US20130218068A1

US20130218068A1 - Therapeutics reservoir

Info

Publication number: US20130218068A1
Application number: US13/880,109
Authority: US
Inventors: Ariel Sverdlik; Or Shabtay; Iris Szwarcfiter; Avital Schauder
Original assignee: Cardiosonic Ltd
Current assignee: Cardiosonic Ltd
Priority date: 2010-10-18
Filing date: 2011-10-18
Publication date: 2013-08-22
Also published as: WO2012052925A1; WO2012052926A2; US20120265227A1; EP2629736A4; WO2012052920A1; EP2629736B1; JP2013543423A; EP2661304A1; EP2629848A1; US20130204242A1; WO2012052926A3; US10967160B2; EP2629736A2; US20130211396A1; EP2629848B1; CN103298441A

Abstract

A method and system of forming at least one therapeutic reservoir in a target tissue by trapping therapeutics in at least a portion of said target tissue by selectively applying energy to said target tissue. Optionally, trapping comprises preventing said therapeutics in said target tissue from being carried away by a circulation. The system can include a catheter with both an ultrasonic element and a drug delivery port, optionally connected to control circuitry.

Description

RELATED APPLICATIONS

This is a PCT application which claims the benefit of priority of U.S. Provisional Patent Applications No. 61/393,947 filed Oct. 18, 2010, and No. 61/453,239 filed Mar. 16, 2011, the contents of which are incorporated herein by reference in their entirety.
The present application is related to co-filed, co-pending and co-assigned PCT to patent applications entitled:
“AN ULTRASOUND TRANSCEIVER AND CONTROL OF A THERMAL DAMAGE PROCESS” (attorney docket no. 52342), which teaches an apparatus and method for performing ultrasonic imaging, such as to provide feedback about the effect of treatment on tissues as described herein;
“ULTRASOUND EMISSION ELEMENT” (attorney docket no. 52344), which teaches an apparatus for generating relatively high intensity ultrasound, such as to apply energy to cause the desired effects in tissue as described herein;
“AN ULTRASOUND TRANSCEIVER AND USES THEREOF” (attorney docket no. 52345), which teaches a method for feedback and control of the ultrasonic emission element, such as to use the same ultrasonic element for treatment and imaging, potentially useful when treating and imaging as described herein;
“AN ULTRASOUND TRANSCEIVER AND COOLING THEREOF” (attorney docket no. 52346), which teaches a method for cooling of the ultrasonic emission element, potentially useful when applying energy as described herein;
“TISSUE TREATMENT” (attorney docket no. 52347), which teaches a method of selectively targeting and treating tissues using ultrasound, potentially useful when applying energy as described herein; and
“SEPARATION DEVICE FOR ULTRASOUND ELEMENT” (attorney docket no. 52348), which teaches a device to prevent the ultrasonic emission element from touching the blood vessel wall, potentially useful for preventing damage to the intima layer when applying energy as described herein;
the disclosures of which are incorporated herein by reference.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to a method of drug delivery and, more particularly, but not exclusively, to a method for trapping drugs to form a drug reservoir in tissue.
Sverdlik et al, in PCT/IL2008/000234, filed Feb. 21, 2008 disclose: “Described is a method of stabilizing blood vessel wall abnormality. The method includes ultrasonically heating at least a portion of the blood vessel wall having the abnormality; monitoring a parameter related to a property of at least a portion of the heated portion of the blood vessel wall; and stopping the heating when the monitored to parameter changes by a predetermined factor or after the monitored parameter changes in a slow enough rate.”
Gossl et at., in “Functional Anatomy and Hemodynamic Characteristics of Vasa Vasorum in the Walls of Porcine Coronary Arteries”, THE ANATOMICAL RECORD PART A 272A:526-537 (2003), disclose “different types and the fine architecture of these vasa vasorum”.
Kirk Patrick Seward in US Provisional Application 2011/0104061 disclose “locally delivering neurotoxic or nerve-blocking agents into the adventitia.”
Altman et al., in “Exploring heart lymphatics in local drug delivery”, Lymphat Res Biol. 2003; 1(1):47-53; discussion 54., disclose “Locally delivered agents can migrate away from the site of delivery through pathways that include lymphatics.”

SUMMARY OF THE INVENTION

There is provided in accordance with an exemplary embodiment of the invention, a method of forming at least one therapeutic reservoir in a target tissue comprising:

- trapping therapeutics in at least a portion of said target tissue by selectively applying energy to said target tissue.

In an exemplary embodiment of the invention, said trapping comprises preventing said therapeutics in said target tissue from being carried away by a circulation. Optionally or alternatively, selectively applying energy comprises applying a sufficient amount of said energy to said target tissue to trap said therapeutics without damaging surrounding non-target tissue.
In an exemplary embodiment of the invention, the method comprises activating said therapeutics in said target tissue.
In an exemplary embodiment of the invention, said trapping comprises maintaining said therapeutics in said target tissue for a period of time sufficiently long for said therapeutics to exert a therapeutic effect.
In an exemplary embodiment of the invention, trapping comprises maintaining said therapeutics in said target tissue after said therapeutics outside said target tissue have been removed from a patient.
In an exemplary embodiment of the invention, said trapping comprises maintaining a sufficient amount of said therapeutics in said target tissue to exert a therapeutic effect.
In an exemplary embodiment of the invention, said energy comprises ultrasound. Optionally, said ultrasound is applied intravascularly to said target tissue. Optionally or alternatively, said ultrasound is unfocused. Optionally or alternatively, a frequency of said ultrasound energy is 5 Mhz-30 Mhz.
In an exemplary embodiment of the invention, said selectively applying energy comprises applying a pattern of energy sufficient to block a volume of at least one of blood vessels in said target tissue and lymph vessels in said target tissue to prevent therapeutics from traversing through said volume of blood vessels. Optionally, said blocking comprises coagulating blood in said vessels. Optionally or alternatively, said blocking comprises denaturing collagen surrounding at least one of said blood vessels and said lymphatic vessels. Optionally or alternatively, said selectively applying energy comprises applying a pattern of energy sufficient to block a volume of at least one of blood vessels and lymphatic vessels and not blocking a sufficient volume of at least one of blood vessels and lymphatic vessels to perfuse tissue surrounding said target tissue.
In an exemplary embodiment of the invention, said selectively applying energy comprises applying a pattern of energy to an arterial wall without damaging an intima of said wall.
In an exemplary embodiment of the invention, said selectively applying energy comprises applying a pattern of energy to a volume of said target tissue to form said therapeutics reservoir having substantially said volume.
In an exemplary embodiment of the invention, said selectively applying energy comprises applying energy in a non-contiguous manner to form a plurality of therapeutics reservoirs.
In an exemplary embodiment of the invention, said volume of said therapeutics reservoir is less than 20 mm³.
In an exemplary embodiment of the invention, said selectively applying energy comprises applying a pattern of energy to a location within said target tissue to form said therapeutics reservoir substantially at said location. Optionally, said target tissue comprises a wall of an artery and said location comprises an adventia layer of said wall. Optionally or alternatively, said target tissue comprises an organ and said location comprises a wall of said organ. Optionally or alternatively, said organ is a prostate. Optionally or alternatively, said artery is a renal artery. Optionally, said therapeutic is neurotoxic to renal nerves in said renal artery wall.
In an exemplary embodiment of the invention, said therapeutics are packaged in a carrier that releases said therapeutics over a period of time. Optionally, a diameter of said carrier is sufficiently small to enter at least one of blood vessels of said target tissue and lymphatic vessels of said target tissue.
In an exemplary embodiment of the invention, detecting said therapeutics in said target tissue by imaging a contrast agent at least one of mixed with and coupled to said therapeutics.
In an exemplary embodiment of the invention, the method comprises injecting said therapeutics into a patient away from said target tissue. Optionally, said injecting comprises injecting said therapeutics upstream of said target tissue. Optionally or alternatively, said injecting comprises injecting said therapeutics systemically.
In an exemplary embodiment of the invention, the method comprises waiting a predetermined amount of time after said injection, for said therapeutics to reach said a trap location.
In an exemplary embodiment of the invention, said trapping comprises trapping to treat a patient. Optionally, said trapping comprises trapping to treat blood vessels of said patient. Optionally, said trapping comprises trapping to reduce restenosis of said blood vessels.
In an exemplary embodiment of the invention, said trapping comprises trapping to treat a prostate of said patient.
In an exemplary embodiment of the invention, said applying energy further comprises applying energy sufficient to treat nerves in said target tissue.
In an exemplary embodiment of the invention, the method comprises blocking at least some of a blood flow to force said therapeutics into ducts of said target tissue.
In an exemplary embodiment of the invention, said therapeutics comprises drugs and said therapeutics reservoir comprises a reservoir of said drugs.
In an exemplary embodiment of the invention, said trapping comprises trapping in vasa vasorum.
In an exemplary embodiment of the invention, said trapping comprises trapping in vessels having a size of less than 0.1 mm.
In an exemplary embodiment of the invention, said trapping comprises providing energy sufficient to trap said therapeutics but not sufficient enough to cause damage to surrounding tissue. Optionally, said surrounding tissue comprises nerves.
There is provided in accordance with an exemplary embodiment of the invention, an ultrasound system for forming a therapeutics reservoir comprising:

- a catheter comprising:
  - a distal end;
  - a proximal end comprising:
    - an ultrasound emission element configured for producing ultrasound energy having sufficient energy to seal tissue thereby trapping therapeutics in blood vessels thereof; and
- a controller configured to control application of said ultrasound energy provide said trapping. Optionally, the system comprises at least one port for release of a fluid to blood, said port located on said proximal end, upstream from said emission element. Optionally, said upstream comprises upstream relative to a flow of blood over said port and said emission element. Optionally, said port is positioned at least 10 mm from said ultrasound emission element.

In an exemplary embodiment of the invention, said port is adapted to allow a flow rate of said fluid of at least 1 mL/second. Optionally or alternatively, said port is positioned substantially in line with said emission element.
In an exemplary embodiment of the invention, the system comprises a container in fluid communication with said port. Optionally, a volume of said container is no more than 2000 mL.
In an exemplary embodiment of the invention, the system comprises an injection mechanism in fluid communication with said port, said mechanism configured to inject said fluid through said port, said controller further configured to control said injection mechanism.
In an exemplary embodiment of the invention, said fluid comprises a neurotoxic drug.
In an exemplary embodiment of the invention, said emission element is configured to emit ultrasound at an intensity of at least 20 Watt/cm².
In an exemplary embodiment of the invention, the system comprises a controller, said controller is configured to control release of said fluid through said port and emission of ultrasonic energy by said ultrasound emission element.
In an exemplary embodiment of the invention, the system comprises a gas bubble containment area adapted to retain a gas bubble when in blood, said gas bubble is coupled to said emission element.
In an exemplary embodiment of the invention, the system comprises an inflatable balloon for blocking at least some flow of blood.
In an exemplary embodiment of the invention, said controller is configured to not cause significant tissue damage during said sealing.
Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.
Implementation of the method and/or system of embodiments of the invention can involve performing or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of embodiments of the method and/or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware or by a combination thereof using an operating system.
For example, hardware for performing selected tasks according to embodiments of the invention could be implemented as a chip or a circuit. As software, selected tasks according to embodiments of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In an exemplary embodiment of the invention, one or more tasks according to exemplary embodiments of method and/or system as described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, the data processor includes a volatile memory for storing instructions and/or data and/or a non-volatile storage, for example, a magnetic hard-disk and/or removable media, for storing instructions and/or data. Optionally, a network connection is provided as well. A display and/or a user input device such as a keyboard or mouse are optionally provided as well.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings and/or images. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

In the drawings:

FIG. 1A is an illustration of systemic drug delivery, useful in practicing some embodiments of the invention;

FIG. 1B is an illustration of local drug delivery, useful in practicing some embodiments of the invention;

FIG. 1C is an illustration of a drug reservoir, in accordance with an exemplary embodiment of the invention;

FIG. 2A is a flowchart of a treatment method, in accordance with an exemplary embodiment of the invention;

FIG. 2B is a flowchart of a more detailed treatment method of FIG. 2A, in accordance with an exemplary embodiment of the invention;

FIG. 3 is an illustration of the human body showing exemplary treatment locations, useful in practicing some embodiments of the invention;

FIG. 4A is an illustration of an exemplary catheter to form the drug reservoir, in accordance with an exemplary embodiment of the invention;

FIG. 4B is an illustration of an exemplary ultrasound treatment system for forming the drug reservoir, used with the catheter of FIG. 4A, in accordance with an exemplary embodiment of the invention;

FIG. 4C is an illustration of blocking blood flow to force therapeutics into ducts of the target tissue, in accordance with some embodiments of the invention;

FIG. 5 is an illustration of selecting the dimensions and/or location of the drug reservoir, in accordance with an exemplary embodiment of the invention;

FIG. 6A-6B are illustrations of various patterns of energy application to trap drugs in tissues, in accordance with an exemplary embodiment of the invention; and

FIGS. 7A-7I are images of experimental results obtained using some embodiments of the invention.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to a method of delivery of therapeutics and, more particularly, but not exclusively, to a method for trapping therapeutics to form a reservoir in tissue. Non-limiting examples of therapeutics include; drugs, vitamins, bacteria, viruses, genetic material, particles with absorbed drugs.
An aspect of some embodiments of the invention relates to applying energy to a target tissue to trap at least one particle of a therapeutic in the target tissue. Optionally, the target tissue is located relatively close to a treatment site, such as tissue to be treated by the therapeutics released from the reservoir. In an exemplary embodiment of the invention trapping comprises providing the therapeutic into ducts that lead into the target tissue, and then clamping the therapeutics inside the ducts by applying energy.
In an exemplary embodiment of the invention, the target tissue is the wall of an artery and/or near-by tissue (non-limiting examples include; adipose tissue, connective tissue, nerves, lymph nodes and/or blood vessels). Optionally, the artery supplies major organs, non-limiting examples include; renal artery (kidney), carotid artery (brain), coronary artery (heart). Alternatively, the artery supplies pathological tissues such as tumors. The target tissue can be located anywhere in the body, such as in tissues having blood vessels and/or comprising of connective tissue. Non-limiting examples include; choroid plexus (brain ventricles), skin, muscle, bones.
In an exemplary embodiment of the invention, drugs supplied to small vessels of the target tissue, and the drugs are trapped in vessels of the target tissue. Optionally, the target tissue is the arterial wall. Optionally, the target tissue is a layer of the arterial wall to and/or surrounding tissue, for example, media, adventitia, connective tissue. One or more non-limiting examples include: blood vessels such as vasa vasorum (e.g., supplying and/or draining the arteriole wall), arterioles, venules and/or capillaries, lymphatic vessels and/or lymph nodes.
In an exemplary embodiment of the invention, energy is selectively applied to the target tissue so as to cause a thermal effect. Optionally, energy is applied to tissue in a way that causes coagulation of blood in vessels. Drugs can be trapped by the coagulated blood. Alternatively or additionally, energy is applied to the tissue in a way that causes geometrical shape changes to the vessels, for example, fully and/or partially obstructing the vessels. Drugs can be trapped by the obstruction of the vessels. Without being bound to theory, sufficiently heating of collagen surrounding the blood and/or lymphatic vessels shrinks the collagen, causing the geometrical changes.
In an exemplary embodiment of the invention, one or more thermal effects are permanent, for example, collagen denaturation. Alternatively or additionally, one or more thermal effects are temporary, for example, blood coagulation.
In an exemplary embodiment of the invention, energy is applied to the target tissue when drugs are present in the vessels of the target tissue. Optionally, the presence of drugs in the target tissue is estimated, for example, drugs are injected upstream of the vasa vasorum and/or arterioles of the target tissue (e.g., into a larger artery and/or vein) and energy is applied to the target tissue after a period of time sufficiently long to allow the drugs to reach the blood vessels of the target tissue. Alternatively or additionally, the presence of drugs in the target tissue is detected, for example, using a contrast agent mixed in and/or bound to the drug and used for imaging. Alternatively or additionally, drugs are injected directly into the target tissue. Injected drugs travel (e.g., diffuse) into the small blood vessels of the target tissue (e.g., vasa vasorum) and/or lymphatic vessels. Optionally, energy is applied to form the drug reservoir before drugs have been removed from the target tissue, such as by blood and/or lymph.
In an exemplary embodiment of the invention, energy is applied to the target tissue to trap drugs in a selectable volume of target tissue. For example, a volume no larger than 1 mm³, 5 mm³, 10 mm³, 30 mm³, 50 mm³, 100 mm³, 1000 mm³, or other smaller, intermediate or larger sizes are used. Optionally, the drug reservoir is made up of small discrete areas within the treated target tissue, for example, of individual particles.
In an exemplary embodiment of the invention, energy is applied to the target tissue to form a drug reservoir having at least one selectable dimension. Non-limiting examples of dimensions include; length, width, thickness, radius. The dimension is selected to be about 0.1 mm, about 0.5 mm, about 1 mm, about 2 mm, about 3 mm, about 5 mm, about 6 mm, about 10 mm, or other smaller, intermediate or larger dimensions are used.
In an exemplary embodiment of the invention, energy is applied to the target tissue to form a drug reservoir of a particular shape. Optionally, the energy is applied to the area requiring treatment (e.g., lesion) to form a drug reservoir having a shape substantially the same as at least part of the target lesion, or the entire lesion. Alternatively or additionally, the shape of the targeted area corresponds to the pattern of applied energy, for example, substantially rectangular (unfocused ultrasound energy from a catheter), substantially spheroidal (focused ultrasound energy applied externally).
In an exemplary embodiment of the invention, energy is applied to the target tissue to form a drug reservoir at a selectable location. Optionally, the reservoir is formed in ducts that are fed by arteries. Optionally, the catheter is inserted in the artery and/or duct and particles are trapped in the area between the duct and the edge of the artery. For example, the distance of the reservoir (e.g., closest point of the reservoir) from the artery lumen wall (e.g., intima layer) is selectable, such as about 0.3 mm, about 0.5 mm, about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, or other smaller, intermediate or larger distances are used. Optionally or alternatively, the location of the drug reservoir in a tissue layer is selectable, for example, in the media, in the adventitia, in the peri-adventitia, outside the arterial wall. Forming the reservoir in the artery is potentially easier, for example, as arteries can be accessed using catheters. Forming the reservoir in arteries is potentially relevant for treatment, for example, because arteries are located throughout the body in major tissues, allowing treatment of those tissues through the artery feeding the tissue.
In an exemplary embodiment of the invention, energy is applied to form the drug reservoir without damaging surrounding and/or nearby tissue. Optionally, direct damage is prevented, for example, damage to the intima due to the thermal effect of the energy. Alternatively or additionally, indirect damage is prevented. For example, some vasa vasorum are blocked and some vasa vasorum are not-blocked, leaving a sufficient amount of blood flow to feed the blood vessel wall.
In an exemplary embodiment of the invention, one or more drug reservoirs are formed in the target tissue, for example, 1, 3, 5, 10, 20, 100, 1000, or other smaller, intermediate or larger numbers of reservoirs are formed. Optionally, the drug reservoirs are non-contiguous and/or non-overlapping, for example, separated from one another by about 0.1 mm, 0.5 mm, 1 mm, 3 mm, or other smaller, intermediate or larger distances. Non-limiting examples of patterns for formation include; checkerboard. Alternatively or additionally, one or more drug reservoirs are formed out of smaller drug reservoirs that are close to one another, such as overlapping and/or contiguous.
In an exemplary embodiment of the invention, the drug trapped in the drug reservoir is prevented from being washed away, such as by blood circulation and/or by lymph. Alternatively, the rate of removal of the drugs trapped in the reservoir is reduced, for example, drugs trapped in coagulated blood can be trapped until the body restores blood flow, at which point the drugs can be washed away. Optionally, the drug not trapped in the reservoir is cleared from circulation, such as by being metabolized by the liver, secreted in the urine, and/or removed by the immune system. Optionally, the un-trapped drug is cleared substantially quickly so as not to exert a therapeutic effect on parts of the body other than the targeted tissue. Alternatively or additionally, the un-trapped drug is sufficiently diluted within the circulation system to a dose below the therapeutic threshold so as not to exert a therapeutic effect on parts of the body other than the targeted tissue.
In an exemplary embodiment of the invention, a sufficient amount and/or concentration of drug is trapped in the reservoir to exert a local therapeutic effect. In an exemplary embodiment of the invention, the local therapeutic effect is exerted relatively close to the arterial wall. For example, the diffusion of drugs can have a therapeutic effect within the drug reservoir, and/or about 0.5 mm, 1 mm, 2 mm, 3 mm, 5 mm, away from the reservoir, or other smaller, intermediate or larger values are used.
In an exemplary embodiment of the invention, the therapeutic effect lingers, for example, by trapping slow release particles, for example, drugs remain trapped in the drug reservoir for at least 6 hours, 12 hours, 24 hours, 48 hours, 3 days, 7 days, 2 weeks, to one month, or other smaller, intermediate or larger time frames are used. Optionally, the time to release the drug is controlled for example, by selecting appropriate slow release drug carriers.
In an exemplary embodiment of the invention, the applied energy is ultrasound. Other non-limiting examples of possibly suitable energy sources include; radiofrequency (RF), microwave, light, electricity (AC and/or DC).
In an exemplary embodiment of the invention, the ultrasound energy is applied from within the body, for example, intravascularly. Alternatively, the ultrasound energy is applied from outside the body.
In an exemplary embodiment of the invention, the ultrasound energy is unfocused. Alternatively, the energy is focused.
In an exemplary embodiment of the invention, the frequency of the applied ultrasound energy is in the range of 1-50 Mhz, 5-40 Mhz, 10-40 Mhz, 5-30 Mhz, 10-20 Mhz, or other smaller, intermediate or larger ranges are used.
An aspect of some embodiments of the invention relates to a catheter for releasing medicine and applying energy to form a drug reservoir in a tissue target. Optionally, the catheter and/or its controller (e.g., electronics or mechanics) co-ordinates the drug release and the application of energy. Optionally, the time of the release of the drug is controlled. Alternatively or additionally, the time of heating of the target tissue is controlled.
In an exemplary embodiment of the invention, the catheter comprises one or more ports, such as along the shaft of the catheter. Optionally, ports are located upstream (e.g., by direction of blood flow), for example, 50 mm relative to the element. Optionally, a liquid injected through the port is released outside of the catheter, such as into an artery.
In an exemplary embodiment of the invention, a container is in fluid communication with the port. Drugs (e.g., in fluid) can flow from container, through the port, and into the surrounding tissue such as blood.
In an exemplary embodiment of the invention, a controller synchronizes release of drugs out of the port and emission of ultrasonic energy to form the drug reservoir. Optionally, the synchronization comprises waiting a period of time after releasing the drug, and applying the energy to trap the drugs.
Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings and/or the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.
Referring now to the drawings, FIG. 1A illustrates the injection of therapeutics such as drugs 104 (shown as black dots) into the vasculature of a patient, such as by needle 106, useful in practicing some embodiments of the invention. Drugs 104 are selected to attempt to have a therapeutic effect on tissue 112. Drugs 104 can be dissolved in an injected solution such as saline and/or encapsulated in a drug delivery carrier. Non-limiting examples of therapeutics such as drugs 104 include one or more of; medications, neurotoxins, inert chemicals, viruses, bacteria, genetic materials, particles containing drugs.
Without being bound to theory, once drugs 104 have entered the blood stream, such as in artery 108, the drugs 104 are carried by flow throughout the vasculature, entering smaller branch vessels 110. In some cases, drugs 104 exert a therapeutic effect systemically, such as on tissues throughout the body perfused by the vasculature. Treatment tissue 112 achieves a therapeutic effect along with potential side effects to surrounding tissues 116 and/or tissues in the rest of the body. Alternatively, drugs 104 are not able to exert a therapeutic effect on treatment tissue 112, surrounding tissues 116 and/or the rest of the body, for example, due to an inadequate concentration. In some cases, drugs 104 are cleared relatively quickly from circulation.
In some embodiments, an embolic agent 114 such as ethanol is injected together with drugs 104. Agent 114 causes blood in artery 108 and/or branch vessels 110 to coagulate. Drugs 104 are caught in the coagulated blood, being prevented and/or reduced from clearance from circulation. Caught drugs 104 exert a therapeutic effect on treatment tissue 112. In some cases, drugs 104 are caught in coagulated vessels outside of the desired target area, also affecting surrounding tissues 116 and/or other tissues in the body.
FIG. 1B illustrates the injection of drugs 104 into a tissue 118, such as muscle, useful in practicing some embodiments of the invention.
Without being bound to theory, once drugs 104 have entered into tissue 118, drugs 104 enter lymphatic network 120. Drug 104 diffuse throughout lymphatic vessels 120 and/or lymph nodes 124 and can be cleared by lymphatic system 120.
Drugs 104 can have a therapeutic effect on treatment tissue 112, surrounding tissues 116 and/or tissues close to lymphatic vessels 120. Alternatively, drugs 104 are cleared away by vessels 120 relatively quickly, and do not achieve a therapeutic effect on tissue 112.

Overview of Treatment

A method of treatment using drug reservoir 122, as shown in FIG. 2A, will be described with reference to FIG. 1C. The flowchart is not meant to be limiting only to the described method. Some steps are optional. FIG. 1C illustrates a drug reservoir 122 trapping drugs 104, such as in branch blood vessels 110 and/or lymphatic vessels 120, in accordance with an exemplary embodiment of the invention.
Referring to FIG. 2A:
At 202, one or more locations in which one or more drug reservoirs such as reservoir 122 will be formed is optionally determined, in accordance with an exemplary embodiment of the invention. For example, the location is determined by a physician based on one or more factors such as; location of disease, ability to access the location to apply energy. Optionally, reservoir 122 is relatively close to tissue requiring treatment 112. Optionally or additionally, reservoir 122 is relatively far from tissue 112, such as in surrounding tissues 116.
In an exemplary embodiment of the invention, the reservoir target location is selected to be one which is perfused by branch blood vessels 110. Alternatively or additionally, the location is perfused by lymphatic network 120.
At 204, the initial parameters for the formation of one or more drug reservoirs 122 are optionally determined, in accordance with an exemplary embodiment of the invention. Non-limiting examples of parameters include; reservoir 122 volume, reservoir 122 shape, at least one dimension having length of x2−x1, width of y2−y1, thickness of to z2−z1, distance (d1) from artery 108, thermal effect to trap drugs 104 in blood vessels 110 and/or lymphatic vessels 120.
In an exemplary embodiment of the invention, parameters such as drug delivery parameters are selected to form a therapeutically active volume 222. For example, drug delivery parameters are selected to trap a sufficient amount of drug 104 in blood vessels 110 and/or lymphatic vessels 120. Active volume 222 is selected to encompass a sufficient amount of target tissue 112. A therapeutic effect can be achieved in target tissue 112 by therapeutically active volume 222.
At 206, energy is applied to form drug reservoir 122, in accordance with an exemplary embodiment of the invention. Parameters related to the application of energy to form drug reservoir 122 are selected according to one or more of the selected drug reservoir formation parameters as in 204. Drugs 104 are trapped by the application of energy in blood vessels 110 and/or lymphatic vessels 120.
Optionally, the formation of the drug reservoir is monitored, and/or feedback is obtained. Optionally, one or more parameters are adjusted.
Optionally, at 208, one or more of 202, 204 and/or 206 are repeated, in accordance with an exemplary embodiment of the invention.

Some Potential Advantages

Some potential advantage of forming a drug reservoir in accordance with an exemplary embodiment of the invention include:

- Relatively improved control of the number, location, shape, volume and/or dimensions of the drug reservoirs, such as to treat a disease in a patient by drugs released from the drug reservoir. For example, by forming the drug reservoirs according to energy deposition patterns. For example, as opposed to forming the reservoir according to vascular and/or lymphatic vessel patterns, such as if using embolic agents injected together with the drug.
- Formation of a relatively small drug reservoir, for example, in blood vessels (e.g., vasa vasorum) too small to be directly accessed using a catheter and/or by injection.
- Formation of the drug reservoir in the walls of arteries, such as arteries supplying critical organs, for example, heart, kidney, brain.
- Formation of the drug reservoir in the wall of an organ, such as the prostate.
- Formation of the drug reservoir in the arterial wall without damaging the inner lumen lining, such as the intima.
- Formation of the drug reservoir in the arterial wall without significant arterial stenosis.
- Ability to treat a wide range of medical conditions, for example, as will be described below.
- Formation of the drug reservoir in arteries with plaque and/or stent, such as to treat diffuse artheriosclerosis.
- Targeted treatment by the drug reservoir, especially in difficult to access sites. For example, of small structures such as nerves in the arterial wall and/or of difficult to access structures such as across the blood brain barrier.
- Preventing and/or reducing damage to surrounding structures. For example, leaving a sufficient amount of collateral blood flow to perfuse nearby tissue, such as the arterial wall.
- Reduction and/or prevention of side effects due to systemic drug delivery, such as lingering drug release.
- Formation of the drug reservoir does not require significant retraining. Based on commonly acquired skills.
- Relatively safer method of drug delivery and/or treatment.
- Drug reservoir can be temporary.
- Local drug delivery, for example, as opposed to systemic drug delivery.

Exemplary Method of Treatment

FIG. 2B is a detailed method of treatment of FIG. 2A, in accordance with an exemplary embodiment of the invention. The method described by the flowchart is not limited to only the described method. Some steps are optional.
Optionally, at 232, a decision to form the drug reservoir is made, for example, as will be described in the section “DECIDING TO TREAT”.
Optionally, at 234, the anatomical location in which the drug reservoir will be formed is selected, for example, as will be described in the section “SELECTING ANATOMICAL LOCATION OF TREATMENT”.
Optionally, at 236, a decision is made with regards to the type of drug and/or delivery of the drug, for example, as will be described in the section “SELECT DRUG DELIVERY PROFILE PARAMETERS”.
Optionally, at 238, a decision is made with regards to the parameters of the formation of the drug reservoir, for example, as will be described in the section “CHOOSE DRUG RESERVOIR FORMATION PARAMETERS”.
Optionally, at 240, the drug is inserted into the patient, such as for delivery to the drug reservoir, for example, as will be described in the section “INSERT DRUG INTO PATIENT”.
Optionally, at 242, the presence of drugs inside the planned reservoir location is determined and/or estimated, for example, as will be described in the section “TRACK DRUG”.
At 244, energy is applied to form the drug reservoir, for example, as will be described in the section “APPLY ENERGY TO FORM RESERVOIR”.
Optionally, at 246 monitoring is performed and/or feedback is obtained, for example, as will be described in the section “FEEDBACK AND/OR MONITOR”.
Optionally, at 248 adjustments are made and/or another reservoir is formed, for example, as will be described in the section “ADJUST/REPEAT”.

Deciding to Treat

In an exemplary embodiment of the invention, a decision to treat by forming a drug reservoir in target tissue is made, for example, by a physician according to clinical indications.
Non-limiting examples of clinical applications are listed in the table below. The applications listed in the table are referenced (e.g., according to numbers) to FIG. 3, which is an illustration of the human body showing the major arteries as reference points, useful in practicing some embodiments of the invention.

Exemplary Clinical Applications


Target	Anatomy	Application Name	#

Renal sympathetic	Renal artery	Renal sympathetic nerve	402
nerves		modulation
Carotid sympathetic	Carotid artery	Carotid sympathetic nerve	404
nerves		modulation
Vagus sympathetic	Aorta	Vagus sympathetic nerve	406
nerve		modulation
Peripheral	Peripheral blood vessels	Peripheral sympathetic	408
sympathetic nerves		nerve modulation
Pain nerves	Spinal cord cannel	Pain nerve modulation	410
Artery media and	All relevant arteries	Restenosis decrease	412
adventitia
Artery media and	All relevant arteries	Vulnerable plaque	414
adventitia		stabilization
Artery media and	All relevant arteries	Atherosclerosis passivation	416
adventitia
Artery media and	All relevant arteries	Plaque volume decrease	418
adventitia
Artery media and	All relevant arteries	Plaque thrombosis	420
adventitia		decrease
Peripheral motor	Limb arteries or veins	Tetanic limb muscle tonus	422
nerves		decrease
Pulmonary vein	Right atrium	Atrial fibrillation	424
		prevention
Cardiac tissue	Coronary arteries	Cardiac arrhythmia	426
pathology		prevention
Tumor	Inferior vena cava	Liver tumor necrosis	428
Sick prostate, colon	Urethra	None-malignant prostate,	430
or bladder tissue		colon or bladder treatment
Malignant prostate,	Urethra	Malignant prostate, colon	432
colon or bladder		or bladder treatment
tissue
Aneurysm wall	All relevant arteries	Artery aneurysms		434
		stabilization
Aneurysm wall	Aorta	Aortic aneurysms		436
		stabilization
Aneurysm wall	Brain arteries	Berry aneurysms sealing	438
Artery media and	Internal Iliac	Erectile dysfunction		440
adventitia		treatment
Drug release to	All relevant tissues	Circulatory system (major
circulatory system		vessels shown in FIG. 3)

Some exemplary medical conditions and their proposed treatment by treating nerves (examples not limited to the nerves described, treating other nerves may achieve a similar clinical outcome) in accordance with an exemplary embodiment of the invention include:

- Frozen shoulder—suprascapular nerve
- Zygapophysial joint pain—cervical medial branch nerves
- Chronic Pelvic Pain (in women)—uterosacral nerve
- Glabellar Frowning—facial nerve
- Phantom Pain—lumbar dorsal root ganglia
- Trigeminal Neuralgia—branches of the trigeminal nerve
- Cluster Headache—trigeminal and/or sphenopalatine ganglions
- Complex Regional Pain Syndrome—stellate ganglion

In some embodiments, electrical signals through nerves are reduced and/or prevented by treatment, for example, by neurotoxic drugs delivered from the drug reservoir. In some embodiments, the applied energy is sufficient to affect nerves.
In some embodiments of the invention, a sufficient amount of neurotoxic drug is released over a relatively short period of time, for example, over several hours or several days. Alternatively, the neurotoxic drug is slowly released over a relatively long period of time, for example, several months.
In some embodiments, malignant tissues (e.g., in the liver) and/or hypertrophic tissues (e.g., in the prostate) are damaged, for example, by using a sufficient high dose of chemotherapy delivered from the drug reservoir. The dose can be delivered over a relatively short period of time, or over a relatively long period of time (e.g., slow release).

Selecting Anatomical Location of Treatment

In an exemplary embodiment of the invention, the anatomical location of the target tissue for placement of the drug reservoir is selected. Optionally, the drug reservoir is located sufficiently close to the region of desired therapeutic effect, so that drugs released from the reservoir achieve the desired therapeutic effect on the tissue.
In an exemplary embodiment of the invention, the drug reservoir is selected to be placed in target tissue that is adequately supplied by blood vessels. For example, by arterioles, vasa vasorum and/or capillaries. Optionally or additionally, the drug reservoir is selected to be placed in target tissue that is drained by the lymphatic system. One or more non-limiting examples of target tissues include, muscles, arterial wall, tumor, bone, and/or other types of tissues such as connective tissue.
In some embodiments of the invention, a decision on the location of treatment is made from one or more different possible anatomical locations. Optionally, a factor in the selection is the location inside the lumen from which ultrasonic energy is applied, for example some locations are more easily accessed by using a catheter than others. For example, it may be easier to apply energy from inside the blood vessel rather than at a bifurcation of blood vessels.
In an exemplary embodiment of the invention, ultrasonic energy is applied invasively, for example, using a catheter and/or an endoscope. Alternatively, ultrasonic energy is applied non-invasively, for example, using high intensity focused ultrasound applied from outside the body. Non-limiting examples from which drug reservoirs can be formed include one or more of, wall of a fluid filled lumen (e.g., blood vessel), wall of a non-fluid filled lumen (e.g., ureter), wall of a fluid filled cavity (e.g., spinal canal), wall of a non-fluid filled cavity (e.g., stomach), wall of a solid organ (e.g., prostate). In some embodiments of the invention, potential spaces between tissues are filled with fluid if needed, for example, to allow ultrasonic energy to reach the target tissue through the fluid.
In some embodiments of the invention, the drug reservoir comprises several to reservoirs placed at selective locations, such as to achieve a combined therapeutic effect. For example, reservoirs can be positioned around the circumference of an artery, such as to treat an occlusion. For example, reservoirs can be positioned on the surface of the prostate to treat prostate cancer. For example, reservoirs can be positioned along the length of the middle cerebral artery, such as to temporal lobe epilepsy.
One non-limiting example of the location for formation of the reservoir is for treatment of resistant essential hypertension by renal denervation. Commonly, renal nerves arise from T10-L2 spinal roots; travel along an aorta and along a renal artery to innervate a kidney. In some anatomies, renal nerves primarily lie within the adventitia and/or surrounding tissue of the renal artery and/or aorta. There are one or more exemplary locations for forming drug reservoirs for renal denervation using neurotoxic drugs. For example, the procedure can be performed at the renal artery (e.g., from inside), at the ostium (e.g., the branch of the renal artery from the aorta) and/or at the aorta (e.g., from inside).

Select Drug Delivery Profile Parameters

In an exemplary embodiment of the invention, one or more drug delivery profile parameters are selected. Drug delivery profile parameters are related to achieving a therapeutic effect by drugs released from the reservoir.
In an exemplary embodiment of the invention, the drug type is selected. Optionally, two or more drugs are selected, such as to achieve a combined therapeutic effect (e.g., synergistic effect). The drug can be selected according to the desired therapeutic effect. Non-limiting examples of therapeutics and their potential therapeutic effects include:

- Restenosis prevention drugs, such as used in drug eluting stents, drug eluting balloons and/or biodegradable stents. For example; sirolimus, paclitaxel.
- Antinflammatory drugs such as steroids.
- Anti-thrombotic drugs, such as heparin, aspirin, ticlopidine, clopidogrel.
- Toxic drugs, such as neurotoxic drugs (e.g., botulinum toxin), chemotherapy agents.
- Genetic material for gene therapy, such as viral vectors.

In an exemplary embodiment of the invention, the amount of drug (e.g., drug 104 as in FIG. 1C) to be trapped in the volume of reservoir 122 (e.g., drug concentration) required to achieve a therapeutic effect, such as by acting on the therapeutic tissue (e.g., tissue 112) is selected. Optionally, the concentration of the drug to be inserted (e.g., injected by needle 106 as in FIG. 1A-1B) into the body is estimated according to the required concentration of drug 104 in drug reservoir 122. Non-limiting examples of the volume of injected drug include; about 0.1 mL, about 0.5 mL, about 1 mL, about 3 mL, about 5 mL, about 10 mL, about 20 mL, about 50 mL, or other smaller, intermediate or larger sizes are used. In some embodiments, the concentration of drug 104 in reservoir 122 is estimated by using look-up tables based on experimental data. In some embodiments, the concentration of drug 104 in reservoir 122 is estimated by imaging the presence of drug 104 in reservoir 122, for example, as will be described below in the section “TRACK DRUG IN TARGET TISSUE”.
In some embodiments of the invention, the drug is selected to become activated at a specific point in time, for example. Optionally, the drug is activated after the formation of the drug reservoir, such as when drugs have been trapped in the reservoir, for example, about 1 minute later, 1 hour later, 12 hours later, 24 hours later, 48 hours later, 7 days later, one month later, or other smaller, intermediate or larger time frames are used. Alternatively or additionally, the drug is activated after the untrapped drugs have been cleared, such as from the body tissues. Alternatively or additionally, the drug is activated upon formation of the drug reservoir, for example, by the same source of energy used to form the drug reservoir. Non-limiting examples of drug activation include; applying external energy (e.g., light, magnetic field, electrical field, ultrasound), such as to cause liposomes carrying the drug to pop.
In an exemplary embodiment of the invention, drugs are packed into a carrier for delivery to the site where the reservoir will be formed. Non-limiting examples of carriers include microspheres and/or liposomes. Optionally, the carrier is biodegradable. Optionally, the carrier is capable of crossing the blood-brain barrier.
In some embodiments, drugs are not packaged, for example, the drug is dissolved in saline.
In some embodiments, the size of the carrier is selected. Optionally, the size of the carrier is sufficiently small to fit inside some blood vessels, such as vasa vasorum and/or arterioles of the target tissue. For example, the average carrier diameter is about 0.01 mm, about 0.03 mm, about 0.05 mm, about 0.07 mm, about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, or other smaller, intermediate or larger values are used. Alternatively or additionally, the carrier is sufficiently small to fit inside lymphatic vessels, such as lymphatic vessels of the target tissue. For example, the average package diameter is about 10 nm, about 20 nm, about 50 nm, about 100 nm, about 200 nm, or other smaller, intermediate or larger values are used. Alternatively or additionally, the size of the carrier is sufficiently large so as not to fit inside certain vessels, for example, lymphatic vessels of the target tissue, but sufficiently small so as to fit inside certain vessels, such as vasa vasorum of the target tissue. For example, the average diameter of the drug package is larger than about 200 nm and smaller than about 0.3 mm, or other smaller, intermediate or larger values are used.
In some embodiments of the invention, flow in the vessel is blocked to force the particles to enter the ducts of the target tissue. Additional details of an exemplary blocking device and method will be described with reference to FIG. 4C below.
In some embodiments, the rate of diffusion of the drug out of the carrier is selected, for example, by using a suitable extended release composition. Optionally, the length of time that the therapeutically effective concentration is maintained in the treated tissue is selected in accordance with the rate of diffusion. Optionally, the rate of diffusion of drugs out of the carrier is sufficiently long such that untrapped drugs are cleared before drugs can exert side effects on tissues other than the treated tissue. Optionally or additionally, the rate of diffusion out of the carrier is sufficiently short such that a therapeutically effective concentration is achieved in the treatment tissue. For example, drugs can be released (e.g., maintaining a therapeutically effective concentration) over 1 hour, 2 hours, 4 hours, 12 hours, 24 hours, 48 hours, 1 week, 2 weeks, 1 month, 2 month, or other smaller, intermediate or larger time frames. In a non-limiting example, the liposome wall is selected according to the selected rate of diffusion. In another example, the rate of biodegradation of the microsphere is selected according to the selected rate of diffusion.
In some embodiments of the invention, one or more materials are released by the reservoir, in addition to or in place of the released drugs. Optionally, materials are coupled to the drugs and/or mixed with the drugs. Optionally, materials enhance the effect of the drugs. Non-limiting examples of materials include:

- thermal enhancement materials to relatively increase heating of the target tissue, such as by relatively increasing the absorption of the energy forming the reservoir. A non-limiting example includes microbubbles.
- trapping enhancement materials to relatively increase the trapping of drugs in the reservoir. Optionally, trapping enhancement materials can be activated, for example, by energy such as ultrasound energy. In some embodiments, trapping enhancement materials at least partially block blood vessels. Non-limiting examples of trapping enhancement materials include; polymers (e.g., that undergo cross linking) and/or soluble collagen.
- drug activation materials activate drugs in the reservoir. A non-limiting example includes ferro-electric particles.

Choose Drug Reservoir Formation Parameters

In an exemplary embodiment of the invention, one or more parameters related to the formation of the drug reservoir are selected. Reference will be made to FIG. 1C, showing reservoir 122 comprised of drugs 104 trapped in lymphatic network 120 and/or vasa vasorum 110. Vessels 136 and/or 120 within reservoir 122 have undergone geometrical changes 130 and/or contain coagulated blood 132. Therapeutically effective volume 222 contains a sufficient concentration drug 104 to treat tissue 112.
In an exemplary embodiment of the invention, drug reservoir 122 is formed in the artery wall and/or surrounding tissue 126 of artery 108. However, it should be understood that the description of forming the drug reservoir is not limited to the artery wall and/or surrounding tissue, but can be formed in any type of tissue anywhere in the body, for example, as described herein.
In an exemplary embodiment of the invention, the location to form reservoir 122 within arterial wall 126 is selected. Optionally, the location for the formation of at least part of reservoir 122 is the adventitia. Alternatively or additionally, the location for the formation of at least part of drug reservoir 122 is the peri-adventitia. Alternatively or additionally, the location is selected in terms of a distance (shown as ‘d1’) from the artery lumen 128. Non-limiting examples of ‘d1’ include, about 0.2 mm, about 0.3 mm, about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 7 mm, or other smaller, intermediate or larger locations are used. Optionally, the radial location within the artery is selected, for example, using angles from 0-360 relative to a point, such as anteriorly. Non-limiting examples include, 0, 90, 180, 270 degrees, or other smaller, intermediate or larger values are used. Optionally, the arc length of the reservoir around the circumference is selected, non-limiting examples include, about 5, 10, 15, 30, 45 degrees, or other smaller, intermediate or larger values are used.
FIG. 5 is a schematic diagram of a cross section of an artery 600, useful in practicing some embodiments of the invention. The layers of the wall of artery 600, from a lumen 602 outwards are: endothelium 604, internal elastic lamina 606, media 608, adventia 610 having vasa vosorum 612 embedded therein, peri-vascular tissue 614 (also called peri-adventitia) including peri-vess (peri-vascular blood vessels (capillaries)) 616, peri-nerv (peri-vascular nerve fibers) 618. Tissues 620, 622 and/or 624 illustrate target to be treated by drugs from the drug reservoir. For example, nerve tissue 620 is commonly located in peri-vascular tissue 614, tumor 622 can be located at least in part in the artery wall and/or outside of the arterial wall and/or brain/organ tissue (normal and/or abnormal). 624 can be located far from the arterial wall, such as outside of the blood-brain barrier.
Referring back to FIG. 1C, in an exemplary embodiment of the invention, the formation of drug reservoir 122 is selected to prevent and/or reduce damage to surrounding tissue outside of reservoir 122 (e.g., non-target and/or healthy tissue). Optionally, direct damage to surrounding tissue is reduced and/or prevented. For example, the formation of reservoir 122 is selected to be as small as possible, while trapping a sufficient amount of drug 104. Alternatively or additionally, indirect damage to tissue is reduced and/or prevented. For example, the formation of drug reservoir 122 is selected to leave open (e.g., unblocked) a sufficient amount of vessels 110 to allow for collateral blood flow 134 (shown as arrows in FIG. 1C) so as to reduce and/or prevent damage to arterial wall 126. For example, at least 10%, 20%, 30%, 50% of the baseline blood flow is maintained, or other smaller, intermediate or larger values are used. Optionally, blood vessels of the drug reservoir 136 are blocked, blood vessels in surrounding tissue 138 are unblocked. Alternatively or additionally, blood vessels of the to drug reservoir 136 are partially obstructed 130, such as by shrinking of surrounding tissues. For example, vessels 136 are partially obstructed preventing drugs 104 from being washed away, but letting blood continue to flow through the partially obstructed vessels 136, for example, blood vessel diameter is reduced by about 30%, about 50%, about 70%, or other smaller, intermediate or larger values are used.
In an exemplary embodiment of the invention, the type of trapping of drugs 104 in reservoir 122 is selected, for example, by the thermal effect. Optionally, blood is coagulated in vessels 136. For example, blood is heated to a temperature sufficient to coagulate blood, about 43, about 45, about 47, about 50, about 55 degrees Celsius, or other smaller, intermediate or larger values are used. Drugs 104 can be trapped in coagulated blood 132. Alternatively or additionally, connective tissue (e.g., collagen) 140 of surrounding vessels 136 is denatured and/or re-shaped. For example, tissue is heated to a temperature sufficient to denature collagen, about 45, about 47, about 50, about 52, about 55, about 58, about 60 degrees Celsius, or other smaller, intermediate or larger values are used. Drugs 104 can be trapped in geometrical changes 130 of vessels 136, for example, in complete or partial obstruction of vessels 136. In some embodiments, denatured collagen becomes shortened.
In an exemplary embodiment of the invention, the formation of drug reservoir 122 is selected to trap drugs in the reservoir permanently, for example, by permanent changes to the vessel geometry 130, such as due to collagen denaturation. Alternatively or additionally, the formation of reservoir 122 is selected to trap drugs 104 temporarily, for example, by blood coagulation 132 that is eventually cleared by the body and/or without collagen denaturation.
FIG. 6A is a radial cross section and FIG. 6B is a longitudinal cross section of artery 108, showing the formation of a plurality of drug reservoirs 150A-E, in accordance with an exemplary embodiment of the invention. Optionally, reservoirs 150A-E are selected to have a combined therapeutic effect on tissues requiring treatment such as tissue 152A (e.g., tumor) and/or tissue 152B (e.g., nerve). For example, reservoirs can be located such that each reservoir treats a different part of the target tissue. The total therapeutic effect of the reservoirs is to treat the entire target tissue. For example, reservoirs can be located such that each reservoir treats the same part of the target tissue. The total therapeutic effect of the reservoirs is to increase the concentration at the target tissue (e.g., using the same drug) and/or to have a synergistic effect at the target tissue (e.g., each reservoir provides a different drug).
In some embodiments of the invention, two or more drug reservoirs 150A-E are selected to be formed, such as in arterial wall 126. Optionally, drug reservoirs 150A-E are separated from one another along the circumference of the vessel wall, for example, about 10, 15, 25, 45, 60, 90, 180 degrees apart, or other smaller, intermediate or larger values are used. Alternatively or additionally, drug reservoirs 150A-E are separated from each other along the length of artery 108, for example, separated by about 0.5 mm, 1 mm, 2 mm, 3 mm, 5 mm, 10 mm, 15 mm, 20 mm, 30 mm, or other smaller, intermediate or larger values are used. Alternatively or additionally, drug reservoirs 150A-E are separated from each other along a radius of the vessel wall, for example, about 0.2 mm, 0.3 mm, 0.5 mm, 1 mm, 2 mm, 3 mm, 5 mm, or other smaller, intermediate or larger values are used.
In some embodiments of the invention, two or more of reservoirs 150A-E are not contiguous. For example, reservoirs 150A-E can be placed in a checkerboard and/or striped pattern along the circumference and/or length of the artery. A potential advantage is preventing and/or reducing damage to non-reservoir tissues, such as by providing sufficient collateral blood flow 134 by unblocked vessels. Alternatively or additionally, two or more of reservoirs 150A-E are contiguous, for example forming a larger reservoir.
Insert Drug into Patient
In an exemplary embodiment of the invention, the drugs (optionally packaged in the carrier) are inserted into the patient. Optionally, drugs are inserted systemically, for example, as illustrated in FIG. 1A. Alternatively or additionally, drugs are inserted locally, for example, as illustrated in FIG. 1B.
In an exemplary embodiment of the invention, the site of insertion of drugs into the body is selected. Optionally, the site of insertion of drugs is selected according to the desired concentration at the site where the reservoir will be formed. Alternatively, the site of insertion of drugs is selected independently of the desired concentration.
In an exemplary embodiment of the invention, the site is selected to be relatively close (e.g., physically close and/or upstream of the blood flow) to the site of formation of the drug reservoir, for example, to relatively increase the concentration of drugs at the reservoir site, for example, 0, about 1 mm, 5 mm, 10 mm, 20 mm, 50 mm, 100 mm, or other smaller, intermediate or larger values are used. Alternatively or additionally, the site is selected to be relatively far from the site of formation of the drug reservoir (e.g., physically far upstream of the blood flow and/or downstream of blood flow), for example, to relatively reduce the concentration of drugs away from the reservoir site, such as to prevent and/or reduce side effects. Non-limiting examples of distances include; about 20 cm, about 50 cm, about 70 cm, about 100 cm, or other smaller, intermediate or larger values are used. In some embodiments, the drugs are injected into the systemic circulation, such as without specific reference to the target site.
In an exemplary embodiment of the invention, drugs are injected into the patient. Non-limiting examples of sites of vascular drug injection include; through the skin into an artery (e.g., femoral artery), through the skin into a vein (e.g., medial cubital vein), directly into an artery such as using a catheter (e.g., hepatic artery), directly into a vein (e.g., saphenous vein). Other non-limiting examples of drug delivery include; subcutaneous, intramuscular, oral (e.g., uptake through gastric mucosa), rectal, submucosal, topical, inhalation.

Track Drug in Target Tissue

In an exemplary embodiment of the invention, the amount of drugs in the drug reservoir target site is estimated. Optionally, a waiting time period follows the systemic drug injection. The wait period can be precalibrated and/or derived based on feedback, such as imaging the target site and waiting until drugs appear at the site. Non-limiting examples of obtaining wait periods include; a mathematical model of drug distribution in the body, collected from experiments, based on physician experience. Non-limiting examples of a wait period include; 1 second, 3 seconds, 5 seconds, 10 seconds, 15 seconds, 30 seconds, 1 minute, 3 minutes, or other smaller, intermediate or larger wait times are used.
Optionally, the wait period is selected to be sufficiently long to allow drugs to reach the reservoir target site. Alternatively or additionally, the wait period is selected to be sufficiently short so that drugs that have reached the target site have not been cleared out of the site, for example, about 1%, 5%, 10%, 20%, 25%, 50% of the drug half life, or other smaller, intermediate or larger values are used. Energy can be applied after the wait period to form the drug reservoir. Non-limiting examples of obtaining wait periods include using data collected from experiments and based on physician experience.
In some embodiments of the invention, the presence of drugs in the drug reservoir is determined. Optionally, imaging of the drug reservoir site is performed to detect the presence of drugs at the site. Optionally, drugs are imaged indirectly, for example, by injecting drugs together with microbubbles. Intravascular ultrasound can be used to perform subharmonic imaging to detect the microbubbles in the target site. Alternatively or additionally, drugs are imaged directly, for example, by coupling the drugs and/or drug carrier to an acoustically dense material, and performing ultrasonic imaging of the target site.

Exemplary Catheter

FIG. 4A illustrates the intravascular application of energy 1234 to form drug reservoir 1210 in wall 1226 of artery 1242. Catheter 1222 comprises an energy emitting element 302 on a distal end, is threaded to the site over guidewire 1202 under image guidance, such as fluoroscopy and/or angiography. Energy 1234 is applied to trap drugs 1228 in vasa vasorum 1216. Catheter 1222 can be moved proximally, distally and/or rotated, such as to form two or more drug reservoirs, for example, as illustrated in FIGS. 6A-6B.
In some embodiments of the invention, catheter 1222 comprises at least one port 1250 and/or one or more pipes 1252 for injection of drugs 1228. For example, 2, 4, 6, 10, 20 or other smaller, intermediate or larger number of ports 1250. Alternatively or additionally, guidewire 1202 comprises one or more ports for injection of drugs. Alternatively or additionally, a sheath surrounding catheter 1222 comprises one or more ports for injection of drugs.
In some embodiments of the invention, pipe 1252 and/or port 1250 is connected to an injection mechanism 1254. Optionally, the connection is at a proximal end of catheter, such as outside the body of the patient. Mechanism 1254 controls the flow rate of drugs 1228 through port 1250 and/or pipes 1252, for example, at least 0.1 mL/second, at least 1 mL/second, at least 10 mL/second or other smaller, intermediate or larger volumes are used.
Optionally, mechanism 1254 comprises a container 1256, such as to hold drugs 1228 (e.g., in solution). The volume of container 1256 is about 0.1 mL, about 1 mL, about 5 mL, about 10 mL, about 20 mL, about 50 mL, about 100 mL, about 500 mL, about 1000 mL, about 2000 mL, about 5000 mL or other smaller, intermediate or larger sizes are used.
Optionally, mechanism 1254 comprises a pump, for example, for automatic administration of drugs 1228. Alternatively or additionally, mechanism 1254 is manually operated.
In some embodiments, ports 1250 are located proximally and/or distally to element 302, for example, upstream of element 302 depending on the direction of blood flow. Port 1250 can be located within element 302, or about 1 mm away, about 3 mm away, about 5 mm away, about 10 mm away, about 30 mm away, about 100 mm away, about 300 mm away, or other smaller, intermediate or larger distances are used. In some embodiments of the invention, ports 1250 are placed along the shaft of catheter 1222, such as spaced apart. Spacing between ports 1250 is about 0.5 mm, about 1 mm, about 3 mm, about 5 mm, about 10 mm, or other smaller, intermediate or larger distances apart. Optionally, at least some of ports 1250 are substantially in line with element 302. Alternatively, at least some of ports 1250 are placed along the circumference of the shaft of catheter 1222, for example, along part of the circumference and/or along the entire circumference.
Drugs 1228 are injected through port 1250 into arterial blood flow 1220. In an exemplary embodiment, at least some drugs 1228 enter circulation in arterial wall 1226 and reach vasa vasorum 1216 at the selected site for the formation of reservoir 1210.
A potential advantage of ports 1250 is injection of drugs 1228 directly into artery 1242. Potentially, a larger amount of drugs 1228 enter the blood vessels of the vessel wall such as vasa vasorum 1216. Another potential advantage is relatively improved control over injection of drugs 1228 and synchronization of the application of energy 1234 to trap drugs 1228 and form reservoir 1210.
FIG. 4C illustrates the use of a flow blocking device (e.g., balloon 1260) to to force drugs 1228 into vasa vasorum 1216, in accordance with some embodiments of the invention. Optionally, balloon 1260 is integrated with catheter 1222. Balloon 1260 can be inflated with saline, such as by the physician. Other devices can also be used to block blood flow, for example, nets, sails.
In some embodiments of the invention, balloon 1260 is located upstream of energy emitting element 302. Optionally balloon 1260 is located downstream of the bifurcation of artery 1242 and vasa vasorum 1216.
In some embodiments of the invention, balloon 1260 is sufficiently inflated to block all of blood flow 1222 through artery 1242. Alternatively, balloon 1260 is sufficiently inflated to leave at least some blood flow 1222 through artery 1242, for example, at least 10%, 30%, 50%, of the baseline flow 1222, or other smaller, intermediate or larger percentages are used.
In some embodiments of the invention, balloon 1260 is inflated before drugs 1228 are injected, for example, 1, 3, 5, 10, 30 seconds, or other smaller, intermediate or larger time periods. Optionally, balloon 1260 is kept inflated for at least a period of time during which energy is applied to form the drug reservoir, for example, for 50%, 70%, 100% of the time, or other smaller, intermediate or larger time frames are used. Optionally, balloon 1216 is kept inflated until the wait time has elapsed.
In some embodiments, balloon 1260 is deflated after some or all of drugs 1228 have been injected. For example, after 50% of drugs injected, 70%, 100%, or other smaller, intermediate or larger values are used.

Apply Energy to Trap Drug in Tissue

In an exemplary embodiment of the invention, energy is applied to the target site to form the drug reservoir. Optionally, energy is applied to form the drug reservoir according to the selected drug reservoir formation parameters. Optionally, the energy deposition profile is selected according to the type of energy delivery system being used. Optionally, the energy deposition profile is selected according to the location of the source of energy.
In some embodiments, element 102 is used to receive ultrasound energy, for example, returning echoes, such as during imaging of tissues. Receiving ultrasound energy can create a voltage across electrodes 302 and/or 304. Optionally, emission element 102 can function both as an emitter and receiver, for example, as a transceiver. Emission element 102 and/or a catheter may be provided with an acoustic/ultrasonic transducer.
In an exemplary embodiment of the invention, ultrasound emission element 102 is an unfocused emission element. For example, the beam produced by element 102 does not focus and/or converge at a point. For example, the beam produced by element 102 stays substantially straight and/or slightly diverges (e.g., about 15 degrees) after leaving element 102. Optionally, element 102 is a widebeam emission element, for example, the beam produced by element 102 diverges more than about 15 degrees after leaving element 102.
In an exemplary embodiment of the invention, ultrasound energy is selected for forming the drug reservoir. Optionally, the ultrasound energy is delivered intravascularly. Optionally or additionally, the ultrasound energy is unfocused. In some embodiments of the invention, other ultrasound configurations are used, non-limiting examples of settings include; delivered from outside the body, focused ultrasound such as high intensity focused ultrasound (HIFU) and/or phased arrays.
In an exemplary embodiment of the invention, one or more types of energy, are applied to the drug reservoir in order to activate the drugs. Optionally, drugs are activated upon formation of the reservoir, such as when drugs have been trapped in the tissue. The activation energy can be in addition to and/or instead of the energy used to form the reservoir.
In an exemplary embodiment of the invention, ultrasound energy is delivered as taught by Sverdlik et al in co-filed PCT application “TISSUE TREATMENT”, attorney docket number 52347 incorporated herein by reference in its entirety.
In some embodiments of the invention, other energy types can be used instead of, or in addition to ultrasound. The selection of the type of energy can depend on the ability to form the desired drug reservoir at the site.
Non-limiting examples include;
Light (e.g., laser): Potentially useful to form the drug reservoir in regions in which air is present between the energy source and the target tissue. For example, on the skin, lungs, prostate, other solid organs.
Microwave: Potentially useful to form the drug reservoir in regions in which air is present between the energy source and the target tissue. For example, on the skin, lungs, prostate, other solid organs.
Radiofrequency: Potentially useful to form the drug reservoir over relatively larger areas, for example, by applying appropriately sized electrodes and/or an appropriate polarity. Potentially useful to form the drug reservoir in the skin.
Electricity (AC and/or DC): Potentially useful to form the drug reservoir in electrically conductive tissue, for example, nerves.

Exemplary Device for Trapping

With further reference to FIG. 4A, a non-limiting example of an exemplary device will be further described. In an exemplary embodiment of the invention, catheter 1222 comprises an acoustic element 102 (e.g., part of transducer 300) to deliver ultrasonic energy 1234 to form reservoir 1210. Optionally, ultrasound energy is produced and/or delivered by an element and/or catheter, such as taught by Sverdlik et al. in co-filed PCT application “ULTRASOUND TRANSDUCER” attorney docket no. 52344 incorporated herein by reference in its entirety.
In an exemplary embodiment of the invention, diameter of catheter 1222 is about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, or other smaller, intermediate or larger sizes are used.
In an exemplary embodiment of the invention, transducer 300 is capable of relatively high intensity ultrasound output. Optionally, transducer 300 is gas-backed, such as with a bubble of gas, such as air. Optionally, transducer 300 comprises a gas bubble containment area adapted to retain the gas bubble when in blood.
Non-limiting examples of high intensity ultrasound include at least 20 watts/cm², at least 30 watts/cm², at least 50 watts/cm², at least 100 watts/cm²or other smaller, intermediate or larger intensities.
In an exemplary embodiment of the invention, ultrasound is applied for a period of no more than 1 second, 3 seconds, 5 seconds, 15 seconds, 30 seconds, 60 seconds, 100 seconds, or other smaller, intermediate or larger times periods are used.
In an exemplary embodiment of the invention, the shape of element 102 is rectangular. Optionally, element 102 is planar. Optionally, a length of element 102 is, for example, about 1 mm, about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, or other smaller, intermediate or larger lengths are used. Optionally, a width of element 102 is for example, about 0.2 mm, about 0.6 mm, about 1.0 mm, about 1.4 mm, about 2.0 mm, or other smaller, intermediate or larger widths are used.
In some embodiments, contact between an acoustic element 102 of transducer 300 and wall 1226 of vessel 1240, is reduced and/or prevented, for example, by a separation device 1204 such as described in PCT application having attorney docket number 52348. Optionally, device 1204 maintains a distance 1218 between element 102 and wall 1226 of at least 1 mm. Optionally, a relatively cool liquid (e.g., blood, injected saline) flows in distance 1218. In an exemplary embodiment of the invention, the liquid cools element 102 and/or wall 1226.
In an exemplary embodiment of the invention, element 102 is cooled. Optionally, cooling occurs by transfer of heat from element 102 to a surrounding fluid such as blood 1220, saline, urine, water, angiography contrast fluids, cerebrospinal fluid, lymph, mucous, stomach acid. Alternatively or additionally, cooling occurs by injection of a volume of a liquid (e.g., saline, radio-opaque dye) through tube 1206, and/or circulation of a liquid through tube 1208. Alternatively or additionally, cooling is increased using an active heat flux, such as a thermoelectric cooler. It should be noted, that herein cooling by blood flow also refers to cooling using other fluids (e.g., saline) in addition to blood, or cooling using other fluids as a substitution for blood cooling. Further details of cooling can be found for example in PCT application having attorney docket number 52346.
In an exemplary embodiment of the invention, a temperature sensing element, such as sensor 308, measures and/or estimates the temperature of element 102. In an exemplary embodiment of the invention, sensor 308 measures the temperature of blood that has flowed 1220 over a surface 1224 of element 102. In an exemplary embodiment of the invention, the temperature of the blood that has flowed 1220 over surface 1224 is used as an estimate of the temperature of element 102.

Exemplary System for Trapping

FIG. 4B illustrates an exemplary ultrasound treatment system 1600 for selectively treating tissues, in accordance with an exemplary embodiment of the invention. System 1600 provides for the control of the ultrasound treatment and/or monitoring of the treatment using catheter 1222, such as illustrated in FIG. 4A.
In an exemplary embodiment of the invention, an operator (e.g., physician performing the procedure) programs a controller 1602 (e.g., computer) for treatment using a user interface 1604 (e.g., keyboard, mouse, monitor). Optionally, treatment is monitored, for example, by viewing feedback parameters on interface 1604.
In an exemplary embodiment of the invention, a power port 1606 provides electrical power to electrodes across element 102, causing element 102 to vibrate at the set frequency, outputting a set ultrasound intensity profile.
In an exemplary embodiment of the invention, one or more functions and/or parameters and/or settings are programmed and/or set into controller 1602 (e.g., automatically determined by software such as according to a treatment plan). Optionally or additionally, one or more functions and/or parameters are selectable (e.g., manually set by a user, automatically selected by software).
One or more non-limiting examples of settable parameters include:

- Impedance of element 102.
- Acoustic feedback is feedback obtained by analyzing echoes of a diagnostic ultrasound signal returning from tissues.
- Estimated or measured flow rate of blood across the surface of the acoustic element can be important for controlling the temperature of the element to prevent overheating.
- Estimated or measured flow rate of blood across the wall of the treatment target (e.g., blood vessel) can be important for estimating the cooling capacity of the blood on the tissues of the wall being heated by ultrasound.
- Efficiency is the estimated efficiency of converting electrical energy into ultrasound energy by the acoustic element. Further details related to efficiency can be found for example in PCT application having attorney docket number 52345.
- Cooling system cools element and/or blood vessel wall to the desired temperature. Optionally, the cooling system is used in combination with the blood flow.
- Impulse excitation is the application of an impulse function (e.g., delta function) to the element, causing the element to vibrate with a decreasing amplitude. Impulse excitation is used to estimate a reduction in efficiency, useful as feedback, for example, to determine one or more of, thrombus formation on the element, the element coming in contact with the vessel wall, mechanical damage to the element.
- Navigation system controls the movement and/or positioning and/or orientation of catheter 1222 and/or transducer 300.
- Pressure is the pressure caused by sound (e.g., acoustic intensity) during treatment and/or imaging.
- Electric power is the applied power to the transducer.
- Reflected electric power from the transducer back to the controller.
- Voltage is the measured and/or applied voltage on the transducer.
- Current is the measured and/or applied current in the transducer.

One or more non-limiting examples of selectable parameters include:

- Frequency of the ultrasound energy produced by vibration of the acoustic element.
- Waveform applied to the acoustic element, for example, a sinusoidal wave form.
- Intensity is the produced ultrasound power divided by the surface area of the acoustic element.
- Pulse duration is the length of a pulse of acoustic energy measured in time.
- Duty cycle is the percentage of time in a single pulse that ultrasound energy is transmitted.
- Temperature threshold is the approximate temperature of the element and/or the liquid (e.g., blood, saline) that should not be exceeded.
- Target temperature is the estimated and/or measured temperature of the targeted area.
- Energy delivery pattern is the spatial and/or temporal combination of one or more of the above variables, for example, a single pulse, a sequence of pulses, a train of pulses.
- Focusing is the setting of non-focused vs. focused ultrasound energy.
- Drug injection volume is the total volume of drugs injected over a period of time. Drug injection can be synchronized to emission of energy to form the drug reservoir and/or to imaging performed of the location where the reservoir is formed.
- Synchronization is the control of the injection of drugs in accordance with the formation of the drug reservoir and/or imaging of the reservoir area.

The table below sets out some examples of the selectable parameters, and provides their theoretical limits, an exemplary treatment range, and an exemplary treatment sub range (e.g., most commonly used settings). It is important to note that some selectable parameters can only be selected from a pre-determined set, for example, in some embodiments, catheters are designed to operate at a specific frequency, in which case the user selects the frequency according to the catheter available.


Exemplary
Treatment	Exemplary	Theoretical
sub range	Treatment range	range	Parameter

			Frequency (MHz):
10-22	8-30	1-60	Treatment
10-25	10-60	1-60	Imaging
10-60	10-100	1-200	Intensity (Watts/sq cm)
50-100	10-100	0.1-100	Duty cycle (%)
0.1-2	0.1-4	0.01-1000	Pulse duration (seconds)
3-60	2-120	0.1-1000	Duration of treatment
			(Seconds) per location
35-70%	20-70%	1-70%	Efficiency (%)
37-51	37-60	37-100	Blood Temp (Celsius)

Some Examples of Expected Effects Associated with Variables

The following are some non-limiting examples illustrating some parameters under control, and their association with some expected treatment effects, in accordance with an exemplary embodiment of the invention:

- Acoustic feedback: imaging of the reservoir region for the desired thermal effects can be used to decide if to continue formation, stop formation or change the formation (e.g., increase or decrease acoustic intensity profile, change positions of catheter).
- Frequency: a relatively lower frequency of ultrasonic energy is able to penetrate relatively deeper into tissue. In some embodiments, relatively lower frequencies are used to form the drug reservoir relatively further away from the blood vessel wall.
- Intensity: a relatively higher intensity of ultrasonic energy is able to penetrate relatively deeper into tissue and/or achieves a relatively higher heating of tissues quicker. In some embodiments, relatively higher intensities are used to achieve relatively larger drug reservoirs. Alternatively or additionally, the drug reservoir is formed further away from the vessel wall.
- Pulse duration: a relatively longer pulse will deliver a relatively larger amount of ultrasonic energy to tissues, achieving a relatively larger drug reservoir.
- Duty cycle: a relatively higher duty cycle will deliver a relatively higher amount of ultrasonic energy to tissues, achieving a relatively larger drug reservoir. In some embodiments, a relatively short duty cycle acts as a train of short pulses separated by delays, the effect of which is described below with reference to ‘formation pattern’.
- Drug Reservoir Formation Pattern: can be applied to form different types of drug reservoirs, for example, a pulse of acoustic energy can be applied, followed by a delay period to allow cooling (e.g., by spreading of heat) before applying another pulse of energy. In another example, a drug reservoir can be formed at one location along the arterial wall, followed by a rotation (e.g., 10 degrees), followed by formation of another drug reservoir.
- Focusing: non-focused application of energy does not require precise anatomical positioning of the distance from the transducer to the target tissue throughout treatment, and achieves a relatively larger reservoir volume using a relatively lower acoustic intensity. Focused application of energy requires precise positioning of the focal point to the target tissue throughout treatment, and to achieves a relatively smaller reservoir volume using a relatively higher intensity (e.g., total intensity at focal point).
  Feedback and/or Monitor

In some embodiments of the invention, energy is applied to the target tissue to form the drug reservoir in an open loop manner. Optionally, energy is applied after the post-injection wait time period has elapsed.
In some embodiments of the invention, energy is applied to the target tissue to form the drug reservoir in a closed loop manner. Optionally, the application of energy and/or the formation of the drug reservoir is monitored.
In some embodiments of the invention, the trapping of drugs in the reservoir is monitored. Optionally, drugs are detected in the reservoir formation target area, energy is applied to the area to form the reservoir, and the presence of the drugs trapped in the reservoir is confirmed.
In some embodiments of the invention, the detection and/or confirmation of the presence of trapped drugs is performed by ultrasound imaging. Optionally a contrast agent is used for imaging, for example, if microbubbles are inserted together with the drugs, subharmonic imaging of the microbubbles suggests the presence of the drugs.
In some embodiments of the invention, the formation of the drug reservoir is monitored. Optionally, imaging of the tissues is performed, such as to detect the deposition of energy to the tissues forming the reservoir. For example, imaging is used to detect thermal effects in the tissues due to the applied energy, such as shrinking of tissues and/or heating of tissues.
In some embodiments of the invention, detection of the presence of drugs in the target reservoir area and/or monitoring of the tissues occurs at the same time as energy is being delivered to form the reservoir (e.g., in parallel). Alternatively or additionally, delivery of energy to form the reservoir occurs in pulses separated by a delay, with the detection of the presence of drugs in the target area and/or monitoring occurring during the delay.
In some embodiments, imaging is performed by using the same ultrasound transducer used for treatment, for example, by treating at a first treatment frequency for a period of time, then imaging at a second diagnostic frequency for another period of time (e.g., analyzing the ultrasonic echoes returning from the tissues). Alternatively or additionally, the same ultrasound transducer is used, but with different electrodes which separate the transducer into an imaging region and a treatment region. Alternatively or additionally, one or more acoustic elements are used, for example, one element for imaging and one element for treatment.
One or more non-limiting examples of ultrasound imaging methods for feedback include, “Measuring the ultrasonic attenuation of the target tissues”, for example, as described by Damianou et al, J Acoust Soc Am. 1997 July; 102(1):628-34, incorporated herein by reference in its entirety. Damianou found that the rate at which the thermal dose was applied was associated with the total attenuation absorption, for example, relatively lower thermal dose rates resulted in relatively larger attenuation coefficients. In some embodiments, the energy applied to the target area is estimated by measuring the attenuation coefficient and/or the absorption. Optionally, the measurements are compared to expected values according to the set energy parameters. Optionally or additionally, the energy profile is adjusted relatively higher or relatively lower according to the comparison, for example, to achieve the resulting thermal effect to the target tissue to form the drug reservoir.
Measuring the ultrasound attenuation coefficient and/or backscatter power for example, as described by Worthington, A. E., et al, Ultrasound in Med. & Biol., Vol. 28, No. 10, pp. 1311-1318, 2002, incorporated herein by reference in its entirety. Worthington found that the attenuation coefficient and/or backscatter power increased with relatively higher temperatures. In some embodiments, the temperature of the target tissues is estimated according to the attenuation coefficient and/or backscatter power. Optionally, the temperature of the tissue is compared to the temperature range and/or threshold required to achieve a desirable effect in the tissues (e.g., collagen denaturation above 55 degrees Celsius). Optionally or additionally, the energy delivery is adjusted relatively higher or relatively lower according to the comparison, for example, to achieve the target temperature in the tissue to form the drug reservoir.
Additional details of imaging using the ultrasound emission element can be found for example in co-filed PCT applications with attorney docket numbers 52342 and 52345.

Adjust/Repeat

In some embodiments of the invention, monitoring of the reservoir formation and/or detection of drugs in the target area is used to increase the level of control of the formation of the reservoir (e.g., in real time, overall effect over several sessions).
In some embodiments, data from feedback and/or monitoring is used to adjust energy delivery parameters (e.g., frequency, intensity), for example, by a look-up table (e.g., stored in a memory), calculations, trial and error (e.g., slowly changing a parameter and/or monitoring changes). Optionally, parameters are adjusted manually (e.g., by a user) using an interface coupled to a controller. Alternatively or additionally, parameters are automatically adjusted, such as by a software module of the controller.
One or more non-limiting examples of adjustments include, increasing the formation of the drug reservoir, reducing the formation of the planned drug reservoir, stopping the formation of the drug reservoir.
In some embodiments, drug injection (e.g., by fluid delivery) is adjusted and/or repeated. For example, if an inadequate amount of drug has been trapped in the reservoir, additional drugs can be released and trapped again. The additional drugs can be trapped in the same reservoir (e.g., applying energy to the same location again) and/or in another reservoir (e.g., applying energy to a different location).
In some embodiments of the invention, the reservoir is formed as a plurality of drug reservoirs, for example, as illustrated in FIGS. 6A-6B. Optionally, one or more of: injecting the drug (e.g., systemically), detecting the drug at the reservoir target site, applying energy to form the reservoir site and/or detecting the amount of drug trapped in the formed reservoir are repeated. Optionally, the reservoir is formed according to the cumulative amount and/or concentration of drugs detected in the reservoir, for example, the reservoir is build up in successive small blocks until a sufficient amount of drug has been trapped. One or more potential advantages include; achieving a desired concentration at the reservoir site, reducing areas of the reservoir that do not contain trapped drugs, leaving a sufficient number of unblocked blood vessels such as between the reservoirs.
In some embodiments of the invention, the catheter is repositioned, for example, moved proximally, distally and/or rotated clockwise or counterclockwise. Alternatively or additionally, one or more energy parameters are adjusted, for example, the ultrasound to frequency and/or intensity are adjusted.
It is expected that during the life of a patent maturing from this application many relevant methods for using energy to form drug reservoirs in tissue will be developed and the scope of the term drug reservoir is intended to include all such new technologies a priori.
As used herein the term “about” refers to ±10%
The terms “comprises”, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”.
The term “consisting of” means “including and limited to”.
The term “consisting essentially of” means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
As used herein, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.
Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein to interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
As used herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non limiting fashion.

Experiments in the Carotid Artery

Study subject: a pig.
Anatomical target: carotid artery.
Length of ultrasonic treatment catheter: 95 cm
Size of catheter: 9 F
Size of surface area of ultrasound element: 6 mm×1 mm
Transducer frequency: 10 Mhz and 20 MHz
Time component of intensity profile: 30 seconds
Drug: India ink was used to simulate drug particles. India ink particles were diluted 1:2-1:10 with saline. Total volume injected was 20 mL.

Experimental Protocol:

The catheter was introduced using standard techniques to a distal location in the common carotid artery. The drug was injected through ports in the catheter up-stream to the transducer, followed by a 5 second waiting period, followed by 30 seconds of application of ultrasonic energy to the arterial wall and surrounding tissue. The ports for releasing the ink where positioned on the catheter upstream from the ultrasonic transducer, at distances of 10, 30, 50 mm.
The process was repeated several times, each time the catheter was moved 10 mm The movement of the catheter was sufficiently long such that application of energy would not overlap.

Histological Processing:

30 min following the procedure, the pig was euthanized by a KCl injection. The carotid arteries were harvest along with the surrounding connective tissue, which were flushed with saline and fixated with 4% formalin overnight. The artery was cut into 3 mm cylinders which were dehydrated and embedded in paraffin blocks. The blocks were cut to 4 μm incisions every 1 mm and H&E staining was performed.

Results:

FIGS. 7A-7I are images from different slides of several locations along the treated artery.

- The arrows in FIG. 7A point to india ink particles in small blood vessels of the arterial wall.
- FIG. 7B shows a venule with blood and ink in its lumen.
- The arrows in FIG. 7C show india ink particles with red blood cells in small blood vessels which supply blood to nerves. All nerves are viable. This result provides support for heating tissue sufficiently to trap the particles without causing damage to nearby nerves.
- FIG. 7D shows india ink particles in small blood vessels.
- FIG. 7E shows india ink in an arteriole in the blood vessel wall.
  FIGS. 7F-7G are images from the same histological slide.
- FIG. 7F is an image of an arteriole with blood and ink in its lumen.
- FIG. 7G shows india ink deposited on the endothelial surface of the artery as well as in the vasa vasorum.

FIGS. 7H-7I are images of india ink mixed with blood in the lumen of small vessels in the perivascular tissue located near nerves. All nerves were viable.

General

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.
Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.
All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

Claims

1. A method of forming at least one therapeutic reservoir in a target tissue comprising:

trapping therapeutics in at least a portion of said target tissue by selectively applying ultrasound energy to said target tissue.

2. (canceled)

3. A method according to claim 1, wherein selectively applying energy comprises applying a sufficient amount of said energy to said target tissue to trap said therapeutics without damaging surrounding non-target tissue.

4. A method according to claim 1, further comprising activating said therapeutics in said target tissue.

5. A method according to claim 1, wherein said trapping comprises maintaining said therapeutics in said target tissue for a period of time sufficiently long for said therapeutics to exert a therapeutic effect and after said therapeutics outside said target tissue have been removed from a patient.

6-8. (canceled)

9. A method according to claim 1, wherein said ultrasound is applied intravascularly to said target tissue.

10. A method according to claim 1, wherein said ultrasound is unfocused.

11. A method according to claim 1, wherein a frequency of said ultrasound energy is between 5 Mhz and 30 Mhz.

12. A method according to claim 1, wherein said selectively applying energy comprises applying a pattern of energy sufficient to block a volume of at least one of blood vessels in said target tissue and lymph vessels in said target tissue to prevent therapeutics from traversing through said volume of blood vessels.

13. (canceled)

14. A method according to claim 12, wherein said blocking comprises denaturing collagen surrounding at least one of said blood vessels and said lymphatic vessels.

15. (canceled)

16. A method according to claim 1, wherein said selectively applying energy comprises applying a pattern of energy to an arterial wall without damaging an intima of said wall.

17. (canceled)

18. A method according to claim 1, wherein said selectively applying energy comprises applying energy in a non-contiguous manner to form a plurality of therapeutics reservoirs.

19. (canceled)

20. A method according to claim 1, wherein said selectively applying energy comprises applying a pattern of energy to a location within said target tissue to form said therapeutics reservoir substantially at said location.

21. A method according to claim 20, wherein said target tissue comprises a wall of an artery and said location comprises an adventia layer of said wall.

22-23. (canceled)

24. A method according to claim 21, wherein said artery is a renal artery.

25. A method according to claim 24, wherein said therapeutic is neurotoxic to renal nerves in said renal artery wall.

26-37. (canceled)

38. A method according to claim 1, further comprising blocking at least some of a blood flow to force said therapeutics into ducts of said target tissue.

39. (canceled)

40. A method according to claim 1, wherein said trapping comprises trapping in vasa vasorum tissue.

41. A method according to claim 1, wherein said trapping comprises trapping in vessels having a size of less than 0.1 mm.

42-43. (canceled)

44. An ultrasound system for forming a therapeutics reservoir comprising:

a catheter comprising:

a distal end;

a proximal end comprising:

an ultrasound emission element configured for producing ultrasound energy having sufficient energy to seal tissue thereby trapping therapeutics in blood vessels thereof; and

a controller which to controls application of said ultrasound energy to provide said trapping.

45. A system according to claim 44, further comprising at least one port for release of a fluid to blood, said port located on said proximal end, upstream from said emission element.

46. (canceled)

47. A catheter according to claim 45, wherein said port is positioned at least 10 mm from said ultrasound emission element.

48. A catheter according to claim 45, wherein said port is adapted to allow a flow rate of said fluid of at least 1 mL/second.

49. A catheter according to claim 45, wherein said port is positioned substantially in line with said emission element.

50-51. (canceled)

52. A catheter according to claim 45, further comprising an injection mechanism in fluid communication with said port, said mechanism configured to inject said fluid through said port, said controller further configured to control said injection mechanism.

53. A catheter according to claim 45, wherein said fluid comprises a neurotoxic drug.

54. A catheter according to claim 44, wherein said emission element is configured to emit ultrasound at an intensity of at least 20 Watt/cm².

55. A catheter according to claim 45, wherein said controller is configured to control release of said fluid through said port and emission of ultrasonic energy by said ultrasound emission element.

56-58. (canceled)