Anchored Cell Sheet Engineering: A Novel Scaffold‐Free Platform for in vitro Modeling

Abstract

Abstract Biofabricated in vitro models hold unrealized potential in accelerating drug discovery and reducing new drug costs, but current models are overly simplified and lack physiological relevance. Certain platforms capable of mimicking in vivo conditions face hurdles such as complexity, high costs, and non‐standardized applications. Existing cell sheet engineering methodologies, despite being physiologically relevant, have technical limitations like creating suitable 3D forms with proper anchorage. An innovative platform is introduced here, designed for in vitro modeling, which capitalizes on 2D culture systems and scaffold‐free cell sheets to create self‐assembling 3D tissue constructs. It provides precise control over cellular behavior, especially ECM production and remodeling. Scaffold‐free muscle fibers and lung epithelial cell cultures served as examples. This platform can fuse various scaffold‐free models to construct assembloids mimicking organ structures and functions. Different tissues can be linked via a fluidic system for body‐level simulations. Moreover, ECM‐rich constructs from cell sheets can create organ‐level ECM scaffolds, and the resulting cell sheet‐derived ECM (CSdECM) can be solubilized to facilitate 2D cellular behavior. This versatile platform, compatible with other cell sheet engineering techniques, is set to revolutionize in vitro modeling.