Manufacturing of Human Tissues as off‐the‐Shelf Grafts Programmed to Induce Regeneration

Abstract Design criteria for tissue‐engineered materials in regenerative medicine include robust biological effectiveness, off‐the‐shelf availability, and scalable manufacturing under standardized conditions. For bone repair, existing strategies rely on primary autologous cells, associated with unpredictable performance, limited availability and complex logistic. Here, a conceptual shift based on the manufacturing of devitalized human hypertrophic cartilage (HyC), as cell‐free material inducing bone formation by recapitulating the developmental process of endochondral ossification, is reported. The strategy relies on a customized human mesenchymal line expressing bone morphogenetic protein‐2 (BMP‐2), critically required for robust chondrogenesis and concomitant extracellular matrix (ECM) enrichment. Following apoptosis‐driven devitalization, lyophilization, and storage, the resulting off‐the‐shelf cartilage tissue exhibits unprecedented osteoinductive properties, unmatched by synthetic delivery of BMP‐2 or by living engineered grafts. Scalability and pre‐clinical efficacy are demonstrated by bioreactor‐based production and subsequent orthotopic assessment. The findings exemplify the broader paradigm of programming human cell lines as biological factory units to engineer customized ECMs, designed to activate specific regenerative processes.