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Active pixel sensor (APS) architectures using two transistors per pixel are reported in this paper for high-resolution low-noise digital imaging applications. The fewer number of on-pixel elements and reduced pixel complexity result in a smaller pixel pitch and increased pixel gain, which makes the two-transistor (2T) APS architectures promising for high-resolution, low-noise, and high-speed digital imaging including emerging medical imaging modalities, such as mammography tomosynthesis and cone beam computed tomography. Measured results from in-house fabricated test pixels using amorphous silicon (a-Si) thin-film transistors, as well as driving schemes for minimizing the threshold voltage metastability problem and increasing frame rate, are presented. The results indicate that a pixel input referred noise value of down to 220 electrons is achievable with a 50- -pixel-pitch a-Si 2T APS.