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. 2021 Oct 18;14(10):1058. doi: 10.3390/ph14101058

Table 1.

In vivo evidence.

Author Aim Strain Type of Wound Age Follow Up Duration Observation Signaling Pathway Involved
Richardson et al. (2013) [34] To demonstrate adult zebrafish as a model for cutaneous wounds Tg(krt4:egfp)gz7, Tg(mpx:GFP)i114, Tg(lyz:;EGFP) nz117, Tg(lyz:dsRED2)nz50, Tg(fli1a:EGFP)y1, Tg(kdrl:HSRAS:mCherry) s896, and Tg(hsp70l:dnfgfr1-EGFP)pd1 Full thickness 6–12 months 4 h–24 days
  • -

    Thin-layer neoepidermis covered the majority of the wounded region at the 6th hour post-wounding.

  • -

    Multiple cell layers of the neoepidermis were formed within 24 h post-wounding.

  • -

    The number of inflammatory cells started to reduce over days.

  • -

    Macrophages were seen at the wounded region on the 4th day post-wounding.

  • -

    Granulation tissue formation was seen as early as 24 h post-wounding.

  • -

    Rapid neovascularization was seen from the 4th day post-wounding.

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    Decreased levels of leukocytes and blood vessels were seen from the 10th day post-wounding.

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    Fully re-stratified wound epidermis, dermal compartments, completely recovered subcutaneous adipocytes, scales, and pigmentation were seen on the 28th day post-wounding.

 Transgenic inhibition of FGF signaling.
Lisse et al. (2016) [36] To access the effectiveness of H2O2 in epidermal wound healing Nacre Epidermal Not specified 0.5 h–4 days
  • -

    Activation of downstream pathway of reactive oxygen species (ROS).

  • -

    Upregulation of MMP9 and MMP13a.

  • -

    Downregulation of npas4a and serpinh1b.

  • -

    Increased expression of cryptochrome (cry1).

  • -

    Rapid activation of cell migration, adhesion, and cytoprotective and anti-apoptotic events.

  • -

    Prolonged NF-κB activity in larvae.

  • -

    Increased levels of Col5a3b and Itgb4.

 Activation of EGF, FOXO1, and IKKα pathways.
Caraguel et al. (2016) [38] To develop a differential approach in wound-healing modelling Danio rerio Full thickness Not specified 2 h–14 days
  • -

    Rapid rate of re-epithelialization process.

  • -

    Rapid migration of epidermal strata cell into the wound.

  • -

    Re-organization of the epidermis in the basal stratum was seen within 24 h.

  • -

    Cell migration in dermal was seen at 72 h post-wounding.

  • -

    Increased level of EGF production in the basal epidermal.

  • -

    Complete wound closure was seen by day 14.

 Activation of EGF pathway.
Richardson et al. (2016) [48] To study the underlying mechanism of cutaneous wound closure TL, edarz3R367W, Tg(actb2:hras-egfp)vu119, Tg(krt4:egfp)gz7, Tg(hsp70l:EGFP), and Tg(hsp70l:dnfgfr1-EGFP)pd1 Partial and full thickness 6–12 months 30 min to 4 days
  • -

    Rapid wound closure with a speed of 500 µm/h.

  • -

    Formation of bilayer, GFP+ superficial cells, and p63+ inner keratinocytes were seen.

  • -

    Wound closure via the purse-string mechanism was seen.

  • -

    Production of concentric rings of actin fibers and non-muscle myosin at the wound edges is seen.

  • -

    Increased migration of keratinocytes to the wound region.

  • -

    Increased loss of surface microridges.

  • -

    Elongation of inner keratinocytes in the superficial layer.

 Regulation of TGFβ/integrin- and Rock/JNK pathway.
Richardson et al. (2016) [33] To study the role of Rho kinase (Rock) in cutaneous wound healing Adult transgenic zebrafish Partial and full thickness 6–12 months 1 h to 15 days
  • -

    Attachment of the inner basal layer with the basement membrane.

  • -

    Outer layer was flattened and consisted of periderm cells.

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    Extension of lamellipodia within a few minutes.

  • -

    Inhibition of TGFβ signaling enhanced keratinocytes proliferation.

  • -

    Activation of receptor tyrosine kinases (RTKs) and G-protein-coupled receptors for rapid wound closure.

 Activation of Rock pathway for the rapid re-epithelialization process.
Seo et al. (2017) [37] To study the efficacy of silver nanoparticles (AgNP) for wound healing Wild-type Danio rerio Epidermal 4 months 2–20 days
  • -

    Absence of toxicity was seen with AgNP concentration >140 mg/L.

  • -

    Faster wound closure with clear margin was seen within 5 h.

  • -

    Complete filling of cavity, re-surfaced epidermal cells, well-formed skin, and immune cells is seen near the wound.

  • -

    Upregulation of TGF-β mRNA in muscle.

  • -

    Increased level of IL-1β, TNF-α, SOD, and catalase.

  • -

    Decreased level of MMP-9 and MMP-13.

 Not specified.
Xiong et al. (2018) [39] To study the effectiveness of a collagen mixture in wound healing Wild-type AB strain Full thickness Not specified 2–5 days
  • -

    Increased formation of new epithelial tissues.

  • -

    Increased production of new blood vessels.

  • -

    Increased level of cell proliferation at the wounded region.

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    Decreased level of cell apoptosis and rapid clearance of death cells at the wounded region.

  • -

    Decreased levels of neutrophils after 18 h of treatment.

  • -

    Suppression of the inflammatory response.

  • -

    Increased expression of Msxb, vegf-A, Wnt3a, RAR, and upregulation of col1a1b.

 Inhibition of TNF-mediated leukocyte chemotaxis.
Vimalraj et al. (2018) [40] To analyze the role of nitric oxide in wound healing Adult Tie2-GFP
transgenic Zebrafish		 Full thickness 8–10 months 48 h–14 days
  • -

    Rapid regeneration of fin and re-growth of blood vessel was seen.

  • -

    Formation of re-epithelial cell without the lag phase was seen.

  • -

    Increased level of granulated cells during early treatment.

  • -

    Mitotic activity of epidermal cells was seen within 24 to 72 h.

  • -

    Increased level of fibroblast synthesis was seen within the deeper layer of tissues.

  • -

    Increased level of collagen deposition was seen in the wounded region.

 Upregulation of the Wnt/β-catenin pathway.
Noishiki et al. (2019) [41] To demonstrate the angiogenesis mechanism during cutaneous wound healing Tg(kdrl:eGFP)s843, Tg(gata1:DsRed)sd2, and Tg(fli1a:mCherry)ncv501 Partial thickness Not specified 2 days–2 months
  • -

    Rapid formation of endothelial cells and pericytes was seen, which lasted up to 2 months.

  • -

    Activation of the angiogenesis process by endothelial cells was seen.

  • -

    Increased production of new blood vessels and the bifurcation process.

  • -

    Activation of VEGF signaling for angiogenesis at the wounded region was seen.

  • -

    Rapid increase in pericytes covering tortuous blood vessels.

 Activation of VEGF signaling pathway.
Liu et al. (2020) [42] To investigate the role of isoliquiritin in angiogenesis during wound healing Tg(fli-1:EGFP), and Tg(mpeg:mCherry) Full thickness 6 months Day 1–the 15th day
  • -

    Rapid wound closure was seen as early as the 5th day.

  • -

    A decrease in wound size was seen from day 3.

  • -

    Formation of a thick epithelial cell layer and degeneration of granulation tissue were seen.

  • -

    Longer duration of angiogenesis was seen in the treatment group.

  • -

    Increased concentration of macrophages was seen at the wounded region.

  • -

    Increased expression of SOD1, TGFβ, and TNF-α were observed.

 Downregulation of VEGFR tyrosine kinase inhibitor II pathway.
Edirisinghe et al. (2020) [43] To scrutinize the ability of Spirulina maxima in wound healing Wild-type AB Full thickness 4 months Day 1–day 10
  • -

    Increased migration of fibroblasts to the wounded region.

  • -

    Rapid regeneration of fin was seen.

  • -

    Rapid wound closure, re-appearance of pigments, and disappearance of wound margins at the wounded site.

  • -

    Rapid process of re-epithelialization, multiple layers of neo-epidermis, and re-appearance of overlapping scales was seen.

  • -

    Rapid remodeling of epidermal tissue and tissue remodeling were observed.

 Upregulation of the Wnt/β-catenin pathway.