1 INTRODUCTION

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) belongs to the stilbenoid group of polyphenols. It consists of two phenol rings linked by an ethylene bridge, which gives rise to two geometric isomers: the active trans-isomer and an inactive cis-isomer.1 Resveratrol has been found in more than 70 different plant species and important dietary sources are grapes (skin and seeds), red wine, peanuts, and soy.2 The so-called “French Paradox” that describes the potential health benefits associated with regular and moderate wine consumption was first correlated to wine polyphenols, especially resveratrol, by Renaud and De Logeril in 1992.3 Since then, resveratrol has received increasing scientific attention regarding its diverse biological activities, including antioxidant, anti-inflammatory, antiobesity, and anticancer properties.

Among these diverse biological effects of resveratrol, the antioxidant properties are most prominent. Resveratrol has been shown to protect cells against hydrogen peroxide-induced oxidative stress, as well as UV-irradiation-mediated cell death. These results were partially attributed to direct effects of resveratrol as a radical scavenger but indirect effects were also observed, where resveratrol was able to modulate cellular antioxidant pathways.4-7

Resveratrol has also been known to interfere with inflammatory responses and to reveal anti-inflammatory properties, as it targets nuclear factor-kB (NFkB), expression of pro-inflammatory cytokines (e.g. interleukin 6, IL6), and also genes involved in eicosanoid production.1, 8 Resveratrol also targets toll-like receptor (TLR) signalling, such as TLR2, TLR3, and TLR4 signalling.9-13 In skin, resveratrol reduces imiquimod-induced, TLR7, TLR8, TLR9-mediated, psoriatic inflammation in animal models, most likely via interfering with NF-kB activation.14, 15 This anti-inflammatory activity of resveratrol can be associated with health benefits for several autoimmune and chronic inflammatory conditions.8

Numerous in vitro and in vivo studies confirmed the inhibitory effects of resveratrol on carcinogenesis in all stages, such as initiation, promotion, and progression.16, 17 Resveratrol serves as a chemopreventive agent18, 19 and displays chemotherapeutic properties that are attributed to its antioxidant, anti-inflammatory, proapoptotic, and antiproliferative features.17, 20 Resveratrol is supposed to target intracellular signalling pathway components including regulators of cell survival and apoptosis, pro-inflammatory mediators, and key components of tumour angiogenesis and metastasis by interfering with a distinct set of transcription factors, upstream kinases, and their regulators.21-23

In vivo studies demonstrated that resveratrol additionally exerted beneficial effects on metabolic syndrome-related alterations, for example, glucose and lipid homeostasis improvement and a reduction in fat mass, blood pressure, low-grade inflammation, and oxidative stress.24-28 Further studies verified that resveratrol mimics caloric restriction via the activation of sirtuin 1 (SIRT 1)26, 29 resulting in improved exercise performance and insulin sensitivity, as well as showing body fat-lowering effects by inhibiting adipogenesis, and increasing lipid mobilisation in adipose tissue.30, 31

These diverse effects of resveratrol are also potentially involved in cutaneous wound healing, scarring, and (photo-) aging of the skin, which is reflected by an increasing number of publications in this field over the past decade. This review will therefore summarise the most relevant studies involving resveratrol in wound healing, scarring, and photo-aging of the skin.

2 METHODS

The online database PubMed was used to review the medical literature covering resveratrol application in wounds, skin aging, and scars. The day the database was accessed was on 28 November 2020, and the last 10 years have been analysed. The following MeSH terms have been used [“Resveratrol”[Mesh] AND (“Wounds and Injuries”[Mesh] OR “Wound Healing”[Mesh] OR “Re-Epithelialization”[Mesh] OR “Skin Aging”[Mesh] OR “Aging”[Mesh] OR “Cicatrix”[Mesh])]. To minimise the risk of missing relevant data, the search term [resveratrol AND (“Wound*” OR “Anti-Aging” OR “Cicatrix” OR “Scar”)] has been used additionally.

All search results were listed in an excel sheet (Microsoft Excel 2016 MSO [16.44] 32-bit) and duplicates have been removed. Titles, abstracts, and if available, full-text articles have been analysed, which concern the exact study purpose. Non-English articles, reviews, commentaries, and studies that aimed at wrong topics were excluded. The remaining studies were included and analysed for their specific content. In order to minimise the bias of wrongful exclusion, each study was evaluated by at least two reviewers (AH and MS), and exclusion decisions were based on the consensus of the reviewing authors. If a discrepancy between the reviewers occurred, the literature was evaluated by a third reviewer (EH).

The initial literature search yielded a total of 942 studies with 539 results in PubMed with MeSH-terms and 403 results in PubMed without MeSH terms. After duplicate exclusion (116 duplicates), 784 studies of the remaining 826 studies were excluded according to the prior mentioned exclusion criteria.

Thirty studies were excluded due to non-English, 217 studies because they were reviews or commentaries, and 538 studies because of wrong topic. In total, 41 studies about the effects of resveratrol have been included. A flowchart, summarising the systematic algorithm, as well as the quantitative results can be found in Figure 1. A summary of in vitro, in vivo, and clinical studies investigating the effects of resveratrol in the context of wound healing, scarring and photo-aging, are presented in Tables 1-3. The included studies can be divided into these major effects: wound healing, antiscarring, and antiaging properties of resveratrol, which will be presented in the following.

Review process depicted in a flowchart

TABLE 1. Summary of in vitro studies investigating the effects of resveratrol on wound healing, scarring, and photo-aging Study topic Author, year Cohort Test substance Setting Effects Wound healing Brakenhielm et al (2001)32 Bovine capillary endothelial cells, chick chorioallantoic membrane 1–100 μg RES discs

Effect of RES on fibroblast growth factor 2 (FGF-2)-induced activation of mitogen-activated protein kinases in bovine capillary endothelial cells; effect of RES in porcine aortic endothelial cell lines; antiangiogenic activity of RES in chick chorioallantoic membrane (1–100 μg per disc.)

Parameters evaluated: FGF-2 and vascular endothelial growth factor (VEGF) receptor-mediated endothelial cell growth and chemotaxis

RES inhibits FGF-2 and VEGF receptor-mediated endothelial cell growth and chemotaxis.

Dose-dependent inhibitory effect on angiogenesis of RES.

Khanna et al (2001)33 Human keratinocytes (line HaCaT) GSPE (grape seed proanthocyanidin extract) containing 5000 ppm trans-RES

Keratinocytes treated with GSPE; washed with GSPE-free medium before, then challenged with H2O2 (hydrogen peroxide) or TNF-α

Parameters evaluated: VEGF

Treatment with GSPE upregulated H2O2 and TNF-α induced VEGF expression and release Chan et al (2002)34 Bacteria and dermatophytes 3.12, 6.25, 12.5, 25, 20, 100 μg/mL RES Susceptibility testing of bacteria (Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa) and dermatophytes (Trichophyton mentagrophytes, Trichophyton tonsurans, Trichophyton rubrum, Epidermophyton floccosum, Microsporum gypseum) in control medium, dimethyl sulphoxide solvent, and RES. RES inhibited the growth of bacteria and dermatophytes in a dose-dependent manner. Higher RES concentration resulted in better growth inhibition of bacteria and dermatophytes. Pastore et al. (2013)35 Human epidermal keratinocytes (HEK) 50 μM RES

HEK from 4 healthy donors: verbascoside (control), RES 50 μM

Parameters evaluated: IL-8 expression, extracellular-signal regulated kinase (ERK), p65, c-Fos, epidermal growth factor receptor (EGFR), NHEK proliferation

IL-8 overexpression, ERK phosphorylation was transiently inhibited, enhanced p65 and EGFR phosphorylation, c-Fos upregulation, NHEK proliferation inhibited Eroğlu et al (2014)36 Normal skin-derived fibroblasts (NSFBs); RES loaded into microparticles consisting of dipalmitoylphosphatidylcholine and hyaluronic acid Cell culture of NSFBs: RES-loaded microparticles Parameters evaluated: cellular proliferation (CP), total glutathione (GSH), oxidised glutathione (GSSG), glutathione peroxidase (GPx), malondialdehyde (MDA), superoxide dismutase (SOD) RES-loaded microparticles increased CP, decreased oxidation in cells by GSH/GSSHG ratio reduction. No effect of RES in GPx, MDA, and SOD.

Abbas et al (2019)37

Human fibroblasts Flavonoids (chrysin, naringenin, RES) with β-sitosterol

Scratch-wound migration assay:

Parameters evaluated: closure rate, cytotoxicity, fibroblasts migration

β-sitosterol combined with RES and β-sitosterol combined with naringenin achieved the best closure rates. No toxic effect on fibroblasts was detected. Comotto et al (2019)38 Human keratinocytes Alginate dressings with natural antioxidants (curcumin; RES)

Determination of the optimal concentration of the active compounds

Parameters evaluated: release rate, cellular growth, bacterial growth

Release rate: burst release followed by a gradual release; 300 μg/mL of RES did not induce any toxicity; curcumin and RES showed an improved cell viability; curcumin was superior regarding anti-microbial properties Meng et al (2019)39 Human adipose stem cells Bacterial cellulose conjugated with RES, collagen conjugated with RES

In vitro biocompatibility:

adipose stem cells were cultured in keratinocyte serum-free medium with foetal bovine serum.

Examination of the samples by immunocytochemical staining.

RES-conjugated bacterial cellulose created a biocompatible environment for stem cell attachment and cell growth. Huang et al (2019)40 Human umbilical vein endothelial cells (HUVECs) 10 μM RES

HUVECs in high glucose medium (HGM), HGM + 10 μM RES, normal glucose medium (NGM), NGM + 10 μM RES

Parameters evaluated: CP, cell migration, apoptosis

RES treatment increased hyperglycemia-impaired endothelial CP.

HGM induced cell migration and apoptosis alleviated by RES

Kaleci et al (2020)41 3 T3 Swiss Albinofibroblasts 1, 5, and 10 μM RES in combination with 500 μM H2O2

Fibroblasts, 4 groups: control group, 500 μM H2O2, RES, 500 μM, H2O2 + RES group

Parameters evaluated: CP, OS (oxidative stress) level, collagen-I-expression, cell migration

RES application showed better CP rates compared to the other groups. Best CP results with 1 μM RES.

RES decreased H2O2-induced high OS.

No impact of RES in collagen-I-expression or cell migration compared to control group.

Scarring Zeng et al (2013)42 Hypertrophic scar-derived fibroblasts (HSFBs) RES 25, 75, 150, 300 and 400 μM

Cell culture of HSFBs and NSFBs from two young female donors: control, RES 25 μM, RES 75 μM, RES 150 μM, RES 300 μM, and RES 400 μM over the time (24 h, 48 h and 72 h)

Parameters evaluated: cell proliferation (CP), cell cycle progression, apoptosis, hydroxyproline, collagen

RES suppressed cell growth, arrested cell cycle progression, triggered apoptosis in a dose- and time-dependent manner (increased effect with longer duration and higher concentration).

RES downregulated mRNA expression of type I and III procollagen in fibroblasts, resulting in significant decreases in hydroxyproline and collagen

Zhai et al (2015)43 Human pathologic scar-derived fibroblasts (PSFBs) RES 10, 50, and 100 μmol/L

Cell culture with fibroblast from 20 patients. 4 groups: control, RES 10, RES 50, 100 μmol

Parameters evaluated: morphological changes in target cells, CP, TGF-β1, Smad-2,3,4,7

Apoptotic morphological alterations and reduced CP in RES-treated pathological scar fibroblasts. Inhibitory effect in CP enhanced with increasing RES concentration. TGF-β1, Smad-2,3,4 negatively and Smad-7 positively correlated with RES concentration. Bai et al (2016)44 HSFBs and NSFBs RES 2.5, 5, 10, 20, and 40 mM

Cell culture of HSFBs and NSFBs from 9 patients. SIRT1 upregulation by RES.

Parameters evaluated: SIRT1, collagen 1, collagen 3, α-smooth muscle Actin (α-SMA), TGF-β1

SIRT1 intensity lower in HSFBs compared to NSFBs. RES down-regulated mRNA levels of collagen 1, collagen 3, α-SMA due to upregulation of SIRT1 in a dose-dependent manner. RES inhibited TGF-β1-induced mRNA/protein level increase of collagen 1, collagen 3, and α-SMA. Tang et al (2017)45 PSFBs and NSFBs RES 10, 50, and 100 μmol/L

Cell culture of PSFBs and NSFBs from patients: control, RES 10 μmol/L, RES 50 μmol/L, 100 μmol/L

Parameters evaluated: mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (70S6K)

Strengthened mTOR and 70S6K expression in PSFBs compared to NSFBs.

Decreased expression of mTOR and 70S6K in dose-dependent manner.

Pang et al (2020)46 HSFBs and NSFBs RES 0, 1, 10, 100 μmol/L

Cell culture of HSFBs and NSFBs: control, RES 1 μmol/L, RES 10 μmol/L, 100 μmol/L over the time (24, 48, 72 h)

Parameters evaluated: cell viability (CV), microRNA-4654, Rheb, 1A/1B-light chain (LC3), Beclin 1

RES decreased CV in dose-dependent manner (increased effect with higher concentration).

RES upregulated microRNA-4654 expression level in dose-dependent manner, thus downregulated Rheb expression level and upregulated autophagy markers LC3 and Beclin 1

Photo-aging Subedi et al (2017)47 NSFBs RES and RESl-enriched rice (RR)

Cell culture with NSFBs from a healthy young male donor

UV-B irradiation and treatment with normal rice, RR and RES afterwards

Parameters evaluated: ROS (reactive oxygen species), MMP-1 (matrix metalloproteinase 1), collagen I

RR demonstrated the most effective reduction of ROS production compared to normal rice or RES alone.

RR induced a downregulation of MMP-1 (matrix metalloproteinase 1), inhibition of inflammatory cascades, and upregulation of collagen type I.

Zhou et al (2018)48 Human keratinocytes (HaCaT cell line) RES (<99%): 2.5, 5, 7.5, and 10 mm

Cell culture with keratinocytes s, UV-B irradiation for 5 min at 10 cm below the lamp (irradiation intensity: 0.1 mW/cm2)

Parameters evaluated: CV, apoptotic rate

Dose-dependent increase of CV of RES pretreated cells and decrease of apoptotic rate.

Increase of HSP27 expression resulting in antiapoptotic effects through inhibiting NF-kB and caspase-3 activation.

Abbreviations: α-SMA, α-smooth muscle actin; CP, cellular proliferation; CV, cell viability; EGFR, epidermal growth factor receptor; ERK, extracellular-signal regulated kinase; FGF-2, fibroblast growth factor 2; GPx, glutathione peroxidase; GSH, total glutathione; GSPE, grape seed proanthocyanidin extract; GSSG, oxidised glutathione; H2O2, hydrogen peroxide; HGM, high glucose medium; HSFBs, hypertrophic scar-derived fibroblasts; HUVECs, human umbilical vein endothelial cells; LC3, 1A/1B-light chain; MDA, malondialdehyde; MMP-1, matrix metalloproteinase 1; NGM, normal glucose medium; NSFBs, normal skin-derived fibroblasts; OS, oxidative stress; PSFBs, pathologic scar-derived fibroblasts; RES: resveratrol; ROS, reactive oxygen species (ROS); RR, resveratrol-enriched rice; SOD, superoxide dismutase; TNF-α, tumour necrosis factor alpha; VEGF, vascular endothelial growth factor. TABLE 2. Summary of in vivo studies investigating the effects of resveratrol wound healing, scarring, and photo-aging Study type Author, year Cohort Test substance Setting Effects Adverse events Wound healing

Brâkenhielm et al (2001)32

Mice (neovascularisation group)

Murine T241 fibrosarcoma (fibrosarcoma model)

C57Bl6/J mice (wound model)

5.7 mg/mL RES

Neovasculariaation group: corneas of mice implanted with VEGF and FGF-2. Oral application of RES. Drinking solutions for mice with RES (equivalent of 3 glasses of red vine) compared to control group (drinking water).

Fibrosarcoma group: oral administration of RES (1 mg/kg per day) for mice with fibrosarcoma

Full-thickness skin wound group: oral administration of RES (1 mg/kg per day) for C57Bl6/J mice

Parameters evaluated: VEGF, FGF-2 vessel density, fibrosarcoma growth, wound healing

Inhibition of VEGF and FGF-2 in RES group and vessel density reduction compared to control group.

RES treatment inhibited fibrosarcoma growth and delayed wound healing.

No minor or

major adverse

events

Khanna et al (2002)49

9 BalbC mice

GSPE containing 5000 ppm trans-RES

Two full-thickness excisional wound in each mice. One of the two wounds treated with 25 mL of 100 mg/mL GSPE for 5 d. Second wound served as control.

Parameters evaluated: wound healing, histology, glutathione/glutathione disulphide ratio

RES treatment increased wound healing and glutathione/glutathione disulphide ratio

RES application presented more well-defined hyperproliferative epithelial region, higher cell density, enhanced deposition of connective tissue, improved histological architecture.

No minor or

major adverse

events

Lin et al (2016)50 30 male Balb/C mice RES ointment (1, 100, 500 ng/mL)

7 groups, full-thickness excision of burn skin wound: vaseline (control), aloe emodin (1, 100, and 500 ng/mL), RES (1, 100, and 500 ng/mL).

Parameters evaluated: wound healing, histology, IL-1β, MCP-1, VEGF

Decreased healing time in RES-treated group compared to control group.

Histology: increased cellular infiltration

IL-1β, MCP-1, and VEGF increased in RES group compared to control group

No minor or

major adverse

events

Poornima et al (2017)51 9 female albino Wistar rats RES and ferulic acid

3 groups of 3 rats, full-thickness excision wounds: controls, chitosan polycaprolactone nanofibres, RES-ferulic-acid-loaded nanofibres.

Parameters evaluated: wound closure rate, wound vicinity, tensile strength, histology

Accelerated healing time in RES-treated group compared to control (15 d vs 20 d).

Smaller wound vicinity in the RES-treated group.

histology showed a higher collagen synthesis and more collagen deposition with tight packing in the RES-treated group

No minor or major adverse events

Gokce et al(2017)52 42 male Wistar albino rats RES-loaded hyaluronic acid and dipalmitoylphosphatidylcholine (DPPC) microparticles in dermal matrix

7 groups of 6 rats, full-thickness wound. Two control groups: non-diabetic control, diabetic control (streptozotocin induced).

Five intervention groups (diabetic wounds, streptozotocin induced): control, RES solution, RES-loaded microparticles, dermal matrix, RES-loaded microparticle impregnated dermal matrix (DM-MP-RES)

Parameters evaluated: histology, wound healing, glutahione (GSH), oxidised glutathione (GSSG), glutahione peroxidase (GPx), malondialdehyde (MDA), superoxide dismutase (SOD)

Highest amount of collagen fibres and efficient re-epithelisation in DM-MP-RES group.

DM-MP-RES application enhanced wound healing process in diabetic conditions, decreased SOD compared to diabetic wound control group and decreased GPx compared to diabetic control group.

No minor or major adverse events Zhao et al (2017)53

female C57BL/6 mice

24 Sprague–Dawley rats (12 wk old)

24 Sprague–Dawley rats (18 mo old)

female New Zealand White rabbits

RES 50 μM

Full-thickness wound

4 groups: control (ethanol), 2 μM metformin, 200 nM rapamycin, 50 μM RES. Agents locally applied to wound beds (100 μL per time in mice / rabbits and 225 μL per time in rats). Chronic application: one time every day and intermittent application: three times every other day in week 1 followed by a treatment-free week. Treatment for 2 wk.

Parameters evaluated: wound healing, vascularisation

RES treatment improved wound healing in young rodents compared to control group. RES group in young rodents presented smaller wound size, thicker epidermis, more collagen deposition, higher number of hair follicles compared to control group.

RES treatment improved vascularisation/number of capillary vessels in young and old rodents compared to control group.

No minor or major adverse events

Berce et al (2017)54 20 male Crl:CD1(ICR) mice Chitosan-sodium hyaluronate-RES polymer sponge (RES: 20 mg)

2 groups of 10 mice, full-thickness wounds: control, chitosan-sodium hyaluronate-RES polymer sponge for 14 d.

Parameters evaluated: wound healing, histology

chitosan-sodium hyaluronate-RES polymer stimulated wound healing, showed bacteriostatic properties and inhibited inflammation.

No minor or

major adverse

events

Lakshmanan et al (2019)55

C57BL/6 mice Electrospun scaffold loaded with RES

Full-thickness ischaemic wound, 4 groups: no treatment, collagen patch, blank scaffolds without RES, scaffolds with RES.

Parameters evaluated: wound healing, histology, thioredoxin-1, hemeoxygenase-1, vascular endothelial growth factor (VEGF), Bcl-2 protein

Treatment with RES-loaded scaffold improved wound healing compared to control group.

Activation of thioredoxin-1, hemeoxygenase-1, VEGF, and Bcl-2 protein in RES-loaded scaffold group.

No minor or

major adverse

events

Christovam et al (2019)56 32 male Wistar rats 2% RES

4 groups of 8 rats, full-thickness wound after 18 d of caloric restriction (CR) / ad libitum diet: control, 2% RES, 30% CR + control solution, 30% CR + 2% RES.

Parameters evaluated: collagen I + III, thiobarbituric acid-reactive substances (TBARS), total sulfhydryl content (TSC), VEGF, SIRT1

Increased expression of collagen I and collagen III in RES groups compared to control.

RES treatment decreased TBARS concentration and inhibited an increase of TSC.

VEGF protein expression in 30% CR + 2% RES group was higher compared to control / 2% RES group.

SIRT1 was higher in 2% RES group compared to control.

No minor or

major adverse

events

Meng et al. (2019)39 18 male Sprague–Dawley rats Bacterial cellulose-conjugated scaffold with 50 μM RES, collagen-conjugated scaffold with 50 μM RES

5 groups, excisional wounds: control, bacterial cellulose (BC), BC + RES, collagen, collagen + RES.

Parameters evaluated: wound area, histology

BC + RES conjugated scaffold induced re-epithelisation and preserved normal collagen pattern.

No minor or

major adverse

events

Li et al (2019)57 12 Male db/db mice 5 mmol/L trans-RES + 5 mmol/L hesperetin

2 groups of 6 mice, full-thickness excision: control, 5 mmol/L tRES +5 mmol/L hesperetin to induce glyoxalase 1 expression.

Parameters evaluated: wound healing

tRES- hesperetin treatment induced faster wound closure with more capillary formation compared to control.

No minor or

major adverse

events

Ávila-Salas et al. (2019)58 25 Sprague-Dawley rats Hydrogels loaded with bioactive compounds (RES, allantoin, dexpanthenol, caffeic acid)

Full-thickness excisional wounds: Madecassol (control), film dressing without bioactive compounds, hydrogels loaded with bioactive compounds (RES, allantoin, dexpanthenol, caffeic acid).

Parameters: wound closure rate, wound size, histology

All four bioactive compounds showed a better and faster re-epithelialisation and a better organisation of the granulation tissue compared to controls. All formulations were associated with a faster wound closure rate than controls.

No minor or

major adverse

events

Huang et al (2019)40 6 db/db mice RES 50 mg/kg/d

Two full-thickness excision wounds in each db/db mice: control wound, 10 μM RES.

RES application 50 mg/kg/d for 4 wk

Parameters evaluated: Ki67, apoptosis, c-Caspase-3, wound healing

Ki67 increased due to RES treatment.

Endothelial cells apoptosis alleviated by RES treatment.

RES decreased c-Caspase-3 intensity.

RES treatment accelerated wound healing.

No minor or

major adverse

events

Orlowski et al (2020)59 C57BL6 female mice Bimetallic Au@AgNPs modified with different polyphenols (with 200 μM RES)

Wound model in vivo: 5 mice per group, splint mouse model, Au@AgNPs with different polyphenols.

Parameters:

Wound healing, transforming growth factor β (TGF-β), VEGF, matrix metallopeptidase 9 (MMP-9), tumour necrosis factor α (TNF-α)

Local lymph node assay: 3 mice per group, splint mouse model: negative control, positive control and a 25% w/v of polyphenol-modified Au@AgNPs in vehicle or corresponding tannin solution were applied

Parameters: lymphocyte proliferation

RES-Au@AgNPs improved wound healing and induced TGF-β expression during the inflammatory phase as well as the expression of VEGF in the remodelling phase of wound healing.

RES-Au@AgNPs inhibited MMP-9 and TNF-α expression.

RES-Au@AgNPs induced down-regulation of lymphocyte proliferation.

No minor or

major adverse

events

Shevelev et al (2020)60 200 male Wistar rats RES

4 groups of 50 rats, full-thickness excision including (1) no infection, (2) S aureus, (3) P aeruginosa, and (4) C albicans. Each group divided into five treatment subgroups: placebo, positive control, RES, dihydroquercetin, dihydromyricetin. 14 d wound evaluation.

Parameters evaluated: wound healing, histology

Decreased healing time in RES-treated group compared to placebo group in a pathogen type-dependent manner. In P aeruginosa RES-treatment subgroup, no wound square reduction compared to placebo group over 14 d. Increased healing rate in RES treatment group on days 10–14.

Decreased infiltration of mast cells and increased infiltration of lymphocytes and macrophages in histological wound area.

No minor or

major adverse

events

Zheng et al (2020)61 18 male Sprague-Dawley rats Host-guest gelatin hydrogel (HGM) loaded with RES and histatin-1

Four full-thickness burn wounds in each rat. Treatment with 4 hydrogels / dressings in each rat: control, HGM, HGM + RES, HGM + Histatin-1, HGM + RES + histatin-1

for 2 wk.

Parameters evaluated: wound healing, interleukin-6 (IL-6), interleukin-1β (IL-1β), TNF-α, transforming growth factor β1 (TGF-β1)