Proof of concept of high-frequency focused ultrasound delivery to the pancreas, using an endoscopic cavitation generator, on human cadaveric model

Aims Pancreatic ductal adenocarcinoma (PDAC) has very poor prognosis. These very disappointing results are due to very dense tumor microenvironment, responsible for fibrosis, hypovascularization and lack of anti-tumor immune cells, all of which hinder the bioavailability and good diffusion of drugs. Targeting this tumor microenvironment by making it less dense is one of the strategies that could make chemotherapy more effective. High-intensity focused ultrasound (HIFU) can modify a tissue target, without damaging the structures crossed by the ultrasound beam. Since endosonography is an attractive and minimally invasive approach for observing pancreatic tissue in humans, we have designed a preclinical prototype coupling an endoscopic cavitation generator to a transducer, able to reach pancreatic parenchyma. Our preliminary work on ex-vivo pig model had shown that this prototype could deliver good-quality B-mode ultrasound imaging of the pancreas via endoscopic approach. The aim of this study was to confirm ultrasound targeting of the pancreatic parenchyma on anatomical cadaveric model, and demonstrate the proof-of-concept of HIFU delivery by this cavitation generator prototype, coupled with contrast agents.

Methods We prepared five cadaveric models: three non-perfused on which, insertion, guidance and B-mode ultrasound images acquisition of the pancreatic parenchyma were performed, and two perfused models (SimLife model), on which power ultrasound delivery coupled with injection of contrast agents was tested. The SimLife technology based on revascularization of human cadaver with a blood avatar, enabling pulsatile arterial circulation and venous turgor. This technology allowed microbubbles to be injected, and led to repermeation of organ microcirculation. The two components of the endoscopic device (imaging probe and endoscopic HIFU probe for therapy) were each controlled by a “Vérasonics” ultrasound machine. Cavitation activity was measured by passive cavitation imaging. The device was then positioned into the stomach via transesophageal approach, after hydrostatic esophageal dilation up to 20 mm Hg, to minimize frictional forces during prototype descent.

Results These tests confirmed that transesophageal navigation to the stomach of the prototype on human cadaver was feasible. This not only enabled targeting pancreatic parenchyma with high-quality B-mode ultrasound images, but also, successful high-intensity focused ultrasound (HIFU) delivery, combined with microbubbles injection to anatomical cadaveric pancreas. Ultrasonic cavitation activity was measurable with maximum negative pressure up to 7.7 MPa (60 V excitation voltage). This established proof-of-concept of ultrasonic cavitation by endoscopic-ultrasound approach (EUS) on perfused human cadaver.

Conclusions Our work establishes proof-of-concept for HIFU-delivery to the pancreas of perfused human cadaveric model, and paves the way for preclinical work with prospect of EUS application of cavitation to pancreatic cancer.

Publikationsverlauf

Artikel online veröffentlicht:
27. März 2025