Creating materials that are capable of catalyzing enzymatic reactions could be important to the treatment of both acute and chronic wounds, as well as other topical diseases. As a first step in the design of catalytic biomaterials, a new class of proteinoid microsphere (PM), that includes amino acids found in phosphatase enzyme active sites, has been constructed. This material can significantly enhance catalytic activity for phosphoester hydrolysis, with observed specific activity increases between 35- and 55-fold. Further specific activity increases occur when metal cations, notably iron or zinc, are added to the PMs. Specific activity increases between 140- and 300-fold for these metal modified systems are measured. The phosphatase activity increase is demonstrated for both aromatic phosphate esters as well as the high-energy phosphate bond of adenosine triphosphate. PMs bind substrate heterogeneously on their surfaces in an enthalpically driven reaction that is defined by an overall favorable free energy, but unfavorable entropy. The catalytic PMs have been successfully blended with polyolefin foam and extruded with PLA. These materials remain fully active. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.