Wounds International Vol 2 Issue 1Product reviewsAdvances in tissue-engineered skin substitutes

Advances in tissue-engineered skin substitutes

01/02/11 | Complex wounds, Skin integrity | Damanhuri M, Boyle J, Enoch,S

Skin substitutes are a heterogeneous group of products aimed at replacing, either temporarily or permanently, the form and function of lost skin. These products are alternatives to standard wound coverage in circumstances when established wound dressings are not appropriate [7].

From a practical point of view, skin substitutes are best classified as:

  • Synthetic, biosynthetic or biological
  • Temporary or permanent
  • Epidermal, dermal or composite.

Synthetic skin substitutes are products of tissue engineering and consist of a microengineered biocompatible polymer matrix. If used in combination with cellular and/or extracellular elements such as collagen, they result in a biosynthetic product. Synthetic and biosynthetic constructs are made to be stable, biodegradable and aimed at providing an adequate environment for the regeneration of tissue. They are intended to maintain their three-dimensional structure for a minimum of three weeks to allow for a growth of blood vessels and fibroblasts and coverage by epithelial cells. Biodegradation takes place after this period [15]. This process should preferably occur without extensive foreign body reaction as this will lead to increased scarring.

Biological skin substitutes (eg allografts or xenografts) are similar to the skin, with an intact and native extracellular matrix allowing for restoration of a more natural new dermis. They also support re-epithelialisation due to the presence of a basement membrane. However, natural constructs can exhibit problems with slow vascularisation. The most widely used biological substitutes worldwide are porcine skin, cadaveric skin and amnion.

Depending on their composition, both synthetic and biological skin substitutes can further be divided into dermal, epidermal or dermo-epidermal replacements. Sustainability is an additional factor that decides the temporary or permanent nature of skin substitutes. Temporary skin substitutes provide transient physiologic wound closure by protecting the wound from trauma, providing a barrier to bacteria and pathogens, and maintaining a moist wound environment until repair of the damaged tissue is complete[6]. Conversely, permanent skin substitutes are designed to provide permanent wound closure, replace the lost skin components (epidermis, dermis or both), and integrate with the recipient tissue [Box 3; Table 1].

Box 3

To culture skin in the laboratory, a skin biopsy from the patient or a donor is obtained to isolate the different cell types [Figure 2]. After trimming all excess fat, it is surface-sterilised in alcohol and placed in an appropriate culture medium. After approximately 24 hours, the epidermis is separated from the dermis and the two layers are then enzymatically treated to digest the bonds that bind the different cell types together (eg the extracellular matrix in the dermis is digested using collagenase to isolate the fibroblasts). Likewise, the epidermal keratinocytes are isolated from the epidermal layer.

Each cell type is allowed to proliferate in its appropriate culture medium. The cultured cell types are then used either in isolation (eg epidermal substitutes such as Epicel® [Genzyme], MyskinTM [Altrika] and ReCell® [Avita Medical]) or in a collagen construct or scaffold (eg in dermal substitutes such as TransCyte® [Advanced BioHealing] and Dermagraft® [Advanced BioHealing]).

Certain dermo-epidermal substitutes can be constructed with keratinocytes, melanocytes and fibroblasts in a collagen hydrogel. Vascular endothelial cells can also be added into the hydrogel to help form capillaries [16-19]. Acellular dermal scaffold (eg Alloderm® [LifeCell], Integra® [Integra LifeSciences Corporation], Biobrane® [Smith & Nephew], Matriderm® [Eurosurgical]) can also be engineered to provide coverage of a deep wound or burn. However, an autograft in the form of a STSG is needed for epithelial cover if a dermal (cellular or acellular) product is used in isolation (without epithelial layer or keratinocytes).

Although a reliable indicator or marker to monitor the effectiveness of an engineered skin substitute would be helpful, to date, they remain largely experimental. Cytokeratin 19 (CK19) is a protein that is expressed in basal keratinocytes and is a marker for epidermal homeostasis and an indicator of young keratinocytes or stem cells [20,21]. CK19 expression indicates a thriving and functional epidermis that signals a potentially successful transplantation. Other keratinocyte stem cell markers include integrin α6 chain (high expression) and the protein CD71 (low expression) [22,23]. The accuracy of these markers has to be corroborated with a reliable bioassay, in this case the formation of a normal-looking stratified epidermis approximately 12 weeks after transplantation. No epidermal marker is currently in clinical use - likewise there is no established dermal marker at present.  

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