Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2000-07-27
2004-05-11
Lateef, Marvin M. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C601S002000, C601S003000, C601S004000, C604S022000
Reexamination Certificate
active
06733450
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention lies in ultrasound methods and apparatus for reducing tissue damage from ischemia by means of insonation. The invention pertains to therapeutic medical systems and, more particularly, to the therapeutic use of ultrasound methods and apparatus for reducing tissue damage from ischemia.
BACKGROUND OF THE INVENTION
The insonation of the instant invention has the goals of reducing edema and promoting microcirculation, recanalization, collateral and interstitial flow, and delivery of lytic agents to clots located in supplying arteries, as well as delivery of nutrients and/or drugs to the ischemic tissue. Goals of the apparatus and method may even extend to clot destruction through a re-enforced focusing of multiple beams.
More particularly, in accordance with the methods and apparatus of the instant invention, at least a portion if not all of an organ affected by ischemia is exposed to low frequency low power ultrasound, preferably generated by a plurality of transducers from directions spanning at least a 45° angle and over at least a one minute period, preferably over an hour period, more preferably over many hours. The system can also be used to maintain and enhance biological tissue function and viability in a setting of reduced perfusion by exposure to ultrasound energy transmission.
The principles taught, demonstrated and tested herein use the reduction of tissue damage from brain ischemia as a preferred embodiment, brain ischemia offering a most difficult test case. The bone attenuation of ultrasound has not received extensive consideration in the art. The effect of the cranium bone structure, in particular, has presented itself as a significant obstacle to insonation of the brain.
Addressing brain ischemia in general, a significant reduction in cerebral blood flow leads to brain ischemia and, if untreated, may cause stroke leading to permanent tissue damage (infarction), severe disability, and, in many cases, death. In particular, an ischemic stroke occurs when a thrombus obstructs cerebral arteries. Systemically-induced thrombolysis with intravenous tissue plasminogen activator (TPA) (see
The National Institutes of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N. Engl J Med
. 1995;333:1581-1587) is the only effective therapy practiced today to reduce damage from ischemic stroke.
Although intravenous tPA improves the outcome of stroke patients (see
The National Institutes of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med
. 1995;333:1581-1587) recanalization is not achieved in a significant portion of arterial occlusions (74% of cerebral arteries) when tPA is given alone (see del Zoppo G J, Poeck K, Pessin M S, Wolpert S M, Furlan A J. Ferbert A, Alberts M J, Zivin J A, Wechsler L, Busse O, Greenlee R, Brass L, Mohr J P, Feldmann E, Hacke W. Kase C S, Biller J, Gress D, Otis S M.
Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol
. 1992; 32:78-86).
Ultrasound in the low MHz-kHz frequency range (see Akiyama M, Ishibashi T. Yamada T. Furuhata H.
Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro
. Abstract of
Neurosurgery
1998; 43:828-832 and Behrens S, Daffertshofer M, Spiegel D, Hennerici M.
Low-frequency, low-intensity ultrasound accelerates thrombolysis through the skull
. Abstract of
Ultrasound Med Biol
1999; 25:269-273) has been shown to promote thrombolysis in vitro models of cerebral arterial thrombosis by substantially increasing the thrombolytic effect of tPA.
In other experiments, ultrasound exposure has been shown to cause various changes such as reversible disaggregation of uncrosslinked fibrin fibers (see Abstract of Braaten J V, Goss R A, Francis C W.
Ultrasound reversibly disaggregates fibrin fibers. Thromb Haemost
1997;78:1063-1068), microcavity formation in the shallow layer of thrombus (see Abstract of Kondo I, Mizushige K, Ueda T. Masugata H, Ohmori K, Matsuo H.
Histological observations and the process of ultrasound contrast agent enhancement of tissue plasminogen activator thrombolysis with ultrasound exposure. Jpn Circ J
1999;63:478-484), and increasing the enzymatic transport of tPA improving uptake and penetration of tPA into clots (see Abstract of Francis C W, Onundarson P T, Carstensen E L, Blinc A, Meltzer R S, Schwarz K, Marder V J.
Enhancement of fibrinolysis in vitro by ultrasound. J Clin Invest
1992; 90:2063-2068).
It has been concluded that ultrasound promotion of drug-induced lysis does not appear to be mediated by thermal or cavitational effects (see Abstract of Suchkova V, Siddiqi F N, Carstensen E L, Dalecki D, Child S, Francis C W.
Enhancement of fibrinolysis with
40-
kHz ultrasound. Circulation
1998;98:1030-1035).
A 2 MHz pulsed wave ultrasound is used in the diagnostic equipment for cerebrovascular studies (see Otis S M, Ringelstein E B.
The transcranial Doppler examination: principles and applications of transcranial Doppler sonography. In
: Tegeler C H, Babikian V L, Gomez C R. Neurosonology.
St Louis:Mosby
, 1996. Pp 113-129). Some have suggested that the ideal frequency for ultrasound mediated thrombolysis appears to be the 1-2.2 MHz range (see Abstract of Blinc A, Francis C W, Trudnowski J L, Carstensen E L.
Characterization of ultrasound
-
potentiated fibrinolysis in vitro. Blood
993;81:2636-2643). However, this level of insonation may not deliver sufficient energy to disrupt a brain clot mechanically, due to the tremendous attenuation of ultrasound through the skull bone (see Abstract of Akiyama M, Ishibashi T. Yamada T. Furuhata H.
Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro
. Cite above
Neurosurgery
1998; 43:828-832 and Behrens S, Daffertshofer M, Spiegel D, Hennerici M
Low-frequency, low
-
intensity ultrasound accelerates thrombolysis through the skull. Ultrasound Med Biol
1999;25:269-273).
The impact of continuous exposure to ultrasound on cerebral ischemic tissue and on cerebral clots in human patients, in vivo, has not been studied before. Its utility, thus, has not previously been raised to the level reached by the instant demonstration. The instant invention is based upon both human and experimental animal model studies involving cerebral ischemic tissue. Methods and techniques suggested and indicated by the undertakings of the instant studies, however, are also applicable, as will be readily appreciated, to other tissue and organs.
Eggleton and Fry (see Eggleton R C, Fry F J. U.S. Pat. No. 3,951,140. Apr. 20, 1976) teach that low intensity ultrasound can be used to potentiate healing of various biological tissues, in particular the heart, by means of combating tissue swelling, increasing permeability of biological membranes, and inducing interstitial flow of fluids under radiation pressure (microstreaming). Although their patent discloses apparatus and method for therapeutic ultrasound insonation of ischemic tissue and energy transmission to infarcted tissue (in particular, the heart), their approach does not extend to teaching the identification of normal donor tissue for promoting collateral and/or interstitial flow, or to teaching methods and apparatus for utilizing beams that span at least 45°, or to utilizing beams that expose an entire organ or tissue to ultrasound.
No specific methods or ultrasound devices are taught by the prior art to particularly penetrate bones or to utilize vasculature in order to sonicate tissue at risk, as well as to sonicate normal tissue of the organ, all designed to limit tissue damage from ischemia. Jolez and Hynynen (see Jolesz F A, Hynynen K U.S. Pat. No. 5,752,515. May 19, 1998) disclose noninvasive methods and apparatus for delivery of various compounds through a blood brain barrier using ultrasound-induced cavitation and heating in a small target area (1 mm
3
-1 cm
3
). However, such hyperthermia exacerbates ischemic brain damage, and such cavitati
Alexandrov Andrei V.
Aronowski Jaroslaw A.
Wojner Anne W.
Lateef Marvin M.
Shah Devaang
Shaper Sue Z.
Texas Systems, Board of Regents
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