Microenvironment‐Based Diabetic Foot Ulcer Nanomedicine

Abstract

Diabetic foot ulcers (DFU), one of the most serious complications of diabetes, are essentially chronic, nonhealing wounds caused by diabetic neuropathy, vascular disease, and bacterial infection. Given its pathogenesis, the DFU microenvironment is rather complicated and characterized by hyperglycemia, ischemia, hypoxia, hyperinflammation, and persistent infection. However, the current clinical therapies for DFU are dissatisfactory, which drives researchers to turn attention to advanced nanotechnology to address DFU therapeutic bottlenecks. In the last decade, a large number of multifunctional nanosystems based on the microenvironment of DFU have been developed with positive effects in DFU therapy, forming a novel concept of “DFU nanomedicine”. However, a systematic overview of DFU nanomedicine is still unavailable in the literature. This review summarizes the microenvironmental characteristics of DFU, presents the main progress of wound healing, and summaries the state‐of‐the‐art therapeutic strategies for DFU. Furthermore, the main challenges and future perspectives in this field are discussed and prospected, aiming to fuel and foster the development of DFU nanomedicines successfully.

Moving beyond nanotechnology to uncover a glimmer of hope in diabetes medicine: Effective nanoparticle‐based therapeutic strategies for the management and treatment of diabetic foot ulcers

“…Nanoparticles can be toxic to cells and tissues, and their use in combination with MSCs could potentially affect the therapeutic efficacy of the cells 85 . In some cases, nanoparticles may even induce cellular toxicity and inflammation, which can further exacerbate the underlying condition of DFUs 86 . Another concern with the use of nanoparticles in MSC‐based therapies is their potential to affect the behavior of MSCs 87 .…”

Ultrasound-Augmented Multienzyme-like Nanozyme Hydrogel Spray for Promoting Diabetic Wound Healing

“…The consequences of diabetic foot ulcers (DFU) include decline in functional status, infection, hospitalization, lower extremity amputation, and even death . In the United States, the cost related to DFU is estimated to be USD 9–13 billion annually, in addition to the expense associated with diabetes. , The convoluted pathogenesis of DFU results in a complex microenvironment characterized by hyperglycemia, hyperinflammation, hypoxia, ischemia, persistent infection, and a wide range variation of pH (7.0–8.9) in chronic phase. , In particular, hyperglycemia upregulates the expression of pro-inflammatory cytokines and induces oxidative stress in nerve cells, and it also leads to glycated hemoglobin, vasoconstriction, red blood cell membrane disorders, hypoxia, complicated bacterial biofilm infections, and eventually a prolonged inflammation phase and nonhealing chronic wounds. − Current treatments for DFU involve auto/allograft and xenograft, cell-based therapy and engineered skin graft, hyperbaric oxygen therapy, negative-pressure therapy, topical drug and growth factor delivery, electrotherapy, ultrasound, and vacuum-assisted closure, − but the outcomes are frequently less than satisfactory. Therefore, development of alternative therapies that are effective, low cost, and safe is highly desired.…”

Radially Electrospun Fibrous Membrane Incorporated with Copper Peroxide Nanodots Capable of Self-Catalyzed Chemodynamic Therapy for Angiogenesis and Healing Acceleration of Diabetic Wounds

“…Specifically, a special tubular collector was customized to guide the formation of a radially structured electrospun fibrous membrane composed of polycaprolactone (PCL), polyvinylpyrrolidone (PVP), and CuO 2 nanoparticles (CPs), which was named as Ran@CP. The incorporation of PVP improved the hydrophilicity of Ran@CP and also helped to rapidly liberate CPs during dissolution in contact with water. , Simultaneously, owing to the mild acidic nature of diabetic wounds, , the CPs functioned as chemical nanoreactors to generate Cu 2+ ions and H 2 O 2 in response to the acidic inner environment of diabetic patients, thus achieving in situ Fenton-type CDT. Meanover, the released Cu 2+ ions could also facilitate angiogenesis by upregulating the angio-related genes.…”

“…The incorporation of PVP improved the hydrophilicity of Ran@ CP and also helped to rapidly liberate CPs during dissolution in contact with water. 39,40 Simultaneously, owing to the mild acidic nature of diabetic wounds, 41,42 the CPs functioned as chemical nanoreactors to generate Cu 2+ ions and H 2 O 2 in response to the acidic inner environment of diabetic patients, thus achieving in situ Fenton-type CDT. Meanover, the released Cu 2+ ions could also facilitate angiogenesis by upregulating the angio-related genes.…”