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Acoustic wave biochemical sensors work by detecting the frequency shifts resulting from the binding of target molecules to a functionalized resonator. Resonator types currently in use or under development include macroscopic quartz crystal microbalances (QCMs) as well as a number of different integrated Micro-electro-mechanical Systems (MEMS) structures. Due to an increased resonator surface area to mass ratio, we believe that membrane-based MEMS systems are particularly promising with regard to sensitivity. Prototypes have been developed [S. Hauan etal, U.S. Patent Application (filed 6 Nov. 2003)] and preliminary calculations [M. J. Bartkovsky etal, paper 385e presented at the AIChE Annual Meeting, Nov. 2003; J. E. Valentine etal, paper 197h presented at the AICHE Annual Meeting, Nov. 2003] indicate significant improvements over other methods, both macroscopic and MEMS based. In this article we describe our work on a MEMS-based acoustic wave biochemical sensor using a membrane resonator. We demonstrate the effects of spatial distributions of mass on the membrane on sensitivity and show how to use this spatial sensitivity to detect multiple targets simultaneously. To do so we derive a function approximating the membrane response surface to spatial mass loadings under the applicable range of conditions. We verify the agreement using finite element methods, and present our initial sensitivity calculations demonstrating the advantages of variable mass loadings.