- In our previous study we proposed the use of chemical penetration enhancers for noninvasive detection of fetus abnormalities that can also be utilized for direct fetal drug delivery. In an attempt to further increase the mass transport rate across the amniotic membrane, thus shortening the procedure and improving the applicability of the proposed procedure, the effect and mechanism of combining ultrasound exposure with chemical penetration enhancers' application were assessed. The combined effect was evaluated in vitro on post-delivery human amniotic membrane and ex vivo on rat's whole amniotic sac. Ultrasound effect has been assessed by dye experiments using a customized image analysis program. Additional insights of ultrasound effect's mechanism on biological membranes are presented. Previously we have determined that chemical penetration enhancers affect the fetal membranes via two mechanisms termed as ‘extractors’ and ‘fluidizers’. In this study, we found that combining ultrasound with a ‘fluidizer’ CPE ( e.g. bupivacaine) results in a synergistic enhancement (90-fold) of fetal membrane's mass transport, while combining ultrasound with ‘extractors’ ( e.g. ethanol and NMP) results in an antagonistic effect. The combined procedure is faster and gain greater accuracy than the applications of sole chemical penetration enhancers.