Title : Advanced multi-stimuli-responsive nanocomposite hydrogels for smart drug delivery and skin tissue regeneration: A comprehensive review
Abstract:
Chronic skin defects, extensive burn injuries, and non-healing diabetic ulcers present formidable clinical challenges worldwide due to persistent inflammation, microvascular disruption, and high susceptibility to microbial infections. Conventional wound dressings fail to adapt dynamically to the rapidly altering microenvironment of repairing cutaneous tissue. Consequently, advanced multi-stimuli-responsive nanocomposite hydrogels have emerged as a revolutionary paradigm in soft tissue engineering and precision medicine. These intelligent platforms mimic the architecture and biochemical complexity of the natural extracellular matrix (ECM) while demonstrating smart behavioral adaptability. By reacting synergistically to endogenous pathological biomarkers—such as tissue pH shifts, elevated reactive oxygen species (ROS) levels, matrix metalloproteinase (MMP) overexpression, and local temperature variations—alongside exogenously applied physical triggers (e.g., near-infrared light, alternating magnetic fields, or electrical stimulation), these hydrogels achieve unprecedented spatiotemporal control over therapeutic delivery.
This comprehensive review critically analyzes recent innovations in combining functionalized inorganic and organic nano-fillers—including metallic nanoparticles (e.g., Ag, Au, TiO?), metal-oxide clusters, carbon-based nanomaterials, and MXene nanosheets—with responsive polymeric networks. We detail advanced chemical and physical crosslinking strategies, particularly dynamic covalent chemistry (such as Schiff base bonds, boronate ester linkages, and Diels-Alder reactions) and non-covalent interactions (metal-ligand coordination, hydrogen bonding, and host-guest chemistry). These dynamic linkages impart vital operational capabilities, including autonomous self-healing, shear-thinning injectability for minimally invasive administration, and superior printability for high-resolution 3D/4D bioprinting of customized tissue scaffolds.
Furthermore, the integration of natural bioactive compounds and fruit/plant-derived phytochemicals (such as polyphenols, curcumin, flavonoid-rich extracts, and essential oils) within nanocomposite networks has unlocked eco-friendly, highly biocompatible therapeutic avenues. Utilizing plant extracts as natural reducing and capping agents enables the green synthesis of metallic nanoparticles (e.g., green-synthesized TiO? or Ag nanoparticles), mitigating chemical toxicity while enhancing antioxidant and anti-inflammatory properties. These phytochemically functionalized hydrogels synergistically scavenge free radicals, downregulate pro-inflammatory cytokines (such as TNF-$\alpha$ and IL-6), and promote fibroblast proliferation. Furthermore, the multi-stimuli responsive matrix enables pH- and temperature-dependent sustained release of lipophilic plant bioactives, overcoming their inherent instability and low bioavailability to significantly accelerate ECM remodeling and wound re-epithelialization.
The multi-stimuli responsiveness enables targeted drug release triggered by pathological transitions in wound microenvironments. Under acidic inflammatory conditions (a pH drop from healthy skin's ~5.5 down to 6.0–6.5 or alkaline chronic wound states up to pH 8.5), as well as local temperature elevations (37°C to 40°C), these hydrogels modulate their mesh size and degradation kinetics. This smart trigger mechanism reduces initial burst release by 30–50% while extending the sustained release of growth factors (such as VEGF and bFGF) or microRNAs over a targeted duration of 7 to 21 days. In vivo quantitative models demonstrate that such multi-responsive nanocomposites accelerate full-thickness skin defect closure rates, achieving >95% re-epithelialization within 12–14 days (compared to 21+ days in untreated controls), while significantly promoting angiogenesis with a 2 to 3-fold increase in microvessel density.
Finally, this review highlights the current translational landscape and engineering bottlenecks. Key obstacles—such as long-term degradation kinetics, immune cell interactions, systemic nanotoxicity, batch-to-batch reproducibility, and regulatory compliance for clinical translation—are thoroughly discussed.
