Tissue Fabrication and Regeneration by Cell Sheet Technology
Cell-based therapy for regenerating damaged/diseased tissues/organs has expanded rapidly, and several thousand patients have received the therapy. 1 , 2–3 Although the feasibility of the therapy has been established, the low uptake ratio of cells at target tissues/organs has become problematic in the case of cell injection therapy with dissociated cells. 4 , 5 For overcoming the shortcoming, tissue engineering methodology has appeared as the second generation of cell-based therapy, which shows its feasibility and advantage, and clinical therapies with bioengineered tissues have already been 1310performed in various fields. 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14–15 Three-dimensional biodegradable scaffolds, including inorganic materials, such as calcium phosphate, hydroxyapatite, etc.; synthetic polymers, such as polycaprolactone, poly(glycolic acid), poly(lactide-co-glycolide), poly-L-lactic acid, polyurethane, etc.; or biological materials, such as alginate, agarose, collagen, fibrin, gelatin, hyaluronic acid, etc., have been used for the methodology. 16 , 17–18 However, the authors’ laboratory has developed a scaffold-free tissue engineering methodology, cell sheet technology, based on the use of an intelligent temperature-responsive culture surface, which shows reversible hydrophobic/hydrophilic via temperature alternations. 19 , 20 Confluent cells cultured on the surface are able to be harvested as an intact cell sheet by decreasing temperature simply. 21 Because cell sheets are able to be harvested without any protease treatment, harvested cell sheets have intact cell–cell junctions and a rich extracellular matrix (ECM). 22 , 23 , 24 , 25–26 Therefore, cell sheets maintain their functional coupling abilities and functional 3D biological tissues can be simply fabricated by only layering the cell sheets. 21 , 27 , 28 Fabricated 3D cell sheet tissues can adhere efficiently to target tissues, and, for example, an intensively beating heart tissue can adhere firmly without any suturing and cell loss after the transplantation. 5 , 21 , 29 Thus, the transplantation can show significantly more effective therapeutic effects and tissue regeneration than those of the injection of dissociated cells. 5 , 30 Clinical trials with cell sheets have already been performed in six fields. 31 In this chapter, (1) temperature-responsive culture surface and cell sheet technology and (2) 3D tissue fabrication using cell sheets and cell sheet therapy are discussed.