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Introduction: Simulations based on computational musculoskeletal models are powerful tools for evaluating the effects of potential biomechanical interventions, such as implementing a novel prosthesis. However, the utility of simulations to evaluate the effects of varied prosthesis design parameters on gait mechanics has not been fully realized due to the lack of a readily-available limb loss-specific gait model and methods for efficiently modeling the energy storage and return dynamics of passive foot prostheses. The purpose of this study was to develop and validate a forward simulation-capable gait model with lower-limb loss and a semi-active variable-stiffness foot (VSF) prosthesis. Methods: A seven-segment 28-DoF gait model was developed and forward kinematics simulations, in which experimentally observed joint kinematics were applied and the resulting contact forces under the prosthesis evolved accordingly, were computed for four subjects with unilateral below-knee amputation walking with a VSF. Results: Model-predicted resultant ground reaction force (GRFR) matched well under trial-specific optimized parameter conditions (mean R²: 0.97, RMSE: 7.7% body weight (BW)) and unoptimized (subject-specific, but not trial-specific) parameter conditions (mean R²: 0.93, RMSE: 12% BW). Simulated anterior-posterior center of pressure demonstrated a mean R² = 0.64 and RMSE = 14% foot length. Simulated kinematics remained consistent with input data (0.23 deg RMSE, R² > 0.99) for all conditions. Conclusions: These methods may be useful for simulating gait among individuals with lower-limb loss and predicting GRFR arising from gait with novel VSF prostheses. Such data are useful to optimize prosthesis design parameters on a user-specific basis. [ABSTRACT FROM AUTHOR]