Microbubble-Enhanced Cell Membrane Permeability in High Gravity Field

Cell permeability controls the transportation of extracellular materials through cell membranes, which plays a critical role in drug and gene delivery. This work reports an innovative method to enhance the cell permeability through cell-bubble interactions in a high gravity field. In the presence of microbubbles, the cell membrane permeability of mammalian cells was significantly increased in the high gravity field, and up to 80% THP-1 and 70% MCF-7 cells were permeabilized by using FITC-Dextranwith averagemolecularweight of 40 and 70 kDa as fluorescent markers which were found to locate in both cytoplasm and cell nucleus by using a confocal microscope. Micro-scale pores were detected on the cell membrane by a scanning electron microscope after the cellmicrobubble interactions in the high gravity field. The delivery efficiency of FITC-Dextran could be further enhanced in gravity field of higher strength and in solutions with higher volume fraction of microbubbles, though the cell viability would also fall under extreme conditions. A simplified model was proposed to compare the contributions of surface forces (i.e., Derjaguin–Landau–Verwey–Overbeek (DLVO) interaction force and membrane undulation force) with hydrodynamic force associatedwith cell-bubble interactions in the high gravity field. The hydrodynamic force was found to dominate the cell-bubble interaction while the DLVO force and membrane undulation force only play an important role at small separation (<10 nm) and low relative velocity of approach (i.e., low gravity field strength). The enhanced cell membrane permeability and formation of micro-scale pores are mainly due to themicrobubble-cell interactions through collision and/ or cavitation effects from the bursting of microbubbles. Our results have important implications in many bioengineering processeswhich are dependent on cellmembrane permeability. Keywords—Cell membrane permeability, Microbubbles, DLVO force, Hydrodynamic force, High gravity field, Cavitation, THP-1 monocytes, MCF-7 cells. INTRODUCTION Cell membrane, a key component in cell structure, separates the cytoplasm from the outside environment. It also protects the cells and provide pathway for signal transduction and nutrition transfer. Cell permeability is a direct measurement about how easy an extracellular material can go in and out of the cytoplasm through the cell membrane. Cell usually selectively uptakes extracellular materials through endocytosis process. However for some of the materials, like cancer drug or genetic drug, it is very hard to enter the cells based on cells’ own endocytosis ability. Numerous methods have been developed to increase the cell membrane permeability. Lipid and polymer composed particles have been utilized to increase cells’ endocytosis ability. Physical-based methods including electroporation and sonoporation are also investigated. For electroporation, the results from many studies hypothesize that transient holes could be formed when a transmembrane voltage is applied over the cells. If the electric field magnitude applied does not exceed a threshold, the cell surface will eventually recover via the cells’ selfrepairing mechanism. Sonoporation relies on pressure pulses or temperature increases to stimulate a change in the cell’s permeability. In order to improve sonoporation efficiency, microbubbles were used in experiments. The unstable pressure environment causes microbubbles to oscillate or burst. Thereafter, it has been argued that fluid motion, acoustic radiation force or acoustic cavitation will help increase the cell membrane permeability. Qiu showed scanning election microscopy (SEM) images of pores on cell membranes due to the bursting of microbubbles. Address correspondence to Jie Chen, Department of Electrical and Computer Engineering, University of Alberta, W6-050, ECERF, Edmonton, AB T6G 2V4, Canada. Electronic mail: [email protected] Cellular and Molecular Bioengineering, Vol. 6, No. 3, September 2013 ( 2013) pp. 266–278 DOI: 10.1007/s12195-013-0279-6 1865-5025/13/0900-0266/