investigation of inertial cavitation of sonosensitive and

Investigation of Inertial Cavitation of Sonosensitive and Biocompati-

ble Nanospheres in Flow Through Tissue Mimicking Phantoms Em-

ploying Focused Ultrasound

Benedikt George, Department of Microsystems Engineering - IMTEK, Laboratory for Electrical Instrumentation and

Embedded Systems, Albert-Ludwigs-University Freiburg, Freiburg, Germany, [email protected]

Ula Savsek, Department of Chemistry and Pharmaceutics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlan-

gen, Germany, [email protected]

Dagmar Fischer, Department of Chemistry and Pharmaceutics, Friedrich-Alexander-University Erlangen-Nuremberg,

Erlangen, Germany, [email protected]

Helmut Ermert, Section of Experimental Oncology and Nanomedicine, University Hospital Erlangen, Erlangen, Ger-

many, [email protected]

Stefan J. Rupitsch, Department of Microsystems Engineering - IMTEK, Laboratory for Electrical Instrumentation and

Embedded Systems, Albert-Ludwigs-University Freiburg, Freiburg, Germany, [email protected]

Introduction

In drug delivery applications for chemotherapeutics, a promising approach is the use of drug carriers to reduce the total

amount of cytostatics while minimizing side effects. In addition, the carriers, loaded with the drug, can be guided to the

tumorous tissue via the vascular system, allowing a local drug release. In our case, drug release is activated due to the

sonosensitive behavior of the nanospheres by inertial cavitation caused by focused ultrasound. For measuring the

cavitation effect, a passive cavitation detection (PCD) setup has been employed. So far, the nano carriers were simply

filled in laboratory vessels, which did not mimic blood vessels in tissue. Now, we designed flow-through tissue mimicking

phantoms to investigate the cavitation behavior in thin vessels as well as to verify our drug delivery approach for its

clinical suitability.

Methods

The flow-through tissue-mimicking phantoms feature a square cross sectional layout which each having a centrally ex-

tending channel representing a blood vessel. The phantoms have lateral edge lengths of 20, 40, and 60 mm, the diameters

dc of the vessel mimicking flow-through channels are 1, 2, and 3 mm, respectivly, which are typical blood vessel diame-

ters. The phantoms’ material consist of a polyvinyl alcohol-water mixture whose sound velocity and acoustic wave im-

pedance are comparable to the corresponding values of biological tissue. Cavitation is excited by a burst signal with the

characteristic parameters burst length = 0.6 ms, duty cycle = 0.02%, frequency f = 750 kHz, wavelength 𝜆 ≈1.5 mm,

negative pressure amplitude = 1.25 MPa yielding the mechanical Index MI ≈ 1.44. Thus, the maximal MI = 1.9, allowed

for diagnostic ultrasound levels, is not exceeded. During the cavitation investigation, the nanospheres are pumped through

the phantom. The flow velocities correspond to the physiological velocities in blood vessels (vf = 0.05 m/s - 0.1 m/s).

Results

Investigations have shown that the drug releasing cavitation effect associated to the sonosensitive and biocompatible

nanospheres also occures in fine vessel structures, even in the case of vessel diameters dc < 𝜆. These results confirm the

applicability of our drug delivery approach in chemotherapy.

S349Abstracts – BMT 2021 – Hannover, 5 – 7 October • DOI 10.1515/bmt-2021-6055 Biomed. Eng.-Biomed. Tech. 2021; 66(s1): S349–S353 • © by Walter de Gruyter • Berlin • Boston

http://www.imtek.uni-freiburg.de/

mailto:[email protected]




http://www.imtek.uni-freiburg.de/

Passive Acoustic Mapping for ultrasound therapy monitoring

Sarah Therre, Department of Ultrasound, Fraunhofer Institute for Biomedical Engineering, Sankt Ingbert, Germany,

[email protected]

Wolfgang Bost, Department of Ultrasound, Fraunhofer Institute for Biomedical Engineering, Sankt Ingbert, Germany,

[email protected]

Holger Hewener, Department of Ultrasound, Fraunhofer Institute for Biomedical Engineering, Sankt Ingbert, Germany,

[email protected]

Steffen Tretbar, Department of Ultrasound, Fraunhofer Institute for Biomedical Engineering, Sankt Ingbert, Germany,

[email protected]

Marc Fournelle, Department of Ultrasound, Fraunhofer Institute for Biomedical Engineering, Sankt Ingbert, Germany,

[email protected]

Introduction

Therapeutic ultrasound is an emerging technology limited by the lack of inexpensive monitoring methods. While MR-

based approaches offer a precise monitoring of thermal ablation, the high initial and operational costs of MR imaging

limit the widespread use. Ultrasound imaging systems on the other hand come at low cost and are commonly available in

clinical environments.

During the application of therapeutic ultrasound, cavitation events may occur due to high acoustic pressures above the

cavitation threshold. Oscillating and collapsing bubbles generate a characteristic broadband signal which can be recorded

by an ultrasound array. By applying passive beamforming algorithms, an image showing the origin of cavitation bubbles

can be created. These methods are generally referred to as Passive Acoustic Mapping (PAM). In this way, cavitation

events can be not only detected but also localized during the treatment procedure, which is crucial in order to control the

treated area. Limitations of PAM are the limited spatial resolution (especially in axial direction) and the numerical com-

plexity of the reconstruction algorithms.

Methods

In this study, multiple reconstruction algorithms as well as different transducer geometries and setups were being com-

pared, concerning their suitability for PAM. This involved the use of conventional linear transducers, but also of more

sophisticated variants like matrix and sparse spiral arrays. Our own numerical model was used to generate cavitation

signals from known locations. In an experimental setup, cavitation in water and in a tissue phantom was created by a

spherical focusing transducer.

Results

In our numerical studies, we could show that the axial FWHM of the point spread function was over five times lower

when using a 11x11 matrix array (2 MHz, 2.8125 mm pitch) compared to a 32x32 matrix array (3 MHz, 0.3 mm pitch).

A second 32x32 array (4 MHz, 0.94 mm pitch) showed merely a less than two times smaller axial FWHM as the 11x11

variant with similar aperture size, considering that its higher frequency also influences the resolution in a positive way.

Our simulations suggest that the resolution mainly depends on the aperture size rather than the number of elements. The

experiments allowed to confirm our numerical findings regarding the achievable reconstruction quality.

Conclusion

Based on our combination of experimental and numerical work, we defined an ideal setup for PAM-based ultrasound

therapy monitoring. This ideal setup is meant to be integrated in an ultrasound research platform enabling online moni-

toring during HIFU therapy.


Acoustic-kinetic joint analysis: Synchronization and Evaluation of ki-netic measurement data in AEA (Acoustic Emission Analysis) based diagnosis of arthritic knee joint defects. Subke Joerg, THM University of Applied Sciences, Giessen, Germany, [email protected] Schneider Benedict, THM University of Applied Sciences, Giessen, Germany, benedict [email protected] Hanitz Fiona, THM University of Applied Sciences, Giessen, Germany, [email protected] Wolf Udo, University of Applied Sciences Fulda, Germany, [email protected]

Introduction During a clinical study the AEA (Acoustic Emission Analysis) of arthritic defects in the knee joint was enhanced by the addition of kinetic measurement data. This enhanced AEA based method permits a non-invasive diagnosis and assessment of arthritic joint damage at an early stage.

Methods The diagnostic procedure includes three separate measurements that contribute in different ways to an extended diagno-sis of the disease pattern. During a series of three knee bends a force plate provides data of the ground force while a video-based gait analysis records the corresponding movement and the angles of hip-, knee-, and ankle joints. At the same time AEA detects the acoustic anomalies of damaged cartilage and the absolute angle of the system. The patterns of the kinetic data were analysed to define the instants of time to correlate the data of the 3 measurement systems.

Results The analysis of the force data yield a pattern with 8 phases. By means of the stance phase between the knee bends the instants of time are defined to synchronize force and video based data. In a second step the synchronization of video based data was done by means of the absolute angle of the AEA system.

Conclusion The superposition of kinetic data and the acoustic emission permits a preliminary graphic representation and assessment of the measurement data. The procedure will be applied for the analysis of patients in a clinical study.


Clinical case study in acoustic-kinetic joint analysis: Synchronization and Evaluation of kinetic measurement data in AEA (Acoustic Emission Analysis) based diagnosis of arthritic knee joint defects Subke Joerg, THM University of Applied Sciences, Giessen, Germany, [email protected] Schneider Benedict, THM University of Applied Sciences, Giessen, Germany, benedict [email protected] Hanitz Fiona, THM University of Applied Sciences, Giessen, Germany, [email protected] Krüger Sabine, Osteopathiepraxis, Ludwigsburg, Germany, [email protected] Junker Heinz-Otto, Klinik Rheumazentrum Mittelhessen, Bad Endbach, Germany, [email protected] Schwalbe Hans-Joachim, BoneDiaS GmbH&Co.KG, Greifenstein, Germany, [email protected] Wolf Udo, University of Applied Sciences Fulda, Germany, [email protected]

Introduction In patients with arthritic knee joint defects the course of movement, the application of muscle forces and the degree of freedom of the joints of the lower limbs differs significantly from the corresponding data of a healthy proband.

Methods The enhanced acoustic-kinetic joint analysis based on AEA, ground force reaction measurements and video enhanced gait analysis permits the correlation of force data, joint angles and acoustic emission significant of defective joint carti-lage regions. This diagnostic procedure permits a quantifiable and detailed non evasive diagnosis of lesion patterns in the arthritic knee joint by means of a synchronization algorithm.

Results The AEA shows lesion signals in the first and third knee bend of the patient. The lesion signals are assigned to the joint angles and ground reaction force. Comparing the kinematical data there is a shift between the curves of the hip and the knee angle. Overall the force data represent an unbalance between the left and the right leg during the knee bends.

Conclusion The presentation of the three measurement systems, the method, the synchronization of the data sets and their final as-sessment as well as the occurring difficulties during a case of a clinical study are discussed. This would be helpful in regard to further patients of the clinical study.


Opening the blood-brain barrier using ultrasound and microbubbles to deliver nanochemotherapeutics to pediatric brain tumors

Jan-Niklas May, Institute of Experimental Molecular Imaging, University Clinic RWTH Aachen, Aachen, Germany, [email protected]

Anshuman Dasgupta, Institute of Experimental Molecular Imaging, University Clinic RWTH Aachen, Aachen, Germany, [email protected]

Anne Rix, Institute of Experimental Molecular Imaging, University Clinic RWTH Aachen, Aachen, Germany, [email protected]

Fabian Kiessling, Institute of Experimental Molecular Imaging, University Clinic RWTH Aachen, Aachen, Germany, [email protected]

Twan Lammers, Institute of Experimental Molecular Imaging, University Clinic RWTH Aachen, Aachen, Germany, [email protected]

Introduction

Diffuse intrinsic pontine gliomas (DIPG) are an aggressive, pediatric brain tumor affecting several hundreds of children in Europe per year. Due to the tumor’s location, radiotherapy and surgery can only be performed in a limited way and as the blood-brain barrier (BBB) remains largely intact, the accumulation of potentially effective chemotherapeutic agents is minimized. Drug delivery into the tumor can be improved by opening the BBB in a temporarily and spatially controlled manner via the combination of ultrasound and microbubbles, named sonopermeation. In this project, we further combine sonopermeation by the encapsulation of drugs into nanomedicine formulations to ensure a medium- to long-term release of drugs at the pathological site.

Methods

Differently shaped poly(n-butyl cyanoacrylate) microbubbles as well as fluorophore-labeled nanomedicine formulations were synthesized and injected into mice to evaluate their effect on either BBB opening itself or on the accumulation and penetration of nanomedicine formulations into the brain via optical imaging (CT-FMT and microscopy). To identify optimal drug combinations, an extensive in vitro screening was performed and drug-loaded nanomedicine formulations are being prepared for in vivo therapy studies.

Results

The opening of the BBB could be improved by using rod-shaped PBCA microbubbles compared to spherical PBCA microbubbles, possibly due to different fluid mechanics. Additionally, smaller sized polymers (10 nm) were found to accumulate more and penetrate deeper into the brain than larger sized liposomes (100 nm), indicating the impact of the type of microbubbles and nanomedicine formulation on the extent of drug delivery. Within the drug screening experiment, the combination of anthracyclines and HDAC inhibitors (e.g. doxorubicin and panobinostat) was found to be effective and could already be encapsulated in nanomedicine formulations to be applied in therapy studies.

Conclusion

Sonopermeation assisted BBB opening facilitates the delivery of nanomedicine formulations into the brain. As it provides a new treatment strategy, patients can potentially benefit from this precise and personalized therapy. A slow release of drugs at the pathological site might on the one hand increase the efficacy per therapy cycle, which could lead to a decrease in the total number of therapy cycles, resulting taken together in an improvement of the quality of life. Eventually, these findings contribute to the treatment of CNS disorders by extending the number of drug candidates that can be successfully delivered via sonopermeation to pathological sites.


investigation of inertial cavitation of sonosensitive and

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