Bioreactors for engineering patient-specific tissue grafts

Bioreactors have the potential to advance the clinical application of cell-based therapies. Cell expansion bioreactors have been used commercially for therapeutic applications; however, bioreactor-based engineering of 3D tissue grafts remains challenging owing to the complexity of tissue architectures, cellular heterogeneity and the lack of non-invasive, tissue-specific biomarkers with which to assess graft viability and maturation. Consequently, only a few bioreactor-based start-up companies that engineer patient-specific tissue grafts have emerged. In this Review, we discuss patient-specific bioreactors that can be used to engineer skin, small-diameter arteries and musculoskeletal tissues. We evaluate the impact of precision manufacturing, including 3D bioprinting, automation and non-invasive sensing, on optimizing the biological, chemical and physical parameters of the bioreactors that are required for specific tissue regeneration. We discuss the commercially available tissue-engineering bioreactors and the potential of digital twins and automation, and we outline the scientific and regulatory pathways that must be followed to enable the translation of tissue-specificbioreactors to the clinic. Bioreactors enable the cultivation of mammalian cells in a closely monitored and controlled microenvironment. This Review discusses bioreactor technologies and closed-loop set-ups for producing patient-specific engineered-tissue grafts, including skin, small-diameter arteries and musculoskeletal tissues, with a particular focus on commercialization and regulatory considerations.