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This study examined how spatially heterogeneous orientations, captured by high-resolution imaging and embedded in image-based finite element models, could provide novel mechanistic insights into tissue micromechanics. Serial block-face scanning electron microscopy (SBF-SEM) captured collagen architecture from fresh human skin dermis. Voxel-level 3D fibre orientations were extracted via structure tensor analysis. Voxel-based hexahedral meshes with element-level orientations were implemented in Abaqus\/Standard with custom UMATs\u00ae user subroutines for invariant-based transversely isotropic hyperelasticity, and compared to classical models with spatially uniform fibre distributions under various loading conditions. Spatial heterogeneity significantly altered micromechanical responses. Under pseudo-homogeneous uniaxial extension aligned with the mean fibre orientation, Models 1A (uniform orientation, no dispersion), 1B (uniform orientation with dispersion), and 1C (spatially heterogeneous orientations) yielded nominal stresses at 44.6% Green\u2013Lagrange strain differing by a factor of four (0.5, 0.8 and 2.1\u00a0MPa, respectively). Model 1C's maximum principal logarithmic strain showed a broader range with a secondary peak at 0.5 versus unimodal peaks at 0.3 for Models 1A\/B. With a purely quadratic fibre energy, Model 1C recovered exponential-like macroscopic stiffening for fibre moduli of 25\u2013500\u00a0MPa, confirming the J-shape arises from microstructural mechanism rather than through fibre material nonlinearity. The methodology delivers quantitative mechanistic insights into dermal micromechanics and generalises to a wide range of soft tissues from cornea and cartilage to arteries and lungs.<\/jats:p>","DOI":"10.1007\/s10237-026-02090-6","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T02:15:20Z","timestamp":1782440120000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating serial block-face SEM with voxel-based finite element analysis for high-fidelity micromechanical modelling of anisotropic soft tissues: application to human dermis"],"prefix":"10.1007","volume":"25","author":[{"given":"Jia","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orestis L.","family":"Katsamenis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georges","family":"Limbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"2090_CR1","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1109\/38.933522","volume":"21","author":"J Ahrens","year":"2001","unstructured":"Ahrens J, Brislawn K, Martin K, Geveci B, Law CC, Papka M (2001) Large-scale data visualization using parallel data streaming. 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