Four‐dimensional immuno‐mechanobiomaterials: Dynamic material cues that program host response to prevent fibrosis and enable regeneration

Abstract

Foreign body responses and fibrosis remain major barriers to the long‐term success of implantable biomaterials and regenerative scaffolds. Conventional biomaterials are typically designed with static mechanical and chemical properties, despite the highly dynamic nature of wound healing and immune activation. Here, we define and critically examine ‘4D immuno‐mechanobiomaterials’: time‐programmed or stimuli‐responsive materials whose evolving physical properties, degradation behaviour and bioactive presentation are engineered to steer immune–stromal dynamics away from chronic inflammation and fibrosis towards functional tissue regeneration. We first summarise current understanding of mechanotransduction in innate and adaptive immune cells and its role in fibrotic encapsulation versus constructive remodelling. We then map the design space of 4D biomaterials, including viscoelastic and stress‐relaxing networks, dynamically crosslinked hydrogels, shape‐morphing and load‐responsive scaffolds, and mechanically active or self‐oscillating systems, highlighting case studies that link time‐varying material properties to specific host response phenotypes in vivo. Emerging experimental and computational tools for quantifying mechano‐immune crosstalk across length and time scales are evaluated, alongside limitations in model systems and metrics. Finally, we discuss translational and regulatory challenges, including manufacturing control of time‐dependent properties and preclinical assessment of immune safety. We conclude with design principles and open questions for deploying 4D immuno‐mechanobiomaterials to reliably prevent biomaterial‐driven fibrosis in the clinic.