The long-term objective is to develop and optimize a novel, noninvasive, iontophoretic approach for clinical monitoring via the skin. The low-level current density drives both charged and highly polar (yet neutral) compounds across the skin at rates much greater than passive diffusion. As the skin offers a uniquely accessible body surface across which information can be extracted, we hypothesize that truly noninvasive and highly sensitive devices, which exploit uniquely paired flows of at least two substances, can be developed for iontophoretic monitoring applications. The research strategy will optimize iontophoretic and sensing technology to satisfy three key criteria for success: (a) fundamental understanding of electrotransport across the skin; (b) reproducible enhancement of transdermal permeability to identify clinical monitoring opportunities via the skin; and (c) characterization and validation of simple, user-friendly devices for sample collection coupled with sensitive and specific analytical tools. The specific aims of the project are:- [1] To refine understanding of electrotransport across the skin; to exploit the interactions (and independence) of solute and ion flows in the presence of an applied electric field. [2] To demonstrate that the simultaneous, 'reverse iontophoretic' extraction of a target analyte, together with an endogenous substance of essentially constant concentration within the body, can offer truly noninvasive, clinical monitoring. [3] To engineer simple, elegant, prototypical devices, of small volume (100 mu-L or less), into which reverse iontophoretically extracted samples may be efficiently collected. [4] To couple these systems to highly sensitive and specific chromatographic and electrochemical analytical tools both off-line and, eventually, on-line, in situ. Proof-of-principle targets three analytes of significant interest: glucose, phenylalanine and lithium. Furthermore, the bioengineering and analytical chemistry advances envisaged will allow broad, 'mass-screening' of the substances extracted (and extractable) by reverse iontophoresis revealing additional opportunities for the approach. In summary, this project aims to evaluate iontophoretic bioengineering technology in vivo in man; specifically, applications with respect to clinical chemistry and therapeutic drug monitoring are foreseen.