Nanoindentation-Informed Skin Bilayer Modeling Links Stiffness Heterogeneity to Curvature Localization Under Glycation and Carbonyl Stress

Glycation and reactive carbonyl stress are protein-modifying processes associated with skin aging, but how they alter local tissue mechanics and deformation-prone behavior remains unclear. Here, reconstructed human epidermis (RHE) and three-dimensional (3D) collagen gels were used as epidermal-like and collagen-rich skin surrogate compartments. Nanoindentation mapping showed that accelerated glycation and carbonyl stress increased the effective Young’s modulus and stiffness heterogeneity in both models, with 2.34–5.85-fold increases in the mean modulus and 1.09–1.31-fold increases in normalized neighbor contrast across four treatment–model combinations: glycated RHE, glycated 3D collagen gel, carbonyl-stressed RHE and carbonyl-stressed 3D collagen gel. Nanoindentation-derived stiffness profiles were incorporated into reduced-order virtual bilayer nonlinear post-buckling simulations. Under imposed end-shortening strains of 1%, 5%, and 10%, glycation- and carbonyl-stress-informed bilayers showed increased predicted peak curvature and localized folding index values. Profile-control simulations were then used to separate average stiffening from spatial stiffness variation. Uniform-mean profiles failed to reproduce the curvature localization response, whereas heterogeneity-preserving mean-matched profiles retained elevated curvature-based outputs. These findings suggest that spatial stiffness heterogeneity, rather than stiffening alone, contributes to predicted curvature localization in skin surrogate bilayers. Beyond mechanistic insight, the nanoindentation–simulation workflow may provide a mechanics-based readout for evaluating prospective cosmetic interventions.