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Direct-detection CMOS image sensors optimized for charged-particle imaging applications, such as electron microscopy and particle physics, have been designed, fabricated and characterized. Based on standard silicon CMOS active pixel sensor (APS) technology, the sensor arrays uses an 8 to 20 mum epitaxial layer that acts as a thicker sensitive region in the generation and collection of ionization electrons resulting from impinging high-energy particles. A range of optimizations to this technology have been developed via simulation and experimental device design. These include the simulation and measurement of charge collection efficiency versus recombination, effect of diode size and stray capacitance versus signal gain and noise, and the effect of different epitaxial silicon depths and the energy of incident electrons. Results from several experimental devices are presented and compared with simulations, including measurements from two prototypes that systematically and independently vary pixel pitch and diode area.