Chrit T. W. Moonen

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands

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Publications (326)901.32 Total impact

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    ABSTRACT: Microbubbles (MBs) in combination with ultrasound (US) can enhance cell membrane permeability, and have the potential to facilitate the cellular uptake of hydrophilic molecules. However, the exact mechanism behind US- and MB-mediated intracellular delivery still remains to be fully understood. Among the proposed mechanisms are formation of transient pores and endocytosis stimulation. In our study, we investigated whether endocytosis is involved in US- and MB-mediated delivery of small molecules. Dynamic fluorescence microscopy was used to investigate the effects of endocytosis inhibitors on the pharmacokinetic parameters of US- and MB-mediated uptake of SYTOX Green, a 600 Da hydrophilic model drug. C6 rat glioma cells, together with SonoVue(®) MBs, were exposed to 1.4 MHz US waves at 0.2 MPa peak-negative pressure. Collection of the signal intensity in each individual nucleus was monitored during and after US exposure by a fibered confocal fluorescence microscope designed for real-time imaging. Exposed to US waves, C6 cells pretreated with chlorpromazine, an inhibitor of clathrin-mediated endocytosis, showed up to a 2.5-fold significant increase of the uptake time constant, and a 1.1-fold increase with genistein, an inhibitor of caveolae-mediated endocytosis. Both inhibitors slowed down the US-mediated uptake of SYTOX Green. With C6 cells and our experimental settings, these quantitative data indicate that endocytosis plays a role in sonopermeabilization-mediated delivery of small molecules with a more predominant contribution of clathrin-mediated endocytosis.
    Physical Biology 07/2015; 12(4):046010. DOI:10.1088/1478-3975/12/4/046010 · 3.14 Impact Factor
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    ABSTRACT: While respiratory motion compensation for magnetic resonance (MR)-guided high intensity focused ultrasound (HIFU) interventions has been extensively studied, the influence of slow physiological motion due to, for example, peristaltic activity, has so far been largely neglected. During lengthy interventions, the magnitude of the latter can exceed acceptable therapeutic margins. The goal of the present study is to exploit the episodic workflow of these therapies to implement a motion correction strategy for slow varying drifts of the target area and organs at risk over the entire duration of the intervention. The therapeutic workflow of a MR-guided HIFU intervention is in practice often episodic: Bursts of energy delivery are interleaved with periods of inactivity, allowing the effects of the beam on healthy tissues to recede and/or during which the plan of the intervention is reoptimized. These periods usually last for at least several minutes. It is at this time scale that organ drifts due to slow physiological motion become significant. In order to capture these drifts, the authors propose the integration of 3D MR scans in the therapy workflow during the inactivity intervals. Displacements were estimated using an optical flow algorithm applied on the 3D acquired images. A preliminary study was conducted on ten healthy volunteers. For each volunteer, 3D MR images of the abdomen were acquired at regular intervals of 10 min over a total duration of 80 min. Motion analysis was restricted to the liver and kidneys. For validating the compatibility of the proposed motion correction strategy with the workflow of a MR-guided HIFU therapy, an in vivo experiment on a porcine liver was conducted. A volumetric HIFU ablation was completed over a time span of 2 h. A 3D image was acquired before the first sonication, as well as after each sonication. Following the volunteer study, drifts larger than 8 mm for the liver and 5 mm for the kidneys prove that slow physiological motion can exceed acceptable therapeutic margins. In the animal experiment, motion tracking revealed an initial shift of up to 4 mm during the first 10 min and a subsequent continuous shift of ∼2 mm/h until the end of the intervention. This leads to a continuously increasing mismatch of the initial shot planning, the thermal dose measurements, and the true underlying anatomy. The estimated displacements allowed correcting the planned sonication cell cluster positions to the true target position, as well as the thermal dose estimates during the entire intervention and to correct the nonperfused volume measurement. A spatial coherence of all three is particularly important to assure a confluent ablation volume and to prevent remaining islets of viable malignant tissue. This study proposes a motion correction strategy for displacements resulting from slowly varying physiological motion that might occur during a MR-guided HIFU intervention. The authors have shown that such drifts can lead to a misalignment between interventional planning, energy delivery, and therapeutic validation. The presented volunteer study and in vivo experiment demonstrate both the relevance of the problem for HIFU therapies and the compatibility of the proposed motion compensation framework with the workflow of a HIFU intervention under clinical conditions.
    Medical Physics 07/2015; 42(7):4137. DOI:10.1118/1.4922403 · 3.01 Impact Factor
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    ABSTRACT: Thermal ablation with high intensity focused ultrasound (HIFU) is an emerging noninvasive technique for the treatment of solid tumors. HIFU treatment of malignant tumors requires accurate treatment planning, monitoring and evaluation, which can be facilitated by performing the procedure in an MR-guided HIFU system. The MR-based evaluation of HIFU treatment is most often restricted to contrast-enhanced T1 -weighted imaging, while it has been shown that the non-perfused volume may not reflect the extent of nonviable tumor tissue after HIFU treatment. There are multiple studies in which more advanced MRI methods were assessed for their suitability for the evaluation of HIFU treatment. While several of these methods seem promising regarding their sensitivity to HIFU-induced tissue changes, there is still ample room for improvement of MRI protocols for HIFU treatment evaluation. In this review article, we describe the major acute and delayed effects of HIFU treatment. For each effect, the MRI methods that have been-or could be-used to detect the associated tissue changes are described. In addition, the potential value of multiparametric MRI for the evaluation of HIFU treatment is discussed. The review ends with a discussion on future directions for the MRI-based evaluation of HIFU treatment. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 06/2015; DOI:10.1002/mrm.25758 · 3.40 Impact Factor
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    ABSTRACT: To investigate the effect of the aqueous and fatty tissue magnetic susceptibility distribution on absolute and relative temperature measurements as obtained directly from the water/fat (w/f) frequency difference. Absolute thermometry was investigated using spherical phantoms filled with pork and margarine, which were scanned in three orthogonal orientations. To evaluate relative fat referencing, multigradient echo scans were acquired before and after heating pork tissue via high-intensity focused ultrasound (HIFU). Simulations were performed to estimate the errors that can be expected in human breast tissue. The sphere experiment showed susceptibility-related errors of 8.4°C and 0.2°C for pork and margarine, respectively. For relative fat referencing measurements, fat showed pronounced phase changes of opposite polarity to aqueous tissue. The apparent mean temperature for a numerical breast model assumed to be 37°C was 47.2 ± 21.6°C. Simulations of relative fat referencing for a HIFU sonication (ΔT = 29.7°C) yielded a maximum temperature error of 6.6°C compared with 2.5°C without fat referencing. Variations in the observed frequency difference between water and fat are largely due to variations in the w/f spatial distribution. This effect may lead to considerable errors in absolute MR thermometry. Additionally, fat referencing may exacerbate rather than correct for proton resonance frequency shift-temperature measurement errors. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 05/2015; DOI:10.1002/mrm.25727 · 3.40 Impact Factor
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    ABSTRACT: High-intensity focused ultrasound allows for minimally invasive, highly localized cancer therapies that can complement surgical procedures or chemotherapy. For high-intensity focused ultrasound interventions in the upper abdomen, the thoracic cage obstructs and aberrates the ultrasonic beam, causing undesired heating of healthy tissue. When a phased array therapeutic transducer is used, such complications can be minimized by applying an apodization law based on analysis of beam path obstructions. In this work, a rib detection method based on cavitation-enhanced ultrasonic reflections is introduced and validated on a porcine tissue sample containing ribs. Apodization laws obtained for different transducer positions were approximately 90% similar to those obtained using image analysis. Additionally, the proposed method provides information on attenuation between transducer elements and the focus. This principle was confirmed experimentally on a polymer phantom. The proposed methods could, in principle, be implemented in real time for determination of the optimal shot position in intercostal high-intensity focused ultrasound therapy. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.
    Ultrasound in medicine & biology 04/2015; 41(6). DOI:10.1016/j.ultrasmedbio.2015.01.024 · 2.10 Impact Factor
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    ABSTRACT: The endothelial cells of vessels, the interstitial matrix and the distance between the tumor cells and vessels, are the major penetration barriers for intravenously administered anticancer drugs in reaching tumor cells after intravenous injection. The availability of a tumor tissue-mimicking model that includes both the endothelial cell layer and the extracellular matrix would be beneficial to assess drug penetration in early stages of drug development. Here, we propose a novel in vitro model for studying the above mentioned barriers. Human umbilical vein endothelial cells were cultured as a single layer on a collagen type-I coated permeable cell culture insert. After culturing for five days, the insert was superimposed on collagen type-I gel containing cancer cells. The system was evaluated for assessing penetration-enhancement by ultrasound triggered microbubble cavitation. Our model allowed visualization of the penetration distance of a model drug (fluorescein isothiocyanate-Dextran 500,000-conjugated, FD500) from the endothelial cell layer into the cancer cell containing collagen matrix upon different sonication treatments. Initial results showed that the model allows the visualization of drug penetration and that the endothelial cell layer is affecting this. The presented in vitro model aims to mimic vessels and stromal tissue in cancer, and thus can aid in the assessment of drug penetration in the case of tumor-targeted drug delivery, and in the reduction and refinement of animal studies. Copyright © 2015. Published by Elsevier B.V.
    International Journal of Pharmaceutics 01/2015; 482(1-2). DOI:10.1016/j.ijpharm.2015.01.039 · 3.79 Impact Factor
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    ABSTRACT: Ultrasound (US) induced cavitation can be used to enhance the intracellular delivery of drugs by transiently increasing the cell membrane permeability. The duration of this increased permeability, termed temporal window, has not been fully elucidated. In this study, the temporal window was investigated systematically using an endothelial- and two breast cancer cell lines. Model drug uptake was measured as a function of time after sonication, in the presence of SonoVue™ microbubbles, in HUVEC, MDA-MB-468 and 4T1 cells. In addition, US pressure amplitude was varied in MDA-MB-468 cells to investigate its effect on the temporal window. Cell membrane permeability of HUVEC and MDA-MB-468 cells returned to control level within 1-2h post-sonication, while 4T1 cells needed over 3h. US pressure affected the number of cells with increased membrane permeability, as well as the temporal window in MDA-MB-468 cells. This study shows that the duration of increased membrane permeability differed between the cell lines and US pressures used here. However, all were consistently in the order of 1-3h after sonication. Copyright © 2014. Published by Elsevier B.V.
    International Journal of Pharmaceutics 12/2014; 482(1-2). DOI:10.1016/j.ijpharm.2014.12.013 · 3.79 Impact Factor
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    ABSTRACT: Dynamic MR-imaging can provide functional and positional information in real-time, which can be conveniently used on-line to control a cancer therapy, e.g. using High Intensity Focused Ultrasound or Radio Therapy. However, a precise realtime correction for motion is fundamental in abdominal organs to ensure an optimal treatment dose associated with a limited toxicity in nearby organs at risk. This paper proposes a real-time direct PCA-based technique which offers a robust approach for motion estimation of abdominal organs and allows correcting motion related artifacts. The PCA was used to detect spatio-temporal coherences of the periodic organ motion in a learning step. During the interventional procedure, physiological contributions were characterized quantitatively using a small set of parameters. A coarse-to-fine resolution scheme is proposed to improve the stability of the algorithm and afford a predictable constant latency of 80 ms. The technique was evaluated on 12 free-breathing volunteers and provided an improved real-time description of motion related to both breathing and cardiac cycles. A reduced learning step of 10 s was sufficient without any need for patient-specific control parameters, rendering the method suitable for clinical use.
    IEEE Transactions on Medical Imaging 11/2014; 34(4). DOI:10.1109/TMI.2014.2371995 · 3.80 Impact Factor
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    ABSTRACT: Local drug delivery by hyperthermia-induced drug release from thermosensitive liposomes (TSLs) may reduce the systemic toxicity of chemotherapy, whilst maintaining or increasing its efficacy. Relaxivity contrast agents can be co-encapsulated with the drug to allow the visualization of the presence of liposomes, by means of R2 *, as well as the co-release of the contrast agent and the drug, by means of R1, on heating. Here, the mathematical method used to extract both R2 * and R1 from a fast dynamic multi-echo spoiled gradient echo (ME-SPGR) is presented and analyzed. Finally, this method is used to monitor such release events. R2 * was obtained from a fit to the ME-SPGR data. Absolute R1 was calculated from the signal magnitude changes corrected for the apparent proton density changes and a baseline Look-Locker R1 map. The method was used to monitor nearly homogeneous water bath heating and local focused ultrasound heating of muscle tissue, and to visualize the release of a gadolinium chelate from TSLs in vitro. R2 *, R1 and temperature maps were measured with a 5-s temporal resolution. Both R2 *and R1 measured were found to change with temperature. The dynamic R1 measurements after heating agreed with the Look-Locker R1 values if changes in equilibrium magnetization with temperature were considered. Release of gadolinium from TSLs was detected by an R1 increase near the phase transition temperature, as well as a shallow R2 * increase. Simultaneous temperature, R2 * and R1 mapping is feasible in real time and has the potential for use in image-guided drug delivery studies. Copyright © 2014 John Wiley & Sons, Ltd.
    NMR in Biomedicine 11/2014; 27(11). DOI:10.1002/nbm.3182 · 3.56 Impact Factor
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    Focused Ultrasound Symposium, Washington DC; 10/2014
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    ABSTRACT: Background Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) has recently emerged as an effective treatment option for painful bone metastases. We describe here the first experience with volumetric MR-HIFU for palliative treatment of painful bone metastases and evaluate the technique on three levels: technical feasibility, safety, and initial effectiveness. Methods In this observational cohort study, 11 consecutive patients (7 male and 4 female; median age, 60 years; age range, 53–86 years) underwent 13 treatments for 12 bone metastases. All patients exhibited persistent metastatic bone pain refractory to the standard of care. Patients were asked to rate their worst pain on an 11-point pain scale before treatment, 3 days after treatment, and 1 month after treatment. Complications were monitored. All data were prospectively recorded in the context of routine clinical care. Response was defined as a ≥2-point decrease in pain at the treated site without increase in analgesic intake. Baseline pain scores were compared to pain scores at 3 days and 1 month using the Wilcoxon signed-rank test. For reporting, the STROBE guidelines were followed. Results No treatment-related major adverse events were observed. At 3 days after volumetric MR-HIFU ablation, pain scores decreased significantly (p = 0.045) and response was observed in a 6/11 (55%) patients. At 1-month follow-up, which was available for nine patients, pain scores decreased significantly compared to baseline (p = 0.028) and 6/9 patients obtained pain response (overall response rate 67% (95% confidence interval (CI) 35%–88%)). Conclusions This is the first study reporting on the volumetric MR-HIFU ablation for painful bone metastases. No major treatment-related adverse events were observed during follow-up. The results of our study showed that volumetric MR-HIFU ablation for painful bone metastases is technically feasible and can induce pain relief in patients with metastatic bone pain refractory to the standard of care. Future research should be aimed at standardization of the treatment procedures and treatment of larger numbers of patients to assess treatment effectiveness and comparison to the standard of care.
    10/2014; 2:16. DOI:10.1186/2050-5736-2-16
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    ABSTRACT: During MR-guided high-intensity focused ultrasound (HIFU) therapy, ultrasound absorption in the near field represents a safety risk and limits efficient energy deposition at the target. In this study, we investigated the feasibility of using T2 mapping to monitor the temperature change in subcutaneous adipose tissue layers. The T2 temperature dependence and reversibility was determined for fresh adipose porcine samples. The accuracy was evaluated by comparing T2 -based temperature measurements with probe readings in an ex vivo HIFU experiment. The in vivo feasibility of T2 -based thermometry was studied during HIFU ablations in the liver in pigs and of uterine fibroids in human patients. T2 changed linearly and reversibly with temperature with an average coefficient of 5.2 ± 0.1 ms/°C. For the ex vivo HIFU experiment, the difference between the T2 -based temperature change and the probe temperature was <0.9°C. All in vivo experiments showed temperature-related T2 changes in the near field directly after sonications. As expected, considerable intersubject variations in the cooling times were measured in the in vivo porcine experiments. The reversibility and linearity of the T2 -temperature dependence of adipose tissue allows for the monitoring of the temperature in the subcutaneous adipose tissue layers. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 10/2014; 72(4). DOI:10.1002/mrm.25025 · 3.40 Impact Factor
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    ABSTRACT: Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) allows for noninvasive thermal ablation under real-time temperature imaging guidance. The purpose of this study was to assess the feasibility and safety of MR-HIFU ablation of liver tissue in a clinically acceptable setting. The experimental protocol was designed with a clinical ablation procedure of a small malignant tumor in mind; the procedures were performed within a clinically feasible time frame and care was taken to avoid adverse events. The main outcome was the size and quality of the ablated liver tissue volume on imaging and histology. Secondary outcomes were safety and treatment time.
    Investigative Radiology 09/2014; DOI:10.1097/RLI.0000000000000091 · 4.45 Impact Factor
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    ABSTRACT: Rationale and Objectives Magnetic resonance–guided high-intensity focused ultrasound (MR-HIFU) ablation of tumors in the liver dome is challenging because of the presence of air in the costophrenic angle. In this study, we used a porcine liver model and a clinical MR-HIFU system to assess the feasibility and safety of using intrapleural fluid infusion (IPI) to create an acoustic window for MR-HIFU ablation in the liver dome. Materials and Methods Healthy adult Dalland land pigs (n = 6) under general anesthesia were used with animal committee approval. Degassed saline (200–800 mL) was infused into the intrapleural space under ultrasound guidance. A clinical 1.5-T MR-HIFU system was used to perform sonications (4-mm treatment cells, 300–450 W, 20–30 seconds) in the liver dome under real-time MR thermometry. An intercostal firing technique was used to prevent rib heating in one experiment. Technical success was defined as a temperature increase (>10°C) in the target area. After termination, the animal was examined for thermal damage to liver, diaphragm, pleura, lung, or intercostal muscle. Results An acoustic window was established in all animals. A temperature increase in the target area was achieved in all animals (max. 47°C–67°C). MR thermometry showed no heating outside the target area. Intercostal firing effectively reduced rib heating (55°C vs. 42°C). Postmortem examination revealed no unwanted thermal damage. One complication occurred, in the first experiment, because of an ill-suited needle (displacement of the needle). Conclusions The results indicate that IPI may be used safely to assist MR-HIFU ablation of tumors in the liver dome. For reliable tissue coagulation, IPI must be combined with an intercostal sonication technique. Considering the proportion of patients with tumors in the liver dome, IPI widens the applicability of MR-HIFU ablation for liver tumors considerably.
    Academic Radiology 08/2014; 21(12). DOI:10.1016/j.acra.2014.06.015 · 2.08 Impact Factor
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    Chrit Moonen, Ine Lentacker
    Advanced drug delivery reviews 04/2014; DOI:10.1016/j.addr.2014.04.002 · 12.71 Impact Factor
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    ABSTRACT: Real-time motion estimation has a growing interest for the guidance of interventional procedures in mobile organs. For this purpose, combined magnetic resonance (MR) imaging and ultrasound (US) echography systems can now provide both MR- and US- images, which can be exploited simultaneously for improved target tracking. For this purpose, two tracking strategies can be investigated: While indirect tracking methods rely on a calibration obtained prior to the intervention, direct tracking methods perform the target localization directly on the continuously acquired position. The current paper describes real-time methodological developments designed for the guidance of non-invasive interventional procedures, using a combined MR/US imaging system: A GPU (Graphics Processing Unit) optimized processing pipeline is proposed for both direct and indirect approaches, in conjunction with simultaneous high-frame-rate MR and echography. Experiments on a moving ex-vivo target were performed with MR-guided HIFU (High Intensity Focused Ultrasound) during continuous ultrasound echography. Real-time US echography-based tracking during MR-guided HIFU heating was achieved with heated area dimensions similar to those obtained for a static target.
    2014 IEEE 11th International Symposium on Biomedical Imaging (ISBI 2014); 04/2014

Publication Stats

9k Citations
901.32 Total Impact Points


  • 2012–2015
    • University Medical Center Utrecht
      • Division of Imaging
      Utrecht, Utrecht, Netherlands
  • 2014
    • Netherlands Institute for Space Research, Utrecht
      Utrecht, Utrecht, Netherlands
  • 2003–2012
    • University of Bordeaux
      Burdeos, Aquitaine, France
  • 2000–2012
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1998–2012
    • Université Victor Segalen Bordeaux 2
      • Centre de Résonance Magnétique des Systèmes Biologiques
      Burdeos, Aquitaine, France
  • 1991–2011
    • Georgetown University
      • Department of Pharmacology
      Rockville, MD, United States
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 2007
    • Centre Hospitalier Universitaire de Bordeaux
      Burdeos, Aquitaine, France
  • 2006
    • Aarhus University Hospital
      • Institute of Clinical Medicine
      Århus, Central Jutland, Denmark
  • 2005
    • University of Tours
      Tours, Centre, France
  • 1989–2005
    • National Institutes of Health
      • • Laboratory of Research Technologies
      • • Office of Intramural Research
      Maryland, United States
  • 2004
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1993–1996
    • National Institute of Mental Health (NIMH)
      • Clinical Brain Disorders Branch
      Bethesda, MD, United States
    • Royal College of Surgeons of England
      Londinium, England, United Kingdom
  • 1994
    • College of Saint Elizabeth
      Washington, Washington, D.C., United States
  • 1982–1991
    • Wageningen University
      • Laboratory of Biochemistry
      Wageningen, Provincie Gelderland, Netherlands
  • 1988
    • University of California, Davis
      • Department of Pediatrics
      Davis, California, United States