Microenvironmental dynamics of diabetic wounds and insights for hydrogel-based therapeutics

Abstract

The rising prevalence of diabetes has underscored concerns surrounding diabetic wounds and their potential to induce disability. The intricate healing mechanisms of diabetic wounds are multifaceted, influenced by ambient microenvironment, including prolonged hyperglycemia, severe infection, inflammation, elevated levels of reactive oxygen species (ROS), ischemia, impaired vascularization, and altered wound physicochemical properties. In recent years, hydrogels have emerged as promising candidates for diabetic wound treatment owing to their exceptional biocompatibility and resemblance to the extracellular matrix (ECM) through a three-dimensional (3D) porous network. This review will first summarize the microenvironment alterations occurring in the diabetic wounds, aiming to provide a comprehensive understanding of its pathogenesis, then a comprehensive classification of recently developed hydrogels will be presented, encompassing properties such as hypoglycemic effects, anti-inflammatory capabilities, antibacterial attributes, ROS scavenging abilities, promotion of angiogenesis, pH responsiveness, and more. The primary objective is to offer a valuable reference for repairing diabetic wounds based on their unique microenvironment. Moreover, this paper outlines potential avenues for future advancements in hydrogel dressings to facilitate and expedite the healing process of diabetic wounds.

Keywords: Diabetic wound microenvironment; hydrogel-based therapies; skin regeneration; wound healing.

Figure 1.

Illustration of recent hydrogels in accelerating diabetic wound healing.

Figure 2.

The glucose-responsive hypoglycemic hydrogels: (a) the glucose-responsive TMB/Fe²⁺/PF127 hydrogel based on GOx and its application in promoting diabetic wound healing. Reproduced with permission. Copyright 2023, American Chemical Society, (b) con A-DexG based system and its glucose-responsive and hypoglycemic effect mechanism in vitro. Reproduced with permission. Copyright 2018, Elsevier B.V, and (c) the glucose-responsive ODEX-DA/HTCC hydrogels based on PBA for releasing insulin NPs to exert hypoglycemic effect. Reproduced with permission. Copyright 2023, Springer Nature.

Figure 3.

The anti-inflammatory hydrogels based on modulation of macrophage polarization and decreasing the expression of MMP-9 in diabetic wound: (a) the GDFE hydrogel could effectively activate macrophages polarization to M2 phenotype, and remarkably accelerated wound healing. Reproduced with permission. Copyright 2021, Wiley-VCH GmbH, (b) the AFG/GelMA hydrogel by natural adhesive from snail mucus improved the healing of diabetic wound via promoting macrophage polarization to M2 phenotype. Reproduced with permission. Copyright 2023, Elsevier Ltd, (c) evaluation of the GBTF hydrogel on macrophage polarization in diabetic wound. Reproduced with permission. Copyright 2023, Elsevier B.V, and (d) the L-carnosine@curcumin loaded SF hydrogel and its biological mechanism of MMP-9 inactivation in the diabetic wound process. Reproduced with permission. Copyright 2019, Elsevier B.V.

Figure 4.

The antibacterial hydrogels in diabetic wounds: (a) the CS/HA hybrid hydrogels. Reproduced with permission. Copyright 2023, Elsevier Ltd, (b) the bacteria-killing efficiency of EACPA hydrogel against E. coli and S. aureus. Reproduced with permission. Copyright 2021, Wiley-VCH GmbH, (c) the sHG-AMP with the precisely controlled release of AMP in response to bacterial infection in diabetic wound. Reproduced with permission. Copyright 2023, American Chemical Society, and (d) the GOx@MnS NPs and its mechanism for treating MRSA infected diabetic wound. Reproduced with permission. Copyright 2023, American Chemical Society.

Figure 5.

ROS-scavenging hydrogels in diabetic wounds: (a) the ROS-responsive multifunctional injectable HA@Cur@Ag hydrogel promoted wound healing via regulating oxidative stress (The intercellular ROS was stained green by DCFH-DA). Reproduced with permission. Copyright 2023, Wiley-VCH GmbH, (b) the fabrication of EGAP@HG based on GA and its application in diabetic wound healing. Reproduced with permission. Copyright 2022, Elsevier Ltd, (c) the immunomodulatory AuPt@melanin-incorporated (GHM3) hydrogel for facilitating wound healing. Reproduced with permission. Copyright 2023, American Chemical Society, and (d) MnCoO@PDA/CPH hydrogel with high ROS scavenging capacity in vitro. Reproduced with permission. Copyright 2023, American Chemical Society.

Figure 6.

The angiogenic hydrogels in diabetic wounds: (a)the self-adaptive DFO@G-QCSFP hydrogel released DFO@G on demand to promote angiogenesis and accelerated the wound healing of diabetic rats. Reproduced with permission. Copyright 2022, Elsevier B.V, (b) the CS-DA/PF/TA/3D-Exo hydrogel exhibited stronger vascular promoting ability. Reproduced with permission. Copyright 2023, Elsevier B.V, (c) the Gel-VH-EVs released the VH-EVs to enhance angiogenesis in diabetic wound via HIF-1α mediated pathway. Reproduced with permission. Copyright 2022, Elsevier Ltd, and (d) VEGF–aPMNEM–ECM hybrid hydrogel promoted diabetic wound repair through enhancing the long-distance reproduction of VEGF. Reproduced with permission. Copyright 2023, Springer Nature.

Figure 7.

The pH responsive hydrogels in diabetic wounds: (a) the insulin-loaded hydrogels with pH-responsive property attributed to the inherent instability of the hydrazone bond under acidic conditions. Reproduced with permission. Copyright 2021, Elsevier Ltd, (b) The FCAB/D hydrogel loaded with DFO possess pH response based on Schiff bone. Reproduced with permission. Copyright 2023, Elsevier B.V, (c) the GCM hydrogel with pH-responsive ability to deliver drug on-demand and facilitated diabetic wound healing. Reproduced with permission. Copyright 2023, American Chemical Society, and (d)the pH-responsive multifunctional hydrogel by loading antibacterial AgNPs and the angiogenic drug DFO. Reproduced with permission. Copyright 2021, Elsevier B.V.