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    ABSTRACT: Encapsulation of cytotoxic drugs into liposomes enhances pharmacokinetics and improves passive accumulation in tumors. However, stable liposomes have limited drug release, and thus action, at the target site. This inefficient and unpredictable drug release is compounded by a lack of low-cost, non-invasive methods to map release in real time. We present a new liposomal vehicle that is exclusively triggered by inertial cavitation. Ultrasound exposure of these liposomes in the absence of SonoVue® provided no increase in drug release, whilst with SonoVue® at inertial cavitation pressure levels a substantial (30%) and significant (p < 0.001) increase was observed in vitro. A 16-fold increase in the level of drug release within tumors was similarly observed in the presence of inertial cavitation following intravenous delivery. Passive acoustic mapping of inertial cavitation sources during delivery was also found to correlate strongly with the presence of release. However, variability in tumor perfusion indicated that uneven distribution of micron-sized SonoVue® may limit this approach. Nano-scale cavitation nuclei, which may more readily co-localize with 140 nm liposomes, were thus developed and showed similar cavitation energies to SonoVue® in vitro. These nano-nuclei may ultimately provide a more reliable and uniform way to trigger drug release in vivo.
    The Journal of the Acoustical Society of America 11/2013; 134(5):4050. DOI:10.1121/1.4830780
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    ABSTRACT: The localization of microbubbles to a target site has been shown to be essential to their effectiveness in ultrasound mediated drug delivery and gene therapy. The incorporation of super paramagnetic nanoparticles into the microbubble coating enables them to be manipulated using an externally applied magnetic field. Magnetic microbubbles have been shown to be effective in therapeutic delivery both in vitro and in vivo in a mouse model. The aim of this experiment was to determine under what conditions in the human body magnetic microbubbles can be successfully imaged and targeted. Different flow rates and shear rates were generated in a tissue mimicking phantom and targeting was observed using a 9.4 MHz ultrasound imaging probe. For the highest shear rates, targeting was also observed optically. Results indicate that magnetic microbubbles can be successfully targeted at shear rates found in the human capillary system (>1000/s) and at flow rates found in the veins and smaller arteries (~200 ml/s). Successful retention was also demonstrated in a perfused porcine liver model simulating conditions in vivo. This study provides further evidence for the potential of magnetic microbubbles for targeted therapeutic delivery.
    The Journal of the Acoustical Society of America 11/2013; 134(5):3992. DOI:10.1121/1.4830560
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    ABSTRACT: The sampling schedule for chemical exchange saturation transfer imaging is normally uniformly distributed across the saturation frequency offsets. When this kind of evenly distributed sampling schedule is used to quantify the chemical exchange saturation transfer effect using model-based analysis, some of the collected data are minimally informative to the parameters of interest. For example, changes in labile proton exchange rate and concentration mainly affect the magnetization near the resonance frequency of the labile pool. In this study, an optimal sampling schedule was designed for a more accurate quantification of amine proton exchange rate and concentration, and water center frequency shift based on an algorithm previously applied to magnetization transfer and arterial spin labeling. The resulting optimal sampling schedule samples repeatedly around the resonance frequency of the amine pool and also near to the water resonance to maximize the information present within the data for quantitative model-based analysis. Simulation and experimental results on tissue-like phantoms showed that greater accuracy and precision (>30% and >46%, respectively, for some cases) were achieved in the parameters of interest when using optimal sampling schedule compared with evenly distributed sampling schedule. Hence, the proposed optimal sampling schedule could replace evenly distributed sampling schedule in chemical exchange saturation transfer imaging to improve the quantification of the chemical exchange saturation transfer effect and parameter estimation. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 11/2013; 70(5). DOI:10.1002/mrm.24567
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    ABSTRACT: Compelling evidence suggests the limitation and shortcomings of the current and well established cell culture method using multi-well plates, flasks and Petri dishes. These are particularly important when cell functions are sensitive to the local microenvironment, cell-cell and cell-extracellular matrix interactions. There is a clear need for advanced cell culture systems which mimic in vivo and more physiological conditions. This review summarises and analyses recent progress in three dimensional (3D) cell culture with perfusion as the next generation cell culture tools, while excluding engineered tissue culture where three dimensional scaffold have to be used for structural support and perfusion for overcoming mass transfer control. Apart from research activities in academic community, product development in industry is also included in this review.
    Biotechnology advances 10/2013; 32(2). DOI:10.1016/j.biotechadv.2013.10.006
  • Therapeutic delivery 10/2013; 4(10):1213-1215. DOI:10.4155/tde.13.94
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    ABSTRACT: Objective: To combine multiple 3D volumes of the same fetal femur into one composite image data set using image registration and wavelet-based fusion. Fused and single data sets were compared in terms of image quality and femur volume (FV) measurement repeatability. Method: In healthy pregnant volunteers, six volumes of the same femur were acquired and fused into a composite data set. Image quality scores were given to the fused and single data sets by an independent assessor in a blinded fashion; repeatability of FV measurement was assessed using coefficients of variation (CV), intraclass correlation coefficients (ICC) and Bland-Altman plots. Results: Fusion was successful in 24 out of 25 cases. Median image quality score was 7/10 in fused data sets, compared to 6/10 in single data sets (p = 0.096). Repeatability of FV measurement was better in fused data sets (intraobserver CV 4.6% and ICC 0.987; interobserver CV 4.9%, ICC 0.985) compared to single ones (intraobserver CV 5.8%, ICC 0.977; interobserver CV 10.0%, ICC 0.931). The measured FV was significantly higher in fused data sets (mean FV 1.7 vs. 1.3 ml, p < 0.001). Conclusion: Image registration and wavelet-based fusion can improve image quality and FV repeatability; it also results in an increased FV measurement.
    Fetal Diagnosis and Therapy 09/2013; 34(3). DOI:10.1159/000354342
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    ABSTRACT: In dynamic positron emission tomography (PET) neuroimaging studies, where scan durations often exceed one hour, registration of motion-corrupted dynamic PET images is necessary in order to maintain the integrity of the physiological, pharmacological, orbiochemical information derived from the tracer kinetic analysis of the scan. In this work, we incorporate a pharmacokinetic model, which is traditionally used to analyse PET data following any registration, into the registration process itself in order to allow for a groupwise registration of the temporal time frames. The new method is shown to achieve smaller registration errors and improved kinetic parameter estimates on validation data sets when compared with image similarity based registrationapproaches. When applied to measured clinical data from 10 healthy subjects scanned with [(11)C]-(+)-PHNO (a dopamine D3/D2 receptor tracer), it reduces the intra-class variability on the receptor binding outcome measure,further supporting improvements in registration accuracy. Our method incorporates a generic tracer kinetic model which makes it applicable to different PET radiotracers to remove motion artefacts and increase the integrity of dynamic PET studies.
    NeuroImage 08/2013; 84. DOI:10.1016/j.neuroimage.2013.08.031
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    ABSTRACT: This paper presents the AutoQual elastography method: a novel algorithm that improves the quality of 2D displacement field calculation from ultrasound radio frequency (RF) sequences of acutely ruptured Achilles tendons to determine image-lateral strain fields and has potential use for ligaments and muscles. This method uses 2D bicubic spline interpolation of the RF signal, Quality Determined Search, Automatic Search Range and Adaptive Block Size components as a novel combination that is designed to improve continuity and decrease displacement field noise, especially in areas of low signal strength. We present a simple experiment for quantitatively comparing the AutoQual method to a multiscale (MS) elastography method from ultrasound RF sequences of a 5% agar phantom for rigid body motion and known lateral strain loads with speeds up to 5mm/s. We finally present examples of four in vivo Achilles tendons in various damage states and with manual or artificially controlled passive flexion of the foot. Results show that the AutoQual method offers a substantial improvement on the MS method, achieving similar performance for rigid body tracking at all speeds, a lower normalized square error at all strains induced and a more continuous strain field at higher compression rates. AutoQual also showed a greater average normalized cross correlation for image blocks in the area of interest, a lower standard deviation of the strain field and a visually more acceptable point tracking for in vivo examples. This work demonstrates lateral ultrasound elastography which is robust to the complex passive motion of the Achilles and to various imaging artifacts associated with imaging tendon rupture. This method potentially has a wide clinical application for assessing in vivo strains in and hence mechanical function of any near skin surface tissues that are longitudinally loaded.
    Journal of Biomechanics 08/2013; 46(15). DOI:10.1016/j.jbiomech.2013.07.044
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    ABSTRACT: Increasing individuals diagnosed with type II diabetes pose a strong demand for the development of more effective anti-diabetic drugs. However, expensive, ethically controversial animal-based screening for anti-diabetic compounds is not always predictive of the human response. The use of in vitro cell-based models in research presents obviously ethical and cost advantages over in vivo models. This study was to develop an in vitro three-dimensional (3D) perfused culture model of islets (Islet TF) for maintaining viability and functionality longer for diabetic drug efficacy tests. Briefly fresh isolated rat islets were encapsulated in ultrapure alginate and the encapsulated islets were cultured in TissueFlex(®), a multiple, parallel perfused microbioreactor system for 7 days. The encapsulated islets cultured statically in cell culture plates (3D static) and islets cultured in suspension (2D) were used as the comparisons. In this study we demonstrate for the first time that Islet TF model can maintain the in vitro islet viability, and more importantly, the elevated functionality in terms of insulin release and dynamic responses over a 7-day culture period. The Islet TF displays a high sensitivity in responding to drugs and drug dosages over conventional 2D and 3D static models. Actual drug administration in clinics could be simulated using the developed Islet TF model, and the patterns of insulin release response to the tested drugs were in agreement with the data obtained in vivo. Islet TF could be a more predictive in vitro model for routine short- and long-term anti-diabetic drug efficacy testing.
    PLoS ONE 08/2013; 8(8):e72612. DOI:10.1371/journal.pone.0072612
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    ABSTRACT: Passive acoustic mapping (PAM) has been recently demonstrated as a method of monitoring focused ultrasound therapy by reconstructing the emissions created by inertially cavitating bubbles (Jensen et al 2012 Radiology 262 252-61). The published method sums energy emitted by cavitation from the focal region within the tissue and uses a threshold to determine when sufficient energy has been delivered for ablation. The present work builds on this approach to provide a high-intensity focused ultrasound (HIFU) treatment monitoring software that displays both real-time temperature maps and a prediction of the ablated tissue region. This is achieved by determining heat deposition from two sources: (i) acoustic absorption of the primary HIFU beam which is calculated via a nonlinear model, and (ii) absorption of energy from bubble acoustic emissions which is estimated from measurements. The two sources of heat are used as inputs to the bioheat equation that gives an estimate of the temperature of the tissue as well as estimates of tissue ablation. The method has been applied to ex vivo ox liver samples and the estimated temperature is compared to the measured temperature and shows good agreement, capturing the effect of cavitation-enhanced heating on temperature evolution. In conclusion, it is demonstrated that by using PAM and predictions of heating it is possible to produce an evolving estimate of cell death during exposure in order to guide treatment for monitoring ablative HIFU therapy.
    Physics in Medicine and Biology 08/2013; 58(17):5833-5850. DOI:10.1088/0031-9155/58/17/5833
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