An injectable photo-cross-linking silk hydrogel system augments diabetic wound healing in orthopaedic surgery through spatiotemporal immunomodulation

Abstract

Background The complicated hyperglycaemic and chronic inflammation of diabetic wounds in orthopaedic surgery leads to dysregulated immune cell function and potential infection risk. Immune interventions in diabetic wounds face a possible contradiction between simultaneous establishment of the pro-inflammatory microenvironment in response to potential bacterial invasion and the anti-inflammatory microenvironment required for tissue repair. To study this contradiction and accelerate diabetic-wound healing, we developed a photocurable methacryloxylated silk fibroin hydrogel (Sil-MA) system, co-encapsulated with metformin-loaded mesoporous silica microspheres (MET@MSNs) and silver nanoparticles (Ag NPs). Results The hydrogel system (M@M–Ag–Sil-MA) enhanced diabetic-wound healing via spatiotemporal immunomodulation. Sil-MA imparts a hydrogel system with rapid in situ Ultra-Violet-photocurable capability and allows preliminary controlled release of Ag NPs, which can inhibit bacterial aggregation and create a stable, sterile microenvironment. The results confirmed the involvement of Met in the immunomodulatory effects following spatiotemporal dual-controlled release via the mesoporous silica and Sil-MA. Hysteresis-released from Met shifts the M1 phenotype of macrophages in regions of diabetic trauma to an anti-inflammatory M2 phenotype. Simultaneously, the M@M–Ag–Sil-MA system inhibited the formation of neutrophil extracellular traps (NETs) and decreased the release of neutrophil elastase, myeloperoxidase, and NETs-induced pro-inflammatory factors. As a result of modulating the immune microenvironmental, the M@M–Ag–Sil-MA system promoted fibroblast migration and endothelial cell angiogenesis in vivo, with verification of enhanced diabetic-wound healing accompanied with the spatiotemporal immunoregulation of macrophages and NETs in a diabetic mouse model. Conclusions Our findings demonstrated that the M@M–Ag–Sil-MA hydrogel system resolved the immune contradiction in diabetic wounds through spatiotemporal immunomodulation of macrophages and NETs, suggesting its potential as a promising engineered nano-dressing for the treatment of diabetic wounds in orthopaedic surgery. Graphical Abstract

Novel Trends in Hydrogel Development for Biomedical Applications: A Review

“…There are lots of biopolymers that have not been mentioned, such as serum albumin [ 177 ], keratin [ 178 ], resilin [ 179 ] or silk [ 180 ], that have been thoroughly researched for hydrogel production for biomedical applications. This is mainly due to the fact that these materials share the same main drawbacks, which are basically the difficulty of large-scale production of these hydrogels and their poor mechanical properties [ 161 , 162 ].…”

Immunomodulatory biomaterial-based wound dressings advance the healing of chronic wounds via regulating macrophage behavior

“…They also observed deposition and remodeling of collagen type I and III fibers indicating an enhanced tissue repair. Mei et al [ 61 ] produced a silk fibroin hydrogel system, co-encapsulated with metformin-loaded mesoporous silica microspheres and silver nanoparticles. When applied in a wounded diabetic mouse model, a shift from M1 to M2 macrophage phenotype was observed.…”

Effects and Progress of Photo-Crosslinking Hydrogels in Wound Healing Improvement

“…When used, methacrylate silk fibroin (MA-SF) endows the mixed hydrogel system with the ability of rapid in situ photo-crosslinking. It also controls the initial release of therapeutic materials to promote wound regeneration, and firmly adheres to the lifting point of the wound, which can also inhibit bacterial aggregation and create a stable and sterile microenvironment [ 49 , 58 , 62 ]. Sericin (Ser) as another natural fiber protein has also been reported to combine with methacrylate to prepare methacrylated sericin hydrogels (SMH) for wound healing [ 52 ].…”

“…An immunomodulatory drug (M@M-Ag-Sil-MA) has been designed in recent studies, which was further loaded with antibacterial silver nanoparticles (AgNPs), and metformin loaded with mesoporous silicon nanoparticles (MET@MSNs) using photo-crosslinking methacrylate silk fibroin hydrogel (Sil-MA) as a scaffold. Both in vitro and in vivo tests confirmed that this material can induce the effective transformation of macrophages M1 to M2, thereby reducing the inflammatory response for wound healing [ 58 ].…”

“…In addition to the several commonly used animal models listed above, rat/mouse skin infection models are widely used to detect in vivo antimicrobial levels in photo-crosslinking hydrogel [ 48 , 49 , 51 , 61 ]. In addition, there are some special wound model constructions, such as the chronic wound healing model constructed by the diabetic skin defect model [ 37 , 49 , 58 , 62 , 64 , 65 ], the rat/pig mucosal defect model for detecting the wound healing of oral ulcer [ 50 ], and the rabbit focal corneal defect model for detecting the corneal healing [ 60 ].…”