Tissue engineering of replacement skin: the crossroads of biomaterials, wound healing, embryonic development, stem cells and regeneration

Abstract

Advanced therapies combating acute and chronic skin wounds are likely to be brought about using our knowledge of regenerative medicine coupled with appropriately tissue-engineered skin substitutes. At the present time, there are no models of an artificial skin that completely replicate normal uninjured skin. Natural biopolymers such as collagen and fibronectin have been investigated as potential sources of biomaterial to which cells can attach. The first generation of degradable polymers used in tissue engineering were adapted from other surgical uses and have drawbacks in terms of mechanical and degradation properties. This has led to the development of synthetic degradable gels primarily as a way to deliver cells and/or molecules in situ, the so-called smart matrix technology. Tissue or organ repair is usually accompanied by fibrotic reactions that result in the production of a scar. Certain mammalian tissues, however, have a capacity for complete regeneration without scarring; good examples include embryonic or foetal skin and the ear of the MRL/MpJ mouse. Investigations of these model systems reveal that in order to achieve such complete regeneration, the inflammatory response is altered such that the extent of fibrosis and scarring is diminished. From studies on the limited examples of mammalian regeneration, it may also be possible to exploit such models to further clarify the regenerative process. The challenge is to identify the factors and cytokines expressed during regeneration and incorporate them to create a smart matrix for use in a skin equivalent. Recent advances in the use of DNA microarray and proteomic technology are likely to aid the identification of such molecules. This, coupled with recent advances in non-viral gene delivery and stem cell technologies, may also contribute to novel approaches that would generate a skin replacement whose materials technology was based not only upon intelligent design, but also upon the molecules involved in the process of regeneration.

Figure 1

A schematic of the structure of skin.

Figure 2

Transverse sections through an MRL/MpJ ear 21 days post-biopsy punch wounding. The histological organization is blastema-like in structure. (a) shows an ear section stained with Alcian Blue and fast red. The cut end of the cartilage (C) can be seen clearly. Glycosaminoglycan deposits in the mesenchyme are stained blue. The apical epithelium (E) extends away from the cut cartilage. (b) shows a similar ear section stained with anti-Aggrecan-TRITC, a cartilage precursor molecule. The section is counterstained with the nuclear dye, DAPI. Note the formation of cartilage islands (I) in the mesenchyme and the infiltration of Aggrecan into the mesenchyme. HF, hair follicle; SG, sebaceous gland. Scale bar, 100 μm.

Figure 3

A schematic of the requirements to create a fully functional skin substitute.