Implantable thermal treatment method and apparatus

• US 7,819,826 B2
• Filed: 01/23/2003
• Issued: 10/26/2010
• Est. Priority Date: 01/23/2002
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Nau, Will, O'Banion, John P., Bradford, David S., Lotz, Jeffrey C., Diederich, Chris J., Peacock, James C. III
• Primary Examiner(s): Casler; Brian
• Assistant Examiner(s): CWERN, JONATHAN
• Application Number:
  US10/351,450
• Publication Number:
  US 20030225331A1
• Time in Patent Office: 2,833 Days
• Field of Search: 601 2- 3, 607 50- 51, 600/439
• US Class Current: 601/3
• CPC Class Codes: A61B 18/04 by heating by applying electromagnetic radiation A61B18/18; hyperthermia using electric or magnetic fields, radiation or ultrasound A61N
• CPC Class Codes: A61B 2017/00092 using thermocouples
• CPC Class Codes: A61B 2017/00101 using an array of thermosensors
• CPC Class Codes: A61B 2017/00261 Discectomy
• CPC Class Codes: A61B 2018/00339 Spine, e.g. intervertebral disc
• CPC Class Codes: A61B 2090/374 NMR or MRI
• CPC Class Codes: A61B 8/56 Details of data transmission or power supply
• CPC Class Codes: A61N 2007/0078 with multiple treatment transducers
• 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
• CPC Class Codes: A61N 7/02 Localised ultrasound hyperthermia hyperthermia in general A61F7/00
• CPC Class Codes: A61N 7/022 intracavitary

Abstract

A long-term implantable ultrasound therapy system and method is provided that provides directional, focused ultrasound to localized regions of tissue within body joints, such as spinal joints. An ultrasound emitter or transducer is delivered to a location within the body associated with the joint and heats the target region of tissue associated with the joint from the location. Such locations for ultrasound transducer placement may include for example in or around the intervertebral discs, or the bony structures such as vertebral bodies or posterior vertebral elements such as facet joints. Various modes of operation provide for selective, controlled heating at different temperature ranges to provide different intended results in the target tissue, which ranges are significantly effected by pre-stressed tissues such as in-vivo intervertebral discs. In particular, treatments above 70 degrees C., and in particular 75 degrees C., are used for structural remodeling, whereas lower temperatures achieves other responses without appreciable remodeling.

Claims

1. An ultrasound energy delivery system for providing long term treatment to a region of tissue associated with a skeletal joint, comprising:

a long-term implantable ultrasound treatment assembly with an ultrasound transducer; and

a skeletal joint delivery assembly that is adapted to deliver the ultrasound treatment assembly into the body with the ultrasound transducer positioned at a location within the body associated with the skeletal joint;

wherein the ultrasound treatment assembly is adapted to provide long-term delivery of a therapeutic level of ultrasound energy from the location and into the region of tissue;

said therapeutic level of ultrasound energy being sufficient to denervate a nociceptive nerve at said region of tissue;

wherein the skeletal joint delivery assembly comprises a needle;

wherein the ultrasound treatment assembly is adapted to be delivered through the needle to the location; and

wherein the needle is configured to be delivered through bone to the location.

2. The system of claim 1, wherein the skeletal joint delivery assembly comprises a cannula with a sharpened tip that is adapted to puncture a tissue barrier associated with the joint.

3. The system of claim 1, wherein:

the skeletal joint delivery assembly comprises a guidewire; and

the ultrasound treatment assembly is adapted to be delivered over the guidewire to the location.

4. The system of claim 1, wherein:

the skeletal joint delivery assembly comprises a cannula; and

the ultrasound treatment assembly is adapted to be delivered through the cannula to the location.

5. The system of claim 1, wherein the ultrasound treatment assembly is adapted to be steerable to the location.

6. The system of claim 5, wherein the ultrasound treatment assembly is located on a deflectable member.

7. The system of claim 1, wherein the ultrasound treatment assembly is located on a pre-shaped support member.

8. The system of claim 1, wherein the ultrasound transducer is constructed to provide directional thermal therapy to the region of tissue.

9. The system of claim 8, wherein the ultrasound transducer is constructed to deliver a converging field of energy to the region of tissue.

10. The system of claim 8, wherein the ultrasound transducer is constructed to deliver a diverging field of ultrasound energy to the region of tissue.

11. The system of claim 8, wherein the ultrasound transducer is constructed to deliver a substantially collimated field of ultrasound energy to the region of tissue.

12. The system of claim 1, wherein the ultrasound treatment assembly comprises a coupling member positioned so as to couple ultrasound energy from the ultrasound transducer to the region of tissue.

13. The system of claim 12, wherein:

the coupling member comprises a radially extendable member that is adapted to radially extend from a first contracted position relative to the ultrasound transducer to a second extended position relative to the ultrasound transducer that is further away from the ultrasound transducer than the first position; and

the ultrasound transducer is adapted to delivery the ultrasound energy to the region of tissue via the coupling member with the radially extendable member in the second extended position.

14. The system of claim 13, wherein:

the extendable member comprises an inflatable balloon that is adapted to be coupled to a source of inflation medium and to inflate with a pressurized volume of fluid from the source; and

the ultrasound transducer is adapted to deliver the ultrasound energy to the tissue via the fluid and inflatable balloon.

15. The system of claim 1, further comprising:

a temperature control system that is adapted to control the temperature of at least one of the ultrasound transducer or a tissue interface between a region of tissue and the ultrasound treatment assembly during ultrasound energy delivery to the region of tissue.

16. The system of claim 15, wherein the ultrasound treatment assembly is adapted to actively cool the ultrasound transducer or tissue interface.

17. The system of claim 1, further comprising:

a cooling system with a controller;

wherein the ultrasound treatment device is adapted to couple to the cooling system; and

wherein the cooling system via the controller is adapted to cool at least one of the ultrasound transducer and a region of tissue being affected by the ultrasound delivery.

18. The system of claim 17, wherein the cooling system is adapted to cool the ultrasound transducer with a fluid having a temperature less than room temperature.

19. The system of claim 17, wherein the fluid temperature is about zero degrees C.

20. The system of claim 17, wherein the fluid temperature is equal to or greater than about room temperature.

21. The system of claim 17, wherein the cooling system comprises:

a source of fluid medium; and

wherein the cooling system is adapted to circulate fluid from the source through the ultrasound treatment device so as to cool the ultrasound transducer.

22. The system of claim 1, further comprising:

an ultrasound control system with a temperature monitoring system, a controller, and an ultrasound drive system;

wherein the ultrasound treatment assembly is adapted to couple to the ultrasound control system; and

wherein the ultrasound control system is adapted to control the ultrasound energy being emitted by the ultrasound transducer as a function of at least one monitored transient parameter.

23. The system of claim 22, wherein the at least one parameter comprises a parameter related to the operation of the ultrasound transducer.

24. The system of claim 23, wherein the at least one parameter comprises impedance, voltage, current, power, temperature, reflected power, or rates of change thereof.

25. The system of claim 22, wherein the at least one parameter comprises a parameter related to the effects of ultrasound delivery from the ultrasound transducer in tissue.

26. The system of claim 25, wherein the ultrasound control system is adapted to control operation of the ultrasound delivery assembly based upon a temperature monitored at a coupling tissue surface between the tissue and the ultrasound delivery assembly.

27. The system of claim 25, wherein the at least one parameter comprises thermal dose, tissue temperature, depth of thermal penetration, pulse duration, frequency between pulses, or rates of change thereof.

28. The system of claim 22, wherein the at least one parameter is empirically based.

29. The system of claim 22, wherein the at least one parameter comprises a value that is monitored during ultrasound therapy.

30. The system of claim 22, wherein the at least one parameter comprises a value that is calculated based upon another measured parameter.

31. The system of claim 22, wherein the controller is adapted to control the operation of the ultrasound transducer such that the temperature in at least a portion of the tissue within at least a 4 mm depth from the ultrasound transducer is elevated to at least about 70 degrees C. in response to ultrasound energy being delivered thereto from the ultrasound transducer.

32. The system of claim 31, wherein the controller is adapted to control the operation of the ultrasound transducer such that the temperature of the tissue within the 4 mm depth is elevated to at least about 75 degrees C. in response to the ultrasound energy delivery.

33. The system of claim 22, wherein the controller is adapted to control the operation of the ultrasound transducer such that the temperature in tissue within up to at least about a 7 mm depth from the ultrasound transducer is elevated to at least about 70 degrees C.

34. The system of claim 22, wherein the controller is adapted to control the operation of the ultrasound transducer such that the temperature in tissue within up to at least a 10 mm depth from the ultrasound transducer is elevated to greater than about 45 degrees C.

35. The system of claim 22, wherein the controller is adapted to control the operation of the ultrasound transducer such that the temperature within the tissue at up to at least a 4 mm depth from the ultrasound transducer is elevated to an elevated temperature of no more than about 75 degrees C. or less.

36. The system of claim 35, wherein the controller is adapted to control the operation of the ultrasound transducer such that the temperature of the tissue within the 4 mm depth is elevated to an elevated temperature of no more than about 70 degrees C. or less.

37. The system of claim 22, wherein the controller is adapted to control the operation of the ultrasound transducer such that the temperature in tissue within up to at least a 7 mm depth from the ultrasound transducer is elevated to at least 70 degrees C.

38. The system of claim 22, wherein the controller is adapted to control the operation of the ultrasound transducer such that the temperature in tissue within up to at least a 10 mm depth from the ultrasound transducer is elevated to greater than 45 degrees C.

39. The system of claim 22, wherein the at least one monitored parameter relates to at least one of bone growth, pain, or a physiologic function affected by nervous stimulation at the location.

40. The system of claim 22, wherein the controller comprises a long-term implant that is adapted to be implanted within the body of the patient.

41. The system of claim 40, wherein the controller comprises a power source.

42. The system of claim 41, wherein the power source is rechargeable.

43. The system of claim 42, wherein the power source is adapted to be recharged by exposure to a magnetic field across a skin barrier of the patient.

44. The system of claim 40, wherein the controller comprises a microprocessor.

45. The system of claim 44, wherein the controller comprises a monitoring assembly.

46. The system of claim 44, wherein the controller comprises a data storage system.

47. The system of claim 44, wherein the controller is adapted to communicate across the patient'"'"'s skin barrier via wireless communications system so as to provide telemetry with respect to the ultrasound therapy.

48. The system of claim 47, further comprising an external assembly that is adapted to communicate with the controller via wireless signals so as to receive telemetry with respect to the ultrasound therapy.

49. The system of claim 22, further comprising:

a coupling assembly that is adapted to couple to the ultrasound treatment assembly and at least one externally located coupler across the patient'"'"'s skin barrier; and

wherein the controller is adapted to be located externally of the patient'"'"'s body and to couple to the external coupler so as to control the ultrasound treatment assembly for providing ultrasound therapy.

50. The system of claim 1, wherein the ultrasound treatment assembly is adapted to heat tissue up to a distance of at least about 4 mm from the ultrasound transducer to a temperature of at least about 70 degrees C.

51. The system of claim 50, wherein the ultrasound treatment assembly is adapted to heat the tissue within the 4 mm depth to a temperature of at least about 75 degrees C.

52. The system of claim 51, wherein the ultrasound treatment assembly is adapted to heat the tissue at least about 4 mm away from the transducer to the temperature of at least about 75 degrees C. in less than about 5 minutes of ultrasound energy delivery into the tissue.

53. The system of claim 1, wherein the ultrasound treatment assembly is adapted to heat tissue up to a distance of at least about 7 mm from the ultrasound transducer to a temperature of at least about 70 degrees C.

54. The system of claim 1, wherein the ultrasound treatment assembly is adapted to heat tissue up to a distance of at least about 10 mm from the ultrasound transducer to a temperature of at least about 45 degrees C.

55. The system of claim 1, wherein the ultrasound treatment assembly is adapted to heat tissue up to a distance of at least 4 mm from the ultrasound transducer to a temperature of no more than about 75 degrees C. or less.

56. The system of claim 1, wherein the ultrasound treatment assembly is adapted to be positioned within at least a portion of a vertebral body or posterior vertebral element and to provide thermal therapy at least in part to the vertebral body.

57. The system of claim 1, wherein the ultrasound treatment assembly is adapted to be positioned at a location adjacent to a vertebral body or posterior vertebral element and to delivery ultrasound energy to at least a portion of the vertebral body.

58. The system of claim 1, wherein the ultrasound treatment assembly and the skeletal joint delivery assembly are integrated.

59. The system of claim 58, wherein:

the skeletal joint delivery assembly comprises a substantially rigid probe device with a proximal end portion and a distal end portion; and

the ultrasound treatment assembly is located along the distal end portion.

60. The system of claim 1, wherein the ultrasound treatment assembly and skeletal joint delivery assembly are separate devices that cooperate together.

61. The system of claim 1, wherein the skeletal joint delivery assembly comprises a spinal joint delivery assembly.

62. The system of claim 1, wherein the ultrasound treatment assembly and spinal joint delivery assembly together comprise an external directional ultrasound thermal therapy system.

63. The system of claim 1, wherein the ultrasound treatment assembly and spinal joint delivery assembly together comprise an internal directional ultrasound thermal therapy system.

64. The system of claim 1, wherein the ultrasound treatment assembly comprises a single curvilinear ultrasound transducer.

65. The system of claim 1, wherein the ultrasound treatment assembly comprises multiple curvilinear ultrasound transducers.

66. The system of claim 1, wherein the ultrasound transducer is adapted to emit directed, therapeutic ultrasound energy within a treatment zone of less than or equal to about one hundred eighty degrees relative to the ultrasound transducer.

67. The system of claim 66, wherein the treatment zone is less than or equal to about ninety degrees.

68. The system of claim 1, wherein the ultrasound transducer is comprises a curved shape with a radius of curvature that is around a reference axis that is transverse to the longitudinal axis of a support member upon which the ultrasound transducer is mounted.

69. The system of claim 1, wherein the ultrasound transducer is comprises a curved shape with a radius of curvature that is around a reference axis that is aligned with the longitudinal axis of a support member upon which the ultrasound transducer is mounted.

70. The system of claim 69, wherein the set of operating parameters comprises:

ultrasound transmission at about 0.5 W/cm2 aggregate daily treatment of about 15 minutes per day for at least one day over a long-term treatment regime.

71. The system of claim 1, further comprising:

a long-term implantable ultrasound controller that is adapted to control ultrasound energy delivery from the ultrasound treatment assembly.

72. The system of claim 71, wherein the controller is adapted to operate the ultrasound treatment assembly according to a set of operating parameters adapted to stimulate bone growth.

73. The system of claim 72, wherein the set of operating parameters comprises:

a transmission power level between about 0.1 to about 1 W/cm2, and about 1.5 MHz, and at about 1 kHz repetition, and with burst intervals between about 100 to about 200 micro-seconds.

74. The system of claim 73, wherein the set of parameters further comprises:

total aggregate time of ultrasound delivery is between about 10 to 30 minutes per day for at least one day of long-term ultrasound treatment.

75. The system of claim 74, wherein the set of operating parameters comprises:

transmission power between about 0.5 to about 2 W/cm2, operating frequency between about 5 to about 12 MHz, and continuous wave delivery.

76. The system of claim 75, wherein the set of parameters further comprises:

aggregate time of ultrasound delivery between about 5 to about 60 minutes per day over at least one day of long-term ultrasound treatment.

77. The system of claim 74, wherein the set of operating parameters comprises:

pulsed ultrasound delivery over periods of less than or equal to about 70 microseconds, and operating frequency of about 5 MHz.

78. The system of claim 71, wherein the controller is adapted to operate the ultrasound treatment assembly according to a set of operating parameters adapted to enhance drug delivery therapy to the tissue at the location.

79. The system of claim 71, wherein the controller is adapted to operate the ultrasound transducer according to the following set of operating parameters:

transmission power between about 1 to about 30 W/cm2, transmission bursts lasting between 50 to 200 microseconds, repetition between bursts between about 1 Hz to about 5 kHz, and at ultrasound operating frequencies between about 0.5 to about 15 MHz.

80. The system of claim 71, wherein the controller is adapted to operate the ultrasound transducer at operating frequencies between about 12 to about 15 MHz.

81. The system of claim 71, wherein the controller is adapted to operate the ultrasound transducer so as to provide thermal therapy in addition to acoustic nervous stimulation.

82. The system of claim 71, wherein the controller is adapted to operate the ultrasound treatment assembly according to a set of operating parameters adapted to stimulate nervous impulses at the location.

83. The system of claim 71, wherein the controller is adapted to operate the ultrasound treatment assembly according to a set of operating parameters adapted to accomplish at least one of:

regenerate peripheral nerves, repair pseudarthrosis and bone fractures, stimulate bone growth, and stimulate osteogenesis with respect to repairing fractures.

84. The system of claim 83, wherein the set of operating parameters comprises:

transmission power of about 0.5 W/cm2, operating frequency of about 1.5 MHz, treatment interval durations of between about 5 to about 25 minutes per day for at least one day over a long-term treatment regimen.

85. The system of claim 84, wherein the set of operating parameters further comprises total period of therapy of about four weeks.

86. A skeletal joint therapy device, comprising:

a long-term implantable thermal treatment assembly with an energy emitter;

wherein the thermal treatment assembly is adapted to be implanted at a location within a body of a patient; and

a skeletal joint delivery assembly comprising a needle that is adapted to deliver the thermal treatment assembly into the body with the energy emitter positioned at a location within the body associated with the skeletal joint;

wherein the needle is configured to be delivered through bone to the location;

wherein the thermal treatment assembly is adapted to be delivered through the needle to the location;

wherein the energy emitter is adapted to follow a long-term protocol for energy delivery into a region of tissue associated with a skeletal joint; and

wherein the thermal treatment assembly is adapted to heat tissue up to a distance of at least 4 mm from the energy emitter to a temperature of at least 75 degrees C., and is adapted to heat tissue up to a distance of at least about 7 mm from the energy emitter to a temperature of at least about 55 degrees C., and is adapted to heat tissue up to a distance of at least about 10 mm from the energy emitter to a temperature of at least about 45 degrees C.

87. The device of claim 86, wherein the thermal treatment assembly comprises an ultrasound transducer.

88. The device of claim 86, wherein the device further comprises a long-term implantable controller that is adapted to be coupled to and control operation of the thermal treatment assembly according to the long-term protocol and according to a set of operating parameters.

89. The device of claim 88, wherein the controller comprises a long-term internal implant.

90. The device of claim 88, wherein the controller comprises a long-term external unit that is adapted to be coupled to the thermal treatment assembly across a skin barrier.

91. The device of claim 88, wherein the controller comprises a power source with a rechargeable battery.

92. The device of claim 88, wherein the controller is adapted to provide telemetry with respect to the thermal therapy to an external assembly.

93. A long-term implantable ultrasound thermal therapy system, comprising:

a long-term implantable ultrasound heating assembly with an ultrasound transducer and that is adapted to be implanted within a body of a mammal with the ultrasound transducer positioned at a location such that the ultrasound transducer is adapted to deliver a ultrasound energy into a targeted region of tissue in the body from the location;

a skeletal joint delivery assembly comprising a needle that is adapted to deliver the ultrasound heating assembly into the body with the ultrasound transducer positioned at a location within the body associated with the skeletal joint;

wherein the needle is configured to be delivered through bone to the location;

wherein the ultrasound heating assembly is adapted to be delivered through the needle to the location; and

a long-term ultrasound therapy control system that is adapted to be coupled to the ultrasound heating assembly;

wherein the long-term implantable ultrasound therapy control system is adapted to be coupled to and control operation of the ultrasound heating assembly while it is implanted at the location according to a long-term ultrasound thermal therapy protocol

said ultrasound thermal therapy protocol being sufficient to denervate a nociceptive nerve at said region of tissue.

94. The system of claim 93, wherein the therapy control system is adapted to operate the ultrasound transducer such that a substantial portion of the region of tissue being heated by the ultrasound heating assembly does not exceed a maximum temperature of at least about 70 degrees C.

95. The system of claim 93, wherein the therapy control system is adapted to control operation of the ultrasound heating assembly such that a substantial portion of the region of tissue being heated by the ultrasound heating assembly does not exceed a maximum temperature of at least about 75 degrees C.

96. The system of claim 93, wherein the control system comprises a long-term internally implantable controller that is adapted to be coupled with and control the ultrasound heating assembly from within the body.

97. The system of claim 93, wherein the control system comprises a long-term external controller that is adapted to be coupled with and control the ultrasound heating assembly from externally of the body and across a skin barrier.

98. A long-term directional ultrasound spinal thermal therapy system, comprising:

a long-term implantable ultrasound delivery assembly with a directional ultrasound transducer that is adapted to be positioned at a location associated with a spinal joint and to deliver a directed, therapeutic amount of ultrasound energy from the location and to a region of tissue associated with the spinal joint; and

a skeletal joint delivery assembly comprising a needle that is adapted to deliver the ultrasound delivery assembly into the body with the ultrasound transducer positioned at the location;

wherein the ultrasound treatment assembly is adapted to be delivered through the needle to the location;

said therapeutic amount of ultrasound energy being sufficient to denervate a nociceptive nerve at said region of tissue;

wherein the needle is configured to be delivered through bone to the location.

99. A long-term implantable skeletal joint ultrasound delivery system, comprising:

a long-term implantable ultrasound treatment assembly with an ultrasound transducer and a coupling member; and

a skeletal joint delivery assembly comprising a needle;

wherein the ultrasound treatment assembly is adapted to be delivered through the needle to be implanted within a body of a mammal with the ultrasound transducer positioned at a location within the body associated with a skeletal joint; and

wherein the ultrasound transducer is adapted to deliver a therapeutic amount of ultrasound energy to a region of tissue associated with the skeletal joint via the coupling member and according to a long-term ultrasound treatment protocol;

said therapeutic level of ultrasound energy being sufficient to denervate a nociceptive nerve at said region of tissue;

wherein the needle is configured to be delivered through bone to the location.

100. A long-term implantable ultrasound thermal therapy system, comprising:

a long-term implantable ultrasound heating assembly with an ultrasound transducer;

a delivery assembly comprising a needle that is adapted to deliver the ultrasound heating assembly into the body with the ultrasound transducer positioned at a location within the body;

wherein the ultrasound heating assembly is adapted to be delivered through the needle to the location;

wherein the needle is configured to be delivered through bone to the location; and

a control system that is adapted to be coupled to the ultrasound heating assembly and to control operation of the ultrasound heating assembly according to a long-term ultrasound thermal therapy protocol and such that a region of tissue being heated by the ultrasound heating assembly exceeds a temperature of at least about 70 degrees C.

101. An ultrasound thermal therapy system, comprising:

a delivery assembly comprising a needle that is adapted to deliver a long-term implantable ultrasound heating assembly to a location within the body of a patient;

wherein the ultrasound heating assembly is adapted to be delivered through the needle to the location, to be implanted at the location and to couple with an ultrasound controller from the location, and also with a curvilinear ultrasound transducer having a concave surface with a radius of curvature around a reference axis such that ultrasound energy transmitted therefrom converges into a region of tissue at a target location;

said transmitted ultrasound energy being sufficient to denervate a nociceptive nerve at said region of tissue;

wherein the needle is configured to be delivered through bone to the location.

102. The system of claim 101, wherein the reference axis is transverse to the longitudinal axis of the distal end portion.

103. A method for providing long-term, invasive treatment to a region of tissue associated with the spine in a body of a patient, comprising:

positioning a delivery assembly at a location associated with the region of tissue;

wherein the delivery assembly comprises a needle;

delivering a long-term ultrasound transducer implant through the needle to said location; and

implanting the long-term ultrasound transducer implant at the location; and

delivering a therapeutic level of ultrasound energy from the transducer to the tissue to denervate a nociceptive nerve at said region of tissue.

104. A method as recited in claim 103, wherein positioning a delivery assembly at a location associated with the region of tissue comprises positioning the delivery assembly through at least a portion of a vertebral body to the location, said vertebral body comprising a bony mass located above a lower vertebral endplate and below an upper vertebral endplate.

105. A method for providing long-term medical treatment for a medical condition associated with a spinal joint in a body of a patient, comprising:

positioning a delivery assembly at a location within a vertebral body associated with the joint;

wherein the delivery assembly comprises a needle;

delivering an ultrasound transducer through the needle to said location;

implanting the ultrasound transducer at the location for a long-term; and

emitting ultrasound energy from the transducer at the location so as to provide a therapeutic effect to at least a portion of the joint and according to a long-term ultrasound therapy protocol.

106. A method as recited in claim 105, further comprising:

denervating a nociceptive nerve within said vertebral body according to said long-term ultrasound therapy protocol.