“…6 b, c, bacterial load in wound tissues was positively correlated with the healing of wound, and complete biofilm elimination was only obtained in the treatment group of Fe 3 O 4 -GOx on the 15th day of treatment. This phenomenon means that the inflammation phase of wound healing in DU will be greatly shortened by the treatment of Fe 3 O 4 -GOx nanozyme to recover the normal orchestrated course of wound-healing cascades [ 53 ]. Furthermore, the collagen deposition as well as blood vessel density of wound tissues in the four treatment groups were investigated.…”
The management of diabetic ulcer (DU) to rescue stalled wound healing remains a paramount clinical challenge due to the spatially and temporally coupled pathological wound microenvironment that features hyperglycemia, biofilm infection, hypoxia and excessive oxidative stress. Here we present a pH-switchable nanozyme cascade catalysis (PNCC) strategy for spatial–temporal modulation of pathological wound microenvironment to rescue stalled healing in DU. The PNCC is demonstrated by employing the nanozyme of clinically approved iron oxide nanoparticles coated with a shell of glucose oxidase (Fe3O4-GOx). The Fe3O4-GOx possesses intrinsic glucose oxidase (GOx), catalase (CAT) and peroxidase (POD)-like activities, and can catalyze pH-switchable glucose-initiated GOx/POD and GOx/CAT cascade reaction in acidic and neutral environment, respectively. Specifically, the GOx/POD cascade reaction generating consecutive fluxes of toxic hydroxyl radical spatially targets the acidic biofilm (pH ~ 5.5), and eradicates biofilm to shorten the inflammatory phase and initiate normal wound healing processes. Furthermore, the GOx/CAT cascade reaction producing consecutive fluxes of oxygen spatially targets the neutral wound tissue, and accelerates the proliferation and remodeling phases of wound healing by addressing the issues of hyperglycemia, hypoxia, and excessive oxidative stress. The shortened inflammatory phase temporally coupled with accelerated proliferation and remodeling phases significantly speed up the normal orchestrated wound-healing cascades. Remarkably, this Fe3O4-GOx-instructed spatial–temporal remodeling of DU microenvironment enables complete re-epithelialization of biofilm-infected wound in diabetic mice within 15 days while minimizing toxicity to normal tissues, exerting great transformation potential in clinical DU management. The proposed PNCC concept offers a new perspective for complex pathological microenvironment remodeling, and may provide a powerful modality for the treatment of microenvironment-associated diseases.
Graphical Abstract
“…6 b, c, bacterial load in wound tissues was positively correlated with the healing of wound, and complete biofilm elimination was only obtained in the treatment group of Fe 3 O 4 -GOx on the 15th day of treatment. This phenomenon means that the inflammation phase of wound healing in DU will be greatly shortened by the treatment of Fe 3 O 4 -GOx nanozyme to recover the normal orchestrated course of wound-healing cascades [ 53 ]. Furthermore, the collagen deposition as well as blood vessel density of wound tissues in the four treatment groups were investigated.…”
The management of diabetic ulcer (DU) to rescue stalled wound healing remains a paramount clinical challenge due to the spatially and temporally coupled pathological wound microenvironment that features hyperglycemia, biofilm infection, hypoxia and excessive oxidative stress. Here we present a pH-switchable nanozyme cascade catalysis (PNCC) strategy for spatial–temporal modulation of pathological wound microenvironment to rescue stalled healing in DU. The PNCC is demonstrated by employing the nanozyme of clinically approved iron oxide nanoparticles coated with a shell of glucose oxidase (Fe3O4-GOx). The Fe3O4-GOx possesses intrinsic glucose oxidase (GOx), catalase (CAT) and peroxidase (POD)-like activities, and can catalyze pH-switchable glucose-initiated GOx/POD and GOx/CAT cascade reaction in acidic and neutral environment, respectively. Specifically, the GOx/POD cascade reaction generating consecutive fluxes of toxic hydroxyl radical spatially targets the acidic biofilm (pH ~ 5.5), and eradicates biofilm to shorten the inflammatory phase and initiate normal wound healing processes. Furthermore, the GOx/CAT cascade reaction producing consecutive fluxes of oxygen spatially targets the neutral wound tissue, and accelerates the proliferation and remodeling phases of wound healing by addressing the issues of hyperglycemia, hypoxia, and excessive oxidative stress. The shortened inflammatory phase temporally coupled with accelerated proliferation and remodeling phases significantly speed up the normal orchestrated wound-healing cascades. Remarkably, this Fe3O4-GOx-instructed spatial–temporal remodeling of DU microenvironment enables complete re-epithelialization of biofilm-infected wound in diabetic mice within 15 days while minimizing toxicity to normal tissues, exerting great transformation potential in clinical DU management. The proposed PNCC concept offers a new perspective for complex pathological microenvironment remodeling, and may provide a powerful modality for the treatment of microenvironment-associated diseases.
Graphical Abstract
“…Early in wound healing, inflammatory cells secrete several key inflammatory cytokines to promote local or systemic defence responses, which are critical for wound healing [ 36 ]. However, chronic diabetic wounds are in the long-term inflammatory phase due to macrophage dysfunction, which hinders the development of damaged tissue to the proliferation and remodelling phase of wound healing [ 9 , 13 ], and the high expression of MMP-9 in chronic diabetic wounds was also an important reason for the non-healing [ 15 ]. To simulate chronic inflammation and oversecretion of MMP-9 in chronic diabetic wounds, LPS was used to induce macrophages (RAW264.7) to secrete inflammatory factors and MMP-9 via the 3 mitogen-activated protein kinase (MAPK) pathways and the NF- B signalling pathway [ 20 , 49 , 50 ].…”
Section: Resultsmentioning
confidence: 99%
“…To further study the mechanism by which the CBP@Cel&INS hydrogel promoted wound healing, the typical pre-healing factors were analysed. The typical chronic diabetic wound was in the inflammation phase for a long time [ 11 , 13 ]. As the typical pro-inflammatory cytokine and the anti-inflammatory cytokine, TNF- and IL-10 were important indicators of inflammatory response during the early healing phase [ 8 ], on day 7 (the phase of inflammation in naturally healing chronic diabetic wounds), compared with the gauze group and the HeraDerm group, the concentration of TNF-α increased and the concentration of IL-10 decreased in the hydrogel III group, and the highest levels of IL-10 and almost no levels of TNF- were detected in hydrogel IV treated wounds, suggesting that the anti-inflammatory effect of hydrogel Ⅲ was limited, and hydrogel Ⅳ had excellent anti-inflammatory properties ( Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Prolonged hyperglycaemia leads to advanced glycation end-products (AGEs) accumulation in skin tissues, resulting in a series of changes in histology and cytology, such as cell dysfunction and reduced secretion of multiple growth factors, especially inflammatory cell dysfunction, which exacerbates and prolongs the inflammatory phase of chronic diabetic wounds [ [9] , [10] , [11] ]. Aberrant inflammation causes the upregulated secretion of pro-inflammatory factors, further disturbing the balance of MMPs and tissue inhibitors of metalloproteinases (TIMPs) and leads to the oversecretion of MMPs in wounds, especially the amount of MMP-9—which was enhanced 14 times in diabetic ulcers than in traumatic wounds [ 4 , [12] , [13] , [14] ]. The high concentration of MMPs, which degrade a variety of growth factors and matrix proteins required for wound healing, is considered as one of the main reasons for the transformation of acute wounds into chronic wounds [ 3 , 4 ].…”
“…8 A) [ 87 ]. Recently, curcumin has been increasingly used in inhibiting oxidative stress and inflammation, in protecting cells in the central nervous system [ [87] , [88] , [89] ], and in treating chronic ulcers [ 90 , 91 ] and I/R injury [ 92 , 93 ]. Fig.…”
Section: Ros-scavenging Nanomaterials That Promote Oxidative Damage Repair and Mechanisms Governing This Repairmentioning
Reactive oxygen species (ROS) mediate multiple physiological functions; however, the over-accumulation of ROS causes premature aging and/or death and is associated with various inflammatory conditions. Nevertheless, there are limited clinical treatment options that are currently available. The good news is that owing to the considerable advances in nanoscience, multiple types of nanomaterials with unique ROS-scavenging abilities that influence the temporospatial dynamic behaviors of ROS in biological systems have been developed. This has led to the emergence of next-generation nanomaterial-controlled strategies aimed at ameliorating ROS-related inflammatory conditions. Accordingly, herein we reviewed recent progress in research on nanotherapy based on ROS scavenging. The underlying mechanisms of the employed nanomaterials are emphasized. Furthermore, important issues in developing cross-disciplinary nanomedicine-based strategies for ROS-based inflammatory conditions are discussed. Our review of this increasing interdisciplinary field will benefit ongoing studies and clinical applications of nanomedicine based on ROS scavenging.
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