Wound‐healing factors secreted by epidermal keratinocytes and dermal fibroblasts in skin substitutes

Spiekstra, Sander W.; Breetveld, Melanie; Rustemeyer, Thomas; Scheper, Rik J.; Gibbs, Susan

doi:10.1111/j.1524-475x.2007.00280.x

Cited by 138 publications

(139 citation statements)

References 35 publications

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“…Many fibroblasts remain in the lower regions of the dermis, with few cells migrating into the upper regions. However, as we have previously shown that soluble mediators HGF, IL‐6, CCL2, CCL5 and CXCL8 are secreted by SS only when fibroblasts are present (Spiekstra et al, 2007) and as we show that vimentin is detectable in both SS and GS, we can conclude that viable fibroblasts as well as epithelial cells are present in SS and GS.…”

Section: Discussionsupporting

confidence: 78%

“…The major advantage of living skin and oral mucosa substitutes over acellular dressings and biomaterials is their capability to function as a living pump, continuously secreting a cocktail of cytokines, chemokines and growth factors, which promote angiogenesis, granulation tissue formation and re‐epithelialization (Spiekstra, Breetveld, Rustemeyer, Scheper, & Gibbs, 2007). However, no human tissue‐engineered oral substitutes for clinical oral applications are yet commercially available.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of advanced therapy medicinal product gingiva and skin substitutes and their in vitro wound healing potentials

Boink

Roffel

Breetveld

et al. 2017

J Tissue Eng Regen Med

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Skin and oral mucosa substitutes are a therapeutic option for closing hard‐to‐heal skin and oral wounds. Our aim was to develop bi‐layered skin and gingiva substitutes, from 3 mm diameter biopsies, cultured under identical conditions, which are compliant with current European regulations for advanced therapy medicinal products. We present in vitro mode of action methods to (i) determine viability: epithelial expansion, proliferation (Ki‐67), metabolic activity (MTT assay); (ii) characterize skin and gingiva substitutes: histology and immunohistochemistry; and (iii) determine potency: soluble wound healing mediator release (enzyme‐linked immunosorbent assay). Both skin and gingiva substitutes consist of metabolically active autologous reconstructed differentiated epithelium expanding from the original biopsy sheet on a fibroblast populated connective tissue matrix (donor dermis). Gingival epithelium expanded 1.7‐fold more than skin epithelium during the 3 week culture period. The percentage of proliferating Ki‐67‐positive cells located in the basal layer of the gingiva substitute was >1.5‐fold higher than in the skin substitute. Keratins 16 and 17, which are upregulated during normal wound healing, were expressed in both the skin and gingiva substitutes. Notably, the gingiva substitute secreted higher amounts of key cytokines involved in mitogenesis, motogenesis and chemotaxis (interleukin‐6 > 23‐fold, CXCL8 > 2.5‐fold) as well as higher amounts of the anti‐fibrotic growth factor, hepatocyte growth factor (>7‐fold), compared with the skin substitute. In conclusion, while addressing the viability, characterization and potency of the tissue substitutes, important intrinsic differences between skin and gingiva were discovered that may explain in part the superior quality of wound healing observed in the oral mucosa compared with skin.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Comparison of advanced therapy medicinal product gingiva and skin substitutes and their in vitro wound healing potentials

Boink

Roffel

Breetveld

et al. 2017

J Tissue Eng Regen Med

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“…Our previous gingiva had become submerged in culture medium a very strong keratin 13 expression was observed. This findings indicate that the presence of fibroblasts in the dermis in addition to an epithelium will stimulate angioindicates that, in contrast to the other gingiva markers, keratin 13 may be regulated by environmental factors genesis, and therefore wound healing, more than a construct containing only an epithelium (38). Indeed, we (e.g., saliva) rather than intrinsically.…”

Section: Discussionmentioning

confidence: 95%

Comparison of Autologous Full-Thickness Gingiva and Skin Substitutes for Wound Healing

et al. 2008

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Ideally tissue-engineered products should maintain the characteristics of the original tissue. For example, skin represents orthokeratinized epithelium and oral gingiva represents parakeratinized epithelium. The aim of this study was to develop an autologous full-thickness gingiva substitute suitable for clinical applications and to compare it with our autologous full-thickness skin substitute that is routinely used for healing chronic wounds. Autologous full-thickness skin and gingiva substitutes were constructed under identical culture conditions from 3-mm punch biopsies isolated from the upper leg or gingiva tissue, respectively. Both consisted of reconstructed epithelia on acellular dermis repopulated with fibroblasts. To compare the characteristics of the original and reconstructed tissue, differential morphological observations and expression of differentiation markers (keratins 6, 10, and 17 and stratum corneum precursors involucrin, loricrin, and SKALP) were determined. Skin and gingiva substitutes were transplanted onto therapy-resistant leg ulcers or tooth extraction sites in order to determine their effects on wound healing. The tissue-engineered constructs maintained many of the differential histological and immunohistochemical characteristics of the original tissues from which they were derived. The skin substitute was orthokeratinized, and the gingiva substitute was parakeratinized. Transplantation of skin (n = 19) and gingiva substitutes (n = 3) resulted in accelerated wound healing with no adverse effects. As identical culture systems were used to generate both the skin and gingiva substitutes, the differences observed in tissue (immuno)histology can be attributed to intrinsic properties of the tissues rather than to environmental factors (e.g., air or saliva). This study emphasizes the importance of closely matching donor sites with the area to be transplanted. Our results represent a large step forward in the area of clinical applications in oral tissue engineering, which have until now greatly lagged behind skin tissue engineering.

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“…1 Skin substitutes have the ability to deliver cytokines, chemokines, growth factors and competent cells at wound site, thus improving the wound closure. 2,3 Definitive treatment of extensive burns requires that autologous skin be used since other allogenic grafts are rejected after several days/weeks. In a context of the production of engineered living skin substitutes, the use of the patient's own cells oversteps immune incompatibility problems but requires that the production of such skin constructs be initiated only after isolating patient's cells.…”

Section: Introductionmentioning

confidence: 99%

Production of a Bilayered Self-Assembled Skin Substitute Using a Tissue-Engineered Acellular Dermal Matrix

Cloutier

Guignard

Bernard

et al. 2015

Tissue Engineering Part C: Methods

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Our bilayered self-assembled skin substitutes (SASS) are skin substitutes showing a structure and functionality very similar to native human skin. These constructs are used, in life threatening burn wounds, as permanent autologous grafts for the treatment of such affected patients even though their production is exacting. We thus intended to shorten their current production time to improve their clinical applicability. A self-assembled decellularized dermal matrix was used. It allowed the production of an autologous skin substitute from patient's cells. The characterization of SASS reconstructed using a decellularized dermal matrix (SASS-DM) was performed by histology, immunofluorescence, transmission electron microscopy and uniaxial tensile analysis.Using the SASS-DM, it was possible to reduce the standard production time from about eight to four weeks and a half. The structure, cell differentiation and mechanical properties of the new skin substitutes were shown to be similar to the SASS. The decellularization process had no influence on the final microstructure and mechanical properties of the dermal matrix. This model, by enabling the production of a skin substitute in a shorter time frame without compromising its intrinsic tissue properties, represents a promising addition to the currently available burn and wound treatments.

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Wound‐healing factors secreted by epidermal keratinocytes and dermal fibroblasts in skin substitutes

Cited by 138 publications

References 35 publications

Comparison of advanced therapy medicinal product gingiva and skin substitutes and their in vitro wound healing potentials

Comparison of advanced therapy medicinal product gingiva and skin substitutes and their in vitro wound healing potentials

Comparison of Autologous Full-Thickness Gingiva and Skin Substitutes for Wound Healing

Production of a Bilayered Self-Assembled Skin Substitute Using a Tissue-Engineered Acellular Dermal Matrix

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