Therapeutic applications of ultrasound in the presence of microbubbles, droplets, and echogenic nanoparticles for tissue engineering and drug delivery
Open AccessUltrasound can be used for a variety of different applications, spanning diagnostic imaging, therapeutic treatment, and cleaning. To improve the therapeutic use ultrasound and effectively deliver drugs or growth factors, microbubbles, microdroplets, or echogenic nanoparticles can be utilized. This work outlines ways to broaden the use of therapeutic ultrasound and microbubbles, microdroplets, and echogenic nanoparticles for use in tissue engineering and drug delivery through several different subprojects. The first chapter investigates the effects of lipid-coated microbubbles in the presence of low intensity pulsed ultrasound (LIPUS) on human mesenchymal stem cells seeded on 3-dimensionally printed poly(lactic acid) (PLA) porous scaffolds. LIPUS stimulation for 3 minutes a day with 0.5% (v/v) microbubbles resulted in a significant increase in proliferation and osteogenic differentiation biomarkers. Integrating LIPUS and microbubbles promises to be novel and effective strategy for improving current bone tissue engineering and regeneration therapies. The second subproject addresses the significant challenges that researchers today face to effectively create biomimetic constructs in tissue engineering with sustained and controlled delivery of growth factors. We explored addition of phase-shift droplets inside the scaffolds for possible temporal and spatial control of growth factor delivery when exposed to ultrasound. Gelatin Methacrylate (GelMA) is a popular hydrogel used for tissue engineering applications due to its biocompatibility, tunable mechanical properties, and rapid reproducibility. We embedded phase-shift perfluorocarbon droplets within the GelMA resin prior to crosslinking and characterized the acoustic droplet vaporization (ADV) and inertial cavitation (IC) thresholds of the embedded droplets. We were successful in vaporizing a variety of perfluorocarbon cores under different frequencies and inside hydrogels of varying mechanical properties. Acoustic droplet vaporization thresholds in GelMa scaffold were determined as a function of frequency varying scaffold properties. Microbubbles and perfluorocarbon droplets are limited to blood stream circulation and cannot penetrate surrounding tissue due to their larger size, 1-10 µm in diameter. Researchers have sought to develop nano-sized echogenic liposomes and polymersomes for applications requiring tissue penetration but use of these particles is limited by fast clearance and possible immune responses. Exosomes are naturally secreted extracellular bilayer vesicles with diameters ranging 40–130 nm. In the third subproject, we describe a successful rendering of bovine milk derived exosomes to be echogenic and corresponding acoustic characterization. Echogenic exosomes combine the benefits of the acoustic responsiveness of traditional microbubbles while being non-immunogenic and having small-size morphology. In the last section, the effects of ultrasound on healthy breast and endothelial cells are explored. The healthy breast cells show higher proliferation under LIPUS exposure, a contrast to breast cancer cells. These results are promising for low-intensity-ultrasound-based cancer therapy. The permeability of different endothelial cell monolayers was measured as it was exposed to mannitol and ultrasound. Mannitol is a commonly used osmotic agent for opening the blood-brain barrier. The observed differences in permeability magnitude and duration induced by mannitol were contrasted with ultrasound. Despite the cellular effects of ultrasound-induced blood-brain barrier remaining largely unknown, we show that endothelial cells appear to play a role.
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