Sonoporation using microbubble-assisted ultrasound increases the permeability of a biological barrier to therapeutic molecules. Application of this method to the round window membrane could improve the delivery of therapeutics to the inner ear. The aim of this study was to assess the safety of sonoporation of the round window membrane in a sheep model. To achieve this objective, we assessed auditory function and cochlear heating, and analysed the metabolomics profiles of perilymph collected after sonoporation, comparing them with those of the control ear in the same animal. Six normal-hearing ewes were studied, with one sonoporation ear and one control ear for each. A mastoidectomy was performed on both ears. On the sonoporation side, Vevo MicroMarker® microbubbles (MBs; VisualSonics—Fujifilm, Amsterdam, The Netherlands) at a concentration of 2 × 108 MB/mL were locally injected into the middle ear and exposed to 1.1 MHz sinusoidal ultrasonic waves at 0.3 MPa negative peak pressure with 40% duty cycle and 100 μs interpulse period for 1 min; this was repeated three times with 1 min between applications. The sonoporation protocol did not induce any hearing impairment or toxic overheating compared with the control condition. The metabolomic analysis did not reveal any significant metabolic difference between perilymph samples from the sonoporation and control ears. The results suggest that sonoporation of the round window membrane does not cause damage to the inner ear in a sheep model.
Tumor spheroids as well as multicellular tumor spheroids (MCTSs) are promising 3D in vitro tumor models for drug screening, drug design, drug targeting, drug toxicity, and validation of drug delivery methods. These models partly reflect the tridimensional architecture of tumors, their heterogeneity and their microenvironment, which can alter the intratumoral biodistribution, pharmacokinetics, and pharmacodynamics of drugs. The present review first focuses on current spheroid formation methods and then on in vitro investigations exploiting spheroids and MCTS for designing and validating acoustically mediated drug therapies. We discuss the limitations of the current studies and future perspectives. Various spheroid formation methods enable the easy and reproducible generation of spheroids and MCTSs. The development and assessment of acoustically mediated drug therapies have been mainly demonstrated in spheroids made up of tumor cells only. Despite the promising results obtained with these spheroids, the successful evaluation of these therapies will need to be addressed in more relevant 3D vascular MCTS models using MCTS-on-chip platforms. These MTCSs will be generated from patient-derived cancer cells and nontumor cells, such as fibroblasts, adipocytes, and immune cells.
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