Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
1999-11-05
2003-06-10
Casler, Brian L. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S022000
Reexamination Certificate
active
06575956
ABSTRACT:
TECHNICAL FIELD
The present invention relates to ultrasound systems for delivering therapeutic ultrasound energy to a target region of a patient's body.
BACKGROUND OF THE INVENTION
A current standard technique for the delivery of drugs or other substances into the human body is needle injection, in particular, intramuscular injection (IM). A bolus containing the substance is typically injected into muscle where it diffuses through the interstitial fluid or pools between muscle layers and thence diffuses through the same or more distant interstitial fluid. This diffusion might spread over a length of five or more centimeters parallel to the muscle fibers and over a width of perhaps one or two centimeters normal to the fibers. Over a period of time, typically on the order of 10 to 100 minutes, the vascular system of the body takes over and flushes the substance out of the interstitial fluid and into the capillaries. From there, the cardiovascular system widely distributes the substance into the rest of the patient's body.
Newly developed drugs often have application only to specific organs or sections of organs. As such, systemic distribution of the drug throughout the remainder of the body can: (1) dilute very expensive drugs, weakening their effects, (2) generate an effect systemically instead of locally, and (3) widely distribute a drug which may be toxic to other organs in the body. Furthermore, some of the newly developed drugs include DNA in various forms, such DNA being degraded very rapidly by natural mechanisms in the body if delivered systemically, thus preventing a full dose from reaching the designated organ.
In vitro experiments by H. J. Kim, et. al. (Human Gene Therapy, 7, 1339-1346, Jul. 10, 1996) and in vivo experiments by S. Bao, et. al. (Cancer Research 58, 219-221, Jan. 15, 1998) have demonstrated enhanced transfection of DNA into human cell lines by supplementary application of lower frequency ultrasound. While the exact biological response to DNA in conjunction with ultrasound remains unclear, it is accepted that mechanical mechanisms are responsible for the temporary permeabilization of cell membranes and possibly cell nuclear membranes.
Accordingly, it would be desirable to provide ultrasonic devices, kits, and methods for delivering such site-specific drugs in a manner which enhances absorption and/or transfection specifically into the cells within the injection diffusion zone, specifically around the site of their delivery into a target region of a patient's body. Substances thus absorbed directly into the cells or further into the nucleus of the cells have maximum potency at or around the injection site and reduced diffusion throughout the remainder of the body. Furthermore, it would be desirable for the enhancement mechanism to be mechanical in origin, as compared to thermal in origin. Mechanical methods may function to temporally permeabilize cellular membranes as compared to thermal mechanisms which may give rise to tissue inflammation.
By way of example, it has been demonstrated that injection of plasmid DNA which expresses vascular endothelial growth factor (VEGF) promotes growth of collateral vessels in ischemic tissue. Exposure of the same muscle tissue to ultrasound in conjunction with these injections improves the cellular uptake and/or transfection and manifestation of the DNA. The current problem is that these DNA injections are typically directed to specific target muscles. The injection bolus typically follows the muscle fibers, spreading as described above. Furthermore, it has been demonstrated that natural bodily defense mechanisms degrade the potency of DNA, typically by as much as fifty percent in the matter of a few minutes.
Ultrasonic systems which might be ineffectively used for enhanced transfection of DNA or for the cellular uptake of other drugs by various biological cells do exist. Unfortunately, either these systems produce very narrow ultrasound beams due to operation in the focal zone or far field (Fraunhofer zone) or they produce broad irregular fields due to operation in the near field (Fresnel zone). In the first case, the narrow beams cannot deliver a satisfactory dose of ultrasound to the volume of tissue in a time frame short compared to the natural biological destruction of the DNA. In the second case, the irregular fields are characterized by large differences in acoustic intensity both in the lateral direction (parallel to the transducer surface) and in the axial direction (normal to the transducer surface), such differences leading to unpredictable amounts of ultrasound dose.
Systems which operate in the focal zone and far field (Fraunhofer zone) include medical diagnostic ultrasound imaging and Doppler systems. These feature very tight acoustic scanning beams for the purpose of achieving the highest possible lateral resolution. Furthermore, ultrasound tissue exposure in scanning beams is held to the frame rate of the system display, typically 30 Hz. Maximum signal strengths are limited by industry and FDA guidance protocols. These systems furthermore operate at higher frequencies, in the range where longer bursts of ultrasound or continuous ultrasound exposure would create a heating effect due to absorption of the ultrasound energy in the tissues. These systems would be incapable of delivering the mechanical ultrasound effects to achieve acceptable therapeutic effects.
Additional systems which operate with highly focused beams include low frequency lithotripters and high frequency thermal ablation systems. Lithotripters feature short bursts of high intensity ultrasound with a very low burst repetition rate. They cannot provide broad tissue coverage with a high duty cycle. Ablation systems, typically identified as high intensity focused ultrasound (HIFU) systems, function to create thermal lesions in living tissue. While their acoustic beams might be swept through tissue for wide area coverage, their high frequency operation fails to produce mechanical effects in tissue.
Systems which operate in the near field (Fresnel zone) include ultrasound divices for physical therapy applications. These systems typically feature large surface area contact transducers which are intended to develop deep heat in damaged tissues, as compared to mechanical (non thermal) effects.
Currently, no systems exist for distributing a uniform wide beam of ultrasound for a mechanical (substantially non thermal) effect over a large volume of tissue, in a short period of time, so as to promote uniform cellular uptake of drugs and/or to uniformly enhance transfection of DNA over a large tissue volume. Such transcutaneous uniform acoustic intensity would need to be sufficiently powerful so as to cause acceptable cellular absorption and/or transfection yet sufficiently weak to prevent cell lysis or DNA fractionation. More specifically, no system exists for applying a uniform dose of therapeutic ultrasound, in a timely manner, over an area of a spreading injectate bolus.
SUMMARY OF THE INVENTION
The present invention provides systems, methods and kits for delivering a uniform field of ultrasound energy over a wide target region of a patient's body. The present invention offers the advantages of enhancing cellular absorption and/or transfection of therapeutic substances delivered by injection into a patient's body. In another aspect, the present invention is also useful for the treatment of vascular structures at risk from intimal hyperplasia.
Co-pending applications Ser. No. 09/364,616, Ser. No. 09/255,290, and Ser. No. 09/126,011, describe systems for ultrasound enhancement of drug injection.
The present invention provides a variety of wide beam ultrasound delivery systems which have the advantage of delivering therapeutic ultrasound energy over a large tissue volume such that, in preferred aspects, ultrasound energy can be uniformly distributed over the region in which a therapeutic substance has been injected intramuscularly, in a short time frame as compared to the lifetime of the substance at the site of interest. An ad
Brisken Axel F.
Cowan Mark W.
McKenzie John R.
Zuk Robert
Casler Brian L.
Pharmasonics, Inc.
Thanh LoAn H.
Townsend and Townsend / and Crew LLP
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