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. 2023 Feb 9;9(3):e13554.
doi: 10.1016/j.heliyon.2023.e13554. eCollection 2023 Mar.

Heparin-based sericin hydrogel-encapsulated basic fibroblast growth factor for in vitro and in vivo skin repair

Pan Du  1 , Ling Diao  2 , Yichi Lu  1 , Chenyang Liu  2 , Jin Li  1 , Yang Chen  3 , Junfeng Chen  1 , Guozhong Lv  1   2 , Xue Chen  1
Affiliations

Heparin-based sericin hydrogel-encapsulated basic fibroblast growth factor for in vitro and in vivo skin repair

Pan Du et al. Heliyon. .

Abstract

The treatment of full-thickness cutaneous wounds remains a significant challenge in clinical therapeutics. Exogenous growth factor (GF) has been applied in clinics to promote wound healing. However, the retention of GF on the wound bed after its direct application to the wound surface is difficult. Moreover, growth factors (GFs) are always inactivated in the complex wound healing microenvironment due to various factors, which significantly decrease the therapeutic effect. Sericin hydrogel (S) can be used as an effective carrier for GFs owing to its low immunogenicity, good biocompatibility, and good healing-promoting ability. Here, we designed a heparin-based sericin hydrogel (HS) -encapsulated basic fibroblast growth factor (bFGF-HS) to facilitate wound healing and skin regeneration. The hydrogel exhibited a three-dimensional (3D) microporous structure, excellent biodegradability, good adhesiveness, and low cytotoxicity. In vitro release of bFGF from bFGF-HS coacervates revealed that bFGF-HS might control the release of bFGF within 25 days through heparin regulation. bFGF-HS significantly promoted vascularization and re-epithelialization and improved collagen deposition, ultimately accelerating wound healing in vivo in mice. bFGF-HS treated wounds were also found to have more hair follicles and milder inflammatory reactions. Overall, this study provides a new therapeutic approach for full-thickness skin defect wounds using bFGF-HS.

Keywords: Sericin hydrogel; Wound healin; bFGF.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Characterization of the heparin-based sericin hydrogel. Biocompatibility and sustained release of the hydrogel. (a) Inverted vial method: after gelation. (b) The surface, cross-sectional, and skewed cross-section micromorphology of the heparin-based sericin hydrogel. Scale bars, 200 mm. (c) Swelling ratio of the heparin-based sericin hydrogel in PBS (pH 7.4, 4.0, 11.0) at 37 °C. (d) In vitro degradation profiles of heparin-based Sericin hydrogel in PBS (pH 7.4, 4.0, 11.0) at 37 °C. (e) Mechanical properties test of sericin hydrogel and HS hydrogel (length: 10 mm; width: 8 mm; height: 6 mm). Data are shown as mean ± SD (n = 5 for each analysis).
Fig. 2
Fig. 2
Biocompatibility and sustained release of the hydrogel. (a) In vitro bFGF release profiles. (b) Determination of cellular proliferation by the CCK8 assay in growth factor (GF)-loaded HS hydrogel post co-culture with human keratinocytes and dermal fibroblasts. (c) Confocal microscopic observation of the cellular 3D distribution of pre-stained HaCaT (green) and HDFs (red) in bFGF-HS hydrogels after three, five, and seven days of co-culture. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
Mouse wound repair process. (a) Schematic of hydrogel network loading with drug. (b) Experimental scheme for the preparation of bFGF loaded hydrogel sheet and wound healing treatment for full thickness wound. Created with BioRender.com. (c) Representative photographs of the wounds on days 0, 3, 7, and 14, dressed using saline (control), HS hydrogel, bFGF, and bFGF-HS hydrogel. (d) Wound closure over time in the wound healing model. Data are expressed as mean ± SD (n = 5).
Fig. 4
Fig. 4
Pathological examination of wound tissue. Proliferation of skin keratinocytes at wound sites in the different groups at 14 days post-surgery. (a) Hematoxylin and eosin (H&E) images of wounds treated with the different treatment materials for 7 and 14 days. Scale bars = 1 mm. Arrow indicates the epithelial junction. (b) The length of new epidermis at days 7 and 14 post-implantation. (c) Skin thickness at days 7 and 14 post-implantation. (d) Masson's staining images of wound tissues on day 14 post-surgery. Scale bar = 1 mm. (e) Number of hair follicles in the wound area. Scale bar = 200 um.
Fig. 5
Fig. 5
The proliferation of keratinocytes (a) Cutaneous wounds on day 14 post-injury were stained with PCNA antibody (red), Cytokeratin 14 antibody (green), and DAPI antibody (blue) and micrographs were taken. Scale bar = 50 μm. (b) Quantification of the number of proliferating cell nuclear antigen (PCNA)-positive keratinocytes. Data are expressed as mean ± SD (n = 5). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 6
Fig. 6
Inflammation at wound sites in the different groups at 7 and 14 days post-surgery. (a) Immunofluorescent images of the tissue sections stained with the CD68 antibody (red) and DAPI (blue). Scale bars = 50 μm. (b) CD68+ macrophage number per mm2 at wound sites treated with the different materials. (c) The ratio of M2/M1 macrophages (CD163/CD68). Data are expressed as mean ± SD (n = 5). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 7
Fig. 7
Angiogenesis at wound sites in the different groups at 14 days post-surgery. (a) Immunofluorescent images of the tissue sections stained with the CD31 antibody (red), a-SMA antibody (green), and DAPI (blue). Scale bars = 50 mm. (b) Blood vessel numbers per mm2 at wound sites treated with the different materials. (c) Percentage of CD31 vessel volume in the fluorescent images. Data are expressed as mean ± SD (n = 5). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
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