Source: https://patents.google.com/patent/US6602246B1/en
Timestamp: 2019-04-22 02:52:29+00:00

Document:
2003-05-23 Assigned to SARATOGA VENTURES III, L.P., SAPIENT CAPITAL, L.P., DENOVO (Q) VENTURES I, L.P., 2180 ASSOCIATES FUND V, L.P., U.S. VENTURE PARTNERS V, L.P., GUIDANT INVESTMENT CORPORATION, USVP V. INTERNATIONAL L.P., PEQOUT PRIVATE EQUITY FUND III, L.P., DEVOVO VENTURES, I, L.P., USVP V ENTREPRENEUR PARTNERS, L.P. reassignment SARATOGA VENTURES III, L.P. SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CRYOVASCULAR SYSTEMS, INC.
The present invention provides methods, apparatus, and kits for detection and/or treatment of vulnerable plaque of a blood vessel having a lumen surface. Detection methods include sensing a temperature differential along a lumen surface with temperature sensors that thermally couple the lumen surface. Treatment methods include controlled and safe cryogenic cooling of vulnerable plaque to inhibit release of retained fluid within the vulnerable plaque so as to inhibit acute coronary syndrome and to help maintain patency of a body lumen. Treatment methods may include additional treatments, such as primary treatments or passivation.
The present invention relates generally to methods, apparatus, and kits for treating blood vessels. More particularly, the present invention provides methods, apparatus, and kits for treating a lesion, and particularly a vulnerable atherosclerotic plaque, within a patient's vasculature to inhibit harmful releases within the vasculature, such as those which may be responsible for strokes or acute coronary syndromes of unstable angina, myocardial infarction, and sudden cardiac death.
Atherosclerotic plaque is present to some degree in most adults. Plaques can severely limit the bloodflow through a blood vessel by narrowing the open vessel lumen. This narrowing effect or stenosis is often responsible for ischemic heart disease. Fortunately, a number of percutaneous intravascular procedures have been developed for treating atherosclerotic plaque in a patient's vasculature. The most successful of these treatments is percutaneous transluminal angioplasty (PTA). PTA employs a catheter having an expansible distal end, usually in the form of an inflatable balloon, to dilate a stenotic region in the vasculature to restore adequate blood flow beyond the stenosis. Other procedures for opening stenotic regions include directional arthrectomy, laser angioplasty, stents, and the like. Used alone or in combination, these percutaneous intravascular procedures have provided significant benefits for treatment of stenoses caused by plaque.
While treatments of plaque-induced stenoses have advanced significantly over the last few decades, the morbidity and mortality associated with vascular plaques have remained significant. Recent work suggests that plaque may generally fall into one of two different general types: standard stenotic plaques and vulnerable plaques. Stenotic plaque, which is sometimes referred to as thrombosis-resistant plaque, can generally be treated effectively by the known intravascular lumen opening techniques mentioned above. Although the stenoses they induce may require treatment, these atherosclerotic plaques themselves are often a benign and effectively treatable disease.
Unfortunately, as plaque matures, narrowing of a blood vessel by a proliferation of smooth muscle cells, matrix synthesis, and lipid accumulation may result in formation of a plaque which is quite different than a standard stenotic plaque. Such atherosclerotic plaque becomes thrombosis-prone, and can be highly dangerous. This thrombosis-prone or vulnerable plaque may be a frequent cause of acute coronary syndromes.
The characterization of these vulnerable (and potentially life-threatening) plaques is currently under investigation. A number of strategies have been proposed to detect a vulnerable plaque. Proposed strategies include angiography, intravascular ultrasound, angioscopy, magnetic resonance imaging, magnetic resonance diffusion imaging; spectroscopy, infrared spectroscopy, scintigraphy, optical coherence tomography, electron beam computed tomographic scanning, and thermography, all of which have had limited success. In particular, proposed thermography methods detect temperature variations, as vulnerable plaque is typically inflamed and as such gives off more heat than standard stenotic plaque. While current thermography methods show great promise, they continue to suffer from limited temperature sensitivity which may often result in inaccurate detections of vulnerable plaque.
A cryoplasty device and method are described in WO 98/38934. Balloon catheters for intravascular cooling or heating a patient are described in U.S. Pat. No. 5,486,208 and WO 91/05528. A cryosurgical probe with an inflatable bladder for performing intrauterine ablation is described in U.S. Pat. No. 5,501,681. Cryosurgical probes relying on Joule-Thomson cooling are described in U.S. Pat. Nos. 5,275,595; 5,190,539; 5,147,355; 5,078,713; and 3,901,241. Catheters with heated balloons for post-angioplasty and other treatments are described in U.S. Pat. Nos. 5,196,024; 5,191,883; 5,151,100; 5,106,360; 5,092,841; 5,041,089; 5,019,075; and 4,754,752. Cryogenic fluid sources are described in U.S. Pat. Nos. 5,644,502; 5,617,739; and 4,336,691. The following U.S. Patents may also be relevant to the present invention: U.S. Pat. Nos. 5,458,612; 5,545,195; and 5,733,280.
Thermography is described by Ward Casscells et al. in The Vulnerable Atherosclerotic Plague: Understanding, Identification, and Modification, chpt. 13, pp. 231-242 (1999); and L. Diamantopoulos et al. at http://www.eurekalert. org/releases/aha-ati041499.html. The impact of low temperatures on lipid membranes is described by Jack Kruuv in Advances in Molecular and Cell biology, vol. 19, pp. 143-192 (1997); P.J. Quinn in Cryobiology, vol. 22, pp. 128-146 (1985); and Michael J. Taylor, Ph.D. in Biology Of Cell Survival In The Cold, (Harwood Academic Publishers, In Press).
The present invention provides detection and cryotherapy treatment of vulnerable plaque within a blood vessel of a patient. The blood vessel may be any blood vessel in the patient's vasculature, including veins, arteries, and particularly coronary arteries. The vessel will typically be partially stenosed, at least in part from vulnerable plaque. In particular, the present invention may inhibit release of retained fluid within the vulnerable plaque so as to inhibit acute coronary syndrome and to help maintain the patency of a body lumen. The present invention may also provide for the treatment of vulnerable plaque in carotid arteries for stroke prevention. Where the patient's vasculature has both the vulnerable plaque and standard stenotic plaque, the treatment techniques described herein may be selectively directed to the vulnerable plaque, optionally without substantial cooling of the standard stenotic plaque. In other embodiments, both types of plaque may be treated.
In a first aspect, the present invention provides a method for treating vulnerable plaque of a blood vessel. The method comprises cooling the blood vessel adjacent the vulnerable plaque to a temperature sufficient to inhibit release of retained fluid from within the vulnerable plaque into the blood stream. The cooling treatment will often be directed against all or a portion of a circumferential surface of a lumen of the blood vessel, and will preferably inhibit release of lipid-rich liquid being releasably retained by the vulnerable plaque.
Cooling of the vessel may be effected by introducing a catheter into a lumen of the blood vessel. A first balloon is positioned within the vessel lumen adjacent the vulnerable plaque. Cryogenic cooling fluid is introduced into the first balloon and exhausted. A second balloon disposed over the first balloon is expanded to radially engage the vessel lumen. Generally, the temperature of an inside surface of the first balloon will be in the range from about −55° C. to −75° C. and an outside surface of the first balloon will be in the range from about −25° C. to −45° C. The temperature of an outside surface of the second balloon will be in the range from about 10° C. to −40° C., preferably from about 10° C. to −20° C., more preferably from about 5° C. to −10° C.
Usually, the temperature at the cell surface of the blood vessel lumen is in the range from about 10° C. to −40° C., preferably from about 10° C. to −20° C., more preferably from about 5° C. to −10° C. The tissue is typically maintained at the desired temperature for a time period in the range from about 15 seconds to 120 seconds, preferably from 30 seconds to 60 seconds. Vulnerable plaque stabilization may be enhanced by repeating cooling in cycles, typically with from about 1 to 3 cycles, with the cycles being repeated at a rate of about one cycle every 120 seconds.
Surprisingly, cooling temperatures above 0° C. can effect a transition of the vulnerable plaque's lipid core from a disordered cystalline state fluid to a ordered crystalline state solid or gel. Thus, vulnerable plaque can be stabilized by cooling the lipid-rich liquid sufficiently to change a state of the lipid-rich liquid, typically to a highly ordered hexagonal lattice at transition temperatures generally in the range from about 10° C. to −10° C. Cooling may stabilize the vulnerable plaque while inhibiting necrosis and/or apoptosis of tissue adjacent the lipid-rich liquid, particularly of the tissues defining a cap of cells between the lipid-rich liquid and the lumen of the blood vessel. Cooling may also inhibit inflammation and deterioration of the vulnerable plaque. The cooling treatment may further inhibit rupture of the cap of cells of the vulnerable plaque.
In other aspects, the present invention of cooling the vulnerable plaque to inhibit release of lipid-rich liquid may be combined with additional treatments. For example, one adjunctive method may comprise treating the cooled vulnerable plaque with a primary treatment. Suitable primary treatments may include balloon angioplasty, atherectomy, rotational atherectomy, laser angioplasty, or the like, where the lumen of the treated blood vessel is enlarged to at least partially alleviate a stenotic condition. The primary treatment may also include procedures for controlling restenosis, such as stent placement. In the case of arteries, the primary treatment will be effected shortly before, during, or preferably very shortly after the cooling treatment, preferably within 60 seconds of the cooling treatment, more preferably immediately following the cooling of the lipid-rich liquid to a desired temperature. Alternatively, cooling methods may additionally comprise passivating the vulnerable plaque by reducing a size of the lipidrich liquid, changing a cellular consistency or composition of the lipid-rich liquid, enhancing a structural integrity of the cap (e.g. increasing a thickness of the cap), modifying a cellular composition or structural properties of the cap, and/or the like by altering the chemistry or life cycle of the vulnerable plaque.
FIG. 4 illustrates an exploded cross-sectional view of FIG. 1A taken along line 4—4.
FIG. 6 is a cross-sectional view of the catheter taken along line 6—6 in FIG. 5.
FIG. 10B is a cross-sectional view of the catheter taken along line 10B—10B in FIG. 10A.
As used herein, the terms “vulnerable plaque” and “hot plaque” refer to atherosclerotic plaque that is thrombosis-prone. FIGS. 1A and 1B illustrate cross-sectional views of a blood vessel 100 containing a mature vulnerable plaque 102 within a lumen 104 of the vessel. The vulnerable plaque 102 generally comprises a necrotic core 106 of soft, lipid-rich, atheromatous gruel and a fibrous, sclerotic cap 108 of a collagen matrix of smooth muscle cells that covers the core 106. The gruel generally comprises a liquid of esterified cholesterol and low density lipoproteins which is releasably retained by the vulnerable plaque 102. Disruption or fissuring of the cap 108 may cause plaque hemorrhage 110 (release of the highly thrombogenic lipid-rich liquid 106 through the ruptured plaque), as seen in FIG. 2. As a result of plaque hemorrhage 110, the highly thrombogenic lipid-rich liquid 106 is exposed to flowing blood of the vessel lumen 104. As illustrated in FIG. 3, release of the thrombogenic liquid may cause a thrombotic occlusion 112 (blood clot) of the entire vessel lumen, which in turn may be lead to lifethreatening conditions, such as a stroke or sudden cardiac death.
Three determinants of vulnerability are illustrated in FIG. 4, which is an exploded cross-sectional view of FIG. 1A taken along line 4—4. Susceptibility of a vulnerable plaque to rupture may be primarily determined from the size 114 and consistency of the atheromatous core (e.g. a larger core increases chances for rupture), the thickness 116 and structural integrity of the sclerotic cap (e.g. a thinner cap increases chances for rupture), and cap inflammation (e.g. macrophage foam cell 118 infiltration weakens the cap cells 120 and increases chances for rupture). Additionally, vulnerable plaque disruption may be triggered by numerous extrinsic stresses imposed on the plaque. For example, fluctuations in intraluminal blood pressure, pulse pressure, heart contraction, vasospasm, and the like may precipitate disruption of a vulnerable plaque. Alternatively, mechanical stresses caused by primary treatments like PTA or stenting may trigger rupture as well.
Referring now to FIGS. 5 and 6, an exemplary cryotherapy catheter 10 (which is more fully described in application Ser. No. 09/619,583 filed Jul. 19, 2000, the full disclosure of which is incorporated herein by reference) for detecting and treating vulnerable plaque 102 of a blood vessel 100 having a lumen surface 105 (see FIG. 1A) will be described. The catheter 10 comprises a catheter body 12 having a proximal end 14 and a distal end 16 with a cooling fluid supply lumen 18 and an exhaust lumen 20 extending therebetween. A first balloon 22 is disposed near the distal end of the catheter body 12 in fluid communication with the supply and exhaust lumens. A second balloon 24 is disposed over the first balloon 22 with a thermal barrier 26 therebetween.
The thermal barrier 26 may comprise a gap maintained between the balloons 22, 24 by a filament. The filament typically comprises a helically wound, braided, woven, or knotted monofilament. The monofilament may be formed from PET or polyethylene napthlate (PEN), and affixed to the first balloon 22 by adhesion bonding, heat welding, fasteners, or the like. The thermal barrier 26 may also comprise a gap maintained between the balloons 22, 24 by a plurality of bumps on an outer surface of the first balloon 22 and/or an inner surface of the second balloon 24. The plurality of bumps may be formed in a variety of ways. For example, the bumps may be intrinsic to the balloon (created during balloon blowing), or the bumps could be created by deforming the material of the balloon wall, by affixing mechanical “dots” to the balloon using adhesion bonding, heat welding, fasteners, or the like. Alternatively, the thermal barrier 26 may comprise a gap maintained between the balloons 22, 24 by a sleeve. The sleeve may be perforated and formed from PET or rubbers such as silicone and polyurathane.
The vacuum space 52 may be provided by a simple fixed vacuum chamber 64 coupled to the vacuum space 52 by a vacuum lumen 66 of the body 12 via a vacuum port 68 (See FIG. 5). In the exemplary embodiment, a positive displacement pump (ideally being similar to a syringe) is disposed within handle 74 and may be actuated by actuator 75, as seen in FIG. 8A. The vacuum space 52 should comprise a small volume of vacuum in the range from 1 mL to 100 mL, preferably 10 mL or less, as a smaller vacuum space 52 facilitates detection of a change in the amount of vacuum when a small amount of fluid leakage occurs. The cryogenic fluid supply 62 and battery 60 for powering the circuit may be packaged together in an energy pack 70, as seen in FIG. 8B. The energy pack 70 is detachable from a proximal handle 74 of the catheter body and disposable. A plurality of separate replaceable energy packs 70 allow for multiple cryogenic cooling cycles. Additionally, an audio alert or buzzer 76 may be located on the handle 74, with the buzzer providing an audio warning unless the handle is maintained sufficiently upright to allow flow from the fluid supply 62. The cryotherapy catheter may additionally comprise a hypsometer 72 coupled to the volume by a thermistor, thermocouple, or the like located in the first balloon 22 or handle to determine the pressure and/or temperature of fluid in the first balloon 22. The hypsometer allows for accurate real time measurements of variables (pressure, temperature) that effect the efficacy and safety of cryotherapy treatments.
The dual balloon cryotherapy catheter 10 in FIG. 5 also illustrates a temperature sensing mechanism that provides for thermographic detection of vulnerable plaque. A plurality of temperature sensors 78 are affixed to the second balloon 24 so as to provide direct temperature measurements of the lumen surface 105 (see FIG. 1A). The temperature sensors 78 may comprise a plurality of up to 20 thermocouples or thermistors and may be capable of detecting temperature differences greater than 0.1° C. The temperature sensors 78 may be secured to the second balloon 24 at a series of axial and circumferential locations. The plurality of temperature sensors 78 may be affixed by adhesion bonding, heat welding, fasteners, or the like to an outer surface of the second balloon 24, as shown in FIG. 5, or may be alternatively affixed to an inner surface of the second balloon 24. Temperature sensor wires 80 may be secured along the length of the catheter shaft 12 within a thin sleeve 82 formed from PET or rubbers such as silicone and polyurathane, or in the latter case the wires 80 may be threaded through the vacuum lumen 66. A connector 84 at the proximal end 14 of the catheter 10 may also be provided to connect the temperature sensor wires 80 to a temperature readout device for temperature mapping along the lumen surface. Additionally, a circuit 77 may be attached to the connector 84 for measuring a temperature differential ΔT along the lumen surface from temperature measurement T1 and T2 sensed by the temperature sensors 78, as illustrated in the block diagram of FIG. 9. An indicator which is triggered above a threshold temperature differential may also be located on the connector for alerting purposes.
Detection of vulnerable plaque may be carried out by introducing the cryotherapy catheter 10 into a lumen 104 of the blood vessel 100 over a guidewire. The first balloon 22 is positioned within the blood vessel lumen 104 adjacent a plaque. The first balloon 22 is inflated so that the plurality of temperature sensors 78 affixed to the second balloon 24 (which expands upon inflation) thermally couple a surface of the vessel lumen. A temperature differential along the lumen surface 105 is sensed with the sensors. Inflation of balloon 22 may be effected by a gas, such as carbon dioxide, nitrous oxide, or the like, at a pressure in the range from about 5 psi to 50 psi. The balloon 22 will typically be inflated for a time period in the range from 10 to 120 seconds. The balloon catheter may sense for a temperature differential in a static position or as it moving along the lumen surface. Advantageously, temperature sensors 78 thermally engage the lumen surface to allow for direct temperature measurements to be made at specific locations along the lumen surface. This increased temperature sensitivity may in turn lead to improved temperature mapping and accurate vulnerable plaque detections. Cryotherapy catheter 10 may then be used for treating the detected vulnerable plaque as described in more detail below with reference to FIGS. 11A-11C.
Referring now to FIGS. 11A through 11C, use of cryotherapy catheter 10 of FIG. 5 for treatment of vulnerable plaque 102 will be described. As illustrated in FIG. 11A and 11B, catheter 10 will be introduced into a lumen 104 of the blood vessel 100 over a guidewire GW. The first balloon 22 is positioned within the blood vessel lumen 104 adjacent the vulnerable plaque 102. Cryogenic cooling fluid is introduced into the first balloon 22 (in which it often vaporizes) and exhausted. The second balloon 24 expands to radially engage the vessel wall, as illustrated by FIG. 11C. The vaporized fluid serves both to inflate balloon 22 (and expand balloon 24) and to cool the exterior surface of the balloons 22, 24. The blood vessel 100 adjacent the vulnerable plaque 102 is cooled to a temperature sufficient to inhibit release of retained fluid 106 from within the vulnerable plaque 102 into the blood vessel 100. The cooling treatment will be directed at all or a portion of a circumferential surface the vessel lumen. Preferably cooling will inhibit release of lipid-rich liquid being releasably retained by the vulnerable plaque by stabilizing the lipid-rich liquid 106 to a lipid-rich solid or gel 106′ (which is described in more detail in FIGS. 12A-12B below). Heat transfer will also be inhibited between the first and second balloons 22, 24 by the thermral barrier 26 so as to limit cooling of the vulnerable plaque to a desired temperature profile. Additionally, containment of the first and second balloons 22, 24 will be monitored during cooling by the fluid shutoff mechanism (see FIG. 7).
Suitable cryogenic fluids will preferably be non-toxic and may include liquid nitrous oxide, liquid carbon dioxide, cooled saline and the like. The cryogenic fluid will flow through the supply lumen sauid at an elevated pressure and will vaporize at a lower pressure within the first balloon 22. For nitrous oxide, a delivery pressure within the supply lumen 18 will typically be in the range from 600 psi to 1000 psi at a temperature below the associated boiling point. After vaporization, the nitrous oxide gas within the first balloon 22 near its center will have a pressure typically in the range from 15 psi to 100 psi. Preferably, the nitrous oxide gas will have a pressure in the range from 50 psi to 100 psi in a peripheral artery and a range from about 15 psi to 45 psi in a coronary artery.
Generally, the temperature of an inside surface of the first balloon will be in the range from about −55° C. to −75° C. and an outside surface of the first balloon will be in the range from about −25° C. to −45° C. The temperature of an outside surface of the second balloon will be in the range from about 10° C. to −40° C., preferably from about 10° C. to −20° C., more preferably from about 5° C. to −10° C. This will provide a desired treatment temperature in a range from about 10° C. to −40° C., preferably from about 10° C. to −20° C., more preferably from about 5° C. to −10° C. The tissue is typically maintained at the desired temperature for a time period in the range from about 15 to 120 seconds, preferably being from 30 to 60 seconds. Vulnerable plaque stabilization may be enhanced by repeating cooling in cycles, typically with from about 1 to 3 cycles, with the cycles being repeated at a rate of about one cycle every 120 seconds.
In other applications, cooling of the vessel at cooler temperatures may be desirable to provide for apoptosis and/or programmed cell death stimulation of inflamatory cells (e.g. macrophages 118, see FIG. 4) in the vulnerable plaque 102. Apoptosis may be desirable as the presence of such inflamatory cells may trigger cap weakening or erosion which in turn may lead to vulnerable plaque release of the lipid-rich liquid. Cooling at temperatures in the range from about 0° C. to −15° C. may inhibit inflammation and deterioration of the vulnerable plaque, particularly of the tissues defining the cap of cells 108. Alternatively, it may be beneficial to provide for necrosis in the cap cells 108 at cooling temperatures below about −20° C. Cap necrosis may stimulate cellular proliferation and thickening of the cap which in turn may inhibit cap rupture.
expanding a second balloon disposed over the first balloon to radially engage the vessel lumen.
2. A method as in claim 1, wherein a temperature of an outer surface of the first balloon is in the range from about −25° C. to −45° C. and a temperature of an outer surface the second balloon is in the range from about 10° C. to −40° C.
4. A method as in claim 1, wherein the fluid of the vulnerable plaque comprises a lipid-rich liquid.
5. A method as in claim 4, wherein the vulnerable plaque comprises a cap of cells between the lipid-rich liquid and a lumen of the blood vessel.
6. A method as in claim 5, further comprising inhibiting apoptosis of tissue adjacent the lipid-rich liquid.
7. A method as in claim 5, wherein the cooling step inhibits rupture of the cap of cells.
8. A method as in claim 1, wherein the cooling step comprises lowering the temperature of the blood vessel surface from about 10° C. to −40° C. for a time period in the range from about 15 to 120 seconds.
9. A method as in claim 4, further comprising stabilizing the vulnerable plaque by cooling the lipid-rich liquid to a highly ordered hexagonal lattice.
10. A method as in claim 9, wherein the lipid-rich liquid is hardened to at least a gel-state.
11. A method as in claim 1, wherein the cooling inhibits inflammation of the vulnerable plaque.
12. A method as in claim 1, wherein the cooling inhibits deterioration of the vulnerable plaque.
13. A method as in claim 1, further comprising treating the vulnerable plaque with a primary treatment.
14. A method as in claim 4, further comprising passivating the vulnerable plaque by reducing a size or modifing a consistency or composition of the lipid-rich liquid.
15. A method as in claim 14, wherein passivation is carried out by altering the chemistry or life cycle of the vulnerable plaque.
16. A method as in claim 5, further comprising passivating the vulnerable plaque by increasing a thickness of the cap of cells.
Casscells, W., et al., The Vulnerable Atherosclerotic Plaque: Understanding, Identification, and Modification: Chapter 13: Thermography. Armonk, NY: Futura Publishing Company, Inc.; (C)1999. pp. 231-242.
Casscells, W., et al., The Vulnerable Atherosclerotic Plaque: Understanding, Identification, and Modification: Chapter 13: Thermography. Armonk, NY: Futura Publishing Company, Inc.; ©1999. pp. 231-242.
Dalager-Pedersen, S., et al. The Vulnerable Atherosclerotic Plaque: Understanding, Identification, and Modification: Chapter 1: Coronary Artery Disease: Plaque Vulnerability, Disruption, and Thrombosis. Armonk, NY:Futura Publishing Company, Inc.; (C)1999. pp. 1-23.
Dalager-Pedersen, S., et al. The Vulnerable Atherosclerotic Plaque: Understanding, Identification, and Modification: Chapter 1: Coronary Artery Disease: Plaque Vulnerability, Disruption, and Thrombosis. Armonk, NY:Futura Publishing Company, Inc.; ©1999. pp. 1-23.
Diamantopoulos, L., et al. http://www.eurekalert.org/releases/aha-ati0041499.html. "Artery Temperatures Identify Hot Spots on Plaque that May Rupture and Trigger Heart Attack." (Release date: Apr. 20, 1999) 3 pages.
Kruuv, Jack. "Survival of Mammalian Cells Exposed to Pure Hypothermia in Culture." Advances in Molecular and Cell Biology. (1997) 9:143-190.
Quinn, P.J. "A Lipid-Phase Separation Model of Low-Temperature Damage to Biological Membranes." Cryobiology. (1985) 22:128-146.
Taylor, Michael J. Biology of Cell Survival in the Cold. Organ Recovery Systems, Inc. & Allegheny University of Health Sciences. Greenwich, CT: JAI Press, 1996:1-64.
U.S. patent application No. 09/203,011 filed on Dec. 1, 1998 entitled: Apparatus and Method for Cryogenic Inhibition of Hyperplasia, Inventor(s): James Joye et al.
U.S. patent application No. 09/268,205 filed Mar. 15, 1999 entitled: Cryosurgical Fluid Supply, Inventor(s): James Joye et al.
U.S. patent application No. 09/344,177 filed on Jun. 24, 1999 entitled: Cryosurgical Catheter Inhibition of Hyperplasia, Inventor(s): James Joye et al.
U.S. patent application No. 09/510,903 filed on Feb. 23, 2000 entitled: Cryogenic Angioplasty Catheter, Inventor(s): James Joye et al.
U.S. patent application No. 09/511,191 filed on Feb. 23, 2000 entitled: Cryogenic Angioplasty Catheter, Inventor(s): James Joye et al.
U.S. patent application No. 09/619,583 filed on Jul. 19, 2000 entitled: Improved Safety Cryotherapy Catheter, Inventor(s): James Joye et al.

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