Despite significant advances over several decades, very few Tissue Engineered Medical Products (TEMPs) have been clinically or commercially successful, as a significant technology gap, known as the “Valley of Death”, has prevented their scalable, consistent and cost-effective manufacture. This proposal is for the competing renewal of the current “Case Center for Multimodal Evaluation of Engineered Cartilage.” There is a growing need for TEMPs in multiple applications. We therefore believe that now is the time for a bold shift from our original focus on cartilage-centric evaluation technologies to developing, demonstrating, and deploying novel technologies to enable Quality-by-Design manufacturing of a variety of structural tissues, and to, thus, bridge the Valley of Death. The goal of the Center is the adoption of our technologies by the TEMP community at large. Consequently, the Center, will be renamed “Center for Modular Manufacturing of Structural Tissues” (CM2OST), and will apply knowledge and technology developed during the first 5 years to manufacturing-oriented challenges. The Center will be a consortium between CWRU and the Advanced Regenerative Manufacturing Institute (ARMI), and will focus on technologies that enable scalable, modular, automated, closed (SMAC) manufacturing. The Specific Aims of the proposal are to 1) Assist our CPs and SPs by pushing the technologies developed at the Center out to them. 2) Develop a cohesive set of innovative technologies, methods, and protocols that enable structural tissue manufacturing through 4 TR&D projects, described below, and 3) Develop a new, state-of-the- art, training and dissemination program. Strategically, we will break the overall R&D program into 4 TR&Ds representing key components of the TEMP assembly-line model. TR&D-1 covers dynamic control of cell pheno- type and function during the manufacturing process, and development of tissue-specific sensors for dynamic non-invasive monitoring of cell phenotype and function. TR&D-2 will develop sensor-enabled scaffolds and novel optode-based optical sensors to automate cell seeding and to monitor metabolites and provide feedback on local and bulk medium conditions. TR&D-3 will develop bio-instructive bioreactors with integrated actuators and sen- sors for feedback control, and will physically integrate them with the Tissue Foundry, an ARMI prototype auto- mated TEMP assembly line. TR&D-4 will integrate sensors and actuators with the automation and data man- agement system of the Tissue Foundry and will perform a manufacturing demonstration run. Demonstrating technologies developed in the TR&Ds will provide insights into TEMP development, process development and automation, and expose unanticipated technology gaps. Each TR&D represents a step in the TEMP assembly- line model, thus, though the technologies are developed independently, each TR&D feeds into the next. TR&Ds, Collaborative and Service Projects synergize, integrating and exploiting e...