Toward Non-Invasive Ultrasound Surgery – TONUS

The first 18 months of this project were devoted to the development of a new means of focusing ultrasound that combines two contradictory concepts. It is a question of being able to focus in depth (which naturally implies concentrating the energy in a small area at a distance from the transmitter) but this time in a volume large enough to allow the destruction of a tumor of 2 to 3 cm in diameter. Moreover, this focusing effect must also be able to be applied through the human ribs since approximately 50% of the liver volume is located behind the thoracic cage. To achieve this innovation, a toroidal ultrasound emitter geometry cut according to two perpendicular truncations has been proposed and a patent has been filed to protect this therapeutic process. Numerical simulations were used to determine the optimal truncation widths to maximize the volume increase in the focal zone and to confirm the possibility of destroying tumors up to 3 cm in diameter.
We also conducted a study on human samples recovered from hepatectomy to determine the acoustic attenuation values of primary and secondary tumors as well as surrounding healthy tissue. This value is crucial because it allows us to determine the amount of energy that will be deposited in the different tissues and therefore to be as precise and efficient as possible during the HIFU treatments. An experimental bench and a dedicated software have been developed. The experimental bench allows the echographic and acoustic characterization of biological samples placed between an ultrasound transmitter and a reflector. The software allows the analysis of the data.

On the basis of a patent resulting from this research project, specifications were drawn up to subcontract the manufacture of the corresponding ultrasound transducer. The definition of the transducer was also accompanied by the design of all the electronics and mechanical parts necessary for the realization of the medical device that will use this transducer. The device was delivered in June 2021 and is currently being characterized for its therapeutic performance.
In parallel with this development, in vivo tests were conducted to ensure the feasibility of the focusing concepts involved. This work was conducted on a porcine model with the treatment probes used prior to this project and used until then under surgical approach. It was thus possible to demonstrate the influence of the tissues located between the ultrasound transmitter 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 to successfully carry out the first non-invasive treatments using toroidal emitters. As the probes were designed for surgical use, the accessible depths were limited, but the work demonstrated the feasibility of the concept and made it possible to define the specifications of the device developed specifically for this project. This part of the research project is currently being published.
This in vivo work has demonstrated the importance of a good knowledge of the acoustic properties of the tissues to be treated. Another study was therefore conducted on human liver samples containing primary and secondary tumors. It was found that the properties of these different tissues (healthy and tumor) show important differences requiring substantial modifications of the treatment parameters depending on the targeted tissue. This work was published in the journal Ultrasound in Medicine and Biology in 2021. Another publication appeared in the IRBM journal in 2021 to describe the possibility of treating in contact with blood vessels under Doppler ultrasound control. Finally, a third publication in the journal Ultrasound in Medicine and Biology in 2020 describes the feasibility of tumor destruction by a toroidal geometry transducer on an in vivo model.
Work on temperature measurements of tissues treated by focused ultrasound using ultrasound imaging has also been undertaken during these first 18 months. Although very preliminary, it appears that a measurement of the backscattered energy could be correlated to the temperature of the tissues.

The next steps in this research project will be to characterize the medical device that has just been delivered before undertaking in vitro trials aimed at confirming the envisaged therapeutic performance, and then to carry out in vivo and preclinical trials aimed at demonstrating the feasibility, efficacy, safety and tolerance of the treatment in order to have the necessary data for the setting up of 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.