The impact of size scales and orientations of polymeric scaffold architectural cues on human macrophage polarisation

Macrophage polarisation is crucial for initiating inflammation in response to biomaterial scaffolds, significantly influencing tissue integration and regeneration<i>in vivo</i>. Modulating macrophage polarisation towards a tissue-regeneration-favouring phenotype through the physical properties of scaffolds offers a promising strategy to enhance tissue regeneration while minimising unfavourable immune responses. However, the critical impact of scaffold physical properties, such as size-scale dimensions, orientation of architectural cues, and local-stiffness of these cues on macrophage polarisation, remains largely unexplored and inadequately understood. This study investigates the combinatorial effects of the physical properties of 3D scaffolds made from poly (<i>ϵ</i>-caprolactone) on human macrophage polarisation. Our findings indicate that the size-scale dimensions and orientation of the architectural cues of the scaffold play crucial roles in determining cell shape, attachment, and the modulation of key gene expression (iNOS, IL-1<i>β</i>, MRC1, ARG), as well as cytokines (TNF-<i>α</i>, IL-10) release associated with the polarisation of human macrophages. Specifically, in scaffolds with architectural cues at larger scales (⩾300 µm diameter), macrophage polarisation is primarily determined by the size-scale of the architectural cues and scaffold stiffness, rather than orientation. Conversely, at smaller scales (⩽15 µm), the orientation of the scaffold's architectural cues plays a more critical role. These insights underscore the pivotal role of scaffold design in modulating immune responses for enhanced tissue regeneration, offering valuable guidance for the rational development of biomaterial scaffolds in regenerative medicine.