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Wearable assistive devices such as ankle-foot orthoses (AFOs) or exoskeletons are commonly evaluated using musculoskeletal simulations, yet the interface between device and body is typically simplified. In reality, this interface consists of biological soft tissue. Soft tissue deformation influences relative movement, force transmission, and the biomechanical effectiveness of assistive devices. However, this aspect is often neglected in simulation-based design. This study therefore investigates the influence of biological soft tissue on human-device interaction within musculoskeletal modeling. A musculoskeletal simulation model was implemented and extended by integrating an AFO. Biological soft tissue behavior at the device-body interface was represented by viscoelastic spring-damper elements. Simulations were performed using gait data from multiple participants across different walking speeds and AFO support profiles representing varying severities of foot drop. In addition, systematic axis misalignments between the orthosis and the ankle joint were introduced. The simulations revealed that biological soft tissue substantially contributes to relative motion between the AFO and the body segment, with displacements reaching up to 20 mm, particularly near the end of the stance phase during gait. The magnitude of relative movement increased with greater muscle weakness and higher required support forces. In contrast, gait speed and axis misalignment produced comparatively smaller effects. Soft tissue deformation also influenced muscle activation patterns, especially in severely weakened conditions, where deviations of up to 13% were observed in the plantarflexor muscles. The findings demonstrate that incorporating biological soft tissue behavior significantly affects predicted human-orthosis interaction and muscle activation in musculoskeletal simulations. Accounting for these deformations potentially improves the realism of simulation-based analyses and supports more accurate evaluation of assistive device performance. Consequently, explicit modeling of biological soft tissue should be considered essential for the development and optimization of effective and comfortable wearable assistive technologies.