Mechanically Dynamic and Immuno-Instructive Biomaterials: Converging Strategies to Direct Cell Fate in Regenerative Microenvironments

Abstract

Tissue regeneration is influenced by the dynamic interactions between cells and the extracellular matrix (ECM), in which the repair outcomes are collectively determined by the evolving mechanical properties and strictly regulated immune responses. Conventional biomaterials, which are typically immunologically inert and mechanically static, are unable to replicate the adaptive and inflammatoryresponsive characteristics of native regenerative microenvironments. Adaptive hydrogel networks, tuneable stiffness, viscoelasticity, stress relaxation, and mechanically dynamic biomaterials have been shown to regulate the fate of stem cells through mechanotransduction pathways that involve Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signalling, cytoskeletal remodelling, and integrins. At the same time, immuno-instructive biomaterials have become important modulators of interactions between biomaterials and immune cells. They affect the functional plasticity of macrophages beyond the traditional M1/M2 framework, guide cytokine profiles, and shape tissue-specific responses like osteoimmunological regulation. Increasing evidence suggests that mechanical cues and inflammatory processes are mechanistically coupled during the healing process, with matrix remodelling influencing immune behaviour and vice versa. A promising approach to the development of ECM-mimetic scaffolds that can orchestrate coordinated tissue repair is provided by convergent design strategies that incorporate immune modulation with mechanical adaptability. The consideration of host responses, degradation kinetics, and translational challenges is still necessary for clinical implementation. Integrating immuno-instructive and mechanically dynamic principles is a biologically informed approach to regulating cell fate in regenerative microenvironments.