At present, developing therapeutic strategies to improve wound healing in individuals with diabetes remains challenging. Exosomes represent a promising nanomaterial from which microRNAs (miRNAs) can be isolated. These miRNAs have the potential to exert therapeutic effects, and thus, determining the potential therapeutic contributions of specific miRNAs circulating in exosomes is of great importance. In the present study, circulating exosomal miRNAs are identified in diabetic patients and assessed for their roles in the context of diabetic wound healing. A significant upregulation of miR‐20b‐5p is observed in exosomes isolated from patients with type 2 diabetes mellitus (T2DM), and this miRNA is able to suppress human umbilical vein endothelial cell angiogenesis via regulation of Wnt9b/β‐catenin signaling. It is found that the application of either miR‐20b‐5p or diabetic exosomes to wound sites is sufficient to slow wound healing and angiogenesis. In diabetic mice, it is found that knocking out miR‐20b‐5p significantly enhances wound healing and promotes wound angiogenesis. Together, these findings thus provide strong evidence that miR‐20b‐5p is highly enriched in exosomes from patients with T2DM and can be transferred to cells of the vascular endothelium, where it targets Wnt9b signaling to negatively regulate cell functionality and angiogenesis.
Extremity skeletal muscle injuries result in substantial disability. Current treatments fail to recoup muscle function, but properly designed and implemented tissue engineering and regenerative medicine techniques can overcome this challenge. In this study, a nanoengineered, growth factor-eluting bioink that utilizes Laponite nanoclay for the controlled release of vascular endothelial growth factor (VEGF) and a GelMA hydrogel for a supportive and adhesive scaffold that can be crosslinked in vivo is presented. The bioink is delivered with a partially automated handheld printer for the in vivo formation of an adhesive and 3D scaffold. The effect of the controlled delivery of VEGF alone or paired with adhesive, supportive, and fibrilar architecture has not been studied in volumetric muscle loss (VML) injuries. Upon direct in vivo printing, the constructs are adherent to skeletal muscle and sustained release of VEGF. The in vivo printing of muscle ink in a murine model of VML injury promotes functional muscle recovery, reduced fibrosis, and increased anabolic response compared to untreated mice. The in vivo construction of a therapeutic-eluting 3D scaffold paves the way for the immediate treatment of a variety of soft tissue traumas.
Fracture healing is a complex process involving various cell types, cytokines, and mRNAs. Here, we report the roles of the circRNA AFF4/miR-7223-5p/PIK3R1 axis during fracture healing. We found that increased expression of PIK3R1 during fracture healing is directly associated with augmented proliferation and decreased apoptosis of MC3T3-E1 cells. Furthermore, miR-7223-5p targeted PI3KR1 and inhibited MC3T3-E1 proliferation while promoting apoptosis. CircRNA AFF4 acted as a sponge of miR-7223-5p, thereby promoting MC3T3-E1 cell proliferation and inhibiting apoptosis. Local injection of circRNA AFF4 into femoral fracture sites promoted fracture healing in vivo while the injection of miR-7223-5p delayed healing. These findings suggest that CircRNA AFF4 promotes fracture healing by targeting the miR-7223-5p/PIK3R1 axis, and suggests miR-7223-5p, CircRNA AFF4, and the miR-7223-5p/PIK3R1 axis are potential therapeutic targets for improving fracture healing.
A major impediment preventing normal wound healing is insufficient vascularization, which causes hypoxia, poor metabolic support, and dysregulated physiological responses to injury. To combat this, the delivery of angiogenic factors, such as vascular endothelial growth factor (VEGF), has been shown to provide modest improvement in wound healing. Here, the importance of specialty delivery systems is explored in controlling wound bed drug distribution and consequently improving healing rate and quality. Two intradermal drug delivery systems, miniaturized needle arrays (MNAs) and liquid jet injectors (LJIs), are evaluated to compare effective VEGF delivery into the wound bed. The administered drug's penetration depth and distribution in tissue are significantly different between the two technologies. These systems' capability for efficient drug delivery is first confirmed in vitro and then assessed in vivo. While topical administration of VEGF shows limited effectiveness, intradermal delivery of VEGF in a diabetic murine model accelerates wound healing. To evaluate the translational feasibility of the strategy, the benefits of VEGF delivery using MNAs are assessed in a porcine model. The results demonstrate enhanced angiogenesis, reduced wound contraction, and increased regeneration. These findings show the importance of both therapeutics and delivery strategy in wound healing.
Emerging evidence highlights the role of the long noncoding RNA (lncRNA) KCNQ1OT1 in fracture healing. Osteoblast proliferation, migration, and survival are pivotal during this process. In this study, we aimed to improve our understanding of the regulatory role of lncRNA KCNQ1OT1 during osteoblast proliferation, migration, and survival. We searched the gene expression omnibus databases and LncBase Experimental V.2 to identify key microRNAs (miRNAs) targets of KCNQ1OT1. MiR‐701‐3p was selected as a differentially expressed miRNA and RNA immunoprecipitation assays were performed to verify its interaction with KCNQ1OT1. Fibroblast growth factor receptor 3 (FGFR3) was also identified as a target of miR‐701‐3p. We further identified KCNQ1OT1 as a competing endogenous RNA of miR‐701‐3p that could influence osteoblast proliferation, migration, and apoptosis in vitro and in vivo. Taken together, our results indicate that the KCNQ1OT1/miR‐701‐3p/FGFR3 axis is an important regulator of osteoblast proliferation, migration, and apoptosis, and provide a new therapeutic avenue for fracture healing.
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