Abstract
Recent knowledge of the cellular and molecular mechanisms underlying cutaneous wound healing has advanced the development of medical products. However, patients still suffer from the failure of current treatments, due to the complexity of healing process and thus novel therapeutic approaches are urgently needed. Previously, our laboratories produced a range of low molecular weight hyaluronic acid (LMW-HA) fragments, where a proportion of the glucosamine moieties were chemically N-acyl substituted. Specifically, N-butyrylation results in anti-inflammatory properties in a macrophage system, and we demonstrate the importance of N-acyl substituents in modulating the inflammatory response of LMW-HA. We have set up an inter-institutional collaborative program to examine the biomedical applications of the N-butyrylated LMW-HA (BHA). In this study, the potentials of BHA for dermal healing are assessed in vitro and in vivo. Consequently, BHA significantly promotes dermal healing relative to a commercial wound care product. By contrast, the “parent” partially de-acetylated LMW-HA (DHA) and the re-acetylated DHA (AHA) significantly delays wound closure, demonstrating the specificity of this N-acylation of LMW-HA in wound healing. Mechanistic studies reveal that the BHA-mediated therapeutic effect is achieved by targeting three phases of wound healing (i.e., inflammation, proliferation and maturation), demonstrating the significant potential of BHA for clinical translation in cutaneous wound healing.
Highlights
Wound healing generally proceeds efficiently after the onset of a lesion, a poor outcome may follow larger injuries or a variety of pathological states, such as infection and vascular disease [1,2]
Results demonstrated that the wound closure efficacy was significantly improved by butyrylated LMW-HA (BHA)-Gel at doses from 0.05 to 1 mg/mL relative to the untreated group (p < 0.05 and p < 0.01) (Figure S3)
Due to the effective wound closure achieved by the BHA-Gel at the dose of 0.25 mg/mL (p < 0.01) at all tested timepoints (Figure S3), this concentration was chosen for the following in vivo experiments
Summary
Wound healing generally proceeds efficiently after the onset of a lesion, a poor outcome may follow larger injuries or a variety of pathological states, such as infection and vascular disease [1,2]. Several hurdles remain for the application of aforementioned approaches to cutaneous lesions; for example, the administration of growth factors lacks appropriate drug delivery systems [8], and the efficacy of cell-based strategies may be dampened by complexities, including the pathological conditions of donors, the onset time and duration of treatment, and the dose and its route of administration [9]. High molecular weight HA (HMW-HA) possesses anti-inflammatory or immunosuppressive activities, while low molecular weight HA (LMW-HA) demonstrates pro-inflammatory or immunostimulatory behaviors [12]. The potential of HA in wound healing is demonstrated preclinically in animals [14,15,16,17], there have been no reports that HA may fully promote different phases of wound repair
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