Health Enabling Advancements through Regenerative Tissue Printing (HEART) - Despite decades of promise, tissue engineering has fallen far short of producing human-scale solid and densely cellular organs, such as liver, lung, kidney, brain, and heart. This inability to recreate human tissues and organs is slowing basic human developmental research, impacting hundreds of thousands of lives per year due to ever-lengthening donor organ waitlists or succumb to organ rejection, and costing countless billions of dollars due to failed drug trials from unrepresentative animal models. With recent advances in stem cell biology, biomaterials, computational modeling, and 3D bioprinting, we now find ourselves on the cusp of producing functional human organs at scale. Cellular differentiation protocols are rapidly improving the function and safety of patient-specific stem cell-derived cells. Simultaneously, our ability to model the behavior of biological tissue could enable automated design of as-of-yet unimagined geometries, and advances in 3D biofabrication promise to turn these models into reality at production-level scales. In particular, the use of bioprinting to rapidly incorporate branched and perfusable vessels that permeate tissue allows, for the first time, the production of thick and viable organs. A bold and dedicated effort to create human organs is now needed to bring tissue engineering out of the Petri dish and into the clinic. The Stanford Organ Engineering Initiative (SOEI) will innovate across cell production, predictive modeling, organ bioprinting hardware and biomaterials, and surgical techniques to validate the first human-scale, patient specific, and functional whole organ in a large animal model within five years. To accomplish this feat, the SOEI will team will innovate across four focus areas working synergistically. The Cell Production team will increase therapeutic cell production capacity via innovations in cell culture, differentiation, and purification technologies. This includes generating multiple cardiovascular cell types (cardiomyocytes, cardiac fibroblasts, cardiac endothelial cells, and epicardial cells) at yields 2-3 orders of magnitude greater than typically produced. The Prediction & Modeling team will create a unified predictive simulation that links tissue geometry, vascularization, perfusion, conduction, and biomechanics to optimize organ design, using both automated vascular network design and printing and multiphysics modeling for optimal cardiac output. The Bioprinting team will increase bioprinting speed by 100-fold to enable the high-resolution production of a functional heart whose design is guided by simulation results. This will be accomplished through the generation of novel tough and anisotropic bio-inks; new high throughput methods of multimaterial 3D printing. The Perfusion, Transplantation, & Validation team will oversee innovative methods to test and transplant a 3D bioprinted heart into a large animal (SCID pig) model to assess organ function in vivo. Data from validation studies will feed back into computational modeling to improve predictions. In summary, integrating cell processing, modeling, and bioprinting at organ scale will introduce new capabilities that offer a truly curative solution for organ failure. While the SOEI will focus on heart biomanufacturing, our proposed innovations in cell production, tissue modeling, and bioprinting of cell-dense and vascularized tissue will advance capabilities across all organ-systems.
