Gradient orientation governs mechanical and regenerative outcomes in functionally graded bone scaffolds: a coupled finite element-agent-based modelling study.

Critical-sized bone defects remain a major clinical challenge, requiring scaffolds that combine mechanical stability with regenerative capacity. Functionally graded scaffolds offer a promising strategy by spatially varying porosity to optimise load transfer and tissue ingrowth. Here, we apply an established coupled poroelastic finite element-agent-based modelling (FEA-ABM) framework as a comparative platform to evaluate six cylindrical scaffold configurations modelled using Ti-6Al-4V material properties: two opposing axial-gradient designs, two opposing radial-gradient designs, and their corresponding uniform controls under physiologically representative loading. Poroelastic finite element analysis was used to compute local shear strain and fluid velocity, which regulated progenitor differentiation, proliferation, apoptosis, and migration in the agent-based model. Simulations representing 150 days of healing showed that axial gradients with larger pores at the host bone interface produced the greatest bone ingrowth, reaching approximately 77% pore occupancy compared with 69% in the uniform axial scaffold and 60% in the opposite axial gradient. In contrast, radial gradients did not substantially alter overall bone regeneration compared with the uniform radial scaffold, but the design with denser peripheral struts markedly improved mechanical performance, reducing volume-weighted P99 von Mises stress to approximately 41 MPa compared with about 57-71 MPa in the radial uniform and opposite radial-gradient designs. These findings reveal a design trade-off between regenerative capacity and structural competence, suggesting that gradient orientation should be selected according to the mechanical and biological requirements of the target defect environment. By applying the FEA-ABM framework consistently across the investigated configurations, this study provides comparative evidence to inform the selection of pore-size-gradient designs according to the regenerative and mechanical requirements of the target defect.