Implementation of safe human robot collaboration for ultrasound guided radiation therapy

This thesis shows that safe human-robot-interaction and Human Robot Collaboration is possible for Ultrasound (US) guided radiotherapy. Via the chosen methodology, all components (US, optical room monitoring and robot) could be linked and integrated and realized in a realistic clinical workflow. US guided radiotherapy offers a complement and alternative to existing image-guided therapy approaches. The real-time capability of US and high soft tissue contrast allow target structures to be tracked and radiation delivery to be modulated. However, Ultrasound guided radiation therapy (USgRT) is not yet clinically established but is still under development, as reliable and safe methods of image acquisition are not yet available. In particular, the loss of contact of the US probe to the patient surface poses a problem for patient movements such as breathing. For this purpose, a Breathing and motion compensation (BaMC) was developed in this work, which together with the safe control of a lightweight robot represents a new development for USgRT. The developed BaMC can be used to control the US probe with contact to the patient. The conducted experiments have confirmed that a steady contact with the patient surface and thus a continuous image acquisition can be ensured by the developed methodology. In addition, the image position in space can be accurately maintained in the submillimeter range. The BaMC seamlessly integrates into a developed clinical workflow. The graphical user interfaces developed for this purpose, as well as direct haptic control with the robot, provide an easy interaction option for the clinical user. The developed autonomous positioning of the transducer represents a good example of the feasibility of the approach. With the help of the user interface, an acoustic plane can be defined and autonomously approached via the robot in a time-efficient and precise manner. The tests carried out show that this methodology is suitable for a wide range of transducer positions. Safety in a human-robot interaction task is essential and requires individually customized concepts. In this work, adequate monitoring mechanisms could be found to ensure both patient and staff safety. In collision tests it could be shown that the implemented detection measures work and that the robot moves into a safe parking position. The forces acting on the patient could thus be pushed well below the limits required by the standard. This work has demonstrated the first important steps towards safe robot-assisted ultrasound imaging, which is not only applicable to USgRT. The developed interfaces provide the basis for further investigations in this field, especially in the area of image recognition, for example to determine the position of the target structure. With the proof of safety of the developed system, first study in human can now follow

Development of positioning devices for MRI-guided high intensity focused ultrasound (HIFU) for abdominal, thyroid and brain, tumours

High intensity focused ultrasound (HIFU) is a promising technology for a variety of therapeutic applications. This concept initiated in 1942 by Lynn Zwemer [1]. HIFU has long been known as a minimal invasive or non-invasive procedure that destroys tissue through ablation. However, it is only in recent years that clinical applications are becoming feasible, with the development of high power ultrasound transducers compatible with the MRI scanner which is used to monitor these non-invasive HIFU applications. New technologies, combined with more sophisticated treatment methods and monitoring methods allow non-invasive procedures in many areas such as the brain, eye, breast, kidney, liver, pancreas, thyroid, uterine fibroids and pancreas. Meanwhile, new investigations are underway for treading cardiac arithmia, strokes, palliative pain treatment of bone metastases and brain disorders such as Parkinson’s disease, essential tremor, and neuropathic pain. These optimistic investigations have encouraged physicians and provided them new valuable tools for medical research

Novel Magnetic Resonance Imaging-Compatible Mechatronic Needle Guidance System for Prostate Focal Laser Ablation Therapy

Advances in prostate cancer (PCa) screening techniques have led to diagnosis of many cases of low-grade and highly localized disease. Conventional whole-gland therapies often result in overtreatment in such cases and debate still surrounds the optimal method of oncologic control. MRI-guided prostate focal laser ablation (FLA) is a minimally invasive treatment option, which has demonstrated potential to destroy localized lesions while sparing healthy prostatic tissue, thereby reducing treatment-related side effects. Many challenges still exist in the development of FLA, including patient selection; tumour localization, visualization, and characterization; needle guidance; and evaluation of treatment efficacy. The objective of this thesis work was to advance and enhance techniques for needle guidance in MRI-guided focal laser ablation (FLA) therapy of PCa. Several steps were taken in achieving this goal. Firstly, we evaluated the overlap between identified lesions and MRI-confirmed ablation regions using conventional needle guidance. Non-rigid thin-plate spline registration of pre-operative and intra-operative images was performed to align lesions with ablation boundaries and quantify the degree of coverage. Complete coverage of the lesion with the ablation zone is a clinically important metric of success for FLA therapy and we found it was not achieved in many cases. Therefore, our next step was to develop an MRI-compatible, remotely actuated mechatronic system for transperineal FLA of prostate cancer. The system allows physicians in the MRI scanner control room to accurately target lesions through 4 degrees of freedom while the patient remains in the scanner bore. To maintain compatibility with the MRI environment, piezoelectric motors were used to actuate the needle guidance templates, the device was constructed from non-ferromagnetic materials, and all cables were shielded from electromagnetic interference. The MR compatibility and needle placement accuracy of the device were evaluated with virtual and phantom targets. The system should next be validated for accuracy and usefulness in a clinical trial where more complex tissue properties and potential patient motion will be encountered. Future advances in modeling the tissue properties and compensating for deformation of the prostate, as well as predicting needle deflection, will further bolster the potential of FLA as option for the management of PCa

Developmental delays and subcellular stress as downstream effects of sonoporation

Posters: no. 2Control ID: 1672434OBJECTIVES: The biological impact of sonoporation has often been overlooked. Here we seek to obtain insight into the cytotoxic impact of sonoporation by gaining new perspectives on anti-proliferative characteristics that may emerge within sonoporated cells. We particularly focused on investigating the cell-cycle progression kinetics of sonoporated cells and identifying organelles that may be stressed in the recovery process. METHODS: In line with recommendations on exposure hardware design, an immersion-based ultrasound platform has been developed. It delivers 1 MHz ultrasound pulses (100 cycles; 1 kHz PRF; 60 s total duration) with 0.45 MPa peak negative pressure to a cell chamber that housed HL-60 leukemia cells and lipid-shelled microbubbles at a 10:1 cell-tobubble ratio (for 1e6/ml cell density). Calcein was used to facilitate tracking of sonoporated cells with enhanced uptake of exogenous molecules. The developmental trend of sonoporated cells was quantitatively analyzed using BrdU/DNA flow cytometry that monitors the cell population’s DNA synthesis kinetics. This allowed us to measure the temporal progression of DNA synthesis of sonoporated cells. To investigate whether sonoporation would upset subcellular homeostasis, post-exposure cell samples were also assayed for various proteins using Western blot analysis. Analysis focus was placed on the endoplasmic reticulum (ER): an important organelle with multi-faceted role in cellular functioning. The post-exposure observation time spanned between 0-24 h. RESULTS: Despite maintaining viability, sonoporated cells were found to exhibit delays in cell-cycle progression. Specifically, their DNA synthesis time was lengthened substantially (for HL-60 cells: 8.7 h for control vs 13.4 h for the sonoporated group). This indicates that sonoporated cells were under stress: a phenomenon that is supported by our Western blot assays showing upregulation of ER-resident enzymes (PDI, Ero1), ER stress sensors (PERK, IRE1), and ER-triggered pro-apoptotic signals (CHOP, JNK). CONCLUSIONS: Sonoporation, whilst being able to facilitate internalization of exogenous molecules, may inadvertently elicit a cellular stress response. These findings seem to echo recent calls for reconsideration of efficiency issues in sonoporation-mediated drug delivery. Further efforts would be necessary to improve the efficiency of sonoporation-based biomedical applications where cell death is not desirable.postprin

A study on the change in plasma membrane potential during sonoporation

Posters: no. 4Control ID: 1680329OBJECTIVES: There has been validated that the correlation of sonoporation with calcium transients is generated by ultrasound-mediated microbubbles activity. Besides calcium, other ionic flows are likely involved in sonoporation. Our hypothesis is the cell electrophysiological properties are related to the intracellular delivery by ultrasound and microbubbles. In this study, a real-time live cell imaging platform is used to determine whether plasma membrane potential change is related to the sonoporation process at the cellular level. METHODS: Hela cells were cultured in DMEM supplemented with 10% FBS in Opticell Chamber at 37 °C and 5% CO2, and reached 80% confluency before experiments. The Calcein Blue-AM, DiBAC4(3) loaded cells in the Opticell chamber filled with PI solution and Sonovue microbubbles were immerged in a water tank on a inverted fluorescence microscope. Pulsed ultrasound (1MHz freq., 20 cycles, 20Hz PRF, 0.2-0.5MPa PNP) was irradiated at the angle of 45° to the region of interest for 1s.The real-time fluorescence imaging for different probes was acquired by a cooled CCD camera every 20s for 10min. The time-lapse fluorescence images were quantitatively analyzed to evaluate the correlation of cell viability, intracellular delivery with plasma membrane potential change. RESULTS: Our preliminary data showed that the PI fluorescence, which indicated intracellular delivery, was immediately accumulated in cells adjacent to microbubbles after exposure, suggesting that their membranes were damaged by ultrasound-activated microbubbles. However, the fluorescence reached its highest level within 4 to 6 minutes and was unchanged thereafter, indicating the membrane was gradually repaired within this period. Furthermore, using DIBAC4(3), which detected the change in the cell membrane potential, we found that the loss of membrane potential might be associated with intracellular delivery, because the PI fluorescence accumulation was usually accompanied with the change in DIBAC4 (3) fluorescence. CONCLUSIONS: Our study suggests that there may be a linkage between the cell membrane potential change and intracellular delivery mediated by ultrasound and microbubbles. We also suggest that other ionic flows or ion channels may be involved in the cell membrane potential change in sonoporation. Further efforts to explore the cellular mechanism of this phenomenon will improve our understanding of sonoporation.postprin