Table 2.

Evidence table of studies included in the synthesis.

Article	Study design	Population	# Patients	Methods	Outcomes	Results	conclusion
Hahn and Supp 48 2017	comparative observational study	in vitro; keloid scars	keloid scar biopsies (N = 24, ♂:15,♀: 9, mean age: 17,5+-12.1y); biopsies of normal skin (N = 24, ♂: 1, ♀: 23, mean age: 31.5+-13.3y)	-in vitro; -colorimetric immunostaining; detection and incubation; photographic imaging (x40)	-immunohistochemistry; -expression of VDR (vitamin D receptor); -quantification of nuclear localization VDR; -photo imaging	-reduced nuclear localization of VDR-protein in keloid scar keratinocytes (p < 0.001); -VDR nuclear localization in skin color: normal skin black < normal skin white (p < 0.001), keloid skin black = white (p > 0.01)	Lower nuclear localization of VDR in keloid was found for scar epidermis compared with normal skin
Zhang et al. 39 2011	pilot study	in vitro; keloid scars	Keloid scar biopsies (N = 7, ♂:5, ♀:2; mean age: 26.5y)	-in vitro, exposure to different concentrations (1 pmol/L-1 to 10 μmol/L-1) of 1,25-dihydroxyvitamin D3 (1,25D) in presence/absence of TFG-B1	-western blot analysis; -immunofluorescence staining; -cell proliferation assay; -cell viability assay; -enzyme linked immunosorbent assay; -gelatin zymography; -collagen synthesis assay	-VDR mRNA and protein expression increased in keloids; -main site of localization of VDR: fibroblast nuclei; -1,25D induced sign. reduction in cell numbers up to 100 nmol-1; -dose dependent decrease in PCNA expression (PCR); -1,25D sign. suppressed TGF-β1-induced ECM production and keloid activation; -reduction of TGF-β1-effects on PAI-A production and increase of MMP-9 activity; in presence of TGF-β1: inducing HGF expression.	supplementation with 1,25D (100 nmol/L-1) decreases cell proliferation in keloids. Vitamin D is capable of inhibiting TGF-β1-mediated tissue remodelling responses in keloid fibroblasts.
Ince et al. 8 2019	RCT	humans	-stage 1: patients with vitamin D level <25 ng/mL and linear hypertrophic scar (N = 84, ♂:45, ♀: 39; mean age 28.6y, mean vit D level of 16.6 ng/mL) -stage 2: patients with vitamin D level <25 ng/mL and linear hypertrophic scar (N = 50, mean age 29.9y, mean vit D level of 15.4 ng/mL); -group 1 (N = 12): no medical/surgical treatment. -group 2 (N = 19): only vitamin D replacement. -group 3 (N = 19): surgical excision and saturation after vitamin D replacement	-2 stage study; -part 1: clinical assessment + history; -part 2: RCT with oral administration of 2000-U vitamin D/day in group 2 and 3	-vitamin D level measurement at 1M-3M-6M-12 M; -pre-post operative digital photography; -blinded POSAS by 3 surgeons	-Stage 1: mean, vitamin D level of 16.6 ng/mL; mean age 26.6y -stage 2: -scar width at 12M: no difference in group 1–2, sign. decrease in group 3 (p < 0.5); -no other significant difference was noted in the groups for scar scores (p > 0.05).	Increasing vitamin D levels to above 25 ng/mL before scar revision, and vitamin D deficiency in patients with HS may help reduce scar width. No mechanism for HS reduction by vitamin D was determined.
Yoon et al. 60 2019	comparative observational study	humans	-patients with hypertrophic scars (N = 486, ♂: 438, mean age: 37.1 + -7.8y, ♀:48, mean age: 33.81 + - 9.4y); split in 2 groups; -group 1: vitamin D deficient: N = 420; vitamin D: 13.3+-3.2 ng/mL, -group 2: vitamin D non-deficient: N = 66; vitamin D: 24.2 + 3.6 ng/mL	-blood sampling and scar evaluation	-blood sampling for 25OH plasma, -trans epidermal water loss (TEWL), -melanin, -erythema, -scar distensibility, -elasticity	-deficient group: 13.3+-3.2 ng/mL; -sign. correlation deficiency-smoking/depressive mood (p = 0.046; p = 0.038); no sign. association between deficiency-pain (p = 0.765); mean erythema level: 437.3 + -53.6 AU. -in deficient group, 25 OHD status: -sign. difference Uf, Ua/Uf, Ur/Uf, Uv/Ue (p = 0.017, p = 0.045, p = 0.021, p = 0.024) -non-deficient group: vitamin D 24.2 + 3.6 ng/mL; mean erythema level: 434.5+-55.2 AU. -in non-deficient group, 25OHD status: no sign. influence on dependent variables. -deficient vs non-deficient: -sign. higher mean values melanin and TEWL (p = 0.032; p = 0.007); -sign. lower Uf, Ua/Uf, Ur/Uf (p < 0.001, p < 0.001, p = 0.014); -sign. higher Uv/Ue (p = 0.016); no sign. difference in H-value (p = 0.095).	Patients with hypertrophic scars and a vitamin D-deficiency showed higher melanin and TEWL values compared to non-deficient patients. Deficient patients were also associated with increased scar rigidity, more fibrous scars and slowed down interstitial fluid movement. Additional vitamin D supplementation may have a potential positive effect on hypertrophic scar healing.
Ramakrishnan et al. 41 2015	cohort study	in vitro; keloid scars	keloids of the ear lobules (N = 5)	-keratinocyte isolation; -isolation of fibroblasts; -treatment of keloid fibroblasts with vitamin D3 (5–50 ng/mL) and treatment with quercetin (5–50 μg/mL); untreated keloid fibroblasts	-photo imaging; -24 h and 48 h cell proliferation; MTT assay; -RNA extraction; -immunocytochemistry	-Vitamin D3 treatment: keloid fibroblasts: -post 24h: negligible reduction in cell proliferation; -post 48h: dose-dependent reduction in cell proliferation with concentrations ranging (25–50 ng/mL; p < 0.05, 35 ng/mL; p < 0.01); -no changes in keratinocytes; -three-fold collagen I decline (20 ng/ml). -Quercetin treatment (5–50 μg/mL): -fibroblasts showed a substantial decrease in cell proliferation(25–35 μg/mL; p < 0.05; 50 μg/mL, P < 0.01) post 48 h; -no changes in keratinocytes; -three-fold decrease in collagen I post 48 h (25 μg/mL). -vit D3 and quercetin: keloid fibroblasts showed decreased Bcl-2 expression	both vitamin D3 and quercetin decreased cellular proliferation and collagen synthesis (dose-dependent). The mechanism thought to be responsible for the decrease in proliferation is the increased cell apoptosis through the decreased Bcl-2 expression.
Park et al. 53 2010	comparative study	in vitro; dermal fibroblasts	human dermal fibroblasts (neonatal foreskin) and human keloid fibroblasts; -4 groups: -group 1: control; -group 2: treatment with LL-37; -group 3: treatment with vitamin C; -group 4: vitamin C treatment with LL-37	-vitamin C (0.5 mM) application or vitamin C treatment followed by 2 h LL-37 treatment (10 nM)	-total RNA measurement; -total collagen measurement (Sircol soluble collagen assay); intracellular ROI level detection (fluorometer); western blot analysis (after 12 h)	-vit C offsets antifibrotic effect of LL-37 in human dermal and keloid fibroblasts; -vit C turned off LL-37-induced ERK and Ets-1 signal; -vitamin C reduces ROI levels induced by LL-37	Vitamin C reversed LL-37-induced ERK and Ets-1 expression in keloid fibroblasts.
Phan et al. 40 2003	comparative study	in vitro; dermal fibroblasts	non treated earlobe keloid fibroblasts (KF) and burn hypertrophic scar fibroblasts (HSF)	-fibroblasts were tested (3x) with 10 different dietary phytochemicals, 7 phenolic acids, 2 flavonols and turmeric curcumin (3 hydroxybenzoic, 4 hydroxycinnamic, 2 flavonols and turmeric)	-MTT assay; -DNA quantification; -cell counting; -transmission and electron microscope scanning (Jeol); -living cells visualization (lattice);-FPCL; -cell cycle analysis; -Annecin V Assay for apoptosis	-fibroblast proliferation in HSFs and KFs: spectrum of inhibitory concentrations of curcumin is as low as from 1 to 5 μg/mL; significant doses are 2.5 and 5 μg/mL (p < 0.01). -PCA: inhibitory dose effects 50–200μg/mL. -Gallic acid: effective from 5μg/mL. -flavonols (quercetin; kaempferol): 20 μg/mL most effective for inhibiting KF proliferation (p < 0.01). -Quercetin was also effective at 5–10 μg/mL (p < 0.01). -collagen lattice contraction (FPCL): PCA, GA, ChA, Quercetin show strong inhibition; dose dependent and reversible.	dietary phytochemicals at determined concentrations could inhibit fibroblast proliferation by inducing cell growth arrest but not apoptosis and fibroblast contraction. The data indicated that quercetin seems to be the most effective compound. Curcumin could stop fibroblast proliferation at low concentrations of 2.5 or 5 μg/mL.
Louw and Dannhauser 55 2000	comparative observational study	humans	-24 h recall and standardized food frequency questionnaire: -keloid prone patients (N = 10, ♂: 2, ♀: 8; 4y-old keloids); -normal black South Africans (N = 80). -total phospholipid blood analyses: keloid patients (N = 20); normal individuals (N = 20)	-dietary evaluation and collection of blood samples	-dietary intake estimation using 24 h recall method; -standardized food frequency questionnaire; -plasma and red blood cell TPL fatty acid analysis	dietary intake: keloid patients: -higher intake (>7–11 g/day) of LA, AA, EFAs omega-6 series; -higher intake of Mg(>67% of the RDA); -lower intake (<1.1–1.5 g/day) of ALA, EPA, DHA, omega-3 series; -lower intake of Ca and Cu control: -higher intake omega-6 series; -slightly lower intake omega-3 series. Blood TPL fatty acids profile: keloid patients: -higher GLA (p < 0.001), LA, AA, ALA, EPA, DHA; -lower ELA	In both diet and the red blood cell TPL fraction, EFAs (higher than required LA and AA), may probably play a contributing role in keloid formations.
Louw 56 2000	comparative study	in vitro; keloids	-keloid patients (N = 20); -normal skin of keloid prone patients (N = 20); -non-keloid prone patients (N = 20)	-biopsies used for lipid extraction and fractionation; -fatty acid analysis	-fatty acid compositions of membrane lipids and keloids	-no significant difference between CEs levels of keloid and keloid prone patients. -Higher AA levels in keloids compared to keloid prone (p < 0.001) and non-keloid prone patients (p = 0.001). -All FFAs were sign. higher compared to keloid prone patients, especially OA (p < 0.001)	high AA levels are responsible for immune reactions during abnormal wound healing. High OA levels seem to be responsible for the continuous immune reactions during keloid formations, supplementation of EFAs can restore EFAD of AA precursors and inflammatory competitors
Alonso and Rioja 59 2016	single-blind trial (prospective clinical trial)	humans	-patients who responded to a solanaceae-free diet (SFD) with itching (N = 20, ♂:9, ♀:11, mean age: 43.55,6y + -17.29)); -controls (N = 10, ♂: 4, ♀: 6, mean age: 42.6y + -11.09)	Topical challenge: -application of solanidine cream and tomatidine cream (0.5 mL) + occlusive dressing; -1 h after application: assessment for presence of pruritus and latency; -scars cleaned after procedure // Systemic challenge: intake of the suspected food, one week SFD-diet	-assessment of pruritus intensity (VAS) + duration	-sign. decrease in pruritis after one week of SFD (p < 0.0001), systemic (intake) vs topical challenge test: pruritus intensity sign. higher in systemic challenge test (p < 0.006); no differences between foods or alkaloids (p = 0.0301, p = 0.667); -no side effects (next to pruritus/paraesthesias) were reported; -symptom mean latency: local challenge test (sign. shorter) < systemic test	A Solanacaea free diet might be useful to avoid pruritus in patients. A diet-based treatment is more harmless and free.
Howling et al. 43 2001	comparative observational study	in vitro; dermal fibroblasts	human dermal fibroblasts from healthy donors	-application of 6 different chitin/chitosan concentration samples (5–500 μg/mL); 1: Chitin-50, 2: Chitin-50 A, 3: CL311, 4: CL311A, 5: CL313, 6: CL313A	-methyl-thymidine cell (fibroblast) proliferation assay; -keratinocyte proliferation assay	-fibroblast proliferation: chitosan CL313, CL313A show strong stimulatory effects for all concentrations (2.5–5-50–500 μg/mL) (p < 0.01). Chitin-50 A showed antiproliferative effects at higher doses (50–500 μg/mL) (p < 0.05). -effect on keratinocyte proliferation: CL313A inhibits HaCaT proliferation by 26% (5 μg/mL) and 20% (50 μg/mL); Chitin-50 showed no effect.	Chitosan CL313 and its shorter chain length fraction CL313A show the greatest mitogenic activity. The deacetylation level of chitosan seems to be one of the main factors. Chitosan (CL313A) may indirectly accelerate fibroblast proliferation. However it does seem to inhibit keratinocyte proliferation. The effect seems to be dependent on the degree of deacetylation. A possible role in wound repair might be connected to highly deacetylated chitosan (CL313A).