Engineering the Immune-Stromal Microenvironment: A Design Framework for Regenerative Biomaterials.

The success of regenerative biomaterials depends not simply on biocompatibility but also on their ability to direct coordinated interactions between immune and stromal compartments that ultimately determine tissue repair, integration, or fibrosis. Rather than viewing inflammation and fibrosis as independent outcomes, this review presents a design framework that links engineered material properties to sequential immune activation, stromal remodeling, and long-term tissue function. We describe how material chemistry, architecture, mechanical properties, degradation behavior, surface modification, and spatiotemporal delivery of bioactive signals shape innate immune sensing, macrophage state transitions, adaptive immune regulation, and the macrophage-fibroblast axis. We further discuss how these interconnected processes regulate extracellular matrix remodeling, vascular adaptation, and fibrotic capsule formation, emphasizing that tissue fate emerges from the coordination of immune and stromal responses rather than from modulation of any single pathway. Drawing on this evidence, we propose a four-layer conceptual framework that organizes engineered inputs, biological processes, stromal responses, and tissue-level outcomes. Rather than functioning as a predictive model, the framework is intended as an evidence-mapping and experimental-design tool that makes explicit where causal links are directly supported, where they are inferred, and where they remain untested. We identify key translational gaps-including study heterogeneity, incomplete stromal and functional assessment, limited clinical validation, and insufficient longitudinal profiling-and propose practical priorities for multiparameter stromal analysis, high-dimensional myeloid phenotyping, intermediate mechanistic models, and application-relevant functional endpoints.