Modulation of macrophages by a paeoniflorin-loaded hyaluronic acid-based hydrogel promotes diabetic wound healing

Hao Yang; Liu Song; Bingxue Sun; Di Chu; Leilei Yang; Meng Li; Huan Li; Yun Dai; Zhuo Yu; Jianfeng Guo

doi:10.1016/j.mtbio.2021.100139

Modulation of macrophages by a paeoniflorin-loaded hyaluronic acid-based hydrogel promotes diabetic wound healing

Mater Today Bio. 2021 Sep 21:12:100139. doi: 10.1016/j.mtbio.2021.100139. eCollection 2021 Sep.

Authors

Hao Yang¹, Liu Song¹, Bingxue Sun¹, Di Chu¹, Leilei Yang¹, Meng Li¹, Huan Li¹, Yun Dai², Zhuo Yu³, Jianfeng Guo¹

Affiliations

¹ School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, China.
² Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun, 130021, China.
³ Department of Hepatopathy, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.

Abstract

The impaired wound healing in diabetes is a central concern of healthcare worldwide. However, current treatments often fail due to the complexity of diabetic wounds, and thus, emerging therapeutic approaches are needed. Macrophages, a prominent immune cell in the wound, play key roles in tissue repair and regeneration. Recent evidence has demonstrated that macrophages in diabetic wounds maintain a persistent proinflammatory phenotype that causes the failure of healing. Therefore, modulation of macrophages provides great promise for wound healing in diabetic patients. In this study, the potential of paeoniflorin (PF, a chemical compound derived from the herb Paeonia lactiflora) for the transition of macrophages from M1 (proinflammatory phenotype) to M2 (anti-inflammatory/prohealing phenotype) was confirmed using ex vivo and in vivo experimental approaches. A hydrogel based on high molecular weight hyaluronic acid (HA) was developed for local administration of PF in experimental diabetic mice with a full-thickness wound. The resultant formulation (HA-PF) was able to significantly promote cutaneous healing as compared to INTRASITE Gel (a commercial hydrogel wound dressing). This outcome was accompanied by the amelioration of inflammation, the improvement of angiogenesis, and re-epithelialization, and the deposition of collagen. Our study indicates the significant potential of HA-PF for clinical translation in diabetic wound healing.

Keywords: Adipic acid dihydrazide, ADH; Angiogenesis; Anti-inflammation; Hydrogel; Macrophage polarization; N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, EDC.HCl; Regenerative medicine; arginase 1, Arg-1; bone marrow-derived macrophages, BMDMs; dimethyl sulfoxide, DMSO; fetal bovine serum, FBS; human umbilical vein endothelial cells, HUVECs; hyaluronic acid, HA; inducible nitric oxide synthase, iNOS; integrated optical density, IOD; interferon-γ, IFN-γ; interleukin-10, IL-10; interleukin-1β, IL-1β; lipopolysaccharide, LPS; macrophage colony-stimulating factor, M-CSF; paeoniflorin, PF; penicillin-streptomycin, P/S; phosphate-buffered saline, PBS; polyvinylidene difluoride, PVDF; scanning electron microscopy, SEM; signal transducer and activator of transcription, STAT; streptozocin, STZ; swelling ratio, SR; transforming growth factor-β, TGF-β; tumor necrosis factor-α, TNF-α; α-smooth muscle actin, α-SMA.