Abstract
We developed a highly stable recombinant human acidic fibroblast growth factor (rh-aFGF) carbomer 940 hydrogel for wound healing. This study aimed to reveal toxicity target organs and the toxicity dose-response in the long-term administration of rh-aFGF carbomer 940 hydrogel in a rabbit skin wound model. New Zealand rabbits were topically administrated rh-aFGF carbomer 940 hydrogel at a daily dose of 900 IU/cm2, 1,800 IU/cm2, and 3,600 IU/cm2 for 28 days. Lyophilized rh-aFGF agent was used as the positive control group. General behavior, serum chemistry, skin irritation, immunogenicity, immunotoxicity, and histopathology were analyzed at designated time points. Results revealed that food intake, body weight, body temperature, heart rate, and eye examinations were all normal, suggesting no obvious toxicity induced by the rh-aFGF hydrogel. Medium and high dose rh-aFGF hydrogel groups and the positive control group displayed increased cell numbers in the local lymph nodes near the site of administration, likely caused mesenteric lymph node follicular hyperplasia, and this observation was alleviated after 14 days of recovery. Immunogenicity studies demonstrated that the serum antibody titer against rh-aFGF increased with the duration and number of drug applications but were not neutralization antibodies. After administration stopped, antibody titer decreased and disappeared in some mice. In summary, the safe dose for long-term administration of rh-aFGF carbomer 940 hydrogel for persistently damaged skin was 900 IU/cm2, which is 10 times that of the proposed clinical dosing.
Highlights
Human acidic fibroblast growth factor, a member of the fibroblast growth factor family (FGF) (Beenken and Mohammadi, 2009; Li, 2019), is a potential therapeutic option for wound healing (Mellin et al, 1995; Wu et al, 2016)
There was no difference in body temperature between the negative control, the recombinant human acidic fibroblast growth factor (rh-aFGF) hydrogel treatment, and the positive control group during the administration period (Figures 1C, D, P > 0.05)
Mesenteric lymph node follicles appeared enlarged, had increased in number, and had expanded germinal centers and sometimes a “starry sky” appearance. This was mostly seen in the high dose and positive control groups (Figure 4C) and was alleviated after the recovery phase. It has been well-documented that aFGF plays an important role in wound healing (Zheng et al, 2015; Hota et al, 2018; Wang et al, 2018; Kawano et al, 2019)
Summary
Human acidic fibroblast growth factor (rh-aFGF), a member of the fibroblast growth factor family (FGF) (Beenken and Mohammadi, 2009; Li, 2019), is a potential therapeutic option for wound healing (Mellin et al, 1995; Wu et al, 2016). Our group previously developed a lyophilized rh-aFGF, which was approved by the Chinese Food and Drug Administration in 2006 for the treatment of deep, partial-thickness burns and skin graft donor sites (Ma et al, 2007; Hui et al, 2018a). This marketed rh-aFGF is a topical lyophilization agent, applied in the form of a spray. SEM imaging showed that the rh-aFGFcarbomer hydrogel contained slight 3D network structures, which allowed the diffusion of growth factors This may be one reason why the rh-aFGF carbomer hydrogen was superior in promoting wound healing compared to the solution. The purpose of this study was to examine skin irritation and the long-term systemic safety of rhaFGF hydrogel in a New Zealand white rabbit skin damage model, exceeding 10 times the clinical dose and with continuous treatment for 28 days, to determine possible adverse reactions
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