Citation: HAN, T. and DAS, D.B., 2015. Potential of combined ultrasound and microneedles for enhanced transdermal drug permeation: a review. European Journal of Pharmaceutics and Biopharmaceutics,89, Additional Information:• NOTICE: this is the author's version of a work that was accepted for publication in European Journal of Pharmaceutics and Biopharmaceutics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive ver- have been developed to overcome the resistance of the stratum corneum to molecular 10 diffusion. In particular, researchers have started to consider the possibility of combining the 11 TDD technologies in order to have further increase in drug permeability. Microneedles (MNs) 12 and ultrasound are both promising technologies. They achieve enhancement in drug 13 permeation via different mechanisms and therefore give a good potential for combining with 14 each other. This review will focus on discussing the potential of this combinational technique 15 along with other important issues, e.g., the mechanisms of ultrasound and MNs as it is these 16 mechanisms which are coupled via the two systems (i.e. MNs and ultrasound). We discuss 17 the possible ways to achieve this combination as well as how this combination would 18 increase the permeability. Some of the undeveloped (weaker) research areas of MNs and 19 sonophoresis are also discussed in order to understand the true potential of combining the two 20 technologies when they are developed further in the future. We propose several hypothetical 21 combinations based on the possible mechanisms involved in MNs and ultrasound. 22Furthermore, we carry out a cluster analysis by which we determine the significance of this 23Page 2 of 54 combinational method in comparison with some other selected combinational methods for 24 TDD (e.g., MNs and iontophoresis). Using a time series analysis tool (ARIMA model), the 25 current trend and the future development of combined MNs and ultrasound are also analysed. 26Overall, the review in this paper indicates that combining MNs and ultrasound is a promising 27 TDD method for the future. 28