System for treatment and imaging using ultrasonic energy and microbubbles and related method thereof

• US 8,622,911 B2
• Filed: 10/24/2008
• Issued: 01/07/2014
• Est. Priority Date: 10/26/2007
• Status: Active Grant

• Current Assignee: University of Virginia Patent Foundation (University of Virginia)
• Original Assignee: University of Virginia Patent Foundation (University of Virginia)
• Inventors: Hossack, John A., Wamhoff, Brian R., Klibanov, Alexander L.
• Primary Examiner(s): ROZANSKI, MICHAEL T
• Application Number:
  US12/739,128
• Publication Number:
  US 20100331686A1
• Time in Patent Office: 1,901 Days
• Field of Search: 600/437, 600/439, 604/22, 604/500, 424/9.5, 424/9.52
• US Class Current: 600/439
• CPC Class Codes: A61B 17/2202 the ultrasound transducer being inside patient's body at the distal end of the catheter
• CPC Class Codes: A61B 2017/22088 ultrasound absorbing, drug activated by ultrasound
• CPC Class Codes: A61B 2017/22089 Gas-bubbles
• CPC Class Codes: A61B 2090/3782 transmitter or receiver in catheter or minimal invasive instrument
• CPC Class Codes: A61B 8/12 in body cavities or body tracts, e.g. by using catheters catheters per se A61M25/00
• CPC Class Codes: A61B 8/445 Details of catheter construction
• CPC Class Codes: A61B 8/481 involving the use of contrast agent, e.g. microbubbles introduced into the bloodstream analysis of echo signal exploiting properties of a contrast enhancer in devices for short-range imaging with acoustic waves G01S7/52039
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61M 37/0092 using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
• CPC Class Codes: A61N 7/00 Ultrasound therapy lithotripsy A61B17/22, A61B17/225; massage using supersonic vibration A61H23/00 ; using ultrasound for introducing media into the body A61M37/0092

Abstract

A method and related system for providing therapy to a treatment site, such as stenosis or other vasculature disease, at one or more locations of a subject, such as the vasculature. The method includes: advancing an ultrasound catheter to or in proximity to the subject'"'"'s treatment site; infusing microbubbles into or proximal to the treatment site; and delivering ultrasonic energy from the ultrasound catheter. The ultrasonic energy may be adapted for: imaging the treatment site, translating the microbubbles into or in the vicinity of the treatment site and/or rupturing the microbubbles.

Claims

1. A method of providing therapy to a treatment site at one or more locations of a subject, said method comprising:

advancing an ultrasound catheter to or in proximity to the subject'"'"'s treatment site, said catheter having a proximal region and distal region;

infusing microbubbles from said distal region of said ultrasound catheter into or proximal to the treatment site;

delivering therapeutic ultrasonic energy from within said distal region of said ultrasound catheter to said microbubbles to focally deliver a therapeutic material to the treatment site; and

delivering imaging ultrasonic energy from within said distal region of said ultrasound catheter to the treatment site to provide real time imaging for guiding precise delivery of said therapeutic material to the treatment site.

2. The method of claim 1, further comprising:

controlling activation of said therapeutic ultrasonic energy.

3. The method of claim 1 wherein said one or more locations comprise at least a portion of an organ.

4. The method of claim 3, wherein said organ comprises hollow organs, solid organs, parenchymal tissue, stromal tissue, and/or ducts.

5. The method of claim 1, where the one or more locations of the subject comprises at least a portion of a tubular structure.

6. The method of claim 5, wherein said tubular structure comprises a blood vessel.

7. The method of claim 6, wherein the treatment site is a vasculature treatment site comprising at least one of the following:

stenosis region or any region exhibiting vascular disease.

8. The method of claim 1, wherein said delivering imaging ultrasonic energy comprises delivering high frequency ultrasound transmission and reception.

9. The method of claim 8, wherein said high frequency comprises a range of about 2 MHz to about 50 MHz.

10. The method of claim 8, wherein said high frequency comprises a range of about 5 MHz to about 30 MHz.

11. The method of claim 8, wherein said high frequency comprises a range of about 12 MHz to about 50 MHz.

12. The method of claim 8, wherein said high frequency comprises a range of about 12 MHz to about 30 MHz.

13. The method of claim 8, wherein said high frequency comprises about 20 MHz.

14. The method of claim 8, wherein said high frequency comprises about 25 MHz.

15. The method of claim 8, wherein said high frequency comprises about 30 MHz.

16. The method of claim 1, wherein said delivering therapeutic ultrasonic energy from said distal region of said ultrasound catheter to said microbubbles to focally deliver a therapeutic material to the treatment site comprises delivering low frequency ultrasound energy to said microbubbles and rupturing at least a portion of said microbubbles.

17. The method of claim 16, wherein said delivering therapeutic ultrasonic energy from said distal region of said ultrasound catheter to said microbubbles to focally deliver a therapeutic material to the treatment site comprises delivering high power ultrasound energy to said microbubbles and rupturing at least a portion of said microbubbles.

18. The method of claim 17, wherein said high power delivering of ultrasonic energy generates acoustic pressure of at least about 20 kPa.

19. The method of claim 17, wherein said high power delivering of ultrasonic energy generates acoustic pressure of at least about 50 kPa.

20. The method of claim 17, wherein said high power delivering of ultrasonic energy generates acoustic pressure of at least about 200 kPa.

21. The method of claim 16, wherein said low frequency comprises a range of about 0.1 MHz to about 10 MHz.

22. The method of claim 16, wherein said low frequency comprises a range of about 0.2 MHz to about 2 MHz.

23. The method of claim 1, wherein said delivering of said therapeutic ultrasonic energy is further adapted for:

providing ultrasonic radiation forces for translating said microbubbles into or in the vicinity of the treatment site.

24. The method of claim 23, wherein said delivering of said therapeutic ultrasonic energy for said translating comprises low frequency ultrasound transmission and reception.

26. The method of claim 24, wherein said low frequency comprises a range of about 0.2 MHz to about 2 MHz.

27. The method of claim 1, further comprising:

delivering said microbubbles from an outlet port located on said catheter for translating said microbubbles into or in the vicinity of the treatment site.

28. The method of claim 1, further comprising:

delivering said microbubbles from a port located on a second catheter or a lumen for translating said microbubbles into or in the vicinity of the treatment site.

29. The method of claim 1, further comprising:

delivering said microbubbles from a microfluidic flow-focusing device located on said catheter for translating said microbubbles into or in the vicinity of the treatment site.

30. The method of claim 1, further comprising:

delivering said microbubbles from a microfluidic flow-focusing device located on a second catheter or a lumen for translating said microbubbles into or in the vicinity of the treatment site.

31. The method of claim 1, wherein said microbubbles comprise a contrast agent.

32. The method of claim 1, wherein said microbubbles comprise a drug composition or agent composition, or drug and agent composition.

33. The method of claim 32, wherein said drug composition or agent composition, or said drug and agent composition, being disposed:

a) in shells of said microbubbles, b) in cores of said microbubbles, c) outside said shells of said microbubbles, or d) any combination of two or more of elements a, b and c.

34. The method of claim 33, wherein said shells comprise lipids, phospholipids, oils, fats, lipopolymers, polymers, proteins, surfactants or combinations thereof.

35. The method of claim 33, wherein a thickness of said shells may vary from monomolecular 1 nm, to multimolecular and multilamellar, up to and including about 1,000 nm.

36. The method of claim 33, wherein a thickness of said shells may vary from monomolecular 0.1 nm, to multimolecular and multilamellar, up to and including about 10,000 nm.

37. The method of claim 32, wherein said drug composition comprises at least one of the following:

antiproliferative, immunosuppressive, or antiinflammatory drug.

38. The method of claim 32, wherein said drug composition may be selected from the group consisting of:

actinomycin-D, batimistat, c-myc antisense, dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus and everolimus, unfractionated heparin, low-molecular weight heparin, enoxaprin, bivalirudin, tyrosine kinase inhibitors, Gleevec, wortmannin, PDGF inhibitors, AG1295, rho kinase inhibitors, Y27632, calcium channel blockers, TRAM-34, IKCa channel blockers, amlodipine, nifedipine, and ACE inhibitors, S1P1 and/or S1P3 receptor antagonists, sphingosine kinase 1 inhibitors, synthetic polysaccharides, ticlopinin, dipyridamole, clopidogrel, fondaparinux, streptokinase, urokinase, r-urokinase, r-prourokinase, rt-PA, APSAC, TNK-rt-PA, reteplase, alteplase, monteplase, lanoplase, pamiteplase, staphylokinase, abciximab, tirofiban, orbofiban, xemilofiban, sibrafiban, roxifiban, an anti-restenosis agent, an anti-thrombogenic agent, an antibiotic, an anti-platelet agent, an anti-clotting agent, an anti-inflammatory agent, an anti-neoplastic agent, a chelating agent, penicillamine, triethylene tetramine dihydrochloride, EDTA, DMSA (succimer), deferoxamine mesylate, a radiocontrast agent, a radio-isotope, a prodrug, antibody fragments, antibodies, gene therapy agents, viral vectors and plasmid DNA vectors.

39. The method of claim 32, wherein said drug composition comprises a coated microbubble that possesses a selected molecular attachment ligand.

40. The method of claim 1, wherein at least a plurality of said microbubbles comprise an internal core filled with a gas, gas-vapor mixture or gas precursor phase, or any combination thereof.

41. The method of claim 40, wherein said gas has a molecular mass from about 10 to about 360.

42. The method of claim 40, wherein said gas has a molecular mass from about 1 to about 3,600.

43. The method of claim 1, wherein said microbubbles comprise a decafluorobutane core.

44. The method of claim 1, wherein at least a plurality of said microbubbles comprise shells, and said shells comprise a gas or mixture of two or more gases or gas precursors.

45. The method of claim 44, wherein said therapeutic ultrasonic energy is provided to at least one of the following:

trigger transference into a gas phase, change volume of a gas core, or destroy the microbubbles.

46. The method of claim 1, wherein said delivering therapeutic ultrasonic energy and said delivering imaging ultrasonic energy comprise:

activating an ultrasound transducer source disposed within said distal region of said catheter.

47. The method of claim 46, wherein said ultrasound transducer source comprises:

a therapeutic transducer for delivering said therapeutic ultrasonic energy; and

an imaging transducer for said imaging of the treatment site.

48. The method of claim 47, wherein said therapeutic transducer and said imaging transducer are essentially longitudinally aligned with one another.

49. The method of claim 47, wherein said therapeutic transducer and said imaging transducer are essentially vertically overlaying one another.

50. The method of claim 46, wherein said ultrasound transducer source comprises:

a) a therapeutic transducer for translating said microbubbles;

b) an imaging transducer for translating said microbubbles;

c) a translating transducer for translating said microbubbles;

d) any combination of elements a, b or c;

e) said ultrasound transducer source is configured to perform any combination of a, b, or c;

or f) said ultrasound transducer source is configured to perform any two of a, b, or c, and any one of a, b, or c.

51. The method of claim 1, further comprising:

gating said imaging ultrasonic energy and said therapeutic ultrasonic energy, whereby they deliver energy temporally exclusively.

52. The method of claim 1, further comprising:

gating said imaging ultrasonic energy and said therapeutic ultrasonic energy, whereby they deliver energy simultaneously or at least partially simultaneously.

53. The method of claim 1, further comprising:

occluding or partially occluding said infusion of microbubbles upstream or downstream from the treatment site.

54. The method of claim 1, further comprising:

occluding or partially occluding said infusion of microbubbles upstream from the treatment site; and

occluding or partially occluding said infusion of microbubbles downstream from the treatment site.

55. The method of claim 1, wherein the treatment site is in a coronary artery.

25. The method of 24, wherein said low frequency comprises a range of about 0.1 MHz to about 10 MHz.

56. An ultrasound catheter system for providing therapy to a treatment site at one or more locations of a subject, the system comprising:

a tubular member having a proximal region and distal region and a lumen, said distal region of said tubular member adapted to advance to or in proximity to the subject'"'"'s treatment site;

a microbubble reservoir in or in hydraulic communication with said lumen of said tubular member, said microbubble reservoir is adapted to release microbubbles that are intended to be located into or in proximity to the treatment site;

a therapeutic ultrasound transducer at said distal region of said tubular member, said therapeutic ultrasound transducer configured to deliver therapeutic ultrasonic energy from within said distal region of said ultrasound catheter to said microbubbles to focally deliver a therapeutic material to the treatment site; and

an imaging ultrasound transducer at said distal region of said tubular member, said imaging ultrasound transducer configured to deliver imaging ultrasonic energy from within said tubular member to the treatment site to provide real time imaging for guiding precise delivery of said therapeutic material to the treatment site, wherein said imaging ultrasound transducer is mounted relative to said therapeutic ultrasound transducer so that the focal delivery of said therapeutic material is aligned with said real time imaging.

57. The system of claim 56 wherein said one or more locations comprise at least a portion of an organ.

58. The system of claim 57, wherein said organ comprises hollow organs, solid organs, parenchymal tissue, stromal tissue, and/or ducts.

59. The system of claim 56, where the one or more locations of the subject comprises at least a portion of a tubular structure.

60. The system of claim 59, wherein said tubular structure comprises a blood vessel.

61. The system of claim 56, wherein the subject'"'"'s treatment site comprises a vascular treatment site, and the vasculature treatment site comprises at least one of the following:

stenosis region or any region exhibiting vascular disease.

62. The system of claim 56, wherein said imaging ultrasound transducer provides ultrasonic energy for said imaging, and said ultrasonic energy for said imaging comprises high frequency ultrasound transmission and reception.

63. The system of claim 62, wherein said high frequency comprises a range of about 2 MHz to about 50 MHz.

64. The system of claim 63, wherein said high frequency comprises a range of about 5 MHz to about 30 MHz.

65. The system of claim 62, wherein said high frequency comprises a range of about 12 MHz to about 50 MHz.

66. The system of claim 62, wherein said high frequency comprises a range of about 12 MHz to about 30 MHz.

67. The system of claim 62, wherein said high frequency comprises about 20 MHz.

68. The system of claim 62, wherein said high frequency comprises about 25 MHz.

69. The system of claim 62, wherein said high frequency comprises about 30 MHz.

70. The system of claim 56, wherein said therapeutic ultrasound transducer transmits and receives low frequency ultrasound energy.

71. The system of claim 70, wherein said therapeutic ultrasound transducer provides ultrasonic energy for effecting therapy, and said ultrasonic energy for said effecting therapy comprises high power.

72. The system of claim 71, wherein high power produces pressure of at least about 20 kPa.

73. The system of claim 71, wherein high power produces pressure of at least about 50 kPa.

74. The system of claim 71, wherein high power produces pressure of at least about 200 kPa.

75. The system of claim 70, wherein said low frequency comprises a range of about 0.1 MHz to about 10 MHz.

76. The system of claim 70, wherein said low frequency comprises a range of about 0.2 MHz to about 2 MHz.

77. The system of claim 56, wherein said therapeutic ultrasound transducer provides therapeutic ultrasonic energy, and said therapeutic ultrasonic energy is further adapted for:

providing ultrasonic radiation forces for translating said microbubbles into or in the vicinity of the treatment site.

78. The system of claim 77, wherein said ultrasonic energy for said translating comprises low frequency ultrasound transmission and reception.

79. The system of claim 78, wherein said low frequency comprises a range of about 0.1 MHz to about 10 MHz.

80. The system of claim 78, wherein said low frequency comprises a range of about 0.2 MHz to about 2 MHz.

81. The system of claim 56, further comprising:

an outlet port disposed on said tubular member in communication with said microbubble reservoir to allow microbubbles to exit from said reservoir, wherein said microbubbles being intended to be translated into or in the vicinity of the treatment site.

82. The system of claim 56, further comprising:

an outlet port disposed on a second tubular member or a lumen in communication with said microbubble reservoir to allow microbubbles to exit from said reservoir, wherein said microbubbles being intended to be translated into or in the vicinity of the treatment site.

83. The system of claim 56, further comprising:

a microfluidic flow-focusing device in communication with said tubular member to allow microbubbles to exit from said reservoir, wherein said microbubbles being intended to be translated into or in the vicinity of the treatment site.

84. The system of claim 56, further comprising:

a microfluidic flow-focusing device in communication with a second tubular member or a lumen to allow microbubbles to exit from said reservoir, wherein said microbubbles being intended to be translated into or in the vicinity of the treatment site.

85. The system of claim 56, wherein said microbubbles comprises a contrast agent.

86. The system of claim 56, wherein said microbubbles comprise a drug composition or agent composition, or a drug and agent composition.

87. The system of claim 86, wherein said drug or agent composition, or said drug and agent composition, being disposed:

a) in shells of said microbubbles, b) in cores or multiple cores of said microbubbles, c) outside said shells of said microbubbles, or d) any combination of two or more of elements a, b and c.

88. The system of claim 87, wherein said shells comprise lipids, phospholipids, oils, fats, lipopolymers, polymers, proteins, surfactants or combinations thereof.

89. The system of claim 87, wherein a thickness of said shells may vary from monomolecular 1 nm, to multimolecular and multilamellar, up to and including about 1,000 nm.

90. The system of claim 87, wherein a thickness of said shells-may vary from monomolecular 0.1 nm, to multimolecular and multilamellar, up to and including about 10,000 nm.

91. The system of claim 86, wherein said drug composition comprises at least one of the following:

antiproliferative, immunosuppressive, or antiinflammatory drug.

92. The system of claim 86, wherein said drug composition may be selected from the group consisting of:

actinomycin-D, batimistat, c-myc antisense, dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus and everolimus, unfractionated heparin, low-molecular weight heparin, enoxaprin, bivalirudin, tyrosine kinase inhibitors, Gleevec, wortmannin, PDGF inhibitors, AG1295, rho kinase inhibitors, Y27632, calcium channel blockers, TRAM-34, IKCa channel blockers, amlodipine, nifedipine, and ACE inhibitors, S1P1 and/or S1P3 receptor antagonists, sphingosine kinase 1 inhibitors, synthetic polysaccharides, ticlopinin, dipyridamole, clopidogrel, fondaparinux, streptokinase, urokinase, r-urokinase, r-prourokinase, rt-PA, APSAC, TNK-rt-PA, reteplase, alteplase, monteplase, lanoplase, pamiteplase, staphylokinase, abciximab, tirofiban, orbofiban, xemilofiban, sibrafiban, roxifiban, an anti-restenosis agent, an anti-thrombogenic agent, an antibiotic, an anti-platelet agent, an anti-clotting agent, an anti-inflammatory agent, an anti-neoplastic agent, a chelating agent, penicillamine, triethylene tetramine dihydrochloride, EDTA, DMSA (succimer), deferoxamine mesylate, a radiocontrast agent, a radio-isotope, a prodrug, antibody fragments, antibodies, gene therapy agents, viral vectors and plasmid DNA vectors.

93. The system of claim 86, wherein said drug composition comprising a coated microbubbles that posses a selected molecular attachment ligand.

94. The system of claim 56, wherein a plurality of said microbubbles comprise an internal core filled with a gas, gas-vapor mixture or gas precursor phase, or any combination thereof.

95. The system of claim 94, wherein said gas has a molecular mass from about 10 to about 360.

96. The system of claim 94, wherein said gas has a molecular mass from about 1 to about 3,600.

97. The system of claim 56, wherein said microbubbles comprise a decafluorobutane core.

98. The system of claim 56, wherein at least a plurality of said microbubbles comprise shells, said shells comprising a gas or mixture of two or more gases or gas precursors.

99. The system of claim 98, wherein said therapeutic ultrasound transducer is configured to deliver therapeutic ultrasound energy to said microbubbles to accomplish at least one of the following:

trigger transference into a gas phase, change volume of a gas core, or destroy the microbubbles.

100. The system of claim 56, wherein said an imaging plane of said imaging ultrasound transducer is coincident with at least one of a point, line or plane of focus of said therapeutic ultrasonic energy.

101. The system of claim 100, wherein said imaging ultrasound transducer comprises an array of imaging transducers and said therapeutic ultrasound transducer comprises an array of therapeutic transducers.

102. The system of claim 100, further comprising a translating transducer for translating said microbubbles.

103. The system of claim 56, wherein said therapeutic ultrasound transducer and said imaging ultrasound transducer are essentially longitudinally aligned with one another.

104. The system of claim 56, wherein said therapeutic ultrasound transducer and said imaging ultrasound transducer are essentially vertically overlaying one another.

105. The system of claim 56, wherein said control circuitry gates said imaging ultrasonic energy and said therapeutic ultrasonic energy such that said imaging ultrasonic energy said therapeutic ultrasonic energy are delivered temporarily exclusively.

106. The system of claim 56, wherein said control circuitry gates said imaging ultrasonic energy and said therapeutic ultrasonic such that said imaging ultrasonic energy and said therapeutic ultrasonic energy are delivered-simultaneously or at least partially simultaneously.

107. The system of claim 56, further comprising an occlusion device or partial-occlusion device configured to be disposed either upstream or downstream from said treatment site to occlude or partially occlude said microbubbles.

108. The system of claim 56, further comprising:

a first occlusion device or partial-occlusion device configured to be disposed upstream from said treatment site to occlude or partially occlude said microbubbles at said treatment site; and

a second occlusion device or partial-occlusion device disposed downstream from said treatment site to occlude or partially occlude said infused microbubbles at said treatment site.

109. The system of claim 56, wherein the treatment site is in a coronary artery.

110. An ultrasound catheter system for providing therapy to a treatment site at one or more locations of a subject, the system comprising:

a tubular member having a proximal region and distal region and a lumen, said distal region of said tubular member adapted to advance to or in proximity to the subject'"'"'s treatment site;

a microbubble reservoir in hydraulic communication with said tubular member, said microbubble reservoir is adapted to release microbubbles that are intended to be located into or in proximity to the treatment site;

a therapeutic ultrasound transducer at said distal region of said tubular member, said therapeutic ultrasound transducer configured to deliver therapeutic ultrasonic energy from said distal region of said ultrasound catheter to said microbubbles to focally deliver a therapeutic material to the treatment site;

an imaging ultrasound transducer at said distal region of said tubular member, said imaging ultrasound transducer configured to deliver imaging ultrasonic energy from said tubular member to the treatment site to provide real time imaging for guiding precise delivery of said therapeutic material to the treatment site, wherein said imaging ultrasound transducer is mounted relative to said therapeutic ultrasound transducer so that the focal delivery of said therapeutic material is aligned with said real time imaging; and

a port in a wall of said tubular member, said port configured to permit passage of said microbubbles from within said tubular member to a location outside of said tubular member.

111. The system of claim 110, wherein said port is located proximally of said therapeutic ultrasound transducer.

112. The system of claim 110, wherein said microbubble reservoir is located inside of said tubular member.

113. The system of claim 110, wherein said microbubble reservoir is in hydraulic communication with said lumen.