CA2633666A1 - Methods and apparatus for pulsed electric field neuromodulation via an intra-to-extravascular approach - Google Patents
Methods and apparatus for pulsed electric field neuromodulation via an intra-to-extravascular approach Download PDFInfo
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- CA2633666A1 CA2633666A1 CA002633666A CA2633666A CA2633666A1 CA 2633666 A1 CA2633666 A1 CA 2633666A1 CA 002633666 A CA002633666 A CA 002633666A CA 2633666 A CA2633666 A CA 2633666A CA 2633666 A1 CA2633666 A1 CA 2633666A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/321—Electromedical belts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
- A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
- A61B18/14—Probes or electrodes therefor
- A61B18/1477—Needle-like probes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
- A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
- A61B18/1206—Generators therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
- A61N1/0507—Electrodes for the digestive system
- A61N1/0514—Electrodes for the urinary tract
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
- A61N1/0551—Spinal or peripheral nerve electrodes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/327—Applying electric currents by contact electrodes alternating or intermittent currents for enhancing the absorption properties of tissue, e.g. by electroporation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
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- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/36007—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation of urogenital or gastrointestinal organs, e.g. for incontinence control
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00053—Mechanical features of the instrument of device
- A61B2018/00214—Expandable means emitting energy, e.g. by elements carried thereon
- A61B2018/0022—Balloons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00053—Mechanical features of the instrument of device
- A61B2018/00214—Expandable means emitting energy, e.g. by elements carried thereon
- A61B2018/00267—Expandable means emitting energy, e.g. by elements carried thereon having a basket shaped structure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
- A61B2018/00345—Vascular system
- A61B2018/00404—Blood vessels other than those in or around the heart
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- A—HUMAN NECESSITIES
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- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
- A61B2018/00434—Neural system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
- A61B2018/00505—Urinary tract
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
- A61B2018/00613—Irreversible electroporation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
- A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
- A61B18/1206—Generators therefor
- A61B2018/1246—Generators therefor characterised by the output polarity
- A61B2018/126—Generators therefor characterised by the output polarity bipolar
Abstract
Methods and apparatus are provided for pulsed electric field neuromodulation, via an intra-to-extravascular approach, e.g., to effectuate irreversible electroporation or electrofusion, necrosis and/or inducement of apoptosis, alteration of gene expression, changes in cytokine upregulation and other conditions in target neural fibers. In some embodiments, the ITEV PEF
system comprises an intravascular catheter having one or more electrodes configured for intra-to-extravascular placement across a wall of patient's vessel into proximity with target neural fibers. With the electrode(s) passing from an intravascular position to an extravascular position prior to delivery of the PEF, a magnitude of applied voltage or energy delivered via the electrode(s) and necessary to achieve desired neuromodulation may be reduced relative to an intravascular PEF system having one or more electrodes positioned solely intravascularly. The methods and apparatus of the present invention may, for example, be used to modulate one or more target neural fibers that contribute to renal function.
system comprises an intravascular catheter having one or more electrodes configured for intra-to-extravascular placement across a wall of patient's vessel into proximity with target neural fibers. With the electrode(s) passing from an intravascular position to an extravascular position prior to delivery of the PEF, a magnitude of applied voltage or energy delivered via the electrode(s) and necessary to achieve desired neuromodulation may be reduced relative to an intravascular PEF system having one or more electrodes positioned solely intravascularly. The methods and apparatus of the present invention may, for example, be used to modulate one or more target neural fibers that contribute to renal function.
Claims (49)
1. Apparatus for pulsed electric field neuromodulation via an intra-to-extravascular approach, the apparatus comprising:
a pulsed electric field generator; and at least one electrode electrically coupled to the pulsed electric field generator, the electrode configured for intravascular delivery and extravascular placement via an intra-to-extravascular approach, wherein the electrode is configured for extravascular delivery of a pulsed electric field to induce neuromodulation.
a pulsed electric field generator; and at least one electrode electrically coupled to the pulsed electric field generator, the electrode configured for intravascular delivery and extravascular placement via an intra-to-extravascular approach, wherein the electrode is configured for extravascular delivery of a pulsed electric field to induce neuromodulation.
2. The apparatus of claim 1, wherein the electrode comprises at least one bipolar electrode pair having a first electrode and a second electrode, the bipolar electrode pair coupled to the pulsed electric field generator.
3. The apparatus of claim 2, wherein the apparatus is configured for extravascular delivery of the pulsed electric field across the bipolar electrode pair.
4. The apparatus of claim 2, wherein the first electrode is configured for extravascular placement via an intra-to-extravascular approach, and the second electrode is configured for intravascular placement.
5. The apparatus of claim 4, wherein the first electrode comprises an active electrode and the second electrode comprises a return electrode.
6. The apparatus of claim 2, wherein both the first electrode and the second electrode are configured for extravascular placement via an intra-to-extravascular approach.
7. The apparatus of claim 2, wherein the first electrode and the second electrode are longitudinally spaced apart from one another in a deployed configuration.
8. The apparatus of claim 2, wherein the first electrode and the second electrode are angularly-aligned with one another relative to a circumference of a patient's vasculature.
9. The apparatus of claim 1 further comprising an external ground pad, wherein the electrode is configured for monopolar extravascular delivery of the pulsed electric field to induce neuromodulation.
10. The apparatus of claim 1 further comprising a piercing element.
configured for intravascular delivery, the piercing element configured to pierce a wall of vasculature of a patient from within the vasculature.
configured for intravascular delivery, the piercing element configured to pierce a wall of vasculature of a patient from within the vasculature.
11. The apparatus of claim 10, wherein the electrode is configured for extravascular placement through a wall piercing created with the piercing element.
12. The apparatus of claim 10, wherein the electrode comprises the piercing element.
13. The apparatus of claim 10, wherein the piercing element comprises a needle or cannula.
14. The apparatus of claim 13, wherein the electrode is configured for extravascular placement through a lumen of the needle.
15. The apparatus of claim 1, wherein the electrode is coupled to a catheter.
16. The apparatus of claim 15, wherein the electrode is coupled to an expandable element of the catheter.
17. The apparatus of claim 1, wherein the electrode is configured for delivery via a catheter.
18. The apparatus of claim 1, wherein the apparatus is configured for extravascular infusion of agents.
19. The apparatus of claim 18, wherein the apparatus is configured for extravascular infusion of agents that enhance neuromodulation or provide protective effects.
20. A method for pulsed electric field neuromodulation via an intra-to-extravascular approach, the method comprising:
intravascularly advancing at least one electrode to a treatment site within vasculature of a patient;
passing a portion of the electrode through at least a portion of a wall of the vasculature to position the electrode at an extravascular location via an intra-to-extravascular approach; and extravascularly delivering a pulsed electric field via the electrode to induce neuromodulation.
intravascularly advancing at least one electrode to a treatment site within vasculature of a patient;
passing a portion of the electrode through at least a portion of a wall of the vasculature to position the electrode at an extravascular location via an intra-to-extravascular approach; and extravascularly delivering a pulsed electric field via the electrode to induce neuromodulation.
21. The method of claim 20, wherein intravascularly advancing at least one electrode to a treatment site within vasculature of a patient further comprises intravascularly moving the electrode to a treatment site within a renal artery of the patient.
22. The method of claim 20, wherein intravascularly advancing at least one electrode to a treatment site within vasculature of a patient further comprises intravascularly moving an intravascular catheter having the electrode to the treatment site within the vasculature of the patient.
23. The method of claim 22, wherein passing a portion of the electrode through at least a portion of a wall of the vasculature to position the electrode at an extravascular location via an intra-to-extravascular approach further comprises expanding an expandable element of the catheter.
24. The method of claim 20, wherein intravascularly advancing at least one electrode to a treatment site within vasculature of a patient further comprises moving the electrode through an intravascular catheter positioned at the treatment site.
25. The method of claim 20, wherein extravascularly delivering a pulsed electric field to induce neuromodulation further comprises extravascularly applying the pulsed electric field to modulate a neural fiber that contributes to renal function.
26. The method of claim 25, wherein modulating a neural fiber that contributes to renal function further comprises inducing an effect in the neural fiber chosen from the group consisting of irreversible electroporation, electrofusion, necrosis, apoptosis, gene expression alteration, cytokine upregulation alteration, and combinations thereof.
27. The method of claim 20 wherein passing a portion of the electrode through at least a portion of a wall of the vasculature to positioning the electrode at an extravascular location via an intra-to-extravascular approach further comprises piercing the wall of the vasculature, and advancing the electrode through the wall piercing.
28. The method of claim 27, wherein piercing the wall of the vasculature further comprises forcing the electrode through the wall of the vasculature.
29. The method of claim 20, wherein advancing at least one electrode to a treatment site further comprises advancing at least one bipolar electrode pair to the treatment site.
30. The method of claim 29, wherein passing a portion of the electrode through at least a portion of a wall of the vasculature to positioning the electrode at an extravascular location via an intra-to-extravascular approach further comprises moving the bipolar electrode pair extravascularly, and wherein extravascularly delivering a pulsed electric field further comprises extravascularly delivering the pulsed electric field across the bipolar electrode pair.
31. The method of claim 29, wherein passing a portion of the electrode through at least a portion of a wall of the vasculature to positioning the electrode at an extravascular location via an intra-to-extravascular approach further comprises positioning a first electrode of the bipolar electrode pair at the extravascular location and positioning a second electrode of the bipolar electrode pair at an intravascular location.
32. The method of claim 20 further comprising infusing an agent to enhance the neuromodulation.
33. The method of claim 20 further comprising infusing an agent to protect non-target tissue.
34. A method for pulsed electric field neuromodulation via an intra-to-extravascular approach, the method comprising:
intravascularly advancing a catheter to a treatment site within vasculature of a patient;
positioning at least one electrode at an extravascular location via the catheter utilizing an intra-to-extravascular approach; and extravascularly delivering a pulsed electric field via the electrode to induce neuromodulation.
intravascularly advancing a catheter to a treatment site within vasculature of a patient;
positioning at least one electrode at an extravascular location via the catheter utilizing an intra-to-extravascular approach; and extravascularly delivering a pulsed electric field via the electrode to induce neuromodulation.
35. The method of claim 34 wherein delivering the pulse electric field induces irreversible electroporation in neural fibers related to renal function.
36. An apparatus for pulsed electric field neuromodulation, comprising:
a pulsed field generator;
an elongated element configured to be moved within a vascular structure of a patient;
at least one electrode having an intravascular portion associated with the elongated element and an extravascular portion configured to be passed through a wall of the vascular structure, wherein the electrode is electrically coupled to the pulsed field generator; and an actuator associated with the electrode, wherein the actuator is configured to move the electrode from a first position in which the extravascular portion of the electrode is within the vascular structure and a second position in which the extravascular portion of the electrode is located at an extravascular location for extravascular delivery of a pulsed electric field.
a pulsed field generator;
an elongated element configured to be moved within a vascular structure of a patient;
at least one electrode having an intravascular portion associated with the elongated element and an extravascular portion configured to be passed through a wall of the vascular structure, wherein the electrode is electrically coupled to the pulsed field generator; and an actuator associated with the electrode, wherein the actuator is configured to move the electrode from a first position in which the extravascular portion of the electrode is within the vascular structure and a second position in which the extravascular portion of the electrode is located at an extravascular location for extravascular delivery of a pulsed electric field.
37. The apparatus of claim 36, wherein the electrode comprises at least one bipolar electrode pair having a first electrode and a second electrode, the bipolar electrode pair coupled to the pulsed field generator.
38. The apparatus of claim 37, wherein the extravascular portion of the electrode comprises the bipolar electrode pair.
39. The apparatus of claim 37, wherein the intravascular portion of the electrode comprises the first electrode of the bipolar electrode pair and the extravascular portion of the electrode comprises the second electrode of the bipolar electrode pair.
40. The apparatus of claim 37, wherein the first electrode and the second electrode are longitudinally spaced apart from one another in the second position.
41. The apparatus of claim 36 further comprising an external ground pad, wherein the extravascular portion of the electrode is configured for monopolar extravascular delivery of the pulsed electric field.
42. The apparatus of claim 36, wherein the actuator comprises a piercing element configured to pierce a wall of the vascular structure during movement of the extravascular portion of the electrode from the first position to the second position.
43. The apparatus of claim 36, wherein the extravascular portion of the electrode comprises a piercing element configured to pierce a wall of the vascular structure during movement of the extravascular portion of the electrode from the first position to the second position.
44. The apparatus of claim 36 further comprising infusate, wherein the apparatus is configured for extravascular infusion of the infusate.
45. The apparatus of claim 44, wherein the infusate comprises neuromodulation-enhancing infusate or protective infusate.
46. The apparatus of claim 36, wherein the actuator comprises an inflatable balloon.
47. The apparatus of claim 36, wherein the actuator comprises an expandable cage or basket.
48. The apparatus of claim 36, wherein the actuator comprises a transition element having a profile configured to direct the extravascular portion of the electrode radially outward as the extravascular portion of the electrode is moved from the first position to the second position.
49. An apparatus for pulsed electric field neuromodulation, comprising:
a pulsed field generator;
a bipolar electrode pair having first and second electrodes, the bipolar electrode pair electrically coupled to the pulsed field generator;
and a catheter having an actuator, wherein the catheter is configured to position the bipolar electrode pair within a vascular structure of a patient, and wherein the actuator is configured to temporarily move non-insulated portions of the bipolar electrode pair from positions within the vascular structure to extravascular positions for extravascular delivery of a bipolar pulsed electric field.
a pulsed field generator;
a bipolar electrode pair having first and second electrodes, the bipolar electrode pair electrically coupled to the pulsed field generator;
and a catheter having an actuator, wherein the catheter is configured to position the bipolar electrode pair within a vascular structure of a patient, and wherein the actuator is configured to temporarily move non-insulated portions of the bipolar electrode pair from positions within the vascular structure to extravascular positions for extravascular delivery of a bipolar pulsed electric field.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US81358905P | 2005-12-29 | 2005-12-29 | |
US60/813,589 | 2005-12-29 | ||
US11/363,867 | 2006-02-27 | ||
US11/363,867 US7620451B2 (en) | 2005-12-29 | 2006-02-27 | Methods and apparatus for pulsed electric field neuromodulation via an intra-to-extravascular approach |
PCT/US2006/048822 WO2007078997A2 (en) | 2005-12-29 | 2006-12-21 | Methods and apparatus for pulsed electric field neuromodulation via an intra-to-extravascular approach |
Publications (2)
Publication Number | Publication Date |
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CA2633666A1 true CA2633666A1 (en) | 2007-07-12 |
CA2633666C CA2633666C (en) | 2016-09-20 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA2633666A Active CA2633666C (en) | 2005-12-29 | 2006-12-21 | Methods and apparatus for pulsed electric field neuromodulation via an intra-to-extravascular approach |
Country Status (6)
Country | Link |
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US (7) | US7620451B2 (en) |
EP (5) | EP2664355B1 (en) |
JP (1) | JP5147719B2 (en) |
CN (2) | CN101426551B (en) |
CA (1) | CA2633666C (en) |
WO (1) | WO2007078997A2 (en) |
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CN109893244B (en) * | 2017-12-08 | 2024-04-19 | Igea有限公司 | Manipulation and control system for expandable electrodes of a handpiece for use in electroporation procedures |
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- 2006-12-21 CN CN200680050078.8A patent/CN101426551B/en not_active Expired - Fee Related
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- 2006-12-21 EP EP13168821.0A patent/EP2656873B1/en not_active Not-in-force
- 2006-12-21 EP EP13168822.8A patent/EP2656874B1/en not_active Not-in-force
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- 2006-12-21 EP EP06847926.0A patent/EP1968692B1/en not_active Not-in-force
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2009
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2011
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2014
- 2014-12-17 US US14/574,262 patent/US9364280B2/en not_active Expired - Lifetime
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2016
- 2016-04-19 US US15/132,445 patent/US10039596B2/en not_active Expired - Fee Related
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2018
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CN109893244A (en) * | 2017-12-08 | 2019-06-18 | Igea有限公司 | The manipulation and control system of the extensible electrode for the handpiece that electroporation process uses |
CN109893244B (en) * | 2017-12-08 | 2024-04-19 | Igea有限公司 | Manipulation and control system for expandable electrodes of a handpiece for use in electroporation procedures |
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US10039596B2 (en) | 2018-08-07 |
US8958871B2 (en) | 2015-02-17 |
EP1968692A2 (en) | 2008-09-17 |
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CA2633666C (en) | 2016-09-20 |
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EP2656873A2 (en) | 2013-10-30 |
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EP2664355B1 (en) | 2016-12-21 |
CN105288847A (en) | 2016-02-03 |
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US20210369334A1 (en) | 2021-12-02 |
EP2656873A3 (en) | 2013-11-27 |
EP2656873B1 (en) | 2016-04-06 |
US20150164583A1 (en) | 2015-06-18 |
CN101426551A (en) | 2009-05-06 |
CN101426551B (en) | 2016-01-20 |
EP2656874A3 (en) | 2013-11-27 |
CN105288847B (en) | 2019-03-12 |
EP2656874B1 (en) | 2016-11-16 |
EP1968692A4 (en) | 2010-03-10 |
JP2009521993A (en) | 2009-06-11 |
US20100057150A1 (en) | 2010-03-04 |
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US20180353237A1 (en) | 2018-12-13 |
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US9364280B2 (en) | 2016-06-14 |
WO2007078997A2 (en) | 2007-07-12 |
US7873417B2 (en) | 2011-01-18 |
EP2664355A1 (en) | 2013-11-20 |
US20110202098A1 (en) | 2011-08-18 |
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