Patent Publication Number: US-2005131339-A1

Title: Ultrasonic surgical instrument for intracorporeal sonodynamic therapy

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 of  FIGS. 1-4 ; and  
       FIG. 13  is a plot of the calculated acoustic intensities of the transducer in accordance with the invention of  FIGS. 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 an ultrasonic system  25  for local delivery of an agent in combination with an intense ultrasound instrument  50  for activating or assisting transport of the agent. Intense ultrasound instrument  50  includes an elongated portion  68 , a housing  74 , a grip  69 , a porous or semi-permeable membrane  55 , and a port  79 . An agent  75  is contained in a container  76  for insertion into port  79 . Insertion of container  76  into port  79  may be done mechanically, or manually by the operator. Intense ultrasound instrument  50  includes a radiating end-effector  60 . Intense ultrasound instrument  50  is connectable to a generator  10  via cable  90 , that supplies electrical energy to radiating end-effector  60  for conversion by transducer  65  to ultrasonic stress waves. Radiating end-effector  60  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.  
      A foot switch  95  is connected to generator  10  via cable  98  to control generator  10  function. A switch  96  and a switch  97  are included with foot switch  95  to control multiple functions. For example, switch  96  could provide a first level of energy to radiate end-effector  60  and a switch  97  could provide a second level of energy to radiate end-effector  60 . Generator  10  may also include a display  80  for providing information to the user, and buttons or switches  81 ,  82 , and  83  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 providing agent  75  to intense ultrasound instrument  50 . In this embodiment, a syringe  77  contains agent  75  for injection to a surgical site within a patient. A plunger  73  may be depressed by the operator to deliver agent  75  to a surgical site via port  78 .  
       FIG. 3  illustrates a method of using an instrument in accordance with the present invention. End-effector  60  is inserted into the body cavity of a patient, and located on or near tissue  40  that includes a spot or lesion  45  for treatment with agent  75 . Spot or lesion  45  may be a cancerous region, a polyp, or other area that would benefit from treatment with agent  75 . Semi-permeable membrane  55  contains agent  75  under instrument-off conditions, once agent  75  has been delivered to semi-permeable membrane  55 . Agent  75  may be delivered to semi-permeable membrane  55  by way of an agent channel  63  ( FIG. 4 ). An alternate embodiment of intense ultrasound instrument  50  contemplates the disposable use of intense ultrasound instrument  50  where semi-permeable membrane  55  is manufactured containing a pre-selected agent  75  located within semi-permeable membrane  55 . The single use embodiment of intense ultrasound instrument  50  comprises disposal of intense ultrasound instrument  50 , semi-permeable membrane  55 , and/or end effector  60 . Alternatively, and not by way of limitation of the invention, membrane  55  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 the ultrasound instrument  50  is energized.  
      When intense ultrasound instrument  50  is activated, agent  75  is driven through semi-permeable membrane  55 , producing agent droplets  77 . A suitable semi-permeable membrane  55  may be formed from, for example, nitrocellulose, tyvek, silicone, ethelyne vinyl acetate, or the like. Semi-permeable membrane  55  may be semi-permeable in specific regions and may be non-permeable in other regions to effectuate targeted release of the agent  75  through membrane  55 . Further, semi-permeable membrane  55  may be bio-compatible and have a tissue adhesive, allowing for the semi-permeable membrane  55  to be left within a body cavity, and/or may be adapted to dissolve within a body cavity. Agent droplets  77  are driven preferentially into tissue  40  by ultrasound energy, as shown below in ultrasound-mediated diffusion experiment results.  
      Intense ultrasound instrument  50  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 of tissue  40  to facilitate enhanced ablation and/or agent droplet  77  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.  
      Agent  75  is injectable into chamber  57  of semi-permeable membrane  55  through port  62  under pressure from syringe  77 , container  76 , or by other suitable means of delivery. Agent  75  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 of elongated portion  68 . Residing inside elongated portion  68  is an agent channel  63 , a coaxial cable  66 , and a lead  64 . Agent channel  63  delivers the agent  75  from the proximal end of intense ultrasound instrument  50  to the radiating end-effector  60  via port  62 . Coaxial cable  66  delivers electrical energy to transducer  65 . In one embodiment, when electrically activated, transducer  65  operates preferably at 0.5-50 MHz, and more preferably at 0.5-10 MHz, and more preferably at 0.5-2 MHz. Lead  64  may be used to transmit a feedback signal from the radiating end-effector  60  to generator  10  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 of coaxial cables  66 , leads  64 , and/or agent channels  63 . Coaxial cable  66  may be designed from any conductive material suitable for use in surgical procedures. In one embodiment of the present invention, agent channel  63  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 in  FIG. 12 ). The acoustic output at source may be ˜20 W/cm 2 . The acoustic intensity around the focal zone may be on the order of 200 W/cm 2 , ( 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 connecting cable  90  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. Membrane  55  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 of ultrasonic system  25  comprises the systemic delivery of agent  75  in cooperation with intense ultrasound instrument  50 . Agent  75  may be ingested, injected or systemically delivered by other suitable means. Intense ultrasound instrument  50  may then be activated on or near tissue  40  where the effects of intense ultrasound are desired.  
       FIG. 5  illustrates an ultrasonic system  125  for local delivery of an agent  175  in combination with an ultrasonic surgical instrument  150  for activating or assisting transport of the agent  175 . Ultrasonic surgical instrument  150  includes an elongated portion  168 , a housing  174 , an electro-mechanical element  165 , for example, a piezoelectric transducer stack, a grip  169 , a semi-permeable membrane  155 , and a port  179 . An agent  175  is contained in a container  176 . Container  176  is insertable into port  179  of a housing  174 . Alternatively, agent  175  may be delivered via a syringe  177  through a port  178  as shown in  FIG. 6 . Ultrasonic surgical instrument  150  includes a contact end-effector  160 . Ultrasonic surgical instrument  150  is connectable to a generator  200  via cable  190 , that supplies electrical energy to a transducer  165  that delivers stress waves to contact end-effector  160  via a waveguide  146  ( FIG. 8 ). In one embodiment, when electrically active, electromechanical element  165  operates preferably at 10-200 kHz, more preferably and more preferably at 10-75 kHz. A clamp arm  170  may be attached to elongated portion  168 , to provide compression of tissue  145  ( FIG. 7 ) between clamp arm  170  and a blade  147  at the distal end of waveguide  146 . Blade  147  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 to  FIG. 7  end-effector  160  may be inserted into the body cavity of a patient, and located on or near tissue  140  that includes a spot or lesion  145  for treatment with agent  175 . Spot or lesion  145  may be a cancerous region, a polyp, or other area that would benefit from treatment with agent  175 . Semi-permeable membrane  155  contains agent  175  under instrument-off conditions once agent  175  has been delivered to semi-permeable membrane  155 . Agent  175  may be delivered to semi-permeable membrane  155  by way of an agent channel  163  ( FIG. 8 ). An alternate embodiment of ultrasonic surgical instrument  150  comprises the single use of ultrasonic sugical instrument  150  where semi-permeable membrane  155  may be manufactured containing a pre-selected agent  175  located within semi-permeable membrane  155 . The single use embodiment of ultrasonic surgical instrument  150  further contemplates disposal of ultrasonic surgical instrument  150 , semi-permeable membrane  155 , and/or end effector  160 . When ultrasonic surgical instrument  150  is activated, agent  175  is driven through semi-permeable membrane  155 , producing agent droplets  177 . A suitable semi-permeable membrane  155  may be formed from, for example, nitrocellulose, tyvek, silicone, ethelyne vinyl acetate, or the like. Agent droplets  177  are then driven preferentially into tissue  140  by ultrasound energy, as shown below in ultrasound-mediated diffusion experiment results. Ultrasonic surgical instrument  150  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 of elongated portion  168 . Residing inside elongated portion  168  may be an agent channel  163 , solid waveguide  146 , and a lead  164 . Agent channel  163  delivers the agent  175  from the proximal end of ultrasonic surgical instrument  150  to the contact end-effector  160 . Lead  164  may be used to transmit a signal from the radiating end-effector  160  to generator  200  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 of leads  164  and/or agent channels  163 . In one embodiment of the present invention, agent channel  163  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 of  FIGS. 1 and 5  and enables operation of a surgical instrument in both the KHz and MHz operating range. Shown is a section of elongated portion  268  of an overall system as shown in  FIG. 5 . Residing inside elongated portion  268  may be an agent channel  263 , a transducer  265  in combination with a coaxial cable  266  for MHz operation, a solid waveguide  246  in combination with end effector  260  for KHz operation, and a lead  264 . Agent channel  263  delivers the agent  275  from the proximal end of coupled ultrasound instrument  250  (not shown) to the semi-permeable membrane  255 . Coaxial cable  266  delivers electrical energy to transducer  265 . In one embodiment, when electrically activated, transducer  265  operates preferably at 0.5-50 MHz. Lead  264  may be used to transmit a signal from the distal end of coupled ultrasound instrument  250  to generator  10  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 of coaxial cables  266 , leads  264 , and/or agent channels  263 . Coaxial cable  266  may be designed from any conductive material suitable for use in surgical procedures. In one embodiment of the present invention, agent channel  263  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 effector  260  (kHz operation) connected to a waveguide  246  in cooperation with a transducer  265  (MHz) connected to a coaxial cable  266  and a semi-permeable membrane  255  connected to agent channel  263 . Waveguide  246  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 waveguide  246  operates at 10-200 kHz. In one embodiment of the present invention, transducer  265  operates preferably at 0.5-50 MHz, and more preferably at 0.5-10 MHz. Accordingly, end effector  260  may be used simultaneously or alternately with transducer  265 , or end effector  260  and transducer  265  may be used independently. The present invention comprises the method of using waveguide  246  with end effector  260  and/or transducer  265  to perform excision, hemostasis, ablation, and/or coagulative necrosis, prior to the delivery of agent  275  to semi-permeable membrane  255 . Following necessary excision and hemostasis, agent  275  may be delivered through agent channel  263  into semi-permeable membrane  255 , or agent  275  may be delivered systemically.  
      When transducer  265  and/or end effector  260  are activated, agent  275  is driven through semi-permeable membrane  255 , producing agent droplets  277 . A suitable semi-permeable membrane  255  may be formed from, for example, nitrocellulose, tyvek, silicone, ethelyne vinyl acetate, or the like. Agent droplets  277  are then driven preferentially into tissue  240  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. The waveguide  246  and associated end effector  260  may be used in cooperation with transducer  265  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 a transducer  265  surrounded by semi-permeable membrane  255 , where agent channel  263  may be within or substantially near transducer  265  to facilitate the delivery of agent  275  into semi-permeable membrane  255  surrounding transducer  265 . In a further embodiment of the present invention, semi-permeable membrane  255  may surround end effector  260 , or may surround both end effector  260  and transducer  265 .  
       FIG. 10  illustrates an ultrasonic system  325  for local delivery of an agent in combination with an intense ultrasound instrument  350  for activating or assisting transport of the agent  375  in combination with a first feedback device  366  and a second feedback device  367 . Feedback devices  366  and  367  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 of  FIG. 1 , but it is evident that feedback devices  366  and  367  are useful in any of the embodiments of the invention presented herein.  
      In one embodiment of the present invention, first feedback device  366  is a piezo sensor attached to the distal portion of end effector  360 , is coupled via wire  370  to a feedback monitor (not shown), in the form of a broad bandwidth pulser-receiver. Feedback device  366  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 the tissue  40 . A further embodiment of the present invention comprises a feedback device  366  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 contemplates feedback device  366  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 nd  or 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 of agent  75  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 of agent  75 , within the treatment volume.  
      A second feedback device  367  may be a thermocouple attached to the elongated portion  368  comprising at least one wire  371 , where at least one wire  371  is attached to both second feedback device  367  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. Wire  371  may be constructed from silver, stainless steel, or other conductive material suitable for use in surgical procedures. Second feedback device  367  may be located at any point along elongated portion  368  depending on the needs of a particular medical application. In one embodiment of the present invention, feedback device  367  may be a thermocouple attached to elongated portion  368 , where the feedback device  367 , 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 of feedback devices  366  and/or feedback devices  367  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% NaN 3  in 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 in  FIG. 11 , illustrating that an ultrasonic surgical instrument  50  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.