The significance of membrane changes in the safe and effective use of therapeutic and diagnostic ultrasound.

The cellular changes, such as alterations in motility and the stimulation of synthesis and secretion, induced by relatively low intensities of therapeutic ultrasound (e.g. 500 mW cm-2, SAPA; 100 mW cm-2 SATA) are primarily non-thermal in origin. They appear to be associated with changes in the permeability of the cell (plasma) membrane and in the transport of ions and molecules across it, effects which have been demonstrated in cells irradiated in suspension. In epithelial tissues, both in vitro and in vivo, it has been demonstrated that not only the cellular membrane transport pathways but also the paracellular or intercellular pathways are affected. Although membrane-mediated effects can be of value therapeutically, they could produce adverse effects if they were to occur during development, for the reception and transmission by the membrane of environmental signals are involved in determination of the fate of each cell. Determination is followed by selective gene expression and differentiation, that is, by the progressive increase in structural complexity brought about by the acquisition of specialised characteristics by various cell groups. Most cells of early embryos are ionically coupled via gap junctions which provide an intercellular pathway for electrochemical signalling and the maintenance of the concentration gradients which provide the cells with positional information. Differentiation of the cells varies according to their location with respect to these gradients. Increase in the intracellular concentration of calcium ions, which has been shown to occur after exposure to therapeutic levels of ultrasound, can decrease the permeability of gap junctions and uncouple cells, in the manner which occurs when they differentiate. Ultrasonically induced increases in calcium ion concentration are thus of considerable clinical significance, since they could affect differentiation and consequently histogenesis. Modification of plasma membrane permeability and transport properties, resulting in changes in the availability and activity of second messengers such as free calcium ions, can have profound effects on cell behaviour. Calcium channels appear to be the first channels to develop in the cell membranes of embryos, and internal calcium ion concentration is known to affect the synthesis of fetal proteins. Although generally reversible at intensities of less than 500 mW cm-2, changes in membrane permeability, particularly to calcium ions, could, if prolonged, have undesirable side effects not only on embryogenesis but on late prenatal and postnatal development. It is therefore recommended that the environmental conditions, thresholds, and mechanisms involved in the production of such changes be determined, so that they can be avoided when ultrasound is used diagnostically on sensitive targets such as embryos and fetuses.