Recent Advances in Immunomodulatory Biomaterial Strategies for Neural Tissue Healing

Central and peripheral nervous system injuries represent major causes of neurological disability worldwide, yet current treatment methods are limited by issues including donor site morbidity, regenerative capacity, and tissue availability. Engineered biomaterials are being investigated as alternative strategies for neural tissue repair, but their regenerative efficacy remains variable, in part because of unresolved neuroinflammation and immune-mediated fibrous tissue formation. This review highlights immunomodulation as an important consideration beyond conventional biocompatibility and focuses on macrophage and microglial responses as key components of biomaterial-mediated neural repair. Here we start by outlining the distinct immunological landscapes of central and peripheral neural injury. We then examine how intrinsic material properties including stiffness, porosity, surface chemistry, electrical characteristics, and fiber alignment can influence immune cell behavior. Within this framework, we survey recent preclinical studies of major biomaterial platforms and distinguish, where experimental controls permit, intrinsic material-mediated effects from those produced by incorporated therapeutic cargos. Finally, we discuss the field's inconsistent phenotyping standards, reliance on rodent models, and common failure to assess long-term immunogenicity. Progress toward translation will require rigorous multi-marker characterization of immune-cell states, tissue- and injury-specific interpretation, standardized longitudinal assessment, and stronger integration of immunological outcomes with regenerative and functional endpoints. Collectively, these considerations position immunomodulation as a central design principle for the development of biomaterials for neural tissue repair. STATEMENT OF SIGNIFICANCE: Neural injuries often fail to heal because inflammation persists and implanted materials can promote scar formation. This review moves beyond describing biomaterials as simply biocompatible by evaluating how their physical and chemical properties actively shape macrophage and microglial behavior. By comparing recent strategies across peripheral and central nervous system repair, we identify immune-cell polarization as a central design target and examine how stiffness, porosity, alignment, surface chemistry, degradation, and therapeutic cargo influence healing. We also highlight major limitations in the literature, including inconsistent immune markers, limited long-term testing, and reliance on rodent models. This framework can guide the development of safer, more effective neural repair materials while improving the rigor and clinical relevance of future studies.