Human Living Skin Equivalents as a Promising Model for Skin Grafts
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Abstract Human skin equivalents (HSEs) are three‐dimensional skin organ culture models raised in vitro. This review gives an overview of common techniques for setting up HSEs. The HSE consists of an artificial dermis and epidermis. 3T3‐J2 murine fibroblasts, purchased human fibroblasts or freshly isolated and cultured fibroblasts, together with other components, for example, collagen type I, are used to build the scaffold. Freshly isolated and cultured keratinocytes are seeded on top. It is possible to add other cell types, for example, melanocytes, to the HSE—depending on the research question. After several days and further steps, the 3D skin can be harvested. Additionally, we show possible markers and techniques for evaluation of artificial skin. Furthermore, we provide a comparison of HSEs to human skin organ culture, a model which employs human donor skin. We outline advantages and limitations of both models and discuss future perspectives in using HSEs.
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Abstract : Skin Equivalents (SE) or Human Skin Equivalents (HSEs) are skin substitutes that can serve as models for testing the skin permeability of agents from formulations, or for evaluation of formulations themselves on the skin. We have developed a collagen based HSE and HSE containing electrospun poly(DTE carbonate) polymer scaffolds in our laboratory. The culture of these full thickness skin equivalents has been optimized by modification of the culture media and conditions required for growth in order to mimic the barrier properties of human skin in vivo. The HSE has been characterized for morphology, lipid composition and barrier properties and compared to a commercially available skin equivalent, and shows similar permeability to a wide range of agents. Skin derived cells were found to populate and proliferate in the electrospun scaffold, which imparts structural stability to the collagen based HSE model. Use of cocultures of human dermal fibroblasts and human keratinocytes, and conditions such as addition of ascorbic acid are being used to look at effects on morphogenesis and barrier properties of the epidermal layer in these HSE models. Once developed, these skin equivalents can serve as effective models for determination of the permeation of chemical warfare agents (CWAs) or their mimics or the barrier properties of creams such as SERPACWA (Skin Exposure Reduction Paste Against Chemical Warfare Agents).
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Recreating the structure of human tissues in the laboratory is valuable for fundamental research, testing interventions and reducing the use of animals. Critical to the use of such technology is the ability to develop tissue models that accurately recreate the microanatomy of the native tissue. In this thesis, we have bioengineered novel models of neonatal and ageing human skin, that recreate the structure of human skin in vitro. These skin equivalents have been applied to investigate the mechanisms of skin ageing, such as the influence of epidermal-dermal interactions.
We have successfully bioengineered a neonatal full thickness skin equivalent that accurately recreates aspects of the microanatomy of human skin. The skin equivalent was generated using a bottom-up tissue engineering approach, whereby the human fibroblasts secrete their own endogenous extracellular matrix proteins within the porous Alvetex® Scaffold. In-depth morphological analyses demonstrate close similarities with native human skin, such as an
organised, stratified and keratinised epidermis, the presence of a robust basement membrane and the deposition of extracellular matrix proteins within the dermal compartment.
Many dermal matrices used in skin tissue engineering are not suitable for ageing studies as they cannot be tailored to recapitulate the age-related decline in extracellular matrix in vitro. We have found that incorporating ageing dermal fibroblasts within the Alvetex® Scaffold, to form a dermal equivalent, enables age-related changes, such as decreased proliferation and reduced synthesis of extracellular matrix proteins, to be recreated in vitro. These ageing dermal equivalents have been applied to investigate the influence of epidermal-dermal interactions during ageing.
Dermal interactions are thought to influence the epidermal morphology during embryogenesis and in adult skin, however there is a paucity of information regarding the importance of epidermal-dermal interactions during ageing. Tissue engineering approaches described within this thesis suggest that an ageing dermis contributes to the age-related epidermal phenotype and influences
epidermal thickness, keratinocyte differentiation and the structure of basal keratinocytes.
In the current ageing demographic, there is a requirement for an ageing skin model for academic and industrial applications. We have bioengineered novel and advanced full thickness skin equivalents representative of female ageing skin, which recreate the structure of human skin in vitro, with regards to epidermal differentiation, the presence of a basement membrane and synthesis of extracellular matrix proteins. The ageing skin equivalents also successfully
recapitulate age-related changes in vitro such as epidermal atrophy, altered keratinocyte differentiation, and reduction of extracellular matrix proteins.
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The current utility of 3D skin equivalents is limited by the fact that existing models fail to recapitulate the cellular complexity of human skin. They often contain few cell types and no appendages, in part because many cells found in the skin are difficult to isolate from intact tissue and cannot be expanded in culture. Induced pluripotent stem cells (iPSCs) present an avenue by which we can overcome this issue due to their ability to be differentiated into multiple cell types in the body and their unlimited growth potential. We previously reported generation of the first human 3D skin equivalents from iPSC-derived fibroblasts and iPSC-derived keratinocytes, demonstrating that iPSCs can provide a foundation for modeling a complex human organ such as skin. Here, we have increased the complexity of this model by including additional iPSC-derived melanocytes. Epidermal melanocytes, which are largely responsible for skin pigmentation, represent the second most numerous cell type found in normal human epidermis and as such represent a logical next addition. We report efficient melanin production from iPSC-derived melanocytes and transfer within an entirely iPSC-derived epidermal-melanin unit and generation of the first functional human 3D skin equivalents made from iPSC-derived fibroblasts, keratinocytes and melanocytes.
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