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Sacran, a large molecular-weight polysaccharide isolated from algae, is composed of 11 types of saccharides, including sulfate and carboxylic acid groups. Because of its unique structure, sacran can form a gel-like sheet in the presence of polyols such as 1,3-butanediol. In addition, those sacran gel-like sheets prevent the evaporation of water and the penetration of chemicals. The results of our previous study suggested that sacran can work as an artificial barrier against external stimuli such as air pollutants which increase the stress on humans. Topically applied sacran was localized at the surface of reconstructed human epidermal equivalents. Those results suggested that sacran inhibits excessive water evaporation from the skin and protects against environmental stimuli by forming an artificial barrier at the skin surface. Then, in a clinical study, we examined the activity of sacran in improving skin problems caused by an impaired epidermal barrier. First, we conducted a use test on a serum formulated with sacran on human volunteers who had impaired skin barrier function. The results showed that sacran provided excellent benefits to improve the maturation of corneocytes. These results suggest that sacran could play an important role in providing optimal skin conditions for keratinocytes to progress through their differentiation.

Tissue engineering of skin is classified into acellular artificial skin and cellular artificial skin. Acellular artificial skin or artificial dermis, is composed of an inner collagen sponge and an outer silicone film. When placed on wounds, the collagen sponge is spontaneously converted into a dermis-like connective tissue. Addition of bFGF or cultured fibroblasts accelerates synthesis of the dermis-like tissue. Cultured epidermis often fails to take on a full-thickness skin defect because of lack of dermal component. Cultured skin with both epidermal and dermal components seems to be an ideal skin substitute, but its take rate is still low. Regeneration of complete skin with skin appendages, vascular networks, elastic fibers and so on is desired.

Tissue engineering is moving rapidly from fundamental research to commercial applications. The first product is an autologous cultured epidermal substitute. Other representative products are allogeneic cultured dermal substitute and allogeneic cultured skin substitute. Surgical closure with auto-skin grafting is the gold standard for treatment of victims with extensive deep skin defects. Therefore, the tissue engineers have to develop the cultured skin substitutes, taking into account the successful application of auto-skin grafting, Kuroyanagi developed an allogeneic cultured dermal substitute, which was composed of a 2-layered spongy matrix of hyaluronic acid and atelo-collagen containing fibroblasts. This product is able to release a number of biologically active substances that are necessary for wound healing. A multi-center clinical study on the use of this product has been performed at 30 hospitals across Japan as the Regenerating Medical Millennium Project of the Ministry of Health, Labor and Welfare.

A typical engineered product is autologous cultured epidermal substitute, which is composed of stratified keratinocytes (in USA). There are two types of allogeneic cultured dermal substitute (CDS) composed of fibroblasts combined with a synthetic scaffold (in USA). Another product is allogeneic cultured skin substitute, which is composed of keratinocytes and fibroblasts combined with a collagen gel (in USA). Recently, however, the commercialization of these allogeneic products has been discontinued. There seem to be some problems in the design of these products. Kuroyanagi et al. developed an allogeneic CDS composed of a fibroblast combined with a 2-layered spongy matrix of hyaluronic acid and collagen. A multicenter clinical study on the use of allogeneic CDS was performed in 30 hospitals across Japan as the Regenerating Medical Millennium Project of the Ministry of Health, Labor and Welfare. The results of clinical study suggest that this type of allogeneic CDS can effectively promote the healing of full-thickness severe skin defects, such as chronic ulcers and burn injuries.

Regenerative tissue engineering is moving rapidly from the fundamental research to the commercial applications. A number of skin substitutes have been produced by in vitro culture techniques. The U.S. Food and Drug Administration has already approved allogeneic skin substitutes. Recently, the Japanese Ministry of Health, Labor and Welfare published the guide-line for regenerative medicine. R & D Center for Artificial Skin of Kitasato University is now the heart of the Regenerating Medical Millennium Project (skin department) of the Ministry of Health, Labor and Welfare since 2000. This center established the banking system for multi-center's clinical study in 27 hospitals across Japan, using the allogeneic cultured dermal substitute composed of hyaluronic acid and collagen spongy matrix with fibroblasts.

An artificial dermis, composed of an inner layer of collagen sponge and an outer silicone layer, was developed by modifying the material reported by Yannas et al. When the artificial dermis is placed on full 14-thickness skin defects, the pores of the inner collagen sponge are infiltrated by fibroblasts and capillaries. This cell-infiltrated membrane is gradually converted into a synthesized connective tissue matrix, similar to true dermis, as the original network of collagen sponge is biodegraded. The secondary skin graft takes easily and postoperative contraction is minimal even if a very thin split-thickness skin graft is used. The requirement for two-stage surgery and long hospitalization remain disadvantages of the material. Consequently, application of the material is limited to cases in which the advantages outweigh the disadvantages. Deep skin defects with partial exposure of bone or muscle appear to be the most suitable indications for the material. Shallow but very wide skin defects also seem to benefit from the application of the material.

In patients with massive burn injuries and very limited skin donor sites, both acute-phase and long-term problems of skin loss must be solved by the use of alternative wound closure materials. Alternative materials can be used for either temporary wound coverage or for permanent wound closure. Recently, allogenic skin grafts have most commonly been used as alternative wound closure material. However, research is ongoing on many new materials to provide a readily available substitute for skin allografts for permanent wound closure. The best approach to the development of alternative permanent wound closure materials is to incorporate the host's own cellular and structural components. Four general strategies have been devised so far based on the type of matrix structure and cellular content: allografts; cultured epidermal grafts; dermal matrix grafts; and cultured-dermal matrix composite grafts. Several approaches using combined alternative wound closure materials have been used, including transplantation of artificial dermal matrix with thin epidermal autografts, and transplantation of artificial dermal matrix containing human fibroblasts. Ultimately, the best candidate materials for permanent wound closure after extensive burn injury must be determined in prospective, randomized, controlled clinical trials.