Cannabidiol-Loaded Smart Hydrogels for Advanced Wound Healing: Drug Delivery Innovations and Therapeutic Perspectives

Abstract: Chronic wounds are a leading healthcare burden worldwide, fueled by intricate pathophysiology and the inadequacy of standard therapies. The present review critically discusses the novel paradigm of incorporating cannabidiol (CBD), a phytocannabinoid with significant anti-inflammatory, antioxidant, antimicrobial, and pro-regenerative capacities, into advanced smart hydrogel platforms for better wound healing and tissue regeneration. We summarize the strong rationale for CBD, focusing on its multimodal pharmacological effects on central pathways (e.g., proinflammatory cytokines, oxidative stress, fibroblast activity, angiogenesis, endocannabinoid system) and reconciling its inherent delivery issues (poor solubility, instability, pharmacokinetics). The review comprehensively addresses the engineering of stimulus-responsive hydrogels (pH-, temperature-, enzyme-, redox-sensitive) to surmount these challenges. Material properties of key interest—biocompatibility, biodegradation tuneability, mechanical cues emulating ECM, and microenvironment control—are addressed together with innovative crosslinking mechanisms (dynamic covalent bonds, supramolecular interactions) as well as state-of-the-art fabrication techniques (3D/4D bioprinting, electrospinning, microfluidics). We have outlined the mechanisms of controlled release of CBD by wound-specific cues and investigated the synergistic interaction between CBD delivery dynamics and hydrogel characteristics in regulating key cellular events (macrophage polarization, re-epithelialization, ECM remodeling). Preclinical proof of principle for CBD-hydrogel therapeutic utility in various wound models (diabetic, infected, burn) is assessed, with discussion of the landscape of clinical translation, regulatory avenues, and ongoing challenges (scalability, standardization, long-term safety). Lastly, the review points to future frontiers such as closed-loop “sense-and-respond” systems, AI-assisted design, personalized point-of-- care manufacturing, and combinatorial strategies. We conclude that smart CBD-loaded hydrogels hold a promising approach to meeting unmet needs in treating chronic wounds by delivering localized, sustained, and physiologically responsive release to realize CBD's full therapeutic potential for regenerative medicine.