Engineering predictive human-relevant models: biomaterials at the interface of biology and function

Discovering pathophysiological pathways and disease treatments relies on access to human-relevant tissue models. Two-dimensional (2D) in vitro cultures and animal models remain foundational to biomedical research; however, 2D systems lack tissue-level complexity, and species-specific differences limit the translational fidelity of animal data. Addressing this gap requires a shift from biologically representative models towards functionally predictive systems capable of generating quantitative, physiologically meaningful readouts of human tissues. Biomaterials have emerged as the critical engineering interface enabling this shift, providing tuneable control over the biochemical, mechanical, and structural cues that govern cell fate and tissue function and dysfunction. In this perspective, we examine four converging domains advancing human-relevant modelling: biomaterial-based non-animal systems that reduce reliance on interspecies extrapolation; organ-on-chip platforms that recreate dynamic, multi-tissue physiological environments; and organoids and 3D bioprinting, which build living tissue complexity from self-organising or engineered cellular systems. Biomechanical validation approaches complete this picture, ensuring engineered constructs faithfully reproduce native tissue function rather than structure alone. We propose that their integration, rather than independent use, provides a framework for next-generation human-relevant models. The future of predictive human modelling lies not in biological complexity alone, but in the deliberate integration of material design, biological organisation, physiological function, and rigorous validation to generate human-relevant systems with greater translational value and reduced reliance on animal experimentation.