CRYOMEDICAL DEVICE FOR PROMOTING ANGIOGENESIS

Abstract: A cryomedical device in which a device body has a cryogenic cooling surface and a reservoir for an angiogenic stimulant. An apertured tissue penetrating element is in fluid communication with the reservoir and is coupled to the device body.

Description: CRYOMEDICAL DEVICE FOR PROMOTING ANGIOGENESIS FIELD OF THE INVENTION This invention relates to vascular growth, and more particularly to an apparatus for using extremely cold temperatures to promote angiogenesis. BACKGROUND OF THE INVENTION Angiogenesis relates to the formation of blood vessels in living tissue. Not surprisingly, vascular growth or the lack thereof significantly affects living tissue. In adults, the body ' s network of blood vessels is stable. However, under certain circumstances, such as physical injury, the body causes new blood vessels to grow. Various drug and gene therapies are under study that show promise in amplifying angiogenesis where it naturally occurs, and promoting it where it does not otherwise occur. Drug and gene therapy, however, can not only be difficult to localize, but the mechanisms by which they operate are also poorly understood and may cause unwanted side effects. It would therefore be desirable to provide an alternative method of promoting vascular growth. The present invention provides a tip for a cyrocatheter, in which a surface defines an inner volume such that the inner volume provides a cryogenic expansion area. An angiogenic stimulant lumen is positioned within the inner volume. The angiogenic stimulant lumen is fluidly isolated from the cryogenic expansion area. A tissue penetrating element is in fluid communication with the angiogenic stimulant lumen and is outwardly protrudabie from the surface. The tissue penetrating element defines an angiogenic stimulant passage and an aperture for permitting angiogenic stimulant to exit tissue penetrating element. SUMMARY OF THE INVENTION The present invention provides a cryomedical device in which a device body has a cryogenic cooling surface and a reservoir for an angiogenic stimulant. An apertured tissue penetrating element is in fluid communication with the reservoir and is coupled to the device body. The angiogenic stimulant is a drug or other fluid which stimulates vascular growth. In other words, the present invention seeks to obtain a balance between minimizing trauma to tissue while maximizing angiogenic response. BRIEF DESCRIPTION OF THE DRAWINGS A more complete understanding of the present invention, and the attendant advantages and features thereof, will be more readily understood by reference to the following detailed description when considered in conjunction with the accompanying drawings, wherein: FIG. 1 is a schematic illustration of an embodiment of a cryosurgical system in accordance with the invention; FIG. 2 is a sectional view of a heart muscle showing placement of the catheter of FIG. 1 ; FIG. 3 illustrates the tip region of one embodiment of the catheter in accordance with the invention; FIGS. 5-8 illustrate alternative tip configurations for cyro-angiogenic treatment; FIGS. 9-1 1 illustrate alternative tip configurations in association with additional treatment structures; FIG. 12 illustrates a device which is arranged to cryogenically cool tissue and inject an angiogenic stimulant therein; FIG. 13 illustrates a shielded device which is arranged to cryogenically cool tissue and inject an angiogenic stimulant therein; FIG. 14 illustrates an angiogenic stimulant reservoir provided as part of a controller; FIG. 15 illustrates an angiogenic stimulant reservoir provided as part of a catheter handle; FIG. 16 illustrates a device body having a collapsible reservoir; FIG. 17 illustrates a device body having a collapsed reservoir after an actuator has been operated; FIG. 18 illustrates a tissue penetrating element having a plurality of apertures on one hemisphere; FIG. 19 illustrates an enlarged view of the tissue penetrating element of FIG. 18; FIG. 20 illustrates an alternate arrangement of a tissue penetrating element having a plurality of apertures at an end portion thereof; FIG. 21 illustrates another alternate arrangement of a tissue penetrating element having a plurality of apertures distributed substantially along the entire length; FIG. 22 illustrates a tissue penetrating element used in conjunction with a device body having a rounded tip; FIG. 23 illustrates a tissue penetrating element used in conjunction with a device body having a pointed tip; FIG. 24 illustrates a tissue penetrating element used in conjunction with a device body having a metallic ring as the tip; FIG. 25 illustrates a device having a tissue penetrating element and stylets; FIG. 26 illustrates a device body having a movable penetration element in a retracted state; and FIG. 27 illustrates a device body having a movable penetration element in an extended state. DETAILED DESCRIPTION OF THE INVENTION FIG. 1 is a schematic illustration of a cryosurgical system in accordance with the invention that can be employed as described below to promote angiogenesis. The system includes a supply of cryogenic or cooling fluid 10 in communication with the proximal end 12 of a flexible catheter 14. A fluid controller 16 is interposed or inline between the cryogenic fluid supply 10 and the catheter 14 for regulating the flow of cryogenic fluid into the catheter in response to a controller command. Controller commands can include programmed instructions, sensor signals, and manual user input. For example, the fluid controller 16 can be programmed or configured to increase and decrease the pressure of the fluid by predetermined pressure increments over predetermined time intervals. In another exemplary embodiment, the fluid controller 16 can be responsive to input from a foot pedal 18 to permit flow of the cryogenic fluid into the catheter 14. One or more temperature sensors 20 in electrical communication with the controller 16 can be provided to regulate or terminate the flow of cryogenic fluid into the catheter 14 when a predetermined temperature at a selected point or points on or within the catheter is/are obtained. For example a temperature sensor can be placed at a point proximate the distal end 22 of the catheter and other temperature sensors 20 can be placed at spaced intervals between the distal end of the catheter and another point that is between the distal end and the proximal end. The cryogenic fluid can be in a liquid or a gas state. An extremely low temperature can be achieved within the catheter, and more particularly on the surface of the catheter by cooling the fluid to a predetermined temperature prior to its introduction into the catheter, by allowing a liquid state cryogenic fluid to boil or vaporize, or by allowing a gas state cryogenic fluid to expand. Exemplary liquids include chlorodifluoromethane, polydimethylsiloxane, ethyl alcohol, HFC's such as AZ-20 (a 50—50 mixture of difluoromethane & pentafluoroethane sold by Allied Signal), and CFC's such as DuPont's Freon. Exemplary gasses include nitrous oxide, and carbon dioxide. The catheter 14 includes a flexible member 24 having a thermally-transmissive region 26 and a fluid path through the flexible member to the thermally-transmissive region. A fluid path is also provided from the thermally-transmissive region to a point external to the catheter, such as the proximal end 12. Although described in greater detail below, exemplary fluid paths can be one or more channels defined by the flexible member 24, and/or by one or more additional flexible members that are internal to the first flexible member 24. Also, even though many materials and structures can be thermally conductive or thermally transmissive if chilled to a very low temperature and/or cold soaked, as used herein, a "thermally-transmissive region" is intended to broadly encompass any structure or region of the catheter 14 that readily conducts heat. For example, a metal structure exposed (directly or indirectly) to the cryogenic fluid path is considered a thermally-transmissive region 26 even if an adjacent polymeric or latex catheter portion also permits heat transfer, but to a much lesser extent than the metal. Thus, the thermally-transmissive region 26 can be viewed as a relative term to compare the heat transfer characteristics of different catheter regions or structures. A thermally-transmissive region or element is not intended to encompass a structure that is excited by RF or other energy source to a point where it begins to radiate heat, for example. Furthermore, while the thermally-transmissive region 26 can include a single, continuous, and uninterrupted surface or structure, it can also include multiple, discrete, thermally-transmissive structures that collectively define a thermally- transmissive region that is elongate or linear. Alternatively, the thermally- transmissive region can be at a single focal location, such as the distal tip of the catheter. Additional details of the thermally-transmissive region 26 and the thermal transfer process are described in greater detail below. In exemplary embodiments of the invention, the thermally-transmissive region 26 of the catheter 14 is deformable. An exemplary deformation is from a linear configuration to an arcuate configuration and is accomplished using mechanical and/or electrical devices known to those skilled in the art. For example, a wall portion of the flexible member 24 can include a metal braid to make the catheter torqueable for overall catheter steering and placement. Additionally, a wire or cable can be incorporated with, or inserted into, the catheter for deformation of the thermally transmissive region 26. The cryogenic system of FIG. 1 is better understood with reference to its use in an operative procedure as shown in FIG. 2. Following the determination of a proposed treatment site within a heart muscle 28 for example, the catheter 14 is directed through a blood vessel 30 to a region within the heart. The thermally - transmissive region 26 is placed proximate to the tissue to be treated. The thermally- transmissive region of the catheter may be deformed to conform to the curvature of the tissue before, during, or after placement against the tissue. The controller 16 allows or causes cryogenic fluid to flow from the cryogenic fluid supply 10 to the fluid path in the catheter 14 and thence to the thermally-transmissive region 26 to treat the desired area. In one embodiment a first conduit is concentric within a second conduit and cooling fluid travels to a thermally-transmissive region proximate a closed distal end of the catheter through a first conduit (fluid path) and is exhausted from the catheter through the second conduit (fluid path). Referring specifically to the embodiment depicted in FIG. 3, multiple thermally-transmissive elements 34 are integral with a distal portion of a catheter having a thermally transmissive tip 32. Thermocouples 35 can be associated with one or more of the elements 34 and the tip 32. Additional details of cryocatheter construction are found in United States Patent Nos. 5, 899,898 and 5,899,899 to Arless, which are incorporated herein by reference. FIGS. 4-8 illustrate alternative embodiments of the thermally transmissive region 26. To the right of each drawing is an illustration of the general shape of the region treated by each embodiment as seen in plan view and as seen in cross-section. More specifically, FIG. 4 depicts a rounded tip, such as element 32 of FIG. 3. FIG. 5 shows a flat, paddle-like tip; and FIG. 6 shows a needle tip suitable for penetrating tissue. FIG. 7 illustrates a non-segmented linear tip. FIG. 8 shows a tip with a separate channel 36 within the tip or beside it to inject drugs directly in the tissue, such as vascular endothelial growth factor (VEGF), before, during or after cooling tissue as described below. The drug(s) can be deposited on the surface of the tissue or injected into the tissue. Angiogenesis can be promoted in selected tissue with the above described devices by injuring tissue over a selected area. For example, to treat ischemia, a cryocatheter as described above, is placed on the heart tissue to be treated. The cooling or thermally transmissive region 26 of the catheter is chilled to a temperature of -20° C to -80° C for five seconds to five minutes and then allowed to warm or thaw to a temperature in the range of 0° C to body temperature. This step is then repeated one or more times. In an exemplary procedure, four or more three or more injuries are made tissue at regular intervals 5-15 mm apart, wherein the tissue is injured to a depth of about 3.0 mm or more to provide a relatively wide and deep treated tissue zone. Treatment zone geometry can be varied widely by varying pip geometry, using tips such as shown in FIGS. 4-8, as well as by varying freeze rate, thaw rate, freeze time, and ultimate temperature. A greater or fewer number of treatment zones can be created as desired to stimulate a greater or lesser area. Freezing the tissue initiates an inflammatory response which triggers an angiogenic process, leading to new blood vessel growth. However, the ability to dose the injury minimizes tissue necrosis while maximizing angiogenic response. Another way to minimize tissue damage, but to trigger an angiogenic reaction, is to apply high frequency electrical or microwave energy to the tissue while cooling the catheter/tissue interface with a cryogenic fluid alternative method. The depth to which tissue is injured can be a significant factor in promoting angiogenesis. Thus, FIG. 9 depicts a cryocatheter 14 with supplemental structures that can increase injury depth, such as one or more thermally conductive wires, needle or stylets 38. In an exemplary embodiment the stylets 38 are stainless steel wires less than 0.050 inches in diameter. Although the stylets 38 can be integrated with the catheter 14, they can be independent therefrom. For example, FIG. 9 shows a cryocatheter 14 disposed within a guide lumen 40 that is part of a shaft portion 42 of the catheter 14. The stylets 38 are disposed within the guide lumen 40 and are axially movable therein. A control mechanism 44 is provided at the proximal end of the catheter that allows the stylets to be advanced and/or retracted individually or in unison. In an exemplary procedure, the catheter 14 is guided to an area of tissue to be treated. Then the one or more stylets 38 are advanced so as to penetrate the tissue to a selected depth. The catheter 14 is cooled, as described above, and one or more iceballs form on and near the tissue that is proximate the thermally transmissive region 26. The stylets 38, which are in or exposed to the one or more iceballs, conduct cold/remove heat from a region of tissue well below the surface. Regarding the procedure described with respect to FIG. 9, it should be noted that not only is a deep region of tissue traumatized by extremely cold temperature, but the tissue is also mechanically traumatized by the stylets 38. The combination of trauma mechanisms is believed to be especially effective in promoting angiogenesis. Another combined trauma device is shown in FIG. 10, wherein a rotatable, ball, wheel or cylinder 46 is secured to the tip 32 of the catheter 14. The cylinder 46 is provided with sharp or rough surface features, such as spikes 48. A thermally conductive support structure 50 conducts heat/cold from the tip 32 to the spikes 48. An introducer/guide catheter 52 is provided to assist with catheter placement. Thus, in an exemplary procedure, the catheter is positioned near tissue as described above, and the tip 32 is cooled. The cold is conducted to the cylinder 46 and to the spikes 48 and thence to the tissue against which the cylinder is pressed and rotated. In alternative procedures, the tissue is traumatized before or after a cooling cycle, or between cool/thaw/cool cycles. Thus, angiogenesis is stimulated by physical and temperature trauma. Yet another way of providing combination trauma is described with respect to FIG. 1 1, wherein a catheter 14 is shown within a guide sheath 54, and is slidable therein. The catheter 14 includes a roughened cooling tip 56. In an exemplary procedure using this catheter, the catheter is placed and the tip is cooled to create an iceball 58. After a region of tissue 60 has frozen and has become part of or joined to the iceball58, the catheter tip 56 is pulled away from the tissue, thereby tearing the region of tissue 60 from the remaining tissue. The roughness of the tip 56 helps to prevent the iceball from separating from the catheter when the catheter is pulled away from the tissue. The sheath 54 can be pushed against the tissue during treatment to shield the tip from surrounding tissue, to help localize the thermal treatment, and to help detach the iceball/frozen tissue from the non-frozen tissue. According to another aspect, angiogenic growth stimulation can be facilitated by delivery of an angiogenic stimulant such as a drug or other fluid directly into the tissue. This injection can occur before, during or after cryoablation has been performed on the tissue area. FIG. 12 shows an example of a device which is arranged to cryogenically cool tissue and inject an angiogenic stimulant therein. A device body 62 includes one or more cryogenic cooling surfaces such as thermally- transmissive elements 34 and a thermally-transmissive tip 32. Of course, various arrangements for providing cryogenic cooling surfaces can be provided as discussed above. A tissue penetrating element 64 is coupled to the device body 62 and includes an aperture 66 through which the angiogenic stimulant is delivered to the tissue. The device body 62 also includes a cryogenic lumen 68 through which a cooling fluid is delivered to the device body 62. The tissue penetrating element 64 is coupled to a reservoir (not shown) containing the angiogenic stimulant via an angiogenic stimulant lumen 70. In operation, the tissue penetrating element 64 is inserted into the tissue, such as myocardial tissue, and the angiogenic stimulant delivered through the lumen 70, through the aperture 66 and into the tissue. As noted above, the angiogenic stimulant delivery can occur before, during or after a cryogenic cooling cycle. FIG. 13 shows another arrangement for the cryomedical device in which a shield 72 is coupled to the device body 62. The shield 72 is preferably non or minimally thermally transmissive such that it shields the tissue from cyroablation. The tissue penetrating element 64 can be made of a highly thermally conductive material such as a metal which is cryogenically cooled along with the thermally transmissive elements of the device body, thereby providing the ability to cryoablate inner portions of tissue. Further, by cooling the tissue penetrating element 64, the cooling operation temporarily affixes the device body to the tissue, providing for increased reliability during cryoablation and/or angiogenic stimulant delivery. The cryomedical device of the present invention includes a reservoir in fluid communication with the tissue penetrating element, such as tissue penetrating element 64. FIG. 14 shows an angiogenic stimulant reservoir 74 provided as part of the controller 16. FIG. 15 shows the angiogenic stimulant reservoir 74 provided as part of a catheter handle 76. The handle 76 provides a way for the operator to insert catheter 14 into the patient, by controlling movement of the catheter within body lumen. The handle 76 can also be equipped with switches, valves and the like which allow the operator to control the actuation of cryogenic fluid into catheter 14 and control delivery of the angiogenic stimulant into the tissue. In the case where the angiogenic stimulant reservoir is provided as part of the controller 16, a lumen such as an angiogenic stimulant lumen 70 couples the reservoir 74 to the tissue penetrating element 64. The lumen 70 is also used to couple the angiogenic stimulant reservoir 74 to the tissue penetrating element 64 in the case where the reservoir 74 is provided in the catheter handle 76 (see FIG. 15). In each of these cases, an actuator is used to respond to the operator's control to force the angiogenic stimulant through the lumen 70 to the tissue penetrating element 64 for injection into the tissue. The actuator can take the form of an electric motor, pneumatic or hydraulic pressurizing device, a mechanical spring driven element or any other form by which fluid is pumped through a lumen. The angiogenic stimulant reservoir can also be provided within the device body. FIG. 16 shows a example of a device body 62 having a collapsible reservoir 78 with an angiogenic stimulant 80 contained therein. The collapsible reservoir 78 is preferably made of any material suitable for biomedical use which can house an angiogenic stimulant. For example, the collapsible reservoir 78 can be made of an impermeable membrane, polymer and the like. The device body 62 also includes within its confines an actuator 82, which when activated, applies compressive pressure to collapse the reservoir 78, thereby forcing the angiogenic stimulant fluid 80 through the tissue penetrating element 64. The actuator 82 includes a spring 84 and/or a shaft 86 coupled to a pressure plate 88. The shaft 86 can be manipulated by the operator via the handle 76 as can the spring 84 to move the pressure plate 88 toward and away from the distal end of the device body 62. The pressure plate 88 applies pressure to collapse the reservoir 78 against a back plate 90 which is fixed to the inner surface of the device body shell. In the alternative, the back plate 90 can be eliminated and the collapsible reservoir 78 instead pressed directly against the distal end 92 of the device body 62. FIG. 17 shows an example of a collapsed reservoir 78 after the actuator 82 has been operated. As shown, the angiogenic stimulant 80 is expulsed from the aperture 66. It is contemplated that the tissue penetrating element can be arranged to inject the angiogenic stimulant in a number of different ways. FIG. 18 shows a tissue penetrating element 94 having a plurality of apertures 96 inserted into tissue 97. Instead of, or in addition to, the aperture being positioned at the distal end of tissue penetrating element 94, such as is the case with aperture 66 in FIG. 12, the tissue penetrating element 94 includes a plurality of apertures 96 positioned substantially along one side of the tissue penetrating element 94. FIG. 19 illustrates an enlarged view of the tissue penetrating element 94 in which the apertures 96 are positioned along an upper side of the tissue penetrating element 94. In other words, in the case of a tubular-shaped tissue penetrating element 94, the apertures 96 are preferably arranged in the same hemisphere around the tissue penetrating element 64. FIG. 20 shows still another arrangement of a tissue penetrating element. As shown in FIG. 20, a tissue penetrating element 98 is arranged with a plurality of apertures 100 at an end portion thereof. As such, one portion of the tissue penetrating element 98, for example, an end portion closest to the device body 62, has no apertures therethrough, while the opposite end contains all of the apertures 100. It is contemplated that the apertures 100 can be placed at the end portion proximal to the device body 62 and the distal portion of tissue penetrating element 98 equipped with no apertures. FIG. 21 shows still another arrangement of a tissue penetrating element. As shown in FIG. 21, a tissue penetrating element 102 includes a plurality of apertures 104 distributed substantially along the entire length of the tissue penetrating element 102. The tissue penetrating elements described herein can be used in conjunction with any suitable device body. For example, FIG. 22 shows the tissue penetrating element 64 used in conjunction with a device body 62 having a rounded tip 106 similar to that shown in FIG. 4. FIG. 23 shows the device body 62 equipped with a pointed tip 108 such as that shown in FIG. 6. Of course, any suitable tip shape can be used in conjunction with the tissue penetrating element 64. FIG. 24 shows a metallic ring 110 as the tip. The metal ring 110 can be used to verify contact with the tissue by obtaining an electric impulse therefrom and can be used to cool the tissue. In addition, the metal ring 110 can be used to partially shield the tissue penetrating element 64. FIG. 25 shows an example of device having a tissue penetrating element 64 and stylets 38. As discussed above, stylets 38 are thermally conductive and cryogenetically treat the tissue 97. It is further contemplated that the tissue penetrating element can be movable such that it can be retracted substantially fully within the device body 62 or extended to protrude from the device body 62 as necessary during deviceoperation. For example. FIG. 26 shows an example of a device body 62 into which the tissue penetrating element 64 is retracted into retraction area 106. The retractor can take the form of a spring or shaft operated by the device user (not shown) which is coupled to the tissue penetrating element. As shown in FIG. 26, the retractor can be a toroidal balloon 108. When the device body 62 is warm, the balloon 108 remains inflated retracting the tissue penetrating element 64 which is fixed to a retraction base 110. By retracting the tissue penetrating element 64 into the device body 62, the tip portion of the device body 62 is available for use as a cryogenic ablation instrument without any portion protruding into the tissue. The balloon 108 is preferably filled with a gas or fluid which, when cooled, compresses. FIG. 27 shows an example of a retractable tip extended to its maximum penetrating position. When the device body 62 is cooled via the injection of a cryogenic gas or fluid via the cryogenic lumen 68, the balloon shrinks, thereby pulling the retraction base 110 toward the retraction area 106, resulting in the extension of the tissue penetrating element 64 outward and into the tissue 97. In the alternative, the retraction base 110 can be spring loaded (not shown) to force the tissue penetrating element 64 outward into an extended position when the device body 62 is cooled. The present invention, therefore, advantageously provides a device which combines cryogenic ablation with the injection of an angiogenic stimulating fluid to facilitate vascular growth. A variety of modifications and variations of the present invention are possible in light of the above teachings. It is therefore understood that, within the scope of the appended claims, the present invention may be practiced otherwise than as specifically described hereinabove. All references cited herein are expressly incorporated by reference in their entirety.

Claims: What is claimed is: 1. A cryomedical device, comprising: a device body having a cryogenic cooling surface; a reservoir for an angiogenic stimulant; an apertured tissue penetrating element in fluid communication with the reservoir and coupled to the device body. 2. The device according to Claim 1, wherein the reservoir is within the device body. 3. The device according to Claim 2, further comprising an actuator, the actuator initiating release of angiogenic stimulant from the reservoir. 4. The device according to Claim 1, further comprising a console in fluid communication with the device body, wherein the reservoir is located within the console. 5. The device according to Claim 1, further comprising a handle in fluid communication with the device body, wherein the reservoir is located within the handle. 6. The device according to Claim 1, wherein the cryogenic cooling surface is comprised of a metal. 7. The device according to Claim 1, wherein the tissue penetrating element is comprised of a metal. 8. The device according to Claim 1, wherein the tissue penetrating element is movably coupled to the device body and movable between an extended position and a retractable position, the tissue penetrating element being substantially fully contained with in the device body in the retractable position. 9. The device according to Claim 1, further comprising a retractor, the retractor causing the tissue penetrating element to move. 10. The device according to Claim 9. wherein the retractor is comprised of an expandable balloon. 11. The device according to Claim 1, wherein the tissue penetrating element is fixedly coupled to the device body. 12. The device according to Claim 1. wherein the tissue penetrating element has a proximal end nearest the reservoir and a distal end opposite the proximal end, the aperture being at the distal end. 13. The device according to Claim 1 , wherein the tissue penetrating element has a wall defining a passage for the angiogenic stimulant, the wall including the aperture. 14. The device according to Claim 13, wherein the wall includes a plurality of apertures. 15. The device according to Claim 14. wherein the wall is further comprised of a first elongated section and a second elongated section coupled to the first elongated section, the plurality of apertures being substantially arranged in one of the first and second elongated sections. 16. The device according to Claim 15, wherein the first elongated section has a first end coupled to the surface and a second end coupled to the second elongated section. 17. The device according to Claim 15, wherein the first elongated section extends longitudinally from the device body and the second elongated section extends longitudinally from the device body. 18. The device according to Claim 1 , further including a shield coupled to the device body, the shield covering at least a part of the tissue penetrating element. 19. The tip according to Claim 18. wherein the shield is comprised of a thermally insulating material. 20. The tip according to Claim 18, where in the tissue penetrating element is a highly thermally conductive material.

Inventors: ABBOUD MARWAN, AUBERT MATHIEU-PHILIPPE, CARROLL SEAN, NAHON DANIEL, SANTOIANNI DOMENIC, WITTENBERGER DAN, ABBOUD, MARWAN, AUBERT, MATHIEU-PHILIPPE, CARROLL, SEAN, NAHON, DANIEL, SANTOIANNI, DOMENIC, WITTENBERGER, DAN
Applicants: CARROLL SEAN, CRYOCATH TECHNOLOGIES INC, CARROLL, SEAN, CRYOCATH TECHNOLOGIES, INC.
Application year: 2000
Main classification: A61M25
IPC codes: A61B17, A61B18, A61F2