A paradigm shift in tissue engineering: from a top–down to a bottom–up strategy

Tissue engineering (TE) was initially designed to tackle clinical organ shortage problems. Although some engineered tissues have been successfully used for non-clinical applications, very few (e.g., reconstructed human skin) have been used for clinical purposes. As the current TE approach has not achieved much success regarding more broad and general clinical applications, organ shortage still remains a challenging issue. This very limited clinical application of TE can be attributed to the constraints in manufacturing fully functional tissues via the traditional top–down approach, where very limited cell types are seeded and cultured in scaffolds with equivalent sizes and morphologies as the target tissues. The newly proposed developmental engineering (DE) strategy towards the manufacture of fully functional tissues utilises a bottom–up approach to mimic developmental biology processes by implementing gradual tissue assembly alongside the growth of multiple cell types in modular scaffolds. This approach may overcome the constraints of the traditional top–down strategy as it can imitate in vivo-like tissue development processes. However, several essential issues must be considered, and more mechanistic insights of the fundamental, underpinning biological processes, such as cell–cell and cell–material interactions, are necessary. The aim of this review is to firstly introduce and compare the number of cell types, the size and morphology of the scaffolds, and the generic tissue reconstruction procedures utilised in the top–down and the bottom–up strategies; then, it will analyse their advantages, disadvantages, and challenges; and finally, it will briefly discuss the possible technologies that may overcome some of the inherent limitations of the bottom–up strategy.