PROJECT SUMMARY / ABSTRACT Finite element analysis has become an indispensable tool for research and discovery in the biomedical sciences. Historically, the lack of an open software environment that was tailored to the needs of the field hampered research progress, dissemination of research and sharing of models and results. To address these issues, we developed the FEBio software suite, a FE framework designed specifically for analysis in biomechanics and biophysics, during our first funding period (FY 2008-2011). FEBio employs mixture theory to account for the multi-constituent nature of biological tissues and fluids, unifying the classical fields of irreversible thermodynamics, solid mechanics, fluid mechanics, mass transport, chemical reactions and electrokinetics. During the second funding period (FY 2012-2015), we implemented chemical reactions between constituents of a mixture and we broadened the target audience for FEBio by developing a plugin environment that made it easy to add features or interface other software with FEBio. During our third funding period (FY 2016-2019), we developed a novel FE framework for simulation of compressible and incompressible CFD, extended this framework to enable analysis of FSI (Fluid-Structure Interaction) problems, and we enhanced algorithmic, analysis and numerical capabilities in FEBio by implementing efficient iterative linear solvers and preconditioners, new nonlinear solution strategies, and adaptive meshing. During our fourth funding period (FY 2020-2023), we introduced significant advances in the modeling of damage mechanics and fatigue failure in biological tissues, as well as the modeling of solute transport in fluid mechanics, fluid-structure interactions, and reactive multiphasic media. We developed a powerful graphical user interface and merged the pre-processing, finite element analysis, and post-processing packages into a single user environment called FEBio Studio. We also integrated the use of image data with the simulation pipeline, from model setup to model validation. In the current application we propose to advance our modeling techniques by (1) developing a modeling framework for thermomechanics in solids, fluids, and mixtures; (2) incorporating experimental data to constrain finite element solutions; (3) modeling immersed solid, biphasic, or multiphasic bodies in fluid domains, accounting for FSI and resolving the fluid shear stress in boundary layers surrounding the body; and (4) facilitating software development by the user community. These new capabilities will expand the applicability of FEBio to new fields of biomedical research, increasing our user base and facilitating scientific advancement.