Focused Ultrasound Treatment of a Spheroid In Vitro Tumour Model

SIMPLE SUMMARY: Ultrasound waves can be applied for diagnostic and therapeutic purposes. Focused ultrasound is approved for tissue ablation, e.g., in the treatment of uterine fibroids or essential tremors. Besides the non-invasive image-guided surgical intervention at temperatures above 55 °C, FUS is investigated in other fields like blood-brain barrier opening, hyperthermia, and neuromodulation. FUS offers potential as an adjuvant therapy in cancer treatment. Therefore, analysis of FUS effects on cancer cells is necessary. We performed studies on two human cancer cell line spheroids using a newly developed high-throughput in vitro FUS applicator with 32 individual transducers. This study aimed to perform basic experiments with a new in vitro FUS device on a 3D tumour model to acquire insight into the effects of FUS at the cellular level. These experiments may contribute to a better understanding and predictions of cancer treatment efficacy. ABSTRACT: Focused ultrasound (FUS) is a non-invasive technique producing a variety of biological effects by either thermal or mechanical mechanisms of ultrasound interaction with the targeted tissue. FUS could bring benefits, e.g., tumour sensitisation, immune stimulation, and targeted drug delivery, but investigation of FUS effects at the cellular level is still missing. New techniques are commonly tested in vitro on two-dimensional (2D) monolayer cancer cell culture models. The 3D tumour model—spheroid—is mainly utilised to mimic solid tumours from an architectural standpoint. It is a promising method to simulate the characteristics of tumours in vitro and their various responses to therapeutic alternatives. This study aimed to evaluate the effects of FUS on human prostate and glioblastoma cancer tumour spheroids in vitro. The experimental follow-up enclosed the measurements of spheroid integrity and growth kinetics, DNA damage, and cellular metabolic activity by measuring intracellular ATP content in the spheroids. Our results showed that pulsed FUS treatment induced molecular effects in 3D tumour models. With the disruption of the spheroid integrity, we observed an increase in DNA double-strand breaks, leading to damage in the cancer cells depending on the cancer cell type

Classification of Distal Growth Plate Ossification States of the Radius Bone Using a Dedicated Ultrasound Device and Machine Learning Techniques for Bone Age Assessments

X-ray imaging, based on ionizing radiation, can be used to determine bone age by examining distal growth plate fusion in the ulna and radius bones. Legal age determination approaches based on ultrasound signals exist but are unsuitable to reliably determine bone age. We present a low-cost, mobile system that uses one-dimensional ultrasound radio frequency signals to obtain a robust binary classifier enabling the determination of bone age from data of girls and women aged 9 to 24 years. These data were acquired as part of a clinical study conducted with 148 subjects. Our system detects the presence or absence of the epiphyseal plate by moving ultrasound array transducers along the forearm, measuring reflection and transmission signals. Even though classical digital signal processing methods did not achieve a robust classifier, we achieved an F1 score of approximately 87% for binary classification of completed bone growth with machine learning approaches, such as the gradient boosting machine method CatBoost. We demonstrate that our ultrasound system can classify the fusion of the distal growth plate of the radius bone and the completion of bone growth with high accuracy. We propose a non-ionizing alternative to established X-ray imaging methods for this purpose

Evaluation of a developed MRI-guided focused ultrasound system in 7 T small animal MRI and proof-of-concept in a prostate cancer xenograft model to improve radiation therapy

Focused ultrasound (FUS) can be used to physiologically change or destroy tissue in a non-invasive way. A few commercial systems have clinical approval for the thermal ablation of solid tumors for the treatment of neurological diseases and palliative pain management of bone metastases. However, the thermal effects of FUS are known to lead to various biological effects, such as inhibition of repair of DNA damage, reduction in tumor hypoxia, and induction of apoptosis. Here, we studied radiosensitization as a combination therapy of FUS and RT in a xenograft mouse model using newly developed MRI-compatible FUS equipment. Xenograft tumor-bearing mice were produced by subcutaneous injection of the human prostate cancer cell line PC-3. Animals were treated with FUS in 7 T MRI at 4.8 W/cm2 to reach ~45 °C and held for 30 min. The temperature was controlled via fiber optics and proton resonance frequency shift (PRF) MR thermometry in parallel. In the combination group, animals were treated with FUS followed by X-ray at a single dose of 10 Gy. The effects of FUS and RT were assessed via hematoxylin-eosin (H&E) staining. Tumor proliferation was detected by the immunohistochemistry of Ki67 and apoptosis was measured by a TUNEL assay. At 40 days follow-up, the impact of RT on cancer cells was significantly improved by FUS as demonstrated by a reduction in cell nucleoli from 189 to 237 compared to RT alone. Inhibition of tumor growth by 4.6 times was observed in vivo in the FUS + RT group (85.3%) in contrast to the tumor volume of 393% in the untreated control. Our results demonstrated the feasibility of combined MRI-guided FUS and RT for the treatment of prostate cancer in a xenograft mouse model and may provide a chance for less invasive cancer therapy through radiosensitization

Encapsulation of Capacitive Micromachined Ultrasonic Transducers (CMUTs) for the Acoustic Communication between Medical Implants

The aim of this work was to extend conventional medical implants by the possibility of communication between them. For reasons of data security and transmitting distances, this communication should be realized using ultrasound, which is generated and detected by capacitive micromachined ultrasonic transducers (CMUTs). These offer the advantage of an inherent high bandwidth and a high integration capability. To protect the surrounding tissue, it has to be encapsulated. In contrast to previous results of other research groups dealing with the encapsulation of CMUTs, the goal here is to integrate the CMUT into the housing of a medical implant. In this work, CMUTs were designed and fabricated for a center frequency of 2 MHz in water and experimentally tested on their characteristics for operation behind layers of Polyether ether ketone (PEEK) and titanium, two typical materials for the housings of medical implants. It could be shown that with silicone as a coupling layer it is possible to operate a CMUT behind the housing of an implant. Although it changes the characteristics of the CMUT, the setup is found to be well suited for communication between two transducers over a distance of at least 8 cm

Encapsulation of Capacitive Micromachined Ultrasonic Transducers (CMUTs) for the Acoustic Communication between Medical Implants

The aim of this work was to extend conventional medical implants by the possibility of communication between them. For reasons of data security and transmitting distances, this communication should be realized using ultrasound, which is generated and detected by capacitive micromachined ultrasonic transducers (CMUTs). These offer the advantage of an inherent high bandwidth and a high integration capability. To protect the surrounding tissue, it has to be encapsulated. In contrast to previous results of other research groups dealing with the encapsulation of CMUTs, the goal here is to integrate the CMUT into the housing of a medical implant. In this work, CMUTs were designed and fabricated for a center frequency of 2 MHz in water and experimentally tested on their characteristics for operation behind layers of Polyether ether ketone (PEEK) and titanium, two typical materials for the housings of medical implants. It could be shown that with silicone as a coupling layer it is possible to operate a CMUT behind the housing of an implant. Although it changes the characteristics of the CMUT, the setup is found to be well suited for communication between two transducers over a distance of at least 8 cm

Real-Time Volumetric Ultrasound Research Platform with 1024 Parallel Transmit and Receive Channels

Volumetric ultrasound imaging is of great importance in many medical fields, especially in cardiology, but also in therapy monitoring applications. For development of new imaging technologies and scanning strategies, it is crucial to be able to use a hardware platform that is as free and flexible as possible and does not restrict the user in his research in any way. For this purpose, multi-channel ultrasound systems are particularly suitable, as they are able to control each individual element of a matrix array without the use of a multiplexer. We set out to develop a fully integrated, compact 1024-channel ultrasound system that provides full access to all transmission parameters and all digitized raw data of each transducer element. For this purpose, we synchronize four research scanners of our latest “DiPhAS” ultrasound research system generation, each with 256 parallel channels, all connected to a single PC on whose GPUs the entire signal processing is performed. All components of the system are housed in a compact, movable 19-inch rack. The system is designed as a general-purpose platform for research in volumetric imaging; however, the first-use case will be therapy monitoring by tracking radiation-sensitive ultrasound contrast agents

Classification of Distal Growth Plate Ossification States of the Radius Bone Using a Dedicated Ultrasound Device and Machine Learning Techniques for Bone Age Assessments

X-ray imaging, based on ionizing radiation, can be used to determine bone age by examining distal growth plate fusion in the ulna and radius bones. Legal age determination approaches based on ultrasound signals exist but are unsuitable to reliably determine bone age. We present a low-cost, mobile system that uses one-dimensional ultrasound radio frequency signals to obtain a robust binary classifier enabling the determination of bone age from data of girls and women aged 9 to 24 years. These data were acquired as part of a clinical study conducted with 148 subjects. Our system detects the presence or absence of the epiphyseal plate by moving ultrasound array transducers along the forearm, measuring reflection and transmission signals. Even though classical digital signal processing methods did not achieve a robust classifier, we achieved an F1 score of approximately 87% for binary classification of completed bone growth with machine learning approaches, such as the gradient boosting machine method CatBoost. We demonstrate that our ultrasound system can classify the fusion of the distal growth plate of the radius bone and the completion of bone growth with high accuracy. We propose a non-ionizing alternative to established X-ray imaging methods for this purpose