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      An intrinsically bioactive hydrogel with on-demand drug release behaviors for diabetic wound healing

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          Abstract

          Prolonged, intense inflammation and excessive oxidative stress hinder diabetic wounds from healing normally, leading to disorders downstream including the postponement of re-epithelialization and extracellular matrix (ECM) formation. Herein, we report a hyaluronic acid (HA) and chitosan based hydrogel (OHA-CMC) with inherent antibacterial and hemostatic activities fabricated via Schiff base reaction. By encapsulating nanotechnologically-modified curcumin (CNP) and epidermal growth factor (EGF) into the hydrogel, OHA-CMC/CNP/EGF exhibited extraordinary antioxidant, anti-inflammatory, and migration-promoting effects in vitro. Meanwhile, OHA-CMC/CNP/EGF presented on-demand drug release in synchrony with the phases of the wound healing process. Specifically, curcumin was rapidly and constantly released to alleviate inflammation and oxidative stress in the early phase of wound healing, while a more gradual and sustained release of EGF supported late proliferation and ECM remodeling. In a diabetic full-thickness skin defect model, OHA-CMC/CNP/EGF dramatically improved wound healing with ideal re-epithelialization, granulation tissue formation, and skin appendage regeneration, highlighting the enormous therapeutic potential this biomaterial holds as a diabetic wound dressing.

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          Highlights

          • OHA-CMC hydrogel showed excellent inherent antibacterial and hemostatic activities.

          • OHA-CMC co-delivered curcumin and EGF with on-demand drug release that met the repair requirements of each healing stage.

          • OHA-CMC/CNP/EGF showed potent antioxidant and anti-inflammation activities, and was capable of promoting cell migration.

          • OHA-CMC/CNP/EGF significantly accelerated diabetic wound healing.

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          Most cited references55

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          Diabetic Foot Ulcers and Their Recurrence.

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            Advances in engineering hydrogels.

            Hydrogels are formed from hydrophilic polymer chains surrounded by a water-rich environment. They have widespread applications in various fields such as biomedicine, soft electronics, sensors, and actuators. Conventional hydrogels usually possess limited mechanical strength and are prone to permanent breakage. Further, the lack of dynamic cues and structural complexity within the hydrogels has limited their functions. Recent developments include engineering hydrogels that possess improved physicochemical properties, ranging from designs of innovative chemistries and compositions to integration of dynamic modulation and sophisticated architectures. We review major advances in designing and engineering hydrogels and strategies targeting precise manipulation of their properties across multiple scales.
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              Diabetes primes neutrophils to undergo NETosis, which impairs wound healing.

              Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.
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                Author and article information

                Contributors
                Journal
                Bioact Mater
                Bioact Mater
                Bioactive Materials
                KeAi Publishing
                2452-199X
                16 May 2021
                December 2021
                16 May 2021
                : 6
                : 12
                : 4592-4606
                Affiliations
                [a ]Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, PR China
                [b ]Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ, 07102, USA
                Author notes
                []Corresponding author. xueqingzhang@ 123456sjtu.edu.cn
                [∗∗ ]Corresponding author. xiaoyang.xu@ 123456njit.edu
                Article
                S2452-199X(21)00216-4
                10.1016/j.bioactmat.2021.04.040
                8141414
                34095619
                e3629fe8-60c2-48b1-af5d-005a0dbcaa07
                © 2021 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 9 March 2021
                : 20 April 2021
                : 24 April 2021
                Categories
                Article

                bioactive hydrogel,drug delivery,anti-inflammation,antioxidant,diabetic wound healing

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