Beyond Conventional: A Review of Phytochemical-Hydrogel Systems Enhanced by AI and 3D Printing for Chronic Wound...

Chronic wounds represent a global healthcare challenge, characterized by persistent inflammation, microbial infection, and compromised tissue regeneration, often refractory to conventional therapies. Natural phytochemicals, with their inherent diverse bioactivities, provide a multi-target approach to modulate inflammation and accelerate tissue repair, overcoming the limitations of single-agent interventions. However, their clinical utility is frequently limited by poor physicochemical stability, low bioavailability, and insufficient retention at the wound site. Advanced hydrogel platforms serve as effective delivery systems, capable of encapsulating these potent compounds to ensure localized, sustained, and on-demand release, addressing critical translational barriers. This review examines the wound-healing mechanisms and molecular targets of key phytochemical classes, critically analyzing their physicochemical limitations. We then discuss the rational design principles of phytochemical hydrogel systems, encompassing stimuli-responsive networks, externally triggered release modalities, and 3D-printed scaffolds for precise spatial drug distribution. We also highlight the emerging role of artificial intelligence in accelerating this field, from predicting hydrogel characteristics and screening novel phytochemicals to optimizing formulation strategies. Finally, we propose a strategic translational roadmap, addressing crucial aspects such as botanical standardization, scalable manufacturing, and regulatory pathways, to support the clinical translation of these systems.