Diabetes, a metabolic illness characterised by excessive blood glucose, impacts 540 million individuals worldwide [1]. Persistent, hard-to-heal wounds are probably the most frequent issues, leading to amputations and even demise which place a major monetary burden [2]. Hyperglycemia inhibits cell proliferation and migration and hinders the re-epithelialization course of, will increase irritation and oxidative stress and extended irritation interval [3]. Diabetes additionally causes blood vessels to constrict, decreasing the quantity of oxygen and vitamins on the wound website, additional impeding therapeutic [4]. In conclusion, diabetic wounds have a posh microenvironment of hyperglycemia, irritation, oxidative stress, ischemia, hypoxia, and an infection, which makes them tough to heal [5]. At current, the remedy strategies for diabetic wounds embody debridement, damaging strain remedy, hyperbaric oxygen remedy, and wound dressing, however they’re restricted by single performance, lack of specificity in bettering diabetic wound microenvironment, and low therapeutic effectiveness [6]. Due to this fact, it’s pressing to develop therapies that may make the most of and enhance the diabetic wound microenvironment to attain efficient therapeutic.
Resulting from persistent hyperglycemia in diabetic wounds, glucose oxidase (GOx) can catalyze glucose into gluconic acid and H2O2 within the presence of O2, however instantly loading GOx on the wound has the disadvantages of quick residence time and half-life. Due to this fact, encapsulation of GOx with the metal-organic framework (MOF) can shield it from interferences like temperature, pH, and protease, whereas excessive porosity and comparative space additionally enhance catalytic effectivity and scale back wound glucose focus. As well as, to scavenge the extreme ROS from endogenous and glucose consumption, nanozymes with a number of enzyme actions are launched to attain this aim. Nanozymes are synthetic enzymes primarily based on nanomaterials, that are extra steady than organic enzymes and have broad-spectrum antioxidant capability and excessive ROS scavenging effectivity, which has attracted individuals’s consideration [7]. In contrast with different nanozymes, MnO2 has good biocompatibility and biodegradability and might catalyze the conversion of endogenous and glucose-oxidized H2O2 to O2, assuaging oxidative stress and hypoxic wound microenvironment [8], [9]. Since Zn-MOF-74 will be synthesized by a light water-based technique, and might successfully shield enzymes and enhance the catalytic effectivity in comparison with different MOFs[10], we selected Zn-MOF-74 to encapsulate GOx (GOx@Zn-MOF-74). The 2 nanozymes have been mixed to enhance the wound microenvironment by way of their cascade response. GOx@Zn-MOF-74 catalyzes the oxidation of glucose on the wound website to H2O2 with the participation of O2, then the O2 produced by MnO2 catalyzed decomposition of H2O2 is provided to GOx@Zn-MOF-74 to proceed the oxidation of glucose and alleviate wound hypoxia. The presence of MnO2 can speed up the oxidation of glucose by GOx@Zn-MOF-74, on the similar time, the H2O2 produced by the method is decomposed by MnO2 to provide O2. Due to this fact, we anticipate that the cascade response of the 2 nanozymes can synergistically scale back the blood glucose focus of the wound, scavenge ROS, and alleviate the hypoxic microenvironment, offering an efficient technique for the remedy of diabetic wounds. Till now, the technique to enhance the diabetic wound microenvironment by using the cascade response of two nanozymes to attain the glucose discount, ROS scavenging, and oxygen supply has not been reported.
Furthermore, nanomaterials can not keep on the wound website for a very long time and react rapidly with the microenvironment, so applicable carriers are wanted to sustained ship them to the wound website. Hydrogel is a perfect wound dressing with a 3D community just like the extracellular matrix (ECM) construction, which might take in wound exudate, preserve the wound moist, and forestall bacterial invasion [11]. Injectable hydrogels with form adaptability can quickly self-heal and keep away from dressing depletion by motion whereas filling irregularly formed wounds [12]. As well as, hydrogels have wonderful biocompatibility, applicable mechanical power, and degradability to permit the formation of recent tissues and promote cell adhesion, proliferation, and differentiation [13]. Hydrogels are additionally a superb provider that can be utilized to ship a wide range of medication, nanoparticles, and liposomes [14]. Amongst them, composite supplies of steel nanoparticles and hydrogels have been broadly used within the biomedical subject [15]. Nevertheless, the above hydrogels lack a responsiveness to excessive ROS and blood glucose ranges in diabetic wounds. Due to this fact, we hypothesize that the responsive traits of phenyl borate ester bond can be utilized to intelligently degrade within the diabetic wound microenvironment with excessive ROS and blood glucose ranges, after which the nanozymes with cascading reactions shall be launched to enhance the wound microenvironment and speed up the therapeutic course of.
On this examine, we designed a glucose-activated cascade oxygen launch hydrogel that may obtain glucose consumption, ROS scavenge, and oxygen launch to enhance the microenvironment of contaminated diabetic wounds and speed up the therapeutic course of. The hydrogel is fashioned by the phenyl borate ester bond between the phenyl boric acid grafted hyaluronic acid (HP) and the three,4,5-trihydroxybenzoic acid grafted lysozyme (LT), and loaded with GOx@Zn-MOF-74 and MnO2 nanozymes by way of the coordination of steel ions (Fig. 1A&B). It’s the primary time an antimicrobial peptide is launched into a cloth by covalent cross-linking and maintains its antimicrobial exercise. As well as, we suggest a win-win strategy to attain glucose-activated microenvironment enchancment by combining some great benefits of the 2 nanozymes. The H2O2 produced by GOx@Zn-MOF-74 catalytic oxidative decomposition of glucose is transformed into O2 by the CAT-like exercise of MnO2, after which O2 is offered to the anoxic wounds and subsequent glucose consumption. The hydrogel with cascade response can successfully enhance the microenvironment of hyperglycemia, extreme ROS, and hypoxia, promote blood vessel formation and collagen deposition, speed up wound therapeutic, and supply a brand new resolution for the remedy of diabetic wounds.
