A bioactive cell sheet interface regulates scaffold–host interactions for cartilage regeneration

Abstract Cartilage tissue engineering remains challenged by uncontrolled scaffold–host interactions after implantation, particularly host tissue infiltration that can disrupt cartilage formation and compromise scaffold integrity. Although biomaterial‐based encapsulation strategies have been developed to reduce host interference, excessive restriction of scaffold–host interface may also limit the exchange of nutrients, oxygen, and metabolic wastes. Therefore, an effective encapsulation strategy must protect the developing tissue from excessive host infiltration while maintaining a permissive environment for tissue formation. Here, we engineered a fibroblast‐based cell sheet to regulate scaffold–host interactions in a nude mice implantation model. Fibroblast cell sheet wrapping protected the scaffold by limiting host cellular infiltration, but cartilage extracellular matrix (ECM) formation was also reduced within the scaffold. Notably, EPC incorporation into the cell sheet restored cartilage ECM deposition and enhanced peri‐scaffold vascularization. These results demonstrate that cell sheet‐based encapsulation can provide not only a protective function against excessive host infiltration but also a bioactive interface that regulates scaffold–host interactions, with EPC incorporation promoting peri‐scaffold vascularization and supporting cartilage matrix formation within the scaffold.