Cell sheet engineering at an inflection point: from pioneering techniques to commercialized products

Cell sheet engineering (CSE), a scaffold- and biomaterial-free biofabrication technique, preserving native extracellular matrix and cell-cell junctions, is re-emerging as a powerful therapeutic modality. With over 70 registered clinical trials worldwide, the technology has demonstrated clinical validity by providing preserved tissue architecture. Recent evolutions such as those in anchored cell sheet engineering, mark an inflection point, enabling formation of more relevant form factors with higher levels of phenotypical and microstructural maturity with improved structural and functional competence, expanding CSE's addressable scope. Regulatory momentum is growing, with the gap between current cell-based release testing and tissue-level function emerging as the central regulatory challenge for living tissue products. Simultaneously, automation is transforming CSE's cost structure, with closed-loop systems potentially reducing manufacturing costs by ∼30% from current facility- and personnel-dominated models. Commercial precedents demonstrate that biologically complex constructs can achieve reimbursement and clinical integration when aligned with procedural workflows and measurable outcomes. This perspective examines how CSE represents a high-value platform for a strategically significant and expandable subset of regenerative medicine, positioned to serve a substantial market segment. Future advances could expand its applications to larger multi-tissues constructs, where recreating native tissue architecture provides decisive therapeutic advantage.