HIFU and the Sonablate® 500

The advanced High Intensity Focused Ultrasound (HIFU) technology resident in the Sonablate® 500 originated over 25 years ago at the Indiana University Medical Center, and has been developed at leading research centers across the United States, Europe and Japan. HIFU is a state-of-the-art technology utilizing the power of ultrasound to destroy deep seated tissue without affecting the surrounding healthy tissue. The HIFU energy is focused sharply from the transducer surface to the targeted tissue in the prostate. Temperature is elevated in the targeted tissue up to 90°C within one second causing cell death. The treatment consists of placing HIFU lesions (each requiring only a few seconds to create) side-by-side until the entire desired volume is treated.

Now the urologist can plan the treatment under ultrasound image guidance, target the prostate and monitor the therapy, all using a single transducer and probe. This design provides maximum precision, flexibility, safety and control for the clinician.

HIFU energy is focused by a patented transducer which integrates ultrasound imaging and therapy in a single device. Transducer Focal Point.

DESIGN PHILOSOPHY

The Sonablate® 500 system (SB-500) is a medical device that uses high intensity focused ultrasound (HIFU) to non-invasively ablate prostatic tissue under imaging ultrasound guidance to treat localized prostate cancer.

It consists of a main console, ultrasound transrectal probe (HIFU and imaging), a pump/chiller unit (SonachillTM), and a probe arm.

System Concept

The Sonablate® system concept for the treatment of prostate tissue has been validated through numerical computer simulations, laboratory measurements, in-vitro tissue experiments, in-vivo animal model measurements, and, most importantly, many clinical trials and clinical procedures around the world (under local and national regulatory approvals). The test procedures used during the manufacturing activities of the device have also been validated and shown to be appropriate to ensure its correct operation.

Sonablate® system design, test, and validation activities started in the late 1980's, and are documented through a long series of patents [1-4], scientific (both technical and clinical) publications in peer-reviewed journals [5-18], and test procedures. Since that time, the Sonablate® system has gone through 3 distinct design iterations: the Sonablate® 1 (initial prototype and original proof of concept, 1992), the Sonablate® 200 (clinical system for the treatment of BPO, 1995), and the Sonablate® 500 (current generation, with commercial production starting in 2001).

Throughout that time, the basic Sonablate® system concepts of:

1. utilizing HIFU to non-invasively ablate prostatic tissue
2. while using imaging ultrasound for treatment planning and monitoring and
3. using a transrectal probe with therapy and imaging capability that is
4. fixed to the patient table using a probe arm

has remained unchanged. Incremental design changes and changes in the manufacturing test procedures have been incorporated as advancements in technology became available, based on user feedback, based on clinical results, and because of Focus Surgery's commitment to the design, manufacture, and the delivery a safe and quality product.

The most critical component of the Sonablate® system, namely its HIFU delivery transducer with con-focal imaging transducer has remained unchanged since its introduction in the SB-1, and small changes made to the transducer housing assembly have not changed its therapeutic and imaging performance. The transducer excitation parameters (HIFU delivery ON/OFF time, and total acoustic power levels) have also remained unchanged after their verification in animal models since that time.

This fact allows the use of accumulated historical technical, clinical, and test/validation data obtained from the previous Sonablate® devices to validate the manufacture, operation, functionality and safety of the current SB500 system.

The system evolution of the Sonablate® and its transrectal probe.

Sonablate® system evolution. Note the constancy of the overall transrectal HIFU treatment approach with image guidance, technology-driven changes in the console, and therapeutically unchanged transrectal probe.

The transrectal approach to the treatment of prostate disease was chosen for the Sonablate® system since it provides an ideal arrangement for focused ultrasound because it permits a non-sterile procedure, is free from hemorrhage and significant trauma, and offers the potential of being performed again in the case of cancer or benign recurrence.

Validation Activities

From a systems perspective, the following fundamental operating parameters are important for the correct operation of the SB500 system:

• HIFU delivery operating frequency
• HIFU transducer geometry (aperture and focal length)
• HIFU delivery ON time
• HIFU delivery OFF time
• In-situ intensity.

Additional important system operations include:

• Delivery of HIFU at the planned treatment site
• Correct lesion spacing/transducer motion
• Correct pump/chiller cooling performance
• Correct ultrasound image formation and image geometry.

From a clinical perspective, the following parameters indicate a successful treatment utilizing HIFU for prostate cancer:

• PSA (Prostate Specific Antigen)
• negative biopsies

And for BPO treatment, the critical parameters are the:

• QMax (Maximum flow rate)
• IPSS (International Prostate Symptom Scores)
• QOL (Quality of Life scores)

The clinical parameters, their significance, and clinical results are discussed elsewhere in this PMR application document.

Design validation of all of these system parameters and operations was accomplished through analytical computer simulations, laboratory measurements, in-vitro tissue experiments, in-vivo animal model measurements, and clinical trials. Manufacturing validation of these parameters is performed through a series of sub-assembly/assembly/system test procedures, and the validation of these procedures is described below.

HIFU Delivery Operating Frequency, ON/OFF Times, In-Situ Intensity
In 1987 feasibility studies demonstrated that focused ultrasound was capable of ablating prostate tissue. From 1987 to 1990 a series of canine studies were performed to determine dosimetry, attenuation of the canine rectal wall and prostate proper, and on and off times of ultrasonic pulses (duty cycle), and to prove accuracy of aiming using ultrasound guidance [5]. Following these extensive studies, a formal canine study was conducted to determine the safety and efficacy of high intensity focused ultrasound to ablate prostate tissue [6].

These feasibility studies concluded that in order to non-invasively ablate the prostatic volume (in a canine model) without causing damage to the rectal wall, the following parameters can be used:

Operating Frequency: 4.0 MHz
HIFU On Time: 3 seconds
HIFU OFF Time: 3 seconds (6 second total duty cycle)
In-Situ Intensity: 1680 W/cm2 [5-8].

These parameters consistently elevated the temperatures in the prostate tissue to above 70êC (as measured with implanted bare wire thermocouples) in 3 seconds, as required for tissue ablation. Engineering calculations based on measured tissue attenuation (10 Np/m/MHz typical) and treatment depth (2.5 cm to 4.0 cm) guided the choice of center frequency, applied intensities, and overall transducer geometry [9,10]. Subsequent clinical trials validated that these HIFU excitation parameters also achieve the desired tissue ablation effect in humans [12-18].

Frequency measurement using a calibrated oscilloscope of the on-board oscillator is used to determine if the operating frequency is within acceptable limits. This is accomplished in test procedures 606-07520-0001 Auxiliary Timer Oscillator Test Procedure and 604-17001-0005 Sonablate® 500 System Test Procedure.

Time measurement using a calibrated oscilloscope is used to determine if the HIFU On/Off times are within acceptable limits. This is accomplished in test procedure 606-07520-0001 Auxiliary Timer Oscillator Test Procedure.
In-Situ intensity I [W/cm2] is a computed parameter that is not easily measured, since it requires to be measured inside the actual prostate being treated. Its value depends on the attenuation of the tissue at the operating frequency (a), the depth of the tissue (d), the size of the focal zone of the transducer, the total acoustic power (P) at the surface of the transducer, and the surface area of the transducer (a), as follows [20]:

Please refer to Section H.3.1 for detailed validation description that allows using the quantitative measurement of the total acoustic power (TAP) using the radiation force method [19] and geometrical transducer information to determine approximate in-situ intensity levels with high-enough accuracy to ensure effective HIFU treatments.

HIFU Transducer Geometry

The clinical specifications dictated the options available for defining the acoustic, mechanical, and electromechanical requirements for the transrectal probe and transducer motion [11]. Focal dimensions are determined by the geometry of the transducer and its operating frequency [9]. Focal dimensions and focal length can also be measured directly using a Schlieren imaging system. Such a system produces Schlieren images of ultrasonic waves in water that can be digitized with a standard video system. The images are generated by Raman-Nath scattering of the light, that is, by diffracting off the index grating generated by the acoustic waves. As a result, the light intensity is proportional (at low intensities) to the squared value of the integral of the acoustic intensity (in its component perpendicular to the light direction) along the light path [21]. Digitizing this image allows for the extraction of the transducer focal dimensions and focal length. This is accomplished in test procedure 606-07510-0021 Transducer Schlieren Test Procedure.

Delivery of HIFU at the Planned Treatment Site, Correct Lesion Spacing/Transducer Motion
Because of the geometry of the probe, the transducer is able to place lesions on a cylindrical surface, whose central axis coincides with the sector axis of rotation of the transducer assembly. If the radius of this cylindrical surface corresponds to the focal length of the transducer, the surface of the cylinder is aligned with the focal spot of the transducer. A cylindrical target placed in front of the probe is thus perfectly suited to verify that HIFU delivery occurs at pre-defined locations, that the spacing between these locations is as specified, and that the entire transducer assembly is correctly being positioned by the motor system of the probe. Acrylic cylinder sections with radii of curvature corresponding to the focal length of the transducer under test are used for this purpose. The absorption of the acrylic material is high, melting when placed in the focal zone of an energized HIFU transducer, and leaving easily visible spots indicative of the locations of the treatment sites, their spacing, and overall transducer motion sequence. This is accomplished with test procedure 606-17500-0001 Acrylic Shell Verification Test Procedure, and an example of such shells is shown below.

Acrylic shell example used in the validation of correct transducer motion, correct lesion placement, and correct lesion spacing.

Cooling Performance

A calibrated thermometer and specified liquid volume is used to determine the cooling performance of the pump/chiller system. Its main function is to keep the rectal wall temperature low, and its secondary function is to cool the HIFU transducer during operation. During manufacture, the cooling performance of the pump/chiller system in combination with the transrectal probe is verified with the 606-07500-0001 Pump-Chiller System Test Procedure. During operation, the temperature of the circulating water in the probe tip is monitored with a thermistor installed in the probe tip. This thermistor is calibrated during the assembly procedure of the probe, by following 204-07000-0001 Probe Temperature Sensor Calibration Procedure.

Image Formation

Correct image formation (both sector and linear) is verified through the use of an ultrasound imaging phantom. Ultrasound phantoms are industry-wide accepted tools to verify, validate, and quantify the imaging performance of any ultrasound imaging system. The phantom used for SB500 imaging system validation and verification is a rectangular phantom that contains 3 cylindrical targets with different contrast properties and 3 wire targets positioned at various depths, as shown below.

Sector (transverse, left), and linear (longitudinal, right) ultrasound image views of the SB500 ultrasound phantom used for ultrasound image validation and verification.

Various quantitative measurements performed on the phantom (such as the determination of the diameter of the cylinders in the linear image, measurement of the wire spacing, and determination of the width of the cylinders in the sector image), and qualitative evaluations performed on the phantom (such as the separation of the 3 cylinders with differing contrast properties) form the basis of the image formation validation process. These measurements are performed in 606-07510-0020 TIRF Assembly Test Procedure and 604-17001-0005 Sonablate® 500 System

Test Procedure.

The above system parameters have been validated through extensive clinical trials under approved protocols from the regulatory agencies in the United States and Japan for the treatment of prostate cancer with good results. The test procedures used during the manufacturing of the SB-500 system have shown to correctly measure and quantify all of the critical parameters of the system to ensure its correct operation during use.

REFERENCES

1. Sanghvi et al, "Ultrasound Intracavity System for Imaging, Therapy Planning, and Treatment of Focal Disease," World Intellectual Property Organization, International Patent WO 93/16641, September 1993.
   
2. Sanghvi et al, "Focused Ultrasound Tissue Treatment Method," United States Patent No. 5676692, October 1997.
   
3. Law et al, "Multifaceted Ultrasound Transducer Probe System and Methods for its use," United States Patent No. 5762066, June 1998.
   
4. Sanghvi et al, "Curved Rectangular/Elliptical Transducer," United States Patent No. 5117832, June 1992.
   
5. R. Bihrle, R. Foster, N. Sanghvi, J. Donohue, and P. Hood, "High Intensity Focused Ultrasound for the Treatment of Benign Prostatic Hyperplasia: Early United States Clinical Experience," The Journal of Urology, Vol. 151, 1271-1275, May 1994.
   
6. R. Foster, R. Bihrle, N. Sanghvi, K. Kopecky, J. Regan, J. Eble, C. Hennige, L. Hennige, and J. Donohue, "Production of prostatic lesions in canines using transrectally administered high intensity focused ultrasound," Eur. Urol., Vol. 23, 330, 1993.
   
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8. N. Sanghvi, R. Foster, R. Bihrle, F. Fry, M. Phillips, and C. Hennige, "Transrectal Ablation of Prostate Tissue using Focused Ultrasound," 1993 IEEE Ultrasonics Symposium Proceedings, pp. 1207-1210.
   
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16. M. Marberger and S. Madersbacher, "Treatment of Benign Prostatic Hyperplasia with High Intensity Focused Ultrasound: A Review," Japanese Journal of Endourology and ESWL, Vol. 7, No. 3, 1994.
    
17. R. Bihrle, R. Foster, N. Sanghvi, J. Donohue, and P. Hood, "High Intensity Focused Ultrasound for the Treatment of Benign Prostatic Hyperplasia: Early United States Clinical Experience," The Journal of Urology, Vol. 151, 1271-1275, May 1994.
    
18. T. Uchida, M. Muramoto, H. Kyunou, M. Iwamura, S. Egawa, and K. Koshiba, "Clinical Outcome of High Intensity Focused Ultrasound for Treating Benign Prostatic Hyperplasia: Preliminary Report," Urology 52 (1), 1998.
    
19. Ultrasound Power Meter UPM-DT-1 & 10 Operating Manual, July 1998, Ohmic Instruments, Co.
    
20. Williams and Wilkins, ed., Therapeutic Heat and Cold, 3rd Edition, 1982, Baltimore, Ch. 7 and 8, L. Frizzell and F. Dunn, authors.
    
21. Intec Research Corp., Operations Manual for the OptisonTM Schlieren System, Rev 940609.

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