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. 2022 May 31;10(6):1286.
doi: 10.3390/biomedicines10061286.

Orchestrating the Dermal/Epidermal Tissue Ratio during Wound Healing by Controlling the Moisture Content

Alexandru-Cristian Tuca  1 , Ives Bernardelli de Mattos  2 , Martin Funk  3 , Raimund Winter  1 , Alen Palackic  1 , Florian Groeber-Becker  2   4 , Daniel Kruse  2 , Fabian Kukla  5 , Thomas Lemarchand  5 , Lars-Peter Kamolz  1   6
Affiliations

Orchestrating the Dermal/Epidermal Tissue Ratio during Wound Healing by Controlling the Moisture Content

Alexandru-Cristian Tuca et al. Biomedicines. .

Abstract

A balanced and moist wound environment and surface increases the effect of various growth factors, cytokines, and chemokines, stimulating cell growth and wound healing. Considering this fact, we tested in vitro and in vivo water evaporation rates from the cellulose dressing epicitehydro when combined with different secondary dressings as well as the resulting wound healing efficacy in a porcine donor site model. The aim of this study was to evaluate how the different rates of water evaporation affected wound healing efficacy. To this end, epicitehydro primary dressing, in combination with different secondary dressing materials (cotton gauze, JELONET◊, AQUACEL® Extra ™, and OPSITE◊ Flexifix), was placed on 3 × 3 cm-sized dermatome wounds with a depth of 1.2 mm on the flanks of domestic pigs. The healing process was analyzed histologically and quantified by morphometry. High water evaporation rates by using the correct secondary dressing, such as cotton gauze, favored a better re-epithelialization in comparison with the low water evaporation resulting from an occlusive secondary dressing, which favored the formation of a new and intact dermal tissue that nearly fully replaced all the dermis that was removed during wounding. This newly available evidence may be of great benefit to clinical wound management.

Keywords: bacterial cellulose dressing; in vivo experiments; moisture balance; secondary wound dressing; wound healing.

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Conflict of interest statement

This manuscript has not been published and is not being considered for publication elsewhere in whole or in part in any language. The study was funded by Evomedis GmbH, Austria, of which the author Martin Funk is a part. This had no influence on the collection, analyses, interpretation, or submission of the manuscript. On behalf of all authors, Alexandru-Cristian Tuca declares that the other authors have no conflicts of interest and nothing to disclose.

Figures

Figure 1
Figure 1
In vitro evaporation from epicitehydro in combination with different secondary dressings. Weight of epicitehydro, relative to initial weight, after incubation at 32 °C for each timepoint. The BNC fleece was incubated without any coverage (orange) and with epicitehydro + cotton gauze (grey), epicitehydro + JELONET◊ (yellow), epicitehydro + AQUACEL® Extra ™ (blue), and epicitehydro + OPSITE◊ Flexifix (purple).
Figure 2
Figure 2
In vivo residual water analysis and healing process after five days of treatment. (A) H&E staining of punch biopsies extracted from the upper right area of the wound. Arrowheads highlight the remaining epicitehydro present on the wounded area. The scale bar represents 500 µm. (B) Histogram of the thickness of the epicitehydro combined with secondary wound dressing on the surface of the wound after five days of treatment. Statistical significance was obtained between all comparisons (p values: ** = 0.0037 and <0.001 for all other comparisons). (C) Histogram of relative residual water content of epicitehydro. All data were statistically different from input and from residual water of epicitehydro combined with OPSITE◊ Flexifix. epicitehydro + cotton gauze and epicitehydro + AQUACEL® Extra ™ showed differences in comparison with epicitehydro + JELONET◊ (p values: ****: <0.0001; ***: 0.0009/0.0004; **: 0.0026). (D) Percentage of re-epithelialization observed at the wound area. Re-epithelialization was higher on the wounds treated with epicitehydro + cotton gauze and epicitehydro + AQUACEL® Extra ™ than on those treated with epicitehydro + OPSITE◊ Flexifix (p values: *: <0.05). (E) Average thickness of the new dermal tissue was obtained from the H&E slide measurement. Thicker tissue was formed on the wounds treated with epicitehydro + OPSITE◊ Flexifix than on those treated with cotton gauze or AQUACEL® Extra ™ as secondary dressing (p values: * 0.0298; **: 0.0064).
Figure 3
Figure 3
H&E staining of the wound edge area for the wounds after 5 days of treatment. Representative microscopies depicting the wound edge area after 5 days of treatment with epicitehydro combined with cotton gauze (A), JELONET◊ (B), AQUACEL® Extra ™ (C), and OPSITE◊ Flexifix (D). The red arrowhead roughly indicates the position of the wound edge. The scale bar represents 100 µm.
Figure 4
Figure 4
Wound healing process of the tissue after seven days of treatment. Percentage re-epithelialization for nonocclusive and occlusive dressings (A) and average thickness of new dermal tissue (B) obtained by the analysis of H&E staining. H&E staining (C) and immunofluorescence staining for anti-α-smooth muscle actin (αSMA, green) (D) of wounds treated with occlusive and nonocclusive secondary wound dressing. Red and white arrowheads indicate the epidermis on top and the end of regenerated dermis at the bottom. The scale bar represents 200 µm. Immunofluorescence staining of skin untreated and treated with nonocclusive and occlusive secondary dressings. Merged images labeled with DAPI (blue), high mobility group protein B1 (HMGB1, red), and αSMA (green) showed a staining pattern for the untreated skin (control) and the wounded skin treated with nonocclusive and occlusive dressing. HMGB1 staining showed undamaged cells under both treatments in comparison with the control group. αSMA staining revealed the presence of vessels in the tissue. The vertical doubled arrow lines indicate the thickness of regenerated dermal tissue containing activated myofibroblasts for both treatments (E). p values: ***: 0.0008; ****: < 0.0001. Scale bar: 100 µm.
Figure 5
Figure 5
Assessment of blood vessel density through immunofluorescence image analysis. (A) Anti-αSMA immunofluorescence staining of blood vessels in the dermis of the analyzed tissue measured using imaging software, which revealed different sizes. (B) Density and distribution of blood vessels (per mm²) for the reminiscent tissue and the newly formed tissue treated with the occlusive (including superficial macerated tissue) and nonocclusive secondary dressing. The scale bar represents 10 µm.
Figure 6
Figure 6
Histological aspects of new dermal tissue infiltrate composition. (A) Diagram with the pathology score, ranging from 0 to 5, for the presence of inflammatory cells in the newly formed dermal tissue: small- to mid-size mononuclear cell (SMC) (including lymphoblast) density; monocyte/histocyte/macrophage (Mo/His/Mac) density; epithelioid macrophage/multinucleate giant cell (EpMa/MGC) density; and granulocyte density, divided into eosinophils and neutrophils in both wounds treated with nonocclusive secondary wound dressing (cotton gauze—CG) and with occlusive dressing (OPSITE◊ Flexifix—OP). (B) Example of hematoxylin and eosin (H&E) sections with four representative sites of the two secondary dressings (nonocclusive and occlusive). Highlighted in a higher magnification (red arrowheads) are examples on both tissues of SMCs (a), Mo/His/Mac (b), EpMa/MGCs (c), and granulocytes (d) as well as the presence of mononuclear cells forming clusters (e). The scale bar represents 20 µm.
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Grants and funding

The study was funded by Evomedis GmbH, Austria, of which the author Martin Funk is a part. This had no influence on the collection, analyses, interpretation, or submission of the manuscript.

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