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Materials, processes and reliability challenges in mixed-signal (Digital, Optical and RF) microvia substrates for System-on-a-package (SOP) technology are presented. Models and methodologies to thermo-mechanically evaluate the microvia substrate reliability are discussed. Upfront process mechanics models with design of simulations approach are presented to evaluate various dielectrics and substrate materials with respect to warpage, dielectric cracking and microvia reliability in multi-layered microvia boards. Systematic optimization studies are conducted to arrive at appropriate set of material and geometry parameters to minimize the inelastic strain in the microvias, the film stress in the dielectric, and the warpage in the substrate. The test vehicles are subjected to liquid-to-liquid thermal shock cycles between -55°C to 125°C to assess reliability and model validation. Material length scale effects due to reduced feature sizes of microvias (10 microns or less) are addressed through computational algorithms to simulate the increased plastic strain hardening effects due to spatial strain gradients. System-level mixed-signal reliability is also discussed taking into consideration component-level reliability as well as statistical implications.