JP2002537013A - Method and apparatus for uniform transdermal therapeutic ultrasound - Google Patents

Abstract

  (57) [Summary] The present invention provides systems, methods and kits for delivering a uniform field of ultrasonic energy over a wide target area of a patient's body. A wide beam ultrasound delivery system that provides a uniform irradiation field to increase uptake of the injected substance and / or increase transfection of DNA in tissue of a human subject, or following vascular injury Used to reduce the amount of intimal hyperplasia in a human subject. The present invention provides the advantage of enhancing cellular absorption and / or transfection of therapeutics delivered by injection to the patient's body. In another aspect, the invention is also useful for treating vasculature at risk for intimal hyperplasia.

Description

DETAILED DESCRIPTION OF THE INVENTION

(Cross-Reference of Related Applications) [0001] The present application is filed with application No. 09 / 364,61, filed on July 29, 1999.
No. 09 / 364,616, filed Feb. 22, 1999, is a continuation-in-part of No. 6 (Attorney Docket No. 17148-001820).
No. 17148-001810), which is incorporated herein by reference.
No. 290 is filed on Jul. 29, 1998, Ser. No. 09 / 126,01.
No. 1 (Attorney Docket No. 17148-001800).

[0002] This application is also related to application Ser. No. 09/223, filed Dec. 30, 1998.
, 230 (Attorney Docket No. 17148-001110)
No. 09 / 223,230 is a provisional application No. 60 / 070,236 filed on Dec. 31, 1997 (Attorney Docket No. 1).
7148-001100).

[0003] This application is also related to application Ser. No. 09/345, filed on Jun. 30, 1999.
No. 661 (Attorney Docket No. 17148-002900), the entire disclosure of which is hereby incorporated by reference in its entirety for all purposes.

TECHNICAL FIELD [0004] The present invention relates to an ultrasound system for delivering therapeutic ultrasound energy to a target area of a patient's body.

BACKGROUND OF THE INVENTION [0005] Current standard techniques for the delivery of drugs or other substances to the human body include needle injection,
In particular, intramuscular injection (IM). A bolus containing a substance is typically injected intramuscularly, where the substance diffuses through or is pooled between muscles, from which the same or different interstitial fluid is removed. Spread through. This diffusion is more than 5 centimeters in length parallel to the muscular fibrils and probably 1 cm perpendicular to the fibrils.
Or it can extend over a width of 2 centimeters. Over a period of time (typically on the order of 10 to 100 minutes), the body's vasculature carries away substances from interstitial fluid into capillaries. From there, the cardiovascular system distributes the substance widely to the rest of the patient's body.

[0006] Newly developed drugs often have application only to specific or selected organs. Thus, the systemic distribution of drugs throughout the rest of the body can (1) dilute very expensive drugs and counteract their effects, and (2) produce effects systemically instead of locally. And (3) widely distribute drugs that may be toxic to other organs of the body. In addition, some of the newly developed drugs include various forms of DNA, which, when delivered systemically, degrade very quickly by the body's natural mechanisms, and therefore The complete dose is prevented from reaching the designated organ.

H. J. In vitro experiments by Kim et al. (Human Gene Thera)
py, 7, 1339-1346, July 10, 1996) and S.I. In vivo experiments by Bao et al. (Cancer Research 58, 219-221,
Jan. 15, 1998) showed enhanced transfection of DNA into human cell lines by the supplemental application of low frequency ultrasound. DNA associated with ultrasound
Although the exact biological response to is unknown, it is accepted that a mechanical mechanism is due to the transient permeability of the cell membrane and possibly the nuclear membrane.

[0008] Thus, for delivering site-specific drugs in a manner that enhances absorption and / or transfection of the drug around the site of delivery of the drug, particularly to the injection diffusion zone, and particularly to a target area of the patient's body. It is desirable to provide ultrasound devices, kits, and methods. Substances thus absorbed directly into the cell or even into the intracellular nucleic acid have maximum efficacy at or around the injection site and "reduce the spread into the rest of the body. Is more desirable as a mechanism of enhancement than is thermal in origin, which renders cell membranes temporarily more permeable than thermal mechanisms that can cause tissue inflammation. May work for you.

As an example, it has been shown that injection of plasmid DNA expressing vascular endothelial growth factor (VEGF) promotes the growth of collateral vessels in ischemic tissue. Exposure of the same muscle tissue to ultrasound associated with these injections improves cellular uptake of DNA and / or transfection and expression. The current problem is that these DNs
A injection is typically directed to a specific target muscle. The injection bolus typically follows the muscle fibers and diffuses as described above. In addition, it has been shown that natural body defense mechanisms degrade DNA potency, typically by 50% in minutes.

[0010] There are ultrasound systems that can be used ineffectively to increase transfection of DNA or to uptake other drugs by various biological cells. Unfortunately, both of these systems produce very narrow ultrasound beams due to operation in the local or far field (Fraunhofer zone), or operate in the near field (Fresnel zone). Generates a wide range of irregular fields. In the first case, a narrow beam may not be able to deliver a sufficient dose of ultrasound to a volume of tissue in a short time compared to the natural biological destruction of DNA. In the second case, the irregular field is characterized by a large difference in sound intensity both in the lateral direction (parallel to the transducer surface) and in the axial direction (perpendicular to the transducer surface). Such differences lead to unexpected amounts of ultrasound dose.

[0011] Systems operating in the local zone and in the far field (Fraunhofer zone) include medical diagnostic ultrasound imaging and Doppler systems. They feature very dense acoustic scanning beams in order to achieve the highest possible lateral resolution. Further, ultrasound tissue exposure in the scanning beam is maintained at the frame rate of the system display (typically 30 Hz). Maximum signal strength is industrial and FD
A Limited by guidance protocol. These systems operate at higher frequencies, to the extent that even longer bursts of ultrasound or continuous ultrasound exposure create a heating effect due to the absorption of ultrasound energy in the tissue. These systems cannot deliver a mechanical ultrasound effect to achieve an acceptable therapeutic effect.

[0012] Additional systems that operate with high local beams include low frequency lithotripters and high frequency thermal ablation systems. The lithotripter is characterized by short bursts of high intensity ultrasound at very low burst repetition rates. They cannot provide wide tissue coverage at high duty cycles. The ablation system is typically identified as a high intensity focused ultrasound (HIFU) system and functions to create thermal damage to living tissue. These acoustic beams can sweep tissue over a wide area of coverage, but their operation at high frequencies cannot create mechanical effects in tissue.

Systems operating in the near field (Fresnel zone) include ultrasound devices for physical therapy applications. These systems typically feature large surface area contact transducers that are intended to generate deep heat in damaged tissue as compared to mechanical (non-thermal) effects.

At present, ultrasound is applied to a beam of uniform width to promote uniform cellular uptake of the drug and / or to uniformly enhance transfection of DNA over large tissue volumes. There is no system for dispensing a large volume of tissue in a short amount of time due to a (thermally non-thermal) effect. Such transcutaneously uniform sound intensity needs to be strong enough to cause acceptable cell absorption and / or transfection, yet weak enough to prevent cell lysis or DNA fractionation. More specifically, over the area of the expanding injection bolus,
There is no system for applying a uniform dose of therapeutic ultrasound in a timely manner.

SUMMARY OF THE INVENTION The present invention provides systems, methods, and kits for delivering a uniform field of ultrasonic energy over a wide target area of a patient's body. The present invention provides the advantage of enhancing cellular absorption and / or transfection of therapeutics delivered by injection to the patient's body. In another aspect, the present invention also provides
Useful for treating vasculature at risk of intimal hyperplasia.

No. 09 / 364,616 (Attorney Docke)
t number 17148-001820), application number 09 / 255,290 (At
torney Socket No. 17148-001810) and Application No. 09 / 126,011 (Attorney Socket No. 17148-181).
001800) describes a system for ultrasound enhancement of drug injection.

The present invention provides beam ultrasound delivery systems of various widths, which have the advantage of delivering therapeutic ultrasound energy over large tissue volumes, so that, in a preferred aspect, ultrasound energy Can be uniformly distributed over the area where the therapeutic substance is injected intramuscularly in a short time frame compared to the life of the substance at the desired site. An advantage of the present invention is that by applying a uniform field of ultrasonic energy over a large tissue volume, cellular uptake of an injected substance, such as therapeutic DNA, can be performed without the injected DNA causing tissue damage. Or that it can be substantially enhanced over the entire area spread without disintegrating the injection. Another advantage of the present invention is that by applying a uniform field of ultrasonic energy over the long length of the vasculature, the healing response blunts intimal hyperplasia without adjacent tissue damage. It can be exercised.

An advantage of the present invention is that it provides a system for both delivering a broad ultrasound beam and scanning the ultrasound beam. Thus, the present invention is particularly well suited to operate in both time-constrained and non-time-constrained conditions as follows.

In the presence of time constraints, therapeutic applications requiring continuous wave (CW) exposure with ultrasound require devices with a wider field of view than the intended sonication area. . In the absence of such time restrictions as those imposed by the natural degradation of DNA in the body, devices with small fields of view can be swept or stepped over the area to be sonicated.

[0020] Also, if a time limit exists, therapeutic applications operating with pulsed wave (PW) exposure by ultrasound may also cause the ultrasound beam to be turned on for a second (or third, or fourth, Cannot move from the first sonicated position to the second (or third, or fourth,...) Sonicated position during the OFF time due to the position of... In some cases, a device having a field of view larger than the area to be sonicated may be required. A very small duty cycle (where the duty cycle is O
N times divided by the ON and OFF times).
The ultrasound beam can be swept across alternative location sizes, the net effect being the same amount of ultrasound exposure (uniform exposure) for all points within the area of interest.

For a preferred aspect, the broad beam ultrasound delivery system of the present invention includes a housing having an opening at its distal end with an ultrasound transducer suspended within the housing. The ultrasonic transducer is positioned in contact with an acoustic couplant material that substantially fills the housing. In a preferred aspect, the acoustic bonding medium material comprises:
Fluids, such as water, oils with water, humectants and / or additives such as antibiotic reagents (to prevent the growth of bacteria or fungi).

A flexible skin contact window (which may be made from any of several different variations, such as silicone rubber, polyethylene, polypropylene, nylon, urethane, etc.) is positioned over the opening at the distal end of the housing. The skin contact window is preferably positioned adjacent to the patient's skin using a possible ultrasonic coupling gel between the window and the skin, so that the therapeutic ultrasonic energy is fluidized from the ultrasonic transducer. It can pass along the filled housing and through the skin contact window and to the patient.

In a preferred aspect of the invention, the housing of the ultrasound delivery system is designed to ensure good coupling of the ultrasound energy to the external configuration of the patient. Further, the housing preferably includes a suitable ultrasonic absorbing material,
As a result, the ultrasonic energy does not propagate to the outer surface of the housing, and thus does not expose the operator of the device to ultrasonic waves. In addition, the housing is preferably designed so as not to interfere with the ultrasound beam, in the form of an unintended stopping of the ultrasound beam.

In various aspects, the piezoelectric elements of the ultrasonic transducer are substantially planar and can be either rectangular, circular or annular in shape. In certain embodiments, the transducer may include a plurality of ring-shaped piezoelectric elements, one disposed concentrically within another. Alternatively, the transducer may comprise a piezoelectric element that is substantially cylindrical in shape. In a further embodiment, the transducer may comprise a single or multiple elements in a three-dimensional piezoelectric shape. Still further, the transducer may comprise a two-dimensional array of individual flat plate piezoelectric elements. Transducer elements of the present invention preferably has a large surface area in the range of typically 0.5cm ² ~1000cm ² in a preferred aspect.

It is understood that the shape of the transducer's piezoelectric element with respect to any and all focusing elements results in a shape of the ultrasound footprint in the tissue, defined as a therapeutically effective ultrasound region. You. Some applications of the system are preferably
A circular footprint may be used, while other applications may preferably use a rectangular shape. By way of example, an unfocused rectangular transducer can result in a rectangular footprint having the long axis of the transducer orthogonal to the long axis of the footprint.

In a preferred aspect, the present invention also includes various systems for directing ultrasonic energy through a fluid-filled housing to a targeted depth in a patient's body. Such systems include, if necessary, bending the piezoelectric ceramic to adapt the width of the beam. Alternatively, the structure of the lens may be mounted on the emitting surface in front of the piezoelectric ceramic to provide the same effect. further,
The reflective surface can be installed in the housing to achieve the same effect. And still further, the reflective acoustic lens can be tailored to the acoustic beam in the fluid contacting medium to adapt the width of the beam.

In a preferred aspect, the rear surface of the piezoelectric ceramic is covered with air to ensure that all acoustic energy is emitted from the front surface of the piezoelectric ceramic. As a result, the heat loss corresponding to the energy radiated behind the device is substantially reduced and maximum efficiency is achieved. Alternatively, the rear surface of the ceramic may instead be covered with a low impedance, slightly damping material, providing the device with some level of structural strength. Preferably, a piezoceramic rim is mounted within the housing to minimize acoustic coupling to the housing.

In an alternative aspect of the invention, first and second mounting systems are provided for connecting the transducer to the interior of the housing, such that the transducer controls a beam of ultrasonic energy. It can be movably coupled for possible reciprocating scanning movements. Preferably, by moving the transducer back and forth in two perpendicular directions, a narrower beam of ultrasound energy can be raster-scanned across the desired volume of tissue in the patient and, over time, the target tissue Uniform illumination can be achieved.

The present invention is particularly well-suited for (but not limited to) use for intramuscular injection of therapeutic substances (eg, DNA). In such aspects, the wide-aperture ultrasound delivery system of the present invention can be used either before, simultaneously with, immediately after, or substantially after injection of a therapeutic substance into a patient. As defined herein, the application of ultrasound "substantially after" injection includes the application of ultrasound during a period prior to a period during which the injected DNA is substantially degraded. . Typically, such time periods are on the order of 15-60 minutes, but are not limited to, and may vary from application to application.

Thus, the present invention is ideally suited for enhancing the cellular absorption of a drug or any other substance into a localized target area of the patient's body, thereby allowing the patient's cardiovascular system to enhance the entire patient's body Prevent unwanted effects of widely dispersed materials.

For example, a particular application of the present invention includes the application of sonicated VEGF therapy for the treatment of ischemic tissue as described above. As a further application,
Treatment of a patient suffering from a disease as a result of a particular protein deficiency.
In particular, such patients may have access to these proteins (eg, EPO for patients with impaired production of red blood cells, Factor VIII or Fa for hemophilia patients).
ctorIX, or angiostatin or endostatin for cancer patients) can be assisted by injection of certain DNA plasmids that stimulate the cells to secrete.

The advantageous application of the system of the invention for ultrasonic exposure of a uniform broad beam is not limited to application in combination with substance injection. For example, the invention also provides, inter alia, any combination of before, concurrently, immediately after, or substantially after vascular intervention or surgery,
Well suited for use in preventing early hyperplasia. Thus, a further advantageous application of the present invention is a uniform and widespread use of ultrasound for mechanical (not thermal) effects that elicit a vascular recovery response along an elongated portion of an artery or vein. The ability to distribute the beam.

[0033] Vascular tissue at risk of intimal hyperplasia (eg, coronary or peripheral arteries following vascular intervention or veins and arteries following graft insertion and fistula creation) may be immediately present after injury. It has been demonstrated that when treated with ultrasound, it experiences reduced hyperplastic loading. In the case of vascular interventions using devices (eg, angioplasty balloons, arthrectomy catheters or stents), the degree of vascular damage can range from a few millimeters to several centimeters or longer.

No. 09 / 223,230 (Attorney Docket No. 17148-0)
01110), and 09 / 345,661 (Attorney Docket No. 17148)
-002900) describes a catheter-based system for delivering an ultrasonic field to an area of tissue.

In addition to including a system for delivering a wide field of uniform ultrasound to the surface of the patient's skin, the present invention also provides a method for inhibiting intimal hyperplasia in the vascular system. An extensive beam aperture system to deliver a wide field of sensitive ultrasound to the area of the tissue.

In accordance with the present invention, the patient receives a broad field of uniform ultrasound exposure from an external source, either during or after an intimal vascular intervention. Such a transcutaneous and uniform sound intensity is preferably of sufficient power to stimulate a healing response, not excessive to elicit an inflammatory response, or lyse blood or tissue cells Not too much output.

The present invention is not limited with respect to the nature of the cells that make up the target site. Such cells may be transcutaneous, intraoperative, or transcutaneous (
percutaneous) muscle tissue or organ tissue that receives the injection. Such cells can include vascular cells.

DESCRIPTION OF SPECIFIC EMBODIMENTS The present invention provides a variety of broad beam ultrasound delivery systems that have the advantage of delivering a uniform delivery of therapeutic ultrasound energy over a larger volume of tissue than conventional systems. I will provide a. The advantage of delivering such a broad beam is that therapeutic ultrasound can be delivered over a target area where a drug, DNA or other therapeutic substance has been injected. Accordingly, the present invention provides a method for administering a drug, DNA or other therapeutic substance, prior to, simultaneously with injection, as it disperses through the muscle tissue or organ area of the patient.
Immediately after injection, or after substantial injection, it can be used to facilitate cell inoculation of drugs, DNA or other therapeutic agents.

These properties of the invention are particularly advantageous because therapeutic injection of DNA into a human patient will typically result in diffusion into the patient's muscle tissue. In particular, ultrasound imaging shows that injections typically follow muscle fibers,
It was illuminated that it could spread over a length of centimeters or more, possibly over a width of usually 1-2 cm perpendicular to the muscle fibers.

[0040] Yet another advantage of the present invention is that a uniform dose of therapeutic ultrasound can be applied to an enlarged area of vascular tissue at risk of intimal hyperplasia (eg, coronary and peripheral nerve arteries following vascular procedures) Or veins and arteries following implantation or creation of a fistula). Thus, the present invention can be used to minimize intimal hyperplasia.

Still another advantage of the present invention is that the bio-effects (cavitation, pressure, high frequency vibration) of the ultrasonic energy delivered by the present invention are, first, essentially minimally thermal. It is mechanical with a contribution (heat due to absorption of energy or energy conversion). Therefore, unnecessary tissue is removed.

In 1991, “Standard for Real-Time Displ”
ay of Thermal and Mechanical Indicie
s on Diagnostic Ultrasound Equipment
American Institute for Ultrasou
nd in Medicine (AIUM) and National Elec
Trial Manufacturers Association (NEM
A) both define the terms "mechanical index" (MI) and "thermal index" (TI) for medical diagnostic ultrasound systems operating in the 1-10 MHz frequency range. I have. Although therapeutic ultrasound is not included within the scope of this criterion, the terms are useful to characterize the sonication.

The mechanical index is calculated by dividing the tissue index by the square root of the frequency F (in MHz).
Peak lean pressure P_ (at the effective point, corrected for attenuation following the beam path)
It is defined as a unit MPa). That is, MI = P_ [MPa] / sqrt (F [MHz]) The allowable range for the medical diagnostic apparatus is up to MI (1.9). The approximate unity MI value described above represents a sound level that can produce a mechanical bioeffect in a human subject.

The thermal index is defined as the product of the average energy W (in mW) times the frequency F (in MHz) divided by a constant 210. That is, TI = W [mW] * F [MHz] / 210 TI of 1 means a temperature increase of 1 ° C. (degrees Celsius) in normally vascularized muscle tissue. The FDA standard for maximum temperature of surface contact ultrasonic devices is:
41 ° C. "Deep heat" ultrasound therapy devices may generate higher temperatures within tissue. However, in the vasoactive area, even slight temperature fluctuations can cause the formation and accumulation of unexpected clots. In addition, the elevated temperature of the tissue can cause inflammation in the treated area. Therefore, TI values above 4 are generally considered a threshold for producing undesirable bioeffects.

[0045] TI values greater than 4 may be calculated by the techniques described above. As defined, the TI parameter represents a steady state condition and has the short term "transient (
transient) irradiation. Typically, using an assumption of 0.3 dB / MHz / cm as the energy absorption rate for vascularized muscle tissue, the appropriate dose of ultrasound will determine the temperature at which thermal energy in the tissue is unacceptable. It can be delivered before it occurs to achieve enhanced cell absorption and / or transfection. Because of the difference in total energy absorption between transient and continuous irradiation, the AIUM definition of TI used herein is referred to as continuous TI, as compared to transient TI.

According to the present invention, ultrasonic energy is provided in a transient TI of less than 4, more preferably less than 2, and most preferably less than 1.

As described, the present invention provides systems and devices for delivering a uniform, broad beam of ultrasonic energy over a fairly large volume of tissue. Thus, a uniform therapeutic effect can be achieved over the desired area of the tissue in a timely manner.

FIG. 1 illustrates an exemplary aspect of the invention, wherein DNA is injected by needle 10 into the musculature 12 of the patient's leg. As described above, the injected DNA spreads rapidly over a section of muscle tissue, region 14. After injection, ultrasonic transducer 1
6 is placed in contact with the tissue, thereby facilitating DNA uptake by directing the ultrasound field to region 14.

FIG. 2 illustrates another exemplary aspect of the present invention, wherein the ultrasound treatment alone, the vein of an arterio-venous (AV) graft 22 of the patient's arm. Oriented to side 20. An ultrasonic transducer 24 with a large viewing area may be placed in the surgical incision 26 and coupled to a sterile fluid (eg, saline) or to the post-operative skin (not shown). It can be located on the top surface. Equivalently (not shown)
The ultrasonic transducer can be placed in a surgical incision for treatment after fistula generation,
It is placed on the patient's skin for treatment of blood vessels after the surgical procedure.

In a preferred aspect of the invention, the ultrasound field is made uniform across the depth of the sample tissue over two orthogonal directions of the sample tissue. FIG. 3 shows a preferred transverse beam distribution 30 of an ultrasonic beam 32 of a broad field transducer 16 placed on the region of mass diffusion 14 within the muscle 12 of the patient's leg 34. In a preferred aspect of the present invention, the sound amplitude is equalized within a defined area 36 on the target area 38. Outside this region of interest, the sound amplitude decreases in any manner. FIG. 4 shows FIG.
7 shows an axial beam distribution 40 for the same clinical configuration as. In a preferred aspect of the invention, the acoustic amplitude is again homogenized within a defined area 42 through the depth 44 of the tissue 14 containing the injected substance. Again, at the proximal or distal to the region of interest, the acoustic beam can take any other amplitude, and the bioeffect retention is maintained within an acceptable range. Preferred and exemplary defined range 36 for uniformity of the ultrasound beam field when scanned
And 42 are within +/- 5 dB over their width or the width of the target area.
More preferably, the uniformity is within +/- 3 dB, most preferably, +/- 1.
. It is within 5 dB.

The area of the target area of the human body varies with the application. For example, for gene therapy, the area of the ultrasound beam field is at least 0.5 cm ² , more preferably at least 1.0 cm ² , and most preferably at least 10 c
m ² .

As shown in FIG. 5, current medical diagnostic ultrasound imaging and Doppler systems pass through a patient's body 52 using a lateral beam width typically in the range of 1 millimeter to 100 microns. Higher frequency (typically 2-30 Mhz)
Designed to electronically or mechanically scan a highly focused and exposed beam 50 of ultrasound. Short transmit bursts, on the order of about 1-3 cycles, provide the best axial resolution. The peak amplitude is limited to just enough energy to output scan the image to the point where resolution drops. While these systems deliver an effectively uniform dose of ultrasound energy across the width of the scan plane 54, the scan plane 54 is typically narrow and one-dimensional, and the frequency is generally
In tissues, the peak amplitude is insufficient for biological effects, mainly due to mechanical effects, and the loading at any one location is poor due to biological effects. Far below what is required for

More specifically, FIG. 6A shows a lateral beam distribution 60 from a representative diagnostic ultrasound imaging system. These distributions are typically 30-50 d from the peak amplitude.
It drops very sharply to B and then substantially widens. Over the scan plane,
The mechanical sweep system typically retains the same peak amplitude as a function of angle, while the stepped array system typically has a 6-12 dB amplitude 62, as shown in FIG. 6A. You can see the variation. At the intersection plane (perpendicular to the capture plane), the beam exhibits a very narrow distribution 64 as shown in FIG. 6B. FIG. 7 shows an axial distribution 70 in which the signal intensity decreases at the center axis of the transducer. Near the band of focus, the beam reaches a peak amplitude, which is relatively uniform over a reasonable depth.

To develop deep heat within the injured muscle 82, a physical treatment transducer 80, as shown in FIG. 8, is typically used. These devices are typically single element, out-of-focus transducers. Due to operation in the near field, these devices present highly irregular ultrasound intensity as both a function of depth and a function of lateral displacement. In fact, FIG. 9 shows a distance of 20 m from the surface.
Shown is a lateral distribution 90 modeled with a 16 mm diameter at 1 m, 1 MHz out-of-focus transducer. A change in signal strength of 1 across the device opening
Exceeds 5 dB. From the transducer surface to the focal length, the shape of the lateral distribution also varies drastically with depth. FIG. 10 shows an axial distribution 100 (ultrasonic intensity along the central axis of the transducer) modeled for the same device. The ultrasonic intensity in the first 30 mm, which is in direct contact with the device and corresponds to the patient's tissue under the device,
Tested to vary over a range of 20 dB. A variant of the body treatment system for laboratory experiments is available from ImaRx corporation of Tucson, AZ.
Tion manufactured by Sonoporator 100, which has a maximum of 2 W / cm ² (MI = 0.2 in the frequency range of 1 MHz).
The ultrasonic wave of 5) is delivered from a 16 mm diameter transducer. This type of device is expected to deliver a beam distribution as described above.

High-intensity, focused ultrasound (HIFU) systems are typically single-element, focused transducers that deliver a beam distribution, similar to transducers in diagnostic imaging systems Use These transducers are then scanned over the patient's body surface, developing a thermal lesion at the depth of focus.

The present invention instead presents a uniform ultrasonic field over a large area, as shown in FIGS. Transcends the performance of existing ultrasound systems shown in each of FIGS.

FIG. 11 is a cross-sectional elevation view of a first embodiment of a current, broad beam, uniform irradiation ultrasound delivery system. Ultrasound delivery system 110 includes a housing 111 having a proximal end 112 and a distal end 114. The ultrasonic transducer 115
As shown, it is located at the proximal end 112 of the housing 111. Preferably,
The housing 111 may be of a generally cylindrical shape and may taper toward a narrow distal end 114 as shown. Preferably, the distal end 114 of the housing 111 is preferably a flexible skin contact window 1 that can be supported against the skin of the patient P.
17 covered. Preferably, a standard acoustic coupling gel is applied between the window 117 and the skin of the patient P to facilitate the transfer of therapeutic ultrasound energy to the patient.

Preferably, the housing 111 is filled with an acoustic coupling material 113, which preferably comprises a fluid, such as water or oil, with or without additives. Fluid 113 flows from transducer 115 to skin contact window 117,
It operates to conduct a beam of ultrasonic energy through the fluid 113.

In one aspect, as shown, the transducer 115 can be preferably flat and circular in shape. In a preferred aspect, the diameter of the transducer 115 is 10 mm
It is in the range of ~100mm, giving a surface area of 0.8cm ² ~80cm ^2.

The transducer 115 may be made of a piezoelectric ceramic material (eg, PZT ceramic, or more specifically, PZT-8 ceramic, or another variation of a rigid piezoelectric ceramic that is optimized for high power operation). Can be made. PZT-8 ceramic material or equivalent is available from OH, Cleveland's Morgan.
Matroc, Inc. Available from the largest suppliers of piezoelectric ceramics. Alternatively, the converter is a Stra, from PA, State College.
tun Technologies, Inc. Can be manufactured from a single crystal piezoelectric material, such as the material manufactured by. Further, the piezoelectric material is not limited and may alternatively be made from a family of materials including lithium niobate, lead titanate, lead metaniobate, various composites, and any other suitable materials. Further, variations in transducer design may also include using magnetostrictive materials, such as ultrasonic driver elements.

The transducer 115 in direct contact with the fluid path medium 113 is shown in FIG. If it is necessary to electrically insulate the transducer from the fluid medium, the transducer may be NY, Woo
ds.Case Corp. 1B manufactured by Hamamatsu
31 can be coated with an insulating material such as acrylic. Alternatively, the front surface of the transducer may function as one or more impedance matching layers for corrugation, mechanical strength, or, as before, electrical isolation. For a single impedance matching layer, a quarter wavelength thick 3103 casting epoxy manufactured by Tra-Con of Bedford, MA is preferred. Ideally, the impedance matching layer will exhibit minimal acoustic attenuation as any absorbed energy heats the delivery device.

An air pocket 118 may be provided on the back side of the transducer 115 so that substantially all of the ultrasonic energy emitted by the transducer 115 is, via the fluid 113, distal to the housing 111. Oriented in the direction of skin contact window 117 at end 114. The air-ceramic interface on the back of the transducer includes a good reflector that returns acoustic energy in a distal direction. Air is also a conductor that is extremely impermeable to ultrasonic energy. Alternatively, low impedance acoustic materials with low acoustic attenuation may be utilized for the mechanical strength of the device.

Preferably, the structural sidewall 111 of the delivery device housing is ideally coated with an anti-reflective, highly absorbent material, such as a high load silicone rubber. Thus, sidelobe energy from the transducer in the housing cannot be scattered to interfere with the previous acoustic beam.

Preferably, the physical size of the delivery device opening at the distal end can be made so that the effect of the beam stop on the previous ultrasound beam is within the uniform specifications of the device (ie (Within the preferred region of uniform ultrasonic irradiation as described in the specification)
3 is a constructive / destructive wave pattern with amplitude varying wells.

FIGS. 12A and 12B show modeled transverse beam distributions 120 and 122 for the system of FIG. 11, featuring a 25.4 mm diameter, 1 MHz out-of-focus transducer. . The beam distribution is controlled by skin contact windows 117-107.
At a depth of mm and 200 mm, this corresponds to an ultrasonic amplitude perpendicular to the axis A2 which coincides with the center of the focal region and the far field of the transducer.

FIG. 13 shows an axial beam distribution 130 modeled for the same transducer. The beam distribution is from the skin contact window 117 (distance = 0) to 1
It corresponds to an ultrasound amplitude along the central axis A2 of the system 110 up to an axial distance of 00 mm.

In this simplest exemplary embodiment, the ultrasonic axial amplitude 130 is 6 d from about 62 mm away from the transducer surface to about 300 mm away from the surface.
It is uniform within B. At a focal length of 107 mm, the lateral distribution 120 is 1
Suggests uniformity within 6 dB on a 0 mm diameter. At a far field of 200 mm, the lateral distribution 122 suggests a uniformity within 6 dB over a 17 mm diameter. The length of the transducer housing 111, and consequently the length of the channel 113, can be adjusted to align either the focal zone or any far field point above the center of the muscle injection point. Such adjustment provides a corresponding ultrasound beam width. It is understood that the lateral beam distributions 120 and 122 of FIGS. 12A and 12B provide a substantially more uniform ultrasound irradiation than the near field distribution 90 of FIG.

Preferably, the uniform and wide field of ultrasonic energy of the present invention is 10d over an axial distance from the skin contact window to a distance beyond the depth of the target area of interest.
And may vary by less than B (and more preferably 6 dB, and most preferably 3 dB).

Also preferably, the uniform and broad field of ultrasonic energy of the present invention is:
It can vary by less than 10 dB (and more preferably 6 dB, and most preferably 3 dB) over a beam width of at least 8 mm, more preferably a beam width of 12 mm, and most preferably a beam width of 35 mm.

FIG. 14 shows a simplified block diagram of an electronic system 140 for driving the converter of FIG. A user operates the system via a user interface 141 to a computer or controller subsystem 142. Via the digital I / O device 143, the computer generates a signal generator 144 that generates an RF drive signal, a modulator 145 that formats the number of cycles per burst and sets a burst rate, a variable gain output amplifier 146, and an impedance matching circuit. 147 and finally the converter 148.

[0071] Even in a further variation of the single element, the broad beam device, the transducer, may be coupled to the patient via a solid acoustic medium or a buffer rod as compared to the fluid medium described above. The solid acoustic medium then acoustically decouples from the delivery device housing. Ideally, the solid medium should have an impedance of the piezoelectric ceramic of the transducer (typically 33 Mrayl) and the impedance of the patient (typically 1
. 5Mrayl) and may ideally have minimal acoustic attenuation (ideally on the order of 0.1 dB / MHz / cm or less). Such attenuation results in attenuation of the ultrasound beam and consequently device heating. Candidate materials for solid media include aluminum metal and glass. For improved acoustic coupling with the patient, these solid media materials function as acoustic impedance matching layers in the form of a quarter wavelength thick intermediate acoustic impedance material, typically consisting of a polymer based or loaded epoxy. Acoustic impedance matching methods are known to those skilled in the art.

In the following paragraphs, further variants of the broad beam ultrasonic transducer of the present invention are presented. All of the arrangements and operating techniques from above apply equally to:

FIG. 15 illustrates an alternative embodiment 150 of the broad aperture ultrasonic beam delivery system of the present invention, in which a curved ultrasonic transducer 155 is suspended within a housing 151. By bending, the transducer 155 reduces the width of the beam of ultrasonic energy B, and this beam of ultrasonic energy B
3 and through the skin contact window 157 and then spread within the patient P. As with the above system, an air pocket 158 is provided to ensure that the maximum ultrasonic energy emitted from the transducer 155 passes toward and into the patient P.

As shown in FIG. 15, the beam B of ultrasonic energy narrows through a focal region 159 located within the fluid 153, whereby a wide uniform field of ultrasonic energy is generated by DNA or other The therapeutic biological material extends beyond the fairly large target area T of the injected patient P. In this way, the distance from the transducer 155 to the target area T may be reduced for a smaller physical size of the delivery device.

FIG. 16 illustrates yet another implementation of the present invention in which an acoustic refraction material 166 is mounted on an ultrasound transducer 165 to form an acoustic beam B at an appropriate depth in a patient P to a focal region 169. The form is shown. In a preferred aspect, the acoustic refraction material 166 comprises
Silicon rubber (convex lens) with an internal sound speed of about 1.0 mm / μsec, or a sound velocity of about 2.5 mm / μsec, compared to water with a velocity of sound of about 1.5 mm / μsec Some sound speed is epoxy or plastic (concave lens)
May be included. Keeping the acoustic impedance of the refractive material close to that of water reduces the amount of internal refraction and standing waves in the device. Further, the skin contact window 167 has a curved shape, which may help further narrow or widen the beam of ultrasonic energy B passing through the window.

The single-element beam profiles shown in FIGS. 12A and 12B can be substantially widened by adding an annulus 172 around the center disk 170 as shown in FIG. In an exemplary embodiment, the outer diameter of the annulus is equal to twice the square root of the outer diameter of the central disk. The gap between the center disk and the annulus is sufficient to prevent acoustic crosstalk between the two members of the piezoceramic.

FIG. 18 shows a simplified schematic diagram of the electrical system 180 driving the converter of FIG. A user operates the system via a user interface 181 of a computer or controller subsystem 182. Via the digital I / O device 183, the computer generates a signal generator 184 for generating the RF drive signal, a modulator 185 for initializing the number of cycles per burst and setting the burst rate, or a time delay or phase shift. Circuit 189, variable gain output amplifiers 186A and 186B, impedance matching circuit 187
A and 187B, and finally converters 188A and 188B. Amplifiers 186A and 186B need not be operated at the same gain setting. Further, the phase shift circuit can be set to any angle from 0 to 360 degrees.

In an exemplary application, the phase shifter is set to zero and the amplifiers 186B and 1
86B had a gain setting with a ratio of 1.0: 0.5. FIG. 19 shows a modeled transverse beam profile 190. Of particular note, the 6 dB beamwidth opens up to 25.5 mm, despite about 10 dB loss in signal strength.

The beam divergence is caused by the reduction of the main lobe and the enhancement of the side lobes of the ultrasound beam. FIG. 20 shows a modeled axial profile 200 for this center disk and annulus pair, which when compared to the modeled axial profile of FIG. 13 shows a 10 dB reduction in the focal zone. FIG. 21A
And 21B are 10 mm proximal and 1 mm relative to the lateral profile of FIG.
Figure 3 shows a modeled transverse beam profile 0mm distal. Current use (
4 illustrates maintaining a wide beam over the depth of the field for current application. Specifically, FIGS. 21A and 21B each show 24
. 3 shows profiles at 3 mm and 26.8 mm 6 dB beamwidth.

It is understood that the present invention is not limited to a single ring around a central disk with a particular amplitude and phase of the drive signal as described above. Indeed, an infinite set of rings with extremely infinite openings can be programmed to produce a perfect square beam profile with no ripple over the beam. With respect to the drive electronics, additional channels including phase shifters or time delays, output amplifiers, and impedance matching circuits are required.

FIG. 22 shows yet another embodiment of the present invention. The cylindrical ultrasonic transducer 225 is
It is suspended in the housing 221. In this aspect of the invention, the transducer 225 preferably has a hollow interior 228 filled with air, so that the ultrasonic energy emitted by the transducer 225 passes through the fluid 223 through a curved acoustic reflection. Pointed radially outward at body 229. The acoustic reflector 229 then reflects, directs, and directs the beam of ultrasonic energy passing through the skin contact window 227 into the patient P. An advantage of the present invention is to provide a compact housing for forming a therapeutic ultrasound beam at a preferred depth inside a patient. This design also provides a larger surface area of the piezoceramic for greater ultrasonic energy delivery.

FIG. 23 shows yet another embodiment of the present invention in which the annular ultrasonic transducer 235 is located near the distal end 234 of the housing 231. Transducer 235 directs the ultrasonic energy through fluid 233 to acoustic reflector 239, which in turn passes the ultrasonic energy through fluid 233 and skin contact window 237 to patient P. In this embodiment, both the transducer 235 and the acoustic reflector 239 can be bent either convex or concave, helping to focus or spread the beam of ultrasonic energy on the target area T of the patient. An advantage of this embodiment of the invention is that a large ratio of transducer cross-sectional area to beam cross-sectional area can be achieved, giving a large margin for drive capability, and therefore the piezoelectric ceramic is driven at a relatively low voltage Is to make it possible. An annulus air pocket 238 is provided behind the transducer 235 so that substantially all of the ultrasonic energy emitted from the transducer 235 is directed to the acoustic reflector 239.

If the area of interest on the patient's body is larger than the area that can be easily covered by only one transducer arrangement, or if it can be covered by successive step-by-step movements of the transducer arrangement, scanning techniques may be used. Can be used. As shown in FIG. 24, the delivery device 240 is configured such that the ultrasound transducer 245 is preferentially mounted on an orthogonal axis and has a pivot position 242 (only one pivot position is shown for ease of illustration). Includes a housing 241 that rotates back and forth to the center. Therefore, converter 2
45 is adapted to rotate about a pivot position 242 in two vertical axes;
This causes the narrowed beam of therapeutic ultrasound energy 249 to travel to the target area T
May be performed.

A representative top plan view of a raster scan 251 generated by the system of FIG. 24 is shown in FIG. In FIG. 25, the smaller diameter focal region 259 is
A raster scan is performed over a larger diameter target area T. If it is desired to achieve a specific loading of the ultrasonic emission at any point in the target area, the physical distance of the continuous emission of the raster scan converter can be adjusted. A specific percentage loading rate requires that the effective beam width of the transducer cover a particular point in the sample for the same percentage of time (where a continuous or higher burst from the transducer) Velocity release is required).

Any of the transducers shown in FIGS. 11, 15, 16, 17, 22 and 23 can be mounted at a pivot location 242 of the delivery device 240 of FIG. All of the individual functions can be assembled in all or part of the assembly of the delivery device.

FIG. 26 illustrates yet another scanning ultrasound delivery device 320. In the scanning ultrasound delivery device 320, a transducer 325 with an air backing cavity is mounted such that the ultrasound beam B exits parallel to the surface of the patient. The ultrasonic beam B passing through the fluid medium 323 is reflected by an acoustic mirror 321 having an air backing 328 and travels through the patient coupling window 327 to the patient P. Providing an air backing behind the mirror eliminates any possibility of ultrasound energy being incident on the mirror due to refraction and re-emission with destructive interference with the main ultrasound beam. The reflecting surface may be flat or curved, and may narrow or widen the ultrasonic beam B. By mounting the transducer on the longitudinal shaft 322, the transducer can be pushed forward or pulled backward, thereby shifting the focus or optimum point of the ultrasound beam to a shallower region or deeper within the patient. Hit the site. By attaching the mirror rotation shaft 324, the mirror can be rotated or toggled, sweeping the ultrasound beam B across the affected area.

FIG. 27 illustrates a still further scanning ultrasound delivery device 260. Scanning ultrasound delivery device 260 includes a number of single element or ring array transducers 265 of the type described above, with or without narrowing or spreading means, for the purpose of illuminating a large area. The transducers can be mounted in a row or arranged in parallel rows (not shown for ease of illustration). Delivery device housing 26
1 includes a fluid 263 for propagation of ultrasonic energy from the transducer 265 into the device housing window 267 and into the patient P. If the transducer 265 is larger in the transverse dimension than the acoustic beam at the patient's target area T, then the transducer:
It can be mounted at an angle as shown.

There are several ways to drive the transducer array in the delivery device 260. In the exemplary technique, the signal generator system 270 includes a central controller 272 that drives a frequency generator 274, as shown in FIG.
, Modulator 275, switch (multiplexer) 279, and amplifier 27
6 and an impedance matching circuit 277 for each transducer 278 in the array
Is provided. The controller continuously switches the signal from the output of the modulator or preamplifier stage to the final amplifier stage of each converter channel and drives all converters continuously during one pulse repetition period. This assumes that the product of the loading rate and the number of devices is less than one. If this assumption cannot be guaranteed,
One or more individual transducers can be assigned to a single channel, and the ultrasound beams being converted do not overlap. In this way, a higher loading factor can be achieved with each transducer.

Thus, in accordance with the present invention, individual converters 265 can be operated such that individual converters 265 are alternately activated, and each converter, or combination of converters, is continuously activated and deactivated. Is done. The advantage of individually controlling the operation of each transducer 265 is that
The system loading rate can be increased. Further, when operating multiple transducers simultaneously, it may be preferable to operate the transducers apart from each other, thereby avoiding constructive or destructive interference between the individual ultrasound beams.

FIG. 29 shows a second embodiment including a plurality of individual ultrasonic transducer elements 281, 282, 283, etc.
4 shows a two-dimensional ultrasonic transducer array 280. In a preferred aspect, the ultrasonic element 28
Each of 1, 282, 283, etc. is suitably individually controlled using a dedicated time delay and output amplifier. This allows the phase of the signal at each element 281, 282, 283, etc., to be adjusted to direct the formed mixed ultrasound beam to a particular location within the patient's body, or to produce a particular beam at a raster scan. A beam having a width may be swept. Each of the elements 281, 282, 283, etc. must be of a sufficiently small size that their beam width covers the entire area of interest.

The transducer array of FIG. 29 may be mounted inside a fluid-filled housing, as described herein, or may be applied directly to the patient's skin.

Experiment Experiment 1 As described in co-pending US patent application Ser. No. 09 / 364,616, FIG.
Prototype hardware as shown in Figure 1 (specifically, a 25.4 mm diameter 1 with a water path distance of 10 cm and a skin contact window of 25.4 mm diameter).
The New Zealand white rabbit's thigh muscle was sonicated using an ultrasound delivery system with an out-of-focus transducer at MHz), followed by injection of β-galactosidase plasmid DNA into the thigh muscle. Plasmid DNA was injected into one of the thigh muscles, immediately followed by sonication over and in the vicinity of the injection site. Each ultrasound exposure had a beam width of approximately 10 mm, a MI level of approximately 1.8 for 60 seconds, a loading of 6% (30 cycles at 1890 Hz repetition rate), and a calculated tissue temperature of less than 5 ° C. It was characterized by a rise.

After 5 days, the animals were sacrificed. Each thigh muscle had nine samples collected in a 3x3 array in the area irradiated with ultrasound. The muscle is a sample
It had dimensions of about 1 × 1 × 0.5 cm (W × L × H). Subsequently, proteins were extracted from the tissues and measured for β-galactosidase enzyme activity and total protein. β-galactosidase activity was normalized to protein content and expressed as activity per protein mass. Subsequently, for each of the white rabbit thigh muscles, the average β-galactosidase activity was calculated from the nine samples.

The results are summarized in Tables 1 and 2. Here, the condition without ultrasonic wave (No US) and the condition of three ultrasonic waves (US) are compared. Expression levels are shown for each treatment containing average β-galactosidase activity from 9-11 rabbits for each group. Ultrasound conditions (1 MHz, 1.8 MI (mechanical index), 6% loading) resulted in a 25-fold enhancement of transfection over No US irradiation conditions and other ultrasound conditions, as described below. With the best results.

[0095]

[Table 1] At low frequency irradiation treated at 193 kHz under similar transfection conditions, the effect of ultrasound was studied and the results are shown in Table 2. 193KHz
, 1.09 MI, and 1.3% loading, an approximately 9-fold increase in β-galactosidase expression was observed compared to the No US condition.

[0096]

[Table 2] In the second part of the experiment, ultrasonic pretreatment was performed. For details,
The above experiment was repeated at 1 MHz, 1.8 MI, 6% DC conditions and 5 US irradiation performed on one injection site as set above. However,
The US was made prior to β-galactosidase plasmid DNA injection. As shown in Table 1 above, 24.5 fold (1%) in β-galactosidase transfection achieved by applying US after β-galactosidase injection.
This US pre-treatment achieved a 10.5-fold (58 / 5.5) increase in β-galactosidase transfection as compared to a 35 / 5.5) increase.

Experiment 2 As described in co-pending US patent application Ser. No. 09 / 364,616,
Complete removal of the internal femoral artery 10 days prior to treatment resulted in ischemia in the hind paw of the rabbit. The rabbit was evaluated in three fields 30 days after treatment. The three fields are the blood pressure ratio (the ratio of the blood pressure at the ankle of the ischemic hind leg compared to the blood pressure of the untreated animal), blood flow (measured at the distal end of the iliac artery with Doppler flow wire) Flow rate) and angiographic score (number of capillaries visible in each square of the grid expressing plasmid DNA in native arteries, collateral and angiographic images). In a first experiment, 100 micrograms of VEGF was injected into the hind paw of a young rabbit. In a second experiment, old rabbits were injected with 500 micrograms of VEGF expressing plasmid DNA. Old rabbits were specially selected for the second experiment. This is because these rabbits have impaired angiogenesis. VE expressing plasmid DNA of these animals
Using higher doses of GF allows demonstration of increased ultrasound in normally plateaued or saturated biological systems.

In both the first and second parts of the experiment, V expressing plasmid DNA
EGF was injected into five places on the thigh muscle, and immediately thereafter, ultrasonic irradiation was performed at seven places adjacent to the injection place. Ultrasound in the range of 1 MHz, 1.8 MI, and 6% loading was provided with the wide beam delivery system shown in FIG. Comparison between the control group of rabbits and the group of sonicated rabbits and the group of non-sonicated rabbits was performed using VE expressing plasmid DNA.
Immediately after the injection of GF.

FIG. 29 shows the results of the blood pressure ratio of the experiment. Here, the blood pressure ratio is derived from blood pressure measurements on the ankle of the ischemic hind foot and on the contralateral outer normal hind foot. In both young and old rabbits, non-sonicated ischemic hind paws remain at 50% of normal, a value that indicates flow through the untreated outer femoral artery.
Most certainly reflects. In older rabbits, mere sonication did not result in higher blood pressure than in control ischemic hind legs.
In young rabbits, treatment with VEGF expressing plasmid DNA without ultrasound did not result in elevated blood pressure. In older rabbits, on the other hand, blood pressure was shown to improve moderately with increasing infusion volume. Finally, in both young and old rabbits, the combination of VEGF expressing plasmid DNA and ultrasound resulted in a substantial improvement in blood pressure to near normal values. These data suggest that there is substantial benefit from the combination of DNA injection and sonication. Figures 31 and 32 show the results of blood flow and angiography scores, respectively, and clearly support the blood pressure results for the same experiment.

Experiment 3 As described in co-pending US patent application Ser. No. 09 / 223,230 (the intensity and duration of the ultrasonic energy can be selected, thereby allowing the surrounding tissue or structure within the artery to be selected). More effective thickening (hy) with new intimal layers without significant damage
perplasia), but a series of in vivo catheter experiments were performed in a porcine animal model.

In particular, 10 seconds to 1000 seconds, preferably 30 seconds to 500 seconds, more preferably 6 seconds
New intimal thickening for vibrational energies having a treatment time in the range of 0-300 seconds and a mechanical index in the range of 0.1-50, preferably 0.2-10, more preferably 0.5-5. By irradiating the target area of the at-risk artery, the proliferation of vascular smooth muscle cells in the new intimal layer of the artery is reduced by at least 2% (compared to untreated controls) after 7 days. Most can be reduced by at least 4%, and sometimes more than 6%.

The reduction in thickening mass obtained after 28 days is typically at least 10%, usually at least 20%, and preferably at least 30%. Such inhibition can be achieved without significant necrosis of smooth muscle cells.

[0103] General, preferred and exemplary values for each of these perimeters are shown in Table 3.

[0104]

[Table 3] Experiments in the application of this task have been performed with ultrasound-based catheters, and similar results have been obtained by manipulating the present invention to provide a suitably uniform area of ultrasound energy over a large target area. It can be obtained by dermal administration.

Experiment 4 As described in co-pending US patent application Ser. No. 09 / 345,661,
In the device configuration of FIG. 11, transcutaneous ultrasound energy (also used for VEGF and β-galactosidase experiments) was used to create fistulas between the femoral artery and the femoral vein, and the carotid artery and the jugular vein. It was applied with a surgical incision in the sheep when performing the implantation during the period. Each of the surgical sites was sonicated three times, first directly irradiating the center of the site, followed by irradiating its periphery and far end. Each ultrasonic irradiation had a beam width of about 10 mm, a MI level of about 3.0 for 120 seconds, and a loading rate of 1% (30 cycles at a repetition rate of 315 Hz).
, And a calculated increase in tissue temperature of less than 3 ° C.

All controls and sonicated implants and fistulas remained patent for one month after generation. Measurements of the initial venous thickness of the graft (including initial thickening) result in a continuous decrease in initial thickness distally from the graft (less in the sonicated group). Growth). For the venous side of the fistula, the maximum initial thickness with the organized thrombus added was 0.45 ± 0.22 mm in the control group and 0.18 ± 0.21 mm in the treated group. This difference was statistically significant.

More specifically, transcutaneous, (or percutaneous) with ultrasound in the range of 1 MHz, 3.0 MI, and 1% loading.
Irradiation of target sites in blood vessels at risk of new intimal thickening for uniform irradiation of neous)) slowed down the thickening affecting the vessel wall.

A common factor in these four experiments (three different animal models) was that the majority of the tissue required sonication. A common result was that the effects of ultrasound treatment were beneficial.

Although the above is a complete description of the preferred embodiment of the invention, various alternatives, modifications, and equivalents may be used. Therefore, it is to be understood that the above description is not intended to limit the scope of the invention, which is defined by the appended claims.

[Brief description of the drawings]

FIG. 1 illustrates an ultrasound system for enhancing transfection of an injected substance in skeletal muscle.

FIG. 2 illustrates an ultrasound system for treating a post-operative vascular incision.

FIG. 3 illustrates a characteristic diagram of a preferred lateral beam superimposed over a target area on a patient's body.

FIG. 4 illustrates a characteristic diagram of a preferred lateral beam superimposed over a target area on a patient's body.

FIG. 5 illustrates conventional, medical diagnostic ultrasound imaging of the human body.

FIG. 6A illustrates a lateral in-plane beam profile from a medical diagnostic imaging system.

FIG. 6B shows a lateral cross-section from a medical diagnostic imaging system.
FIG. 3 illustrates a beam characteristic diagram of FIG.

FIG. 7 illustrates an axial beam profile from a medical diagnostic imaging system.

FIG. 8 illustrates the application of therapeutic ultrasound for “deep heat” processing of human muscle.

FIG. 9 illustrates an exemplary lateral beam profile from an exemplary physical treatment ultrasound system.

FIG. 10 illustrates an exemplary axial beam profile from an exemplary physical treatment ultrasound system.

FIG. 11 is a side sectional elevation view of a first embodiment of the wide aperture beam delivery system of the present invention.

FIG. 12A illustrates an exemplary transverse beam characteristic diagram of the transducer of FIG. 11;

FIG. 12B illustrates another exemplary lateral beam characteristic diagram of the transducer of FIG. 11;

FIG. 13 illustrates an exemplary axial beam profile of the transducer of FIG. 11;

FIG. 14 shows a simplified block diagram of an electronic device for driving the converter of FIG. 11;

FIG. 15 is a side cross-sectional elevation view of a second embodiment of the wide aperture beam delivery system of the present invention with a curved ultrasonic transducer.

FIG. 16 is a side cross-sectional elevation view of a third embodiment of the wide aperture beam delivery system of the present invention comprising an acoustically reflective material attached to a transducer.

FIG. 17 is a front view of the acoustic aperture of the annular array transducer.

FIG. 18 shows a simplified block diagram of the electronic device of FIG.

FIG. 19 illustrates an exemplary lateral beam profile of the transducer of FIG.

FIG. 20 illustrates an exemplary axial beam profile of the transducer of FIG. 17;

FIG. 21A illustrates an exemplary proximal lateral beam profile of the transducer of FIG. 17;

FIG. 21B illustrates a distal lateral beam profile of the transducer of FIG. 17;

FIG. 22 is a side sectional elevation view of a fourth embodiment of the wide aperture beam delivery system of the present invention with a cylindrically shaped transducer.

FIG. 23 is a side cross-sectional view of a fifth embodiment of the wide aperture beam delivery system of the present invention with an annular transducer.

FIG. 24 is a side cross-sectional elevation view of a sixth embodiment of the wide aperture beam delivery system of the present invention adapted to raster scan a therapeutic ultrasound beam.

FIG. 25 is a top plan view of a raster scan generated by the system of FIG. 24;

FIG. 26 is a side cross-sectional elevation view of a sixth embodiment of the wide aperture beam delivery system of the present invention with a depth adjusted transducer and a rotating ultrasonic mirror.

FIG. 27 is a side cross-sectional elevation view of a seventh embodiment of the wide aperture beam delivery system of the present invention comprising a plurality of individual transducers.

FIG. 28 shows a simplified block diagram of an electronic device for driving the converter of FIG. 27.

FIG. 29 is a front view of an eighth embodiment of the wide aperture beam delivery system of the present invention comprising a two-dimensional transducer ray.

FIG. 30 graphically presents blood pressure ratio data for a rabbit ischemic hind limb experiment.

FIG. 31 graphically presents blood flow data for a rabbit ischemic hind limb experiment.

FIG. 32 graphically presents angiographic score data for a rabbit ischemic hind limb experiment.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, (72) Invention NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW Mackenzie, John Earl. United States California 94070, San Carlos, Eaton Avenue 1742 (72) Inventor Cowan, Mark W .. United States 94539, Fremont, Mandan Place 1766 F-term (reference) 4C060 KK50 MM01 MM24 4C167 AA71 AA80 BB45 CC01 CC30 EE01 EE03 EE20 GG16 HH08 HH19

Claims (78)

[Claims] 1. A method for increasing cellular absorption of a substance delivered to a target area of a patient's body, comprising: delivering the substance to the target area; and across a large area of the target area. Applying a uniform field of ultrasonic energy, wherein the ultrasonic energy is of a type and amount sufficient to increase cellular absorption of the substance into the target area. Method. 2. The method of claim 1, wherein the ultrasonic energy is strong enough to cause cell absorption, but weak enough to prevent cell lysis. 3. The method of claim 1, wherein the substance is injected intramuscularly as a bolus into the target area. 4. The method of claim 1, wherein the uniform field comprises a field that varies in intensity laterally across the width of the field by less than 10 dB. 5. The method of claim 1, wherein the uniform field comprises a field that varies in intensity laterally across the width of the field by less than 6 dB. 6. The method of claim 1, wherein the uniform field comprises a field that varies in intensity laterally across the width of the field by less than 3 dB. 7. The method of claim 1, wherein the uniform field is axially across a depth of the target area,
The method of claim 1, comprising a field whose intensity changes by less than 10 dB. 8. The method of claim 1, wherein the uniform field is axially across the depth of the target area,
The method of claim 1, comprising a field whose intensity changes by less than 6 dB. 9. The method according to claim 8, wherein the uniform field is axially across the depth of the target area,
The method of claim 1, comprising a field whose intensity changes by less than 6 dB. 10. The method of claim 1, wherein the uniform field comprises a field that varies in intensity axially across the depth of the target area by less than 3 dB. 11. The method of claim 1, wherein the ultrasonic energy has a mechanical index between 0.1 and 20. 12. The method of claim 1, wherein said ultrasonic energy has a mechanical index between 0.3 and 15. 13. The method of claim 1, wherein said ultrasonic energy has a mechanical index of 0.5 to 10. 14. The method of claim 1, wherein said ultrasonic energy has a transient thermal index of less than 4. 15. The method of claim 1, wherein the ultrasonic energy is applied at a loading of 0.1% to 50%. 16. The method of claim 1, wherein the ultrasonic energy is applied at a loading of between 0.3% and 20%. 17. The method of claim 1, wherein said ultrasonic energy is applied at a loading of 0.5% to 5%. 18. The method of claim 1, wherein said ultrasonic energy is applied at a frequency between 20 kHz and 5 MHz. 19. The method of claim 1, wherein said ultrasonic energy is applied at a frequency between 100 kHz and 1.5 MHz. 20. The method of claim 1, wherein said ultrasonic energy field has a beam width of at least 0.5 cm. 21. The method of claim 1, wherein said ultrasonic energy field has a beam width of at least 1.2 cm. 22. The method of claim 1, wherein said ultrasonic energy field has a beam width of at least 3.5 cm. 23. The method of claim 1, wherein said target area has a percutaneous depth of 1 cm to 4 cm. 24. The method of claim 1, wherein the uniform field of ultrasound energy is applied across a wide area of the target area by a wide beam ultrasound delivery system. A beam ultrasound delivery system comprising: a housing having an opening at a distal end; a skin contact window covering the opening; an ultrasound transducer mounted within the housing; and a contacting at least one surface of the transducer. And an acoustic couplant material that contacts the skin contact window. 25. The method of claim 1, wherein the uniform field of ultrasonic energy is applied across a wide area of the target area while delivering the substance to the target area. 26. The method of claim 1, wherein the uniform field of ultrasonic energy is applied across a large area of the target area before delivering the substance to the target area. 27. The method of claim 1, wherein the uniform field of ultrasonic energy is applied across a large area of the target area immediately after delivering the substance to the target area. 28. The method of claim 1, wherein the uniform field of ultrasonic energy is applied across a large area of the target area 15 to 60 minutes after delivering the substance to the target area. Method. 29. A method for increasing transfection of DNA delivered to a target area of a patient's body, comprising: delivering the DNA to the target area; and across a large area of the target area. Applying a uniform field of ultrasonic energy, said ultrasonic energy being of a type and amount sufficient to increase transfection of said DNA in said target region. 30. The method of claim 29, wherein said DNA comprises an expression vector. The DNA may be VEGF, EPO, Factor VIII, I
30. The method of claim 29, wherein the method expresses a protein selected from the group consisting of factor X, angiostatin, and endostatin. 32. The method of claim 29, wherein the ultrasonic energy is strong enough to cause transfection of the DNA, but weak enough to prevent DNA splitting. 33. The method of claim 29, wherein said DNA is injected intramuscularly as a bolus into said target area. 34. The method according to claim 26, wherein the uniform field is laterally 10 dB across the width of the field.
30. The method of claim 29, comprising a field whose intensity changes by less than. 35. The method of claim 29, wherein the uniform field comprises a field that varies in intensity laterally across the width of the field by less than 6 dB. 36. The method of claim 29, wherein the uniform field comprises a field that varies in intensity laterally across the width of the field by less than 3 dB. 37. The method of claim 29, wherein the uniform field comprises a field that varies in intensity axially across the depth of the target area by less than 10 dB. 38. The method of claim 29, wherein the uniform field comprises a field that varies in intensity axially across the depth of the target area by less than 6 dB. 39. The method of claim 29, wherein the uniform field comprises a field that varies in intensity axially across the depth of the target area by less than 3 dB. 40. The method of claim 29, wherein said ultrasonic energy has a mechanical index between 0.1 and 20. 41. The method of claim 29, wherein said ultrasonic energy has a mechanical index of 0.3 to 15. 42. The method of claim 29, wherein said ultrasonic energy has a mechanical index of 0.5 to 10. 43. The method of claim 29, wherein said ultrasonic energy has a mechanical index of 0.5 to 5. 44. The method of claim 29, wherein said ultrasonic energy has a transient thermal index of less than 4. 45. The method of claim 29, wherein the ultrasonic energy is applied at a loading of 0.1% to 50%. 46. The method of claim 29, wherein said ultrasonic energy is applied at a loading of 0.3% to 20%. 47. The method of claim 29, wherein the ultrasonic energy is applied at a loading of 0.5% to 5%. 48. The method of claim 29, wherein said ultrasonic energy is applied at a frequency between 20 kHz and 5 MHz. 49. The method of claim 29, wherein said ultrasonic energy is applied at a frequency between 100 kHz and 1.5 MHz. 50. The method of claim 29, wherein said ultrasonic energy field has a beam width of at least 0.5 cm. 51. The method of claim 29, wherein said ultrasonic energy field has a beam width of at least 1.2 cm. 52. The method of claim 29, wherein said ultrasonic energy field has a beam width of at least 3.5 cm. 53. The method of claim 29, wherein said target area has a percutaneous depth of 1 cm to 4 cm. 54. The method of claim 29, wherein applying a uniform field of ultrasonic energy comprises: contacting a window of the housing with a patient's skin; and within the housing. Driving the ultrasonic transducer provided in and delivering the ultrasonic energy. 55. The uniform field of ultrasound is applied across the wide area of the target area while delivering the DNA to the target area.
The method described in. 56. The method of claim 29, wherein said uniform field of ultrasound is applied across said large area of said target area before delivering said DNA to said target area. 57. The method of claim 29, wherein said uniform field of ultrasound is applied across said wide area of said target area immediately after delivering said DNA to said target area. 58. The uniform field of ultrasound is applied across the wide area of the target area 15 to 60 minutes after delivering the DNA to the target area.
A method according to claim 29. 59. A method of inhibiting intimal hyperplasia, comprising: applying a uniform field of ultrasonic energy across a large area of a patient's vasculature, the method comprising: Is of a type and amount sufficient to inhibit intimal hyperplasia. 60. The method of claim 59, wherein said ultrasonic energy is applied at a frequency between 100 kHz and 5 MHz. 61. The method of claim 59, wherein said ultrasonic energy is applied with a mechanical index between 0.1 and 50. 62. The method of claim 59, wherein said ultrasonic energy is applied at a loading of 0.1-100%. 63. The ultrasonic energy is applied at a frequency and intensity of 0.1W / cm ² ~100W / cm ² of 100KHz～5MHz, The method of claim 59. 64. A wide beam uniform field ultrasound energy delivery system, comprising: a housing having an opening at a distal end; a skin contact window covering the opening; a plurality of ultrasound waves provided within the housing. A transducer; and an acoustic couplant material that contacts at least one surface of the transducer and contacts the skin contact window. 65. The wide beam uniform field ultrasonic energy delivery system of claim 64, wherein the transducer comprises a plurality of concentric annular elements, one element disposed within another element. 66. The wide beam uniform field ultrasound energy delivery system of claim 64, further comprising: an electronic drive circuit adapted to individually control operation of each of the transducers. ,system. 67. A wide beam uniform field ultrasound delivery system, comprising: a housing having an opening at a distal end; a skin contact window covering the opening; an individual plate transducer mounted within the housing. A two-dimensional array of elements; and an acoustic couplant material that contacts at least one surface of each of the individual transducers and contacts the skin contact window. 68. The wide beam uniform field ultrasound delivery system of claim 67, wherein said individual plate transducer elements are angled with each other to provide coverage of said ultrasound field over a large area. 69. The wide beam uniform field ultrasound delivery system of claim 67, further comprising: an electronic drive circuit adapted to individually control operation of each of the transducers. system. 70. A wide beam uniform field ultrasound delivery system comprising: a two-dimensional array of individual plate transducer elements adapted to be directly connected to a patient without an intermediate fluid connection. . 71. A kit for increasing cellular absorption of a substance delivered to a target area of a patient's body, comprising: an ultrasonic energy delivery system; and a method for using the method of claim 1. Kit with instructions for use. 72. A kit for increasing transfection of DNA delivered to a target area of a patient's body, comprising: an ultrasonic energy delivery system; and a method for using the method of claim 29. Kit with instructions for use. 73. A kit for inhibiting intimal hyperplasia, comprising: an ultrasonic energy delivery system; and instructions for using the method of claim 59. 74. A wide beam uniform field ultrasound delivery system, comprising: a housing having an opening at a distal end; a skin contact window covering the opening; an ultrasound transducer mounted within the housing; An acoustic couplant material in contact with at least one surface of the transducer and in contact with the skin contact window; a first adjustable pedestal connecting the transducer to the interior of the housing; An adjustable platform adapted to couple the transducer for back and forth movement of the beam of ultrasonic energy in a first direction; a first adjustable platform; and the interior of the housing. A second adjustable platform for coupling the transducer, the second adjustable platform for coupling the transducer for back and forth movement of the beam of ultrasonic energy in a second direction. Adapted, wherein the second direction is the first direction Perpendicular to the
A system comprising a second adjustable platform. 75. A wide beam uniform field ultrasound delivery system, comprising: a housing having an opening at a distal end; a skin contact window covering the opening; an ultrasound transducer mounted within the housing; And an acoustic couplant material in contact with at least one surface of the transducer and in contact with the skin contact window, wherein the transducer is centrally located in the housing and an acoustically reflective surface is provided in the housing. The system, which is located around the inner perimeter. 76. A wide beam uniform field ultrasound delivery system, comprising: a housing having an opening at a distal end; a skin contact window covering the opening; an ultrasound transducer mounted within the housing; And an acoustic couplant material in contact with at least one surface of the transducer and in contact with the skin contact window, wherein an acoustically reflective surface is located at the center of the housing, and wherein the transducer is The system, which is located around the inner perimeter. 77. A wide beam uniform field ultrasound delivery system comprising: a housing having an opening at a distal end; a skin contact window covering the opening; an ultrasound transducer mounted within the housing; And an acoustic couplant material that contacts at least one surface of the transducer and contacts the skin contact window, wherein the transducer is disposed in contact with the acoustic couplant material. The system further comprising an acoustic reflective material covering a side surface of the system. 78. A wide beam uniform field ultrasound delivery system comprising: a housing having an opening at a distal end; a skin contact window covering the opening; an ultrasound transducer mounted within the housing; And an acoustic couplant material that contacts at least one surface of the transducer and contacts the skin contact window, wherein the skin contact window narrows the beam of ultrasonic energy passing therethrough. A system having a curved shape.