Toward Non-Invasive Ultrasound Surgery – TONUS

A new method for ultrasound focusing has been developed, combining two contradictory concepts. It involves being able to focus deeply (which naturally implies concentrating energy in a small area at a distance from the emitter) but this time in a sufficiently large volume to allow the destruction of a tumor of 2 cm in diameter. To achieve this innovation, a toroidal ultrasound emitter geometry, cut along two perpendicular truncatures, was proposed, and a patent was filed to protect this therapeutic process. Numerical simulations were conducted to determine the optimal truncation widths to maximize the increase in volume in the focal zone. A prototype was developed based on these innovations.

We also conducted a study on human hepatectomy specimens to determine the acoustic attenuation values of primary and secondary tumors, as well as the surrounding healthy tissues. This value is crucial because it allows for determining the amount of energy that will be deposited in different tissues, ensuring the most precise and effective treatments possible. A measurement bench and dedicated software were developed for this purpose, with technology transfer to the company EDAP. The bench allows for the ultrasonic and acoustic characterization of biological samples placed between an ultrasound emitter and a reflector. The software enables data analysis. A patent was also filed for a strategy using a high-resolution ultrasound probe for targeting the treatment area with infrared guidance, followed by aligning the therapy probe with the imaging probe position.

In terms of imaging, this project also developed a new in vivo estimation method of ultrasound attenuation in biological tissues to deposit optimal energy in the pathological area. Additionally, a temperature measurement method for a range of 37 to 100°C was developed based on the analysis of ultrasound waves backscattered by biological tissues. Both methods have been patented.

All these methods were validated ex vivo on biological tissues, in vivo on an animal model (n=34) for therapeutic trials combining imaging methods and the new HIFU prototype, and in vivo on healthy volunteers (n=12) for the attenuation imaging method.

The definition of the new ultrasonic prototype was also accompanied by the design of all the necessary electronics and mechanical components. The entire system was delivered in June 2021. Its therapeutic performance was characterized through ex vivo and in vivo tests on a porcine animal model. It was thus possible to demonstrate the influence of tissues located between the ultrasonic emitter and the liver on the treatment produced. Measurements of the acoustic characteristics of these intermediate tissues made it possible to apply the necessary corrections and successfully carry out the first non-invasive treatments using toroidal emitter geometry. This in vivo work demonstrated the importance of a good understanding of the acoustic properties of tissues that need to be treated. The results show that the inter-individual variation in these properties can lead to the absence of treatment. Therefore, a patient-specific approach is essential for therapeutic effectiveness and reproducibility.

The feasibility of in vivo attenuation measurement was demonstrated in the liver and kidney on 12 healthy volunteers, allowing the consideration of true patient-specific HIFU treatments in these organs. Moreover, temperature measurement tests through the analysis of ultrasound waves backscattered by biological tissues were feasible in the liver, over a temperature range from 37°C to 90°C, with high reliability of temperature measurements below 75°C. Monitoring can be performed at the ultrasound imaging acquisition rate, with an accuracy of 5°C. These results demonstrated the ability of this method to estimate temperature based on ultrasound images and suggest it could be implemented clinically and potentially applied to other therapies based on thermal effects.

The positioning of the treatment area was also optimized thanks to an infrared guidance system that ensures the alignment of the therapeutic probe with an ultrasound probe used to optimally visualize the pathological area to be targeted. Calibration tests demonstrated an accuracy of around half a millimeter. In vivo trials demonstrated the capability of the focused ultrasound therapy prototype to produce an ablation volume sufficient to destroy hepatic tumors measuring up to 2 cm in diameter, which is the desired clinical objective. The procedure is simple and fast, as the therapy itself lasts 90 seconds once the system is aligned. The entire procedure took less than 30 minutes. The treated areas measured approximately 25 mm wide and 25 mm long, located 5 mm below the liver capsule. These treatments were performed through 15 mm of abdominal wall without secondary lesions.

The next steps of this research project will aim to demonstrate the feasibility, effectiveness, safety, and tolerance of the treatment over longer periods (1 month post-treatment) as well as to undertake the regulatory steps for device compliance in order to obtain the necessary data for initiating a Phase I/II clinical trial.

Patents :

B1- Cambronero S., Melodelima D. Transducteur de thérapie pour le traitement des tissus selon une découpe en croix pour l’émission d’ondes ultrasonores focalisées croisées ou croisées déportées. Brevet déposé le 26 février 2021, n°EP 21305235.0

Peer-rewieved articles in international journals:

P3- Barrere V., Sanchez M., Cambronero S., Dupre A., Rivoire M. Melodelima D. Evaluation of ultrasonic attenuation in primary and secondary human liver tumors and its potential effect on HIFU treatment. Ultrasound in Medicine and Biology. 2021;47(7):1761-1774.

P2- Cilleros C., Dupré A., Vincenot J., Melodelima D. Development of a simple in vitro artery model and an evaluation of the impact of pulsed flow on high-intensity focused ultrasound ablation. Innovation and Research in BioMedical engineering. 2021;42(2):112-119.

P1- Battais A., Barrere V., N’Djin W.A., Dupre A., Rivoire M., Melodelima D. Fast and selective ablation of liver tumors by high-intensity focused ultrasound using a toroidal transducer guided by ultrasound imaging: the results of animal experiments. Ultrasound in Medicine and Biology. 2020;46(12):3286-3295.


Communications in international conferences:

C5- Cambronero S, Melodelima D. Maximization of the pressure using deported focalization from the acoustic axis with a truncated toroidal transducer. 20th International Symposium on Therapeutic Ultrasound, 2021

C4- Cambronero S, Melodelima D. Increase of the treated volume using a toroidal HIFU transducer with a minimal number of elements. IEEE Ultrasonic Symposium 2021

C3- Cambronero S, Dupre A, Rivoire M, Melodelima D. In vivo non invasive HIFU treatment of the liver using a toroidal transducer. 20th International Symposium on Therapeutic Ultrasound, 2021

C2- Cambronero S, Dupre A, Mastier C, Melodelima D. Non-invasive HIFU treatment of the liver using a toroidal transducer. Preclinical study. IEEE Ultrasonic Symposium 2021.

C1- Barrere V., Sanchez M., Rivoire M., Melodelima D. Evaluation of the attenuation coefficient of primary and secondary human liver tumours recovered from hepatectomy. Impact on High Intensity Focused Ultrasound (HIFU) treatments. Proceedings of the IEEE Ultrasonic Symposium, Glasgow, UK, 2019. ? 544-547.

There are two main forms of liver tumors: primary hepatic cancer (cancer that starts in the liver, mainly hepatocellular carcinoma: HCC) and liver metastases from other tumors, mainly of the gastrointestinal tract.
In 201 there were approximately 63 400 new cases of primary liver cancers in Europe and 62 100 deaths. Liver cancer is the 2nd most common cause of cancer death worldwide. Primary liver cancer occurs most commonly in previously damaged livers (viral hepatitis, alcohol abuse and obesity). Treatment involves multiple strategies including liver replacement therapy, local therapy (resection, ablation), and regional therapy. However, to date, only about 25% of the patients are considered to be suitable candidates for curative treatment.
The second most common incident form of cancer in Europe in 2012 was colorectal cancer (371 706, 13% of all incident cases). Nearly half the patients will develop liver metastases at some point during the course of the disease. Whatever the treatment, the survival at 5-years is only about 10% and surgery remains the only potentially curative treatment. However, only 10–20% of patients are eligible for surgery. Techniques involving focal destruction, such as radiofrequency ablation, have been used as a tool to expand the number of patients treated with a curative intent. However, there is a risk of inadequate treatment due to the blood flow, they do not allow reliable real-time monitoring, they require intra-parenchymal introduction of a probe, only small hepatic volumes can be targeted and a high rate of local recurrence has been described.
HIFU is a therapeutic technology allowing the creation of a thermal lesion selectively in biological tissues by focusing ultrasonic energy. Commercial products are currently available for the treatment of uterine fibroids, prostate cancer and abdominal cancers. Although there are many research groups worldwide who are actively working on this technique, the liver is a particularly challenging organ for HIFU treatment due to the combined effect of respiratory-induced motion, partial blocking of the rib cage and high perfusion/flow. Several technical and clinical solutions have been investigated during the past 15 years but to date without providing effective solutions. Although hepatocellular carcinoma and metastatic liver disease require completely separate analysis and study protocols, the technological approach of HIFU treatments is similar.
We have shown at early clinical stage that a new form of treatment using toroidal HIFU transducers can be a promising tool for treating liver metastases. Before developing sophisticated devices a first prototype was built to be used intraoperatively (during surgery). This toroidal HIFU transducer achieved fast, selective, safe and well-tolerated large volume of liver ablation (the ablation rate is more than 30 times faster than any other local therapy) and without puncture in the organ.
Thanks to this initial experience we now aim to move forward a completely non-invasive HIFU treatment in the liver for treating primary and secondary tumors. Based on additional innovations about surface modulation of the emitting surface we recently patented it is now possible to deposit precisely energy inside the liver by taking into account the specificity of intervening tissues and their acoustic characteristics. A pragmatic approach was selected for focusing the ultrasound energy through the rib cage by using a truncated transducer. Ablations created by a toroidal transducer are independent from perfusion. Moreover, in order to compensate respiratory-induced motion, we propose to develop next-generation tools in the fields of HIFU simulation, guidance of the treatment and estimation of the created effect in tissues.