US20050131339A1 - Ultrasonic surgical instrument for intracorporeal sonodynamic therapy - Google Patents

Abstract

The present invention relates, in general, to ultrasonic surgical instruments and, more particularly, to an intracorporeal ultrasonic surgical instrument for sonodynamic therapy. Disclosed is an ultrasonic surgical system comprising: a generator and an instrument comprising: a housing; a transducer; a semi-permeable membrane; a pharmaceutical agent; and an agent delivery system. The transducer is adapted to convert the electrical energy of the generator into mechanical energy. The pharmaceutical agent, delivered into a chamber of the semi-permeable membrane, is driven through the semi-permeable membrane by the mechanical energy. A method in accordance with the present invention comprises the steps of: providing a surgical instrument comprising: a housing; a transducer connected to the housing; a semi-permeable membrane; a pharmaceutical agent; and an agent delivery system; inserting the surgical instrument into a patient; delivering a drug to the patient; and locally activating the drug with the surgical instrument.

Description

CROSS REFERENCE TO RELATED PATENT INFORMATION
• This application is related to, and claims the benefit of, U.S. provisional patent application Ser. No. 60/302,070 filed Jun. 29, 2001, which is hereby incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
• The present invention relates, in general, to ultrasonic surgical instruments and, more particularly, to an ultrasonic surgical instrument for intracorporeal sonodynamic therapy.
BACKGROUND OF THE INVENTION
• Ultrasonic instruments, including both hollow core and solid core instruments, are used for the safe and effective treatment of many medical conditions. Ultrasonic instruments, and particularly solid core ultrasonic instruments, are advantageous because they may be used to cut and/or coagulate organic tissue using energy in the form of mechanical vibrations transmitted to a surgical end-effector at ultrasonic frequencies. Ultrasonic vibrations, when transmitted to organic tissue at suitable energy levels and using a suitable end-effector, may be used to cut, dissect, or cauterize tissue. Ultrasonic instruments utilizing solid core technology are particularly advantageous because of the amount of ultrasonic energy that may be transmitted from the ultrasonic transducer through the waveguide to the surgical end-effector. Such instruments are particularly suited for use in minimally invasive procedures, such as endoscopic or laparoscopic procedures, wherein the end-effector is passed through a trocar to reach the surgical site.
• Ultrasonic vibration is induced in the surgical end-effector by, for example, electrically exciting an electromechanical element, which may be constructed of one or more piezoelectric or magnetostrictive elements in the instrument handpiece. Vibrations generated by the electromechanical element are transmitted to the surgical end-effector via an ultrasonic waveguide extending from the transducer section to the surgical end-effector.
• Another form of ultrasonic surgery is performed by High Intensity Focused Ultrasound, commonly referred to as “HIFU”. HIFU is currently used for lithotripsy procedures where kidney stones are broken up into small pieces by ultrasonic shock waves generated through ultrasound energy focussed into the body from an extracorporeal source. HIFU is also under investigational use for treating ailments such as benign prostatic hyperplasia, uterine fibroids, liver lesions, and prostate cancer.
• Examples of uses of ultrasound to treat the body can be found in U.S. Pat. Nos. 4,767,402; 4,821,740; 5,016,615; 6,113,570; 6,113,558; 6,002,961; 6,176,842 B1; PCT International Publication numbers WO 00/27293; WO 98/00194; WO 97/04832; WO 00/48518; WO 00/38580; WO 98/48711; and Russian Patent number RU 2152773 C1.
• Although the aforementioned devices and methods have proven successful, it would be advantageous to provide an intracorporeal instrument for sonodynamic therapy, and methods of sonodynamic treatment capable of improved outcomes for patients. This invention provides such an intracorporeal instrumennt and method for sonodynamic therapy.
SUMMARY OF THE INVENTION
• The present invention relates, in general, to ultrasonic surgical instruments and, more particularly, to an ultrasonic surgical instrument for intracorporeal sonodynamic therapy. Specifically, the invention relates to an intracorporeal surgical instrument capable of enhanced/controlled delivery and activation of pharmaceutical agents as well as to achieve tissue ablation. Representative pharmaceutical agents include analgesics, anti-inflammatories, anti-cancer agents, bacteriostatics, neuro active agents, anticoagulants, high-molecular weight proteins, for example, for gene delivery, among others. The instrument is designed to operate in the kHz and/or MHz frequency ranges.
• Disclosed is an ultrasonic surgical system comprising a generator and an instrument comprising a housing; a transducer connected to the housing; a depot for chemicals including a semi-permeable membrane, bio-degradable packet, drug impregnated depots and liposomes among others; a pharmaceutical agent; and an agent delivery system. The generator is adapted to provide electrical energy to the transducer. The transducer is adapted to convert the electrical energy into mechanical energy. The agent delivery system delivers the pharmaceutical agent into a chamber of the semi-permeable membrane; and the pharmaceutical agent is driven through the semi-permeable membrane by the mechanical energy. Advantageously, the transducer may be combined with other surgical instruments such as ultrasound, iopntophoretic, laser, electrosurgical, for example RF, and eletroporative devices to achieve tissue ablation as well as the sonodynamic therapy.
• The present invention has application in endoscopic and conventional open-surgical instrumentation as well as application in robotic-assisted surgery.
BRIEF DESCRIPTION OF THE DRAWINGS
• The novel features of the invention are set forth with particularity in the appended claims. The invention itself, however, both as to organization and methods of operation, together with further objects and advantages thereof, may best be understood by reference to the following description, taken in conjunction with the accompanying drawings in which:
• FIG. 1 is a perspective view of an ultrasonic system in accordance with the present invention;
• FIG. 2 is a perspective view of an alternate agent injection device for an ultrasonic instrument in accordance with the present invention;
• FIG. 3 is a perspective view of an ultrasonic surgical end-effector of an ultrasonic system in accordance with the present invention;
• FIG. 4 is a sectioned view of a portion of an intense ultrasound instrument in accordance with the present invention;
• FIG. 5 is a perspective view of an alternate embodiment of an ultrasonic system in accordance with the present invention;
• FIG. 6 is a perspective view of an alternate agent injection device for an alternate embodiment of an ultrasonic instrument in accordance with the present invention;
• FIG. 7 is a perspective view of an ultrasonic surgical instrument end-effector of an ultrasonic system in accordance with the present invention;
• FIG. 8 is a sectioned view of a portion of an ultrasonic surgical instrument in accordance with the present invention;
• FIG. 9 is a sectioned view of a portion of an ultrasonic surgical instrument in accordance with the present invention;
• FIG. 10 is a perspective view of an alternate embodiment of an ultrasonic system in accordance with the present invention;
• FIG. 11 is a graph illustrating the transport of an agent with and without ultrasound energy;
• FIG. 12 is a graph of the response characteristics of a transducer in accordance with the invention ofFIGS. 1-4; and
• FIG. 13 is a plot of the calculated acoustic intensities of the transducer in accordance with the invention ofFIGS. 1-4.
DETAILED DESCRIPTION OF THE INVENTION
• Before explaining the present invention in detail, it should be noted that the invention is not limited in its application or use to the details of construction and arrangement of parts illustrated in the accompanying drawings and description. The illustrative embodiments of the invention may be implemented or incorporated in other embodiments, variations and modifications, and may be practiced or carried out in various ways. Furthermore, unless otherwise indicated, the terms and expressions employed herein have been chosen for the purpose of describing the illustrative embodiments of the present invention for the convenience of the reader and are not for the purpose of limiting the invention.
• It is well known to those skilled in the art that ultrasound operating at kHz frequencies can reversibly change the permeability of cell barriers and/or activate drugs. Most of the work in this area describes the drug delivery applications through the skin, or enhancement of thrombolytic activity in the blood vessels. An approach where a surgeon performs an excision using an ultrasonic surgical instrument, and then “delivers” a chemotherapeutic agent in the treatment field would improve the treatment outcomes.
• The attenuation coefficient for sound at kHz frequencies in tissue is very low, even assuming a radial spread of acoustic energy from the end effector. There is sufficient energy distal from the end effector, from a few millimeters to a couple of centimeters, such that the permeability of cells can be affected. Two examples, which are not intended to limit the scope of the invention, of intracorporeal drug delivery/enhancement are enabled by the present invention. One, local drug delivery in the region of surgical treatment as described earlier. Second, the therapeutic chemical agent is given intravenously, and the drug is activated in a region of interest during an interventional procedure using laparoscopic kHz and/or MHz frequency ultrasound.
• For management of cancers, intra-operative delivery of chemotherapeutic agents and treatment with ultrasound energy is provided by the present invention to increase the efficacy of surgery and reduce recurrence rates, as well as to reduce the risk of seeding healthy sites with cancerous cells during intervention. Such local and site specific drug delivery approaches with kHz and/or MHz frequency ultrasound could be applied in surgical procedures, such as, for example, liver, colon, prostate, lung, kidney, and breast. A surgical patient may further benefit from the increase in treatment volume that may result from a chemical agent used in cooperation with kHz and/or MHz ultrasonic energy as well as from chemical agents used with the present invention that would otherwise be adversely affected if used with other forms of energy. In general, the chemical agents whose efficacy can be enhanced with the present invention may be chemotoxic drugs such as, for example, Paclitaxel, Docetaxel, trademark names of Bristol Meyers-Squibb or antibiotics, bacteriostatics, or cholinesterase inhibitors such as Galantamine, trademark name Reminyl of Johnson and Johnson, that may be delivered locally before completion of a surgical procedure. Chemical agents whose efficacy may be enhanced with the present invention further include local anesthetics such as, but not limited to, Novacaine, anti-inflammatories, corticosteroids, or opiate analgesics.
• FIG. 1 illustrates anultrasonic system25 for local delivery of an agent in combination with anintense ultrasound instrument50 for activating or assisting transport of the agent.Intense ultrasound instrument50 includes anelongated portion68, ahousing74, agrip69, a porous orsemi-permeable membrane55, and aport79. Anagent75 is contained in acontainer76 for insertion intoport79. Insertion ofcontainer76 intoport79 may be done mechanically, or manually by the operator.Intense ultrasound instrument50 includes a radiating end-effector60.Intense ultrasound instrument50 is connectable to agenerator10 viacable90, that supplies electrical energy to radiating end-effector60 for conversion bytransducer65 to ultrasonic stress waves. Radiating end-effector60 comprises a plurality of embodiments including, but not limited to, single element, array-based end effectors, planar transducers, shaped transducers, or end effectors with active-passive element combinations.
• Afoot switch95 is connected togenerator10 viacable98 to controlgenerator10 function. Aswitch96 and aswitch97 are included withfoot switch95 to control multiple functions. For example, switch96 could provide a first level of energy to radiate end-effector60 and aswitch97 could provide a second level of energy to radiate end-effector60.Generator10 may also include adisplay80 for providing information to the user, and buttons or switches81,82, and83 to allow user input into the generator such as, for example, turning the power on, setting levels, defining device attributes or the like.
• FIG. 2 illustrates an alternate means of providingagent75 tointense ultrasound instrument50. In this embodiment, asyringe77 containsagent75 for injection to a surgical site within a patient. Aplunger73 may be depressed by the operator to deliveragent75 to a surgical site viaport78.
• FIG. 3 illustrates a method of using an instrument in accordance with the present invention. End-effector60 is inserted into the body cavity of a patient, and located on ornear tissue40 that includes a spot orlesion45 for treatment withagent75. Spot orlesion45 may be a cancerous region, a polyp, or other area that would benefit from treatment withagent75.Semi-permeable membrane55 containsagent75 under instrument-off conditions, onceagent75 has been delivered tosemi-permeable membrane55.Agent75 may be delivered tosemi-permeable membrane55 by way of an agent channel63 (FIG. 4). An alternate embodiment ofintense ultrasound instrument50 contemplates the disposable use ofintense ultrasound instrument50 wheresemi-permeable membrane55 is manufactured containing apre-selected agent75 located withinsemi-permeable membrane55. The single use embodiment ofintense ultrasound instrument50 comprises disposal ofintense ultrasound instrument50,semi-permeable membrane55, and/orend effector60. Alternatively, and not by way of limitation of the invention,membrane55 could take the form of a biocompatible biodegradable layer that is impregnated with a therapeutic chemical agent with or without the presence of cavitation nuclei. The therapeutic agent may be preferentially delivered at the target site when theultrasound instrument50 is energized.
• Whenintense ultrasound instrument50 is activated,agent75 is driven throughsemi-permeable membrane55, producingagent droplets77. A suitablesemi-permeable membrane55 may be formed from, for example, nitrocellulose, tyvek, silicone, ethelyne vinyl acetate, or the like.Semi-permeable membrane55 may be semi-permeable in specific regions and may be non-permeable in other regions to effectuate targeted release of theagent75 throughmembrane55. Further,semi-permeable membrane55 may be bio-compatible and have a tissue adhesive, allowing for thesemi-permeable membrane55 to be left within a body cavity, and/or may be adapted to dissolve within a body cavity.Agent droplets77 are driven preferentially intotissue40 by ultrasound energy, as shown below in ultrasound-mediated diffusion experiment results.
• Intense ultrasound instrument50 may further comprise the use of a suction system, an irrigation system, a snare, a viewing means, a coolant means, an imaging means, a biopsy system, a gene delivery means, and/or a number of cutting and/or coagulation means such as, for example, laser, iontophoretics, electroporative devices, or electrosurgical energy. The present invention further comprises the seeding oftissue40 to facilitate enhanced ablation and/oragent droplet77 delivery such as the introduction of foreign particles, the introduction of stabilized microbubbles, aeration, and/or a pulse profile designed to meet the needs of a particular medical application.
• Agent75 is injectable intochamber57 ofsemi-permeable membrane55 throughport62 under pressure fromsyringe77,container76, or by other suitable means of delivery.Agent75 may be Vorozole, Paclitaxel, Docetaxel, bacteriostatics, antibiotics, anti-coagulants, glues, genes, chemotoxic agents, or any other agent having properties beneficial to the outcomes of the medical treatment or surgical procedure. Chemical agents whose efficacy may be enhanced with the present invention further include local anesthetics such as, but not limited to, Novacaine, anti-inflammatories, corticosteroids, or opiate analgesics.
• FIG. 4 illustrates a section ofelongated portion68. Residing insideelongated portion68 is anagent channel63, acoaxial cable66, and alead64.Agent channel63 delivers theagent75 from the proximal end ofintense ultrasound instrument50 to the radiating end-effector60 viaport62.Coaxial cable66 delivers electrical energy totransducer65. In one embodiment, when electrically activated,transducer65 operates preferably at 0.5-50 MHz, and more preferably at 0.5-10 MHz, and more preferably at 0.5-2 MHz.Lead64 may be used to transmit a feedback signal from the radiating end-effector60 togenerator10 such as, for example, temperature information from a thermocouple, acoustic noise level from a hydrophone, or the like. The present invention further contemplates the use of a plurality ofcoaxial cables66, leads64, and/oragent channels63.Coaxial cable66 may be designed from any conductive material suitable for use in surgical procedures. In one embodiment of the present invention,agent channel63 comprises at least one lumen constructed from plastic, metal, rubber, or other material suitable for use in surgical procedures.
• A design representative of an intra-corporeal MHz-frequency ablation and Sonodynamic therapy prototype may be, for example, a UTX Model #0008015 (UTX, Inc., Holmes, N.Y.). This may be designed around a 20 cm long tube that fits through a 5 mm trocar. At the distal end of this tube, there is one spherically curved ceramic element (4×15 mm, radius of curvature=25 mm). The transducer design accomplishes narrow bandwidth operation around 2 MHz. (as shown inFIG. 12). The acoustic output at source may be ˜20 W/cm². The acoustic intensity around the focal zone may be on the order of 200 W/cm², (FIG. 13), sufficient to cause tissue ablation in the treatment volume. In addition, there is sufficient acoustic energy range available for accomplishing enhanced drug-delivery or drug activation steps.
• As is known in the art, the connectingcable90 may be shielded coax. If needed, there may be an additional electrical matching network between the power amplifier and the transducer. The front faces of the transducer active surfaces have acoustic matching layers. The transducers are “air-backed.” Thin, 0.125 mm, diameter thermocouples may be attached close to the ceramic faces that help monitor any self heating of the ultrasonic sources.Membrane55 may be silicone, polyurethane, or polyester-based balloons to ensure that most of the energy radiated by the transducer is delivered to the tissue and not reflected back from the source tissue interface.
• A further embodiment ofultrasonic system25 comprises the systemic delivery ofagent75 in cooperation withintense ultrasound instrument50.Agent75 may be ingested, injected or systemically delivered by other suitable means.Intense ultrasound instrument50 may then be activated on ornear tissue40 where the effects of intense ultrasound are desired.
• FIG. 5 illustrates anultrasonic system125 for local delivery of anagent175 in combination with an ultrasonicsurgical instrument150 for activating or assisting transport of theagent175. Ultrasonicsurgical instrument150 includes anelongated portion168, ahousing174, an electro-mechanical element165, for example, a piezoelectric transducer stack, agrip169, asemi-permeable membrane155, and aport179. Anagent175 is contained in acontainer176.Container176 is insertable intoport179 of ahousing174. Alternatively,agent175 may be delivered via asyringe177 through aport178 as shown inFIG. 6. Ultrasonicsurgical instrument150 includes a contact end-effector160. Ultrasonicsurgical instrument150 is connectable to agenerator200 viacable190, that supplies electrical energy to atransducer165 that delivers stress waves to contact end-effector160 via a waveguide146 (FIG. 8). In one embodiment, when electrically active,electromechanical element165 operates preferably at 10-200 kHz, more preferably and more preferably at 10-75 kHz. Aclamp arm170 may be attached toelongated portion168, to provide compression of tissue145 (FIG. 7) betweenclamp arm170 and ablade147 at the distal end ofwaveguide146.Blade147 comprises a plurality of embodiments including, but not limited to, a curved form, a straight form, a ball form, a hook form, a short form, a long form, or a wide form.
• Referring now toFIG. 7 end-effector160 may be inserted into the body cavity of a patient, and located on ornear tissue140 that includes a spot orlesion145 for treatment withagent175. Spot orlesion145 may be a cancerous region, a polyp, or other area that would benefit from treatment withagent175.Semi-permeable membrane155 containsagent175 under instrument-off conditions onceagent175 has been delivered tosemi-permeable membrane155.Agent175 may be delivered tosemi-permeable membrane155 by way of an agent channel163 (FIG. 8). An alternate embodiment of ultrasonicsurgical instrument150 comprises the single use of ultrasonicsugical instrument150 wheresemi-permeable membrane155 may be manufactured containing apre-selected agent175 located withinsemi-permeable membrane155. The single use embodiment of ultrasonicsurgical instrument150 further contemplates disposal of ultrasonicsurgical instrument150,semi-permeable membrane155, and/orend effector160. When ultrasonicsurgical instrument150 is activated,agent175 is driven throughsemi-permeable membrane155, producingagent droplets177. A suitablesemi-permeable membrane155 may be formed from, for example, nitrocellulose, tyvek, silicone, ethelyne vinyl acetate, or the like.Agent droplets177 are then driven preferentially intotissue140 by ultrasound energy, as shown below in ultrasound-mediated diffusion experiment results. Ultrasonicsurgical instrument150 further contemplates the use of a suction system, an irrigation system, a snare, a viewing means, and/or a number of cutting and/or coagulation means such as, for example, laser, iontophoretics, electroporative devices, or electrosurgical energy.
• FIG. 8 illustrates a section ofelongated portion168. Residing insideelongated portion168 may be anagent channel163,solid waveguide146, and alead164.Agent channel163 delivers theagent175 from the proximal end of ultrasonicsurgical instrument150 to the contact end-effector160. Lead164 may be used to transmit a signal from the radiating end-effector160 togenerator200 such as, for example, temperature information from a thermocouple, acoustic noise level from a hydrophone, or the like. The present invention further contemplates the use of a plurality ofleads164 and/oragent channels163. In one embodiment of the present invention,agent channel163 comprises at least one lumen constructed from plastic, metal, rubber, or other material suitable for use in surgical procedures.
• FIG. 9 illustrates an embodiment of the invention that combines the disclosures ofFIGS. 1 and 5 and enables operation of a surgical instrument in both the KHz and MHz operating range. Shown is a section ofelongated portion268 of an overall system as shown inFIG. 5. Residing insideelongated portion268 may be anagent channel263, atransducer265 in combination with acoaxial cable266 for MHz operation, asolid waveguide246 in combination withend effector260 for KHz operation, and alead264.Agent channel263 delivers theagent275 from the proximal end of coupled ultrasound instrument250 (not shown) to thesemi-permeable membrane255.Coaxial cable266 delivers electrical energy totransducer265. In one embodiment, when electrically activated,transducer265 operates preferably at 0.5-50 MHz. Lead264 may be used to transmit a signal from the distal end of coupled ultrasound instrument250 togenerator10 such as, for example, temperature information from a thermocouple, acoustic noise level from a hydrophone, pulse-echo information from the target region, or the like. The present invention contemplates the use of a plurality ofcoaxial cables266, leads264, and/oragent channels263.Coaxial cable266 may be designed from any conductive material suitable for use in surgical procedures. In one embodiment of the present invention,agent channel263 comprises at least one lumen constructed from plastic, metal, rubber, or other material suitable for use in surgical procedures.
• The coupled ultrasonic instrument (not shown) comprises the use of an end effector260 (kHz operation) connected to awaveguide246 in cooperation with a transducer265 (MHz) connected to acoaxial cable266 and asemi-permeable membrane255 connected toagent channel263.Waveguide246 may be coupled to an electromechanical element (not shown) located at the proximal end of the coupled ultrasonic instrument. In one embodiment of the present invention, the electro-mechanical element connected to waveguide246 operates at 10-200 kHz. In one embodiment of the present invention,transducer265 operates preferably at 0.5-50 MHz, and more preferably at 0.5-10 MHz. Accordingly,end effector260 may be used simultaneously or alternately withtransducer265, orend effector260 andtransducer265 may be used independently. The present invention comprises the method of usingwaveguide246 withend effector260 and/ortransducer265 to perform excision, hemostasis, ablation, and/or coagulative necrosis, prior to the delivery ofagent275 tosemi-permeable membrane255. Following necessary excision and hemostasis,agent275 may be delivered throughagent channel263 intosemi-permeable membrane255, oragent275 may be delivered systemically.
• Whentransducer265 and/orend effector260 are activated,agent275 is driven throughsemi-permeable membrane255, producingagent droplets277. A suitablesemi-permeable membrane255 may be formed from, for example, nitrocellulose, tyvek, silicone, ethelyne vinyl acetate, or the like.Agent droplets277 are then driven preferentially intotissue240 by ultrasound energy, as shown below in ultrasound mediated diffusion experiment results. The coupled ultrasonic instrument further comprises the use of a suction system, an irrigation system, a snare, a viewing means, and/or a number of cutting and/or coagulation means such as, for example, laser or electrosurgical energy. Thewaveguide246 and associatedend effector260 may be used in cooperation withtransducer265 to facilitate a local (omnidirectional) tissue effect or a distant (focused) tissue effect depending on the needs of the application. The coupled ultrasound instrument further contemplates atransducer265 surrounded bysemi-permeable membrane255, whereagent channel263 may be within or substantially neartransducer265 to facilitate the delivery ofagent275 intosemi-permeable membrane255 surroundingtransducer265. In a further embodiment of the present invention,semi-permeable membrane255 may surroundend effector260, or may surround bothend effector260 andtransducer265.
• FIG. 10 illustrates anultrasonic system325 for local delivery of an agent in combination with anintense ultrasound instrument350 for activating or assisting transport of theagent375 in combination with afirst feedback device366 and asecond feedback device367.Feedback devices366 and367 may be one or a plurality of piezo sensors, piezo receivers, thermocouples, non-thermal response monitors, thermal response monitors, cavitation monitors, streaming monitors, ultrasonic imaging devices, drug activation monitors, infusion rate controls, source controls, duty cycle controls, frequency controls, or other suitable means of monitoring and/or controlling a surgical procedure. Unless otherwise specified, all “300” series reference numerals have the same function as the corresponding reference numerals ofFIG. 1, but it is evident thatfeedback devices366 and367 are useful in any of the embodiments of the invention presented herein.
• In one embodiment of the present invention,first feedback device366 is a piezo sensor attached to the distal portion ofend effector360, is coupled viawire370 to a feedback monitor (not shown), in the form of a broad bandwidth pulser-receiver.Feedback device366 in the form of a piezo sensor may be driven and controlled by the broad bandwidth pulser-receiver in order to acquire standard A-line (pulse echo) data from the region of interest, and to monitor morphological changes in thetissue40. A further embodiment of the present invention comprises afeedback device366 in the form of a piezo sensor used to estimate the temperature of the treatment volume using ultrasonic (remote) means, such as change in sound speed and/or the attenuation coefficient, and to facilitate monitored therapy. A further embodiment of the present invention contemplatesfeedback device366 in the form of a piezo reciever to actively, and/or passively, monitor the cavitational activity in the therapy zone. Used in cooperation with a broad bandwidth pulser-receiver, this technique can be implemented by recording and processing the broad bandwidth acoustic emissions resulting from the bubble growth and collapse due the therapeutic ultrasound field in the region of treatment. Alternatively, the higher harmonic such as, for example, the 2^ndor 3^rd, or the sub-harmonic response due to the high-power field in the therapeutic zone can be recorded and correlated to the tissue therapy, or to estimate the amount ofagent75 activated. Further, the streaming field resulting from the therapy acoustic field may be monitored using Doppler flow techniques. The strength of the flow signal may be correlated to the magnitude of advection, or delivery ofagent75, within the treatment volume.
• Asecond feedback device367 may be a thermocouple attached to theelongated portion368 comprising at least onewire371, where at least onewire371 is attached to bothsecond feedback device367 and to a feedback monitor (not shown). Feedback monitor (not shown) may be for example, a broad bandwidth pulser-receiver, or other suitable means of monitoring and/or controlling a surgical procedure.Wire371 may be constructed from silver, stainless steel, or other conductive material suitable for use in surgical procedures.Second feedback device367 may be located at any point alongelongated portion368 depending on the needs of a particular medical application. In one embodiment of the present invention,feedback device367 may be a thermocouple attached toelongated portion368, where thefeedback device367, in the form of a thermocouple, monitors the region of interest during ablation and/or drug activation phases.
• The present invention contemplates one or a plurality offeedback devices366 and/orfeedback devices367 used within a system feedback loop to control, for example, the therapy source, pulsing, treatment time, and/or rate of drug infusion, in order to optimize the ablative and drug activation-based treatments.
• Protocol for Ultrasound-Mediated Diffusion Experiments
• A method for treating tissue in accordance with the present invention comprises the steps of: providing a surgical instrument, the instrument comprising: a housing; a transducer connected to the housing; a semi-permeable membrane surrounding the transducer; a pharmaceutical agent; and an agent delivery system; inserting the surgical instrument into a body cavity of a patient; delivering a drug to the patient; and locally activating the drug with the surgical instrument. For purposes herein, locally is defined as within a range of about 0.5 mm to 50 mm from the end-effector of the instrument. Other steps in accordance with the present invention include achieving hemostasis, excising tissue, coagulating tissue, and cutting tissue.
• Experiments were performed to determine if the present invention could transport a chemical agent of interest to a potential therapeutic site. An appropriate agent, Vorozole, a model chemical agent from Janssen Pharmaceutica in Belgium was selected as a chemical drug for permeation through biological barriers.
• The representative 20 kHz and 1 MHz sources are described as follows. The 20 kHz sonicator system is available from Cole Parmer, Inc., Vernon Hills, Ill.—Ultrasonic Homogenizer, Model CPX 400. The 1 MHz source was a custom designed transducer available from UTX, Inc., Holmes, N.Y. (e.g., UTX Model #9908039). A suitable acoustic power output ranges from 1-10 W, pulsed at 5-75% duty cycle. A suitable source geometry ranges from 1-5 MHz, flat geometry (19 mm diameter ceramic disks (preferably PZT-4)). Transducers should be designed for high-power long-term operation (up to 26 hours), air or Corporene-backed (narrow bandwidth tuning), high-temperature epoxy front face matching. Embedded thermocouples in close proximity of the ceramic may provide feedback for the source surface temperature. A number of source cooling schemes may be implemented (for example, transducer housing with a water jacket, or circulating water at the front face of transducer, separated from the drug reservoir by using polymer-based membranes or stainless steel shim stock). The cable for the transducers may be double-shielded coax, teflon coated (high-temperature), or gold braided thin-gauge cable.
• For active diffusion experiments with Vorozole, 16 ml of 5% HP-1-CD with 0.05% NaN₃in water was added into the receptor compartment of glass diffusion cells. A Teflon-coated magnetic stirring bar was also added in the receptor compartment. The Franz cells were then placed on top of a stirring plate set at about 600 rpm.
• To perform the ultrasound-mediated experiments, a 20 kHz and a 1 MHz probe were mounted in the donor compartment close to the skin surface. The formulations were added until the probes were immersed in the liquid and ultrasound sources were turned on.
• The power setting indicated on the 20 kHz system relates to a correspondingly increased acoustic field radiated from the horn tip. The acoustic power radiated by the MHz frequency transducers was nominally ˜4 W for the voltage used in our study at 1 MHz. In addition, the acoustic intensity over time (I_temporal) was a function of the pulsing regime used for a given experiment.
• The experiments were conducted over 20 hours. Samples were collected in the following successive order: 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 20 hours.
• After the incubation period, the receptor fluid was collected and stored at 4° C. until HPLC analysis was performed. The formulation was removed from the donor side with a syringe and Kleenex tissues. The diffusion cells were dismantled and the skin was carefully removed. The surface was cleaned consecutively with a dry Kleenex tissue, an ethanol-wetted tissue and a dry tissue. The skin was evaluated for morphologic changes due to the exposure to ultrasound.
• Parallel experiments for passive diffusion of the drug were conducted whereby the set-up was identical for ultrasound exposure to the tissue, except that the skin was not exposed to any ultrasound energy. The result of the above experiment is illustrated inFIG. 11, illustrating that an ultrasonicsurgical instrument50 increases the transport of Vorazol through tissue. Specification A is 20 kilohertz ultrasound with a tip displacement of approximately 10 micrometers peak-to-peak, 0.5 Seconds on, 12.5% duty cycle. Specification B is 1 Megaherts ultrasound at approximately 4 Watts power, 4 seconds on at 50% duty cycle. Specification C is passive permeation.
• While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Accordingly, it is intended that the invention be limited only by the spirit and scope of the appended claims.

Claims (15)

1. An ultrasonic surgical system comprising:

a housing;

a transducer connected to said housing;

a membrane surrounding said transducer; and

a pharmaceutical agent within the membrane; and

an agent delivery system.

2. The ultrasonic surgical system ofclaim 1, wherein said transducer operates within the range of about 500 kilohertz to about 50 megahertz.

3. The ultrasonic surgical system ofclaim 2, wherein said transducer operates within the range of about 500 kilohertz to about 2 megahertz.

4. The ultrasonic surgical system ofclaim 3, wherein said membrane is porous or semi-permeable.

5. The ultrasonic surgical system ofclaim 1, further comprising a feedback device selected from the group consisting of a non-thermal response monitor, a thermal response monitor, a cavitation monitor, a streaming monitor, an ultrasonic imaging device, a drug activation monitor, an infusion rate control, a source control, a duty cycle control, a piezo sensor, a piezo receiver, a thermocouple, and a frequency control.

6. An ultrasonic instrument comprising:

a housing;

a transducer connected to said housing;

a membrane surrounding said transducer;

a pharmaceutical agent; and

an agent delivery system;

wherein said agent delivery system delivers said pharmaceutical agent into a chamber of said membrane; and

whereby said pharmaceutical agent is driven through said membrane by ultrasonic energy delivered from said transducer.

7. A method of treating tissue comprising the steps of:

a) providing a surgical instrument, said instrument comprising:

a housing;

a transducer connected to said housing;

b) inserting said surgical instrument into the patient;

c) delivering a drug to said patient; and

d) locally activating said drug with said surgical instrument.

8. The method ofclaim 7 further comprising the step of:

e) ablating tissue of said patient with said surgical instrument.

9. An ultrasonic surgical system comprising:

a) a generator;

b) an instrument comprising:

i) a housing;

ii) an electromechanical element contained in an interior portion of said housing;

iii) a waveguide originating at said electromechanical element and terminating at an end-effector extending out of said housing;

iv) a membrane surrounding said end-effector;

v) a pharmaceutical agent; and

vi) an agent delivery system;

wherein said generator is adapted to provide electrical energy to said electromechanical element;

wherein said transducer is adapted to convert said electrical energy into mechanical energy; and

whereby said pharmaceutical agent is driven through said membrane by said mechanical energy.

10. The ultrasonic surgical system ofclaim 9, wherein said electromechanical element operates within the range of about 10 kilohertz to about 200 kilohertz.

11. The ultrasonic surgical system ofclaim 9, wherein said membrane is porous or semi-permeable.

12. An ultrasonic surgical instrument comprising:

a) a housing;

b) a transducer connected to said housing;

c) a membrane adjacent said transducer;

d) a pharmaceutical agent; and

e) an agent delivery system;

wherein said agent delivery system delivers said pharmaceutical agent into a chamber of said membrane.

13. The ultrasonic surgical system ofclaim 12, wherein said transducer operates within the range of about 500 kilohertz to about 50 megahertz.

14. The ultrasonic surgical system ofclaim 12, wherein said transducer operates within the range of about 10 kilohertz to about 200 kilohertz.

15. The ultrasonic surgical system ofclaim 12, wherein said membrane is porous or semi-permeable.

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