasound. Atlantic City, p 24-27, May 19, 1998).
It has now been found that ultraharmonics can be effectively measured in objects subjected to ultrasonic techniques and that measurement of ultraharmonics enhances the capabilities of these techniques. For example, it has now been demonstrated that measurement of ultraharmonics of ultrasound contrast agents in ultrasonic techniques enhances the capabilities of ultrasonic contrast based techniques.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a method of enhancing the capabilities of ultrasonic techniques which comprises subjecting an object to an ultrasonic technique; and measuring the ultraharmonic resonance in the object. In a preferred embodiment, the object comprises an ultrasound contrast agent capable of producing the ultraharmonic resonance. Alternatively, the object may comprise free microbubbles, echogenic scatteres or reflectors capable of producing the ultraharmonic resonance, or cells, tissues or a whole body.
Another object of the present invention is to provide ultrasound instruments and systems which measure ultraharmonics to enhance the capabilities of ultrasonic techniques.
DETAILED DESCRIPTION OF THE INVENTION
In addition to the fundamental frequency (f
0
) generated by ultrasonic techniques, objects when subjected to ultrasonic techniques also generate subharmonic, harmonic and even ultraharmonic (3/2f
0
, 5/2f
0
, etc.) frequencies. Unlike the fundamental frequency and harmonics which can also be generated due to non-linearity of the medium (i.e. surrounding tissue or water), ultraharmonics and subharmonics are characteristic of the object only.
Second harmonic enhancement in objects such as ultrasound contrast agents subjected to an ultrasonic technique is usually below 20 dB and decreases dramatically with increases in diagnostic pressure.
On the other hand, it has now been found that ultraharmonic enhancement of an object subjected to an ultrasonic technique is typically greater than 20 dB and usually increases with increase in diagnostic pressure. Accordingly, the present invention relates to methods and apparatus which measure ultraharmonic signals thereby enhancing the capabilities of ultrasonic techniques including, but not limited to, imaging, Doppler and perfusion techniques. These methods and apparatus are useful in both medical diagnostics and industrial applications.
As demonstrated herein measurement of ultraharmonic signals can be used to obtain higher contrast and signal to noise ratio with respect to tissue or water. In addition, measurement of ultraharmonic signals can be used to obtain higher Doppler resolution as compared to measurement of fundamental frequency. Moreover, since the first ultraharmonic is midway between the fundamental and second harmonic frequency, it is less attenuated than the second harmonics. Thus, ultraharmonics may be used to replace or augment the existing second harmonic techniques, to further harness the benefits of contrast only imaging, and other contrast based harmonic techniques, as described previously for second harmonic contrast based techniques.
Thus, by “enhancing the capabilities” of ultrasonic techniques, it is meant that higher contrast and signal to noise ratio with respect to tissue or water is achieved through measurement of ultraharmonic signals, along with higher Doppler resolution with respect to fundamental imaging techniques and decreased attenuation with respect to harmonics such as second harmonics.
In the method of the present invention, an object is subjected to an ultrasonic technique such as an imaging, Doppler or perfusion technique and the ultraharmonic signal of the object is measured. Examples of objects used in these methods include, but are not limited to, ultrasound contrast agents, free microbubbles, echogenic scatteres and reflectors, cells, tissues and whole bodies.
A series of experiments were performed to demonstrate enhanced capabilities of ultrasonics techniques wherein ultraharmonics were measured. In these experiments, a thin and flexible walled, surfactant based ultrasound contrast agent developed by insonating Span60 and Tween 80 as described in U.S. Pat. No. 5,352,436 was used as the object. Decafluorobutane or octafluoropropane gas was entrapped within the microbubbles of this thin and flexible walled, surfactant based contrast agent to produce ST68-PFC. Experiments were then performed to determine the frequency response of ST68-PFC.
The frequency content of the transmitted ultrasound signal in de-ionized (~18 M) water, 2″(50 mm) from the transducer was recorded as base. An increase in second harmonic and third harmonic generations was observed in deionized water due to non-linear propagation on increasing insonating pressure. Moreover, the generation of higher harmonics due to propagation in tissue is aggravated, since the non-linearity parameter B/A for tissue at diagnostic fr
Basude Raghuveer
Wheatley Margaret A.
Drexel University
Imam Ali M.
Lateef Marvin M.
Licata & Tyrrell P.C.
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