Mechanical Force on Hydrogel Implication on Enhanced Drug Release, Antibacterial, and M2 Macrophage Polarization: New Insights Alleviate Diabetic Wound Healing

Diabetic foot ulcers/chronic wounds are difficult to treat because of dysfunctional macrophage response and decreased phenotype transition from the M1 to M2 status. This causes severe inflammation, less angiogenesis, microbial infections, and small deformation in wound beds, affecting the healing process. The commercial wound dressing material has limited efficacy, poor mechanical strength, extra pain, and new granulated tissue formed in a mesh of gauze. It is desired to create tough, skin-adhesive, antifouling, sustainable M2 phenotype-enabling, and mechanoresponsive drug-releasing hydrogel. To resolve this, zwitterionic poly(sulfobetaine methacrylate) (SB) incorporated with keratin-exfoliated MoS₂ and bee-wax nanoparticles were developed to deliver phenytoin upon application of mechanical forces. Human hair keratin was used for exfoliation of MoS₂, and bee-wax nanoparticles loaded with phenytoin were used as cross-linkers of SB hydrogel. The cross-linked SB-MO₁₅-B hydrogel has high mechanical properties, with more tensile strength and strain of 118 kPa and 1485%. Under external mechanical force, hydrogel deformed to release phenytoin of 38% (tensile) and 24% (compressive), which was higher compared to static condition (12%). The penetration of phenytoin into skin tissue was also improved by the mechanical force applied to the hydrogel. SB-MO₁₅-B hydrogel effectively activates the polarization of macrophages toward the M2 phenotype, promotes cell proliferation, and also shows superior antibacterial properties. <i>In vivo</i> results demonstrate that hydrogel rapidly promotes diabetic wound repair through fast antiinflammation and M2 macrophage polarization. Therefore, a robust mechanoresponsive hydrogel would provide a new strategy to deliver the drug and also tune the M2 macrophage polarization for chronic wound healing.