Multifunctional bioengineered scaffolds and adjunct therapeutic strategies for diabetic foot ulcers

Diabetic foot ulcers (DFUs) are chronic, non-healing wounds that affect up to 34% of diabetic patients. DFUs are complicated by infection in nearly 60% of cases and frequently progress to amputation. DFU pathology is characterized by a persistent inflammatory state, impaired angiogenesis, and infection. This creates a complex microenvironment refractory to standard care, with fewer than 20% of DFUs healing within 8 weeks. In this review article, normal and pathophysiological processes of wound healing, current clinical management strategies, and adjunct therapeutics in the clinical pipeline are discussed, followed by recent advances in multifunctional bioengineered platforms. These platforms are categorized into three main systems: hydrogels, electrospun dressings, and 3D-bioprinted constructs, in addition to hybrid fabrication approaches and the integration of low-temperature plasma therapy as emerging multi-targeted strategies. For hydrogels, stimuli-responsive designs that respond to mechanical force, pH, glucose, and excess reactive oxygen species to actively modulate drug release and scaffold behavior are discussed. For electrospun scaffolds, strategies for controlled, multi-therapeutic delivery, including fiber blending, surface conjugation, and core-shell architectures are reviewed. Next, 3D bioprinting as a platform for patient-specific, cell-laden constructs is presented and covers major fabrication techniques and the emerging potential of handheld in situ bioprinters for accelerating clinical translation. Multi-targeted hybrid approaches that combine these platforms, along with the synergistic integration of low-temperature plasma therapy for broad-spectrum antimicrobial action, biofilm disruption, and immune modulation are emphasized. Unlike prior material-centric reviews, this review adopts a function-driven framework that organizes scaffold systems based on their ability to address key DFU pathologies, including infection, inflammation, impaired angiogenesis, and delayed healing, providing a more clinically relevant perspective. Finally, emerging directions such as artificial intelligence (AI)-guided design, in situ bioprinting, and recent clinical trends are discussed to bridge scaffold design with translational application. STATEMENT OF SIGNIFICANCE: Diabetic foot ulcers present a critical global health challenge characterized by a highly inflammatory microenvironment that remains refractory to standard care. This review elucidates the paradigm shift from passive wound dressings to "intelligent," multifunctional bioengineered scaffolds designed to actively modulate DFUs. We critically examine recent advances in stimuli-responsive hydrogels (pH-, glucose-, and reactive oxygen species-sensitive), mechanically active contractile patches, complex electrospun architectures, and 3D bioprinting. Furthermore, by integrating emerging technologies such as handheld in situ 3D bioprinting, low-temperature plasma therapy, and artificial intelligence-driven design, this work provides a roadmap for the next generation of precision biomaterials capable of overcoming specific biological barriers to regeneration in chronic wounds.