Cell sheet engineering for integrating functional tissue in vivo: Successes and challenges

“Bottom-up” assembly of fully functional cell-based materials has enormous potential for replicating endogenous tissues. Currently, most tissue-engineering strategies are based on incorporating dissociated cells into an artificial three-dimensional matrix of supportive structural elements that direct cellular migration, proliferation, and organization. The matrix provides “top-down” guidance cues that impose assembly directions on the cells; however, the matrix also competes for space and limits fully functional, cell-dense tissues. This article focuses on bottom-up fabrication of functional tissue by cell sheet engineering. Cell sheet engineering is based on the sequential stacking and adhesion of confluent and organized cell monolayers from two-dimensional cell culture without the need for artifical scaffolds or structural intermediates. The resulting functional cellular monolayers (either individually or as stacked sheets) can then be directly implanted into living systems. Clinical successes are highlighted as well as attempts to overcome the vascularization limit often observed in engineered tissues.