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      KGF-2 and FGF-21 poloxamer 407 hydrogel coordinates inflammation and proliferation homeostasis to enhance wound repair of scalded skin in diabetic rats

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          Abstract

          Objective

          The present study focused on the development of a poloxamer 407 thermosensitive hydrogel loaded with keratinocyte growth factor-2 (KGF-2) and fibroblast growth factor-21 (FGF-21) as a therapeutic biomaterial in a scald-wound model of type-2 diabetes in Goto-Kakizaki (GK) rats.

          Research design and methods

          In this study, a poloxamer 407 thermosensitive hydrogel loaded with KGF-2 and/or FGF-21 was prepared and its physical and biological properties were characterized. The repairing effects of this hydrogel were investigated in a scald-wound model of type-2 diabetes in GK rats. The wound healing rate, epithelialization, and formation of granulation tissue were examined, and biomarkers reflecting regulation of proliferation and inflammation were quantified by immunostaining and Western blotting. T tests and analyses of variance were used for statistical analysis via Graphpad Prism V.6.0.

          Results

          A 17.0% (w/w) poloxamer 407 combined with 1.0% (w/w) glycerol exhibited controlled release characteristics and a three-dimensional structure. A KGF-2/FGF-21 poloxamer hydrogel promoted cellular migration without apoptosis. This KGF-2/FGF-21 poloxamer hydrogel also accelerated wound healing of scalded skin in GK rats better than that of a KGF-2 or FGF-21 hydrogel alone due to accelerated epithelialization, formation of granulation tissue, collagen synthesis, and angiogenesis via inhibition of inflammatory responses and increased expression of alpha-smooth muscle actin (α-SMA), collagen III, pan-keratin, transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), and CD31.

          Conclusions

          A KGF-2/FGF-21 poloxamer hydrogel accelerated wound healing of scalded skin in GK rats, which was attributed to a synergistic effect of KGF-2-mediated cellular proliferation and FGF-21-mediated inhibition of inflammatory responses. Taken together, our findings provide a novel and potentially important insight into improving wound healing in patients with diabetic ulcers.

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          Most cited references37

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          Wound repair: role of immune-epithelial interactions.

          G Leoni, P Neumann, R Sumagin … (2015)
          The epithelium serves as a highly selective barrier at mucosal surfaces. Upon injury, epithelial wound closure is orchestrated by a series of events that emanate from the epithelium itself as well as by the temporal recruitment of immune cells into the wound bed. Epithelial cells adjoining the wound flatten out, migrate, and proliferate to rapidly cover denuded surfaces and re-establish mucosal homeostasis. This process is highly regulated by proteins and lipids, proresolving mediators such as Annexin A1 protein and resolvins released into the epithelial milieu by the epithelium itself and infiltrating innate immune cells including neutrophils and macrophages. Failure to achieve these finely tuned processes is observed in chronic inflammatory diseases that are associated with non-healing wounds. An improved understanding of mechanisms that mediate repair is important in the development of therapeutics aimed to promote mucosal wound repair.
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            Role of growth factors and cytokines in diabetic foot ulcer healing: A detailed review

            Mohammad Zubair, Jamal Ahmad (2019)
            Article 0 comments Cited 82 times – based on 0 reviews     Review now
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              Comparative Study of Heparin-Poloxamer Hydrogel Modified bFGF and aFGF for in Vivo Wound Healing Efficiency.

              Jiang Wu, Jingjing Zhu, Chaochao He … (2016)
              Wound therapy remains a clinical challenge. Incorporation of growth factors (GFs) into heparin-functionalized polymer hydrogel is considered as a promising strategy to improve wound healing efficiency. However, different GFs incorporation into the same heparin-based hydrogels often lead to different wound healing effects, and the underlying GF-induced wound healing mechanisms still remain elusive. Herein, we developed a thermos-sensitive heparin-poloxamer (HP) hydrogel to load and deliver different GFs (aFGF and bFGF) for wound healing in vivo. The resulting GFs-based hydrogels with and without HP hydrogels were systematically evaluated and compared for their wound healing efficiency by extensive in vivo tests, including wound closure rate, granulation formation, re-epithelization, cell proliferation, collagen, and angiogenesis expressions. While all GFs-based dressings with and without HP hydrogels exhibited better wound healing efficacy than controls, both HP-aFGF and HP-bFGF hydrogels demonstrated their superior healing activity to improve wound closure, granulation formation, re-epithelization, and blood vessel density by up-regulation of PCNA proliferation and collagen synthesis, as compared to GF dressings alone. More importantly, HP-aFGF dressings exhibited the higher healing efficacy than HP-bFGF dressings, indicating that different a/bFGF surface properties lead to different binding and release behaviors in HP hydrogels, both of which will affect different wound healing efficiency. On the basis of experimental observations, the working mechanisms of different healing effects of HP-GFs on full skin removal wound were proposed. This work provides different views of the design and development of an effective hydrogel-based delivery system for GFs toward rapid wound healing.
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                Author and article information

                Journal
                Journal ID (nlm-ta): BMJ Open Diabetes Res Care
                Journal ID (iso-abbrev): BMJ Open Diabetes Res Care
                Journal ID (hwp): bmjdrc
                Journal ID (publisher-id): bmjdrc
                Title: BMJ Open Diabetes Research & Care
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Electronic): 2052-4897
                Publication date Collection: 2020
                Publication date (Electronic): 19 May 2020
                Volume: 8
                Issue: 1
                Electronic Location Identifier: e001009
                Affiliations
                [1 ]departmentDepartment of Dermatology , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, Zhejiang, China
                [2 ]departmentSchool of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou, Zhejiang, China
                Author notes
                [Correspondence to ] Professor Xiaojie Wang; 18858811123@ 123456126.com ; Dr Qi Hui; huiqi1976@ 123456163.com ; Dr Xiaokun Li; profxiaokunli@ 123456163.com
                Author information
                http://orcid.org/0000-0001-7748-1541
                Article
                Publisher ID: bmjdrc-2019-001009
                DOI: 10.1136/bmjdrc-2019-001009
                PMC ID: 7245451
                PubMed ID: 32434772
                SO-VID: 9987c9b9-e2eb-443b-93ba-ffb9711e2ade
                Copyright © © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
                License:

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Date received : 27 October 2019
                Date revision received : 04 February 2020
                Date accepted : 09 February 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002855, Ministry of Science and Technology of the People's Republic of China;
                Award ID: 2016ZX09101117
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81601695
                Funded by: FundRef http://dx.doi.org/10.13039/501100004731, Natural Science Foundation of Zhejiang Province;
                Award ID: LY17H150002
                Award ID: LY17H300003
                Categories
                Subject: Emerging Technologies, Pharmacology and Therapeutics
                Subject: 1506
                Custom metadata
                special-feature unlocked

                Keywords: type 2 diabetes,wound healing,combination therapy,growth factor(s)
                Data availability:
                Keywords: type 2 diabetes, wound healing, combination therapy, growth factor(s)

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