title: Biomimetic Culture Reactor for Whole-Lung Engineering.
abstract: Decellularized organs are now established as promising scaffolds for whole-organ regeneration. For this work to reach therapeutic practice, techniques and apparatus are necessary for doing human-scale clinically applicable organ cultures. We have designed and constructed a bioreactor system capable of accommodating whole human or porcine lungs, and we describe in this study relevant technical details, means of assembly and operation, and validation. The reactor has an artificial diaphragm that mimics the conditions found in the chest cavity in vivo, driving hydraulically regulated negative pressure ventilation and custom-built pulsatile perfusion apparatus capable of driving pressure-regulated or volume-regulated vascular flow. Both forms of mechanical actuation can be tuned to match specific physiologic profiles. The organ is sealed in an elastic artificial pleura that mounts to a support architecture. This pleura reduces the fluid volume required for organ culture, maintains the organ's position during mechanical conditioning, and creates a sterile barrier allowing disassembly and maintenance outside of a biosafety cabinet. The combination of fluid suspension, negative-pressure ventilation, and physiologic perfusion allows the described system to provide a biomimetic mechanical environment not found in existing technologies and especially suited to whole-organ regeneration. In this study, we explain the design and operation of this apparatus and present data validating intended functions.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut.; Department of Anesthesia, Yale University, New Haven, Connecticut.; Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Micha Sam Brickman
authors.initials: MS
authors.lastname: Raredon
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut.; Department of Anesthesia, Yale University, New Haven, Connecticut.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Rocco
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Services, Yale University , New Haven, Connecticut.
authors.forename: Ciprian P
authors.initials: CP
authors.lastname: Gheorghe
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut.; Department of Anesthesia, Yale University, New Haven, Connecticut.
authors.forename: Amogh
authors.initials: A
authors.lastname: Sivarapatna
authors.affiliation: Department of Anesthesia, Yale University , New Haven, Connecticut.
authors.forename: Mahboobe
authors.initials: M
authors.lastname: Ghaedi
authors.affiliation: Department of Anesthesia, Yale University, New Haven, Connecticut.; Department of Pathology, Yale University, New Haven, Connecticut.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Balestrini
authors.affiliation: Raredon Resources, Inc. , Northampton, Massachusetts.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Raredon
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut.; Department of Anesthesia, Yale University, New Haven, Connecticut.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Calle
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut.; Department of Anesthesia, Yale University, New Haven, Connecticut.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Niklason
keywords: bioprocessing; extracellular matrix; regeneration; tissue engineering