The University of Pittsburgh TraCe (Pitt-TraCe) proposal is rooted in strong expertise and experience in large program Administration, management of Resources and early steps toward Qualification of Drug Development Tools (DDTs). The Pitt-TraCe proposal addresses multiple Food and Drug Administration (FDA) needs that will expand the FDA’s ability to progress regulatory science and decision-making capabilities using our extensive expertise and experience. The overall goal of the Pitt-TraCe proposal is to qualify our patient-derived structured, biomimetic liver Microphysiology Systems (MPS) platform in 4 contexts of use (CoUs) as DDTs that are being made commercially available. To reach this goal, the Pitt-TraCe includes strong administrative, MPS resources and qualification sections to accelerate the translational application of our liver MPS for specific CoUs. We will qualify our externally validated, structured, biomimetic liver MPS that recapitulates critical liver structures and functions with 4 liver cell types mimicking the liver acinus as DDTs. Induced pluripotent stem cell (iPSC)-derived liver cells from non-alcoholic fatty liver disease (NAFLD) patients enrolled in the University of Pittsburgh Medical Center Fatty Liver, Obesity, and Wellness Clinic (UPMC FLOW Clinic) that exhibit heterogeneity based on genetics, environment, and lifestyle will be used to define the role of patient heterogeneity in drug discovery, development, and clinical trials. NAFLD patient-derived liver MPS will serve as the disease background for developing the DDTs since this heterogeneous and progressive disease impacts >25% of the world population. This is a critical platform to define mechanisms of action (MOA) in the liver MPS in medium throughput to complement other high throughput, but simpler liver MPS for other CoU applications. We will qualify 4 CoU liver MPS that can be applied as DDTs including 1) quantifying hepatic clearance and identifying major metabolites; 2) quantifying liver toxicity; 3) drug testing for safety and efficacy; and 4) selecting clinical trial cohorts. Collaborations with pharmaceutical and biotechnology companies will yield materials including cells, media, and reagents critical for the qualification of the DDTs. Through a collaborative effort with Nortis Inc. and BioSystics, Inc., we will implement a medium throughput, high content and automated platform called the Automated Biomimetic Analytic MPS (ABAMPS) platform. The ABAMPS platform will deliver a more efficient and accurate use of structured, biomimetic MPS for MOA studies that will result in commercially available, FDA qualified DDTs.

The University of Pittsburgh TraCe MPS Center’s (Pitt-TraCe) qualified, patient-derived, structured, biomimetic liver Microphysiology Systems (MPS) platform will deliver qualified DDTs that will dramatically improve the efficiency and accuracy in liver safety and efficacy for drug development decisions, especially for complex heterogeneous diseases in precision medicine. These commercially available, qualified DDTs will benefit the drug development process for the pharmaceutical industry and FDA regulatory oversight. In addition, the Automated Biomimetic Analytic MPS (ABAMPS) platform employing commercially available materials from can be harnessed to qualify new organ structured, biomimetic MPS in the future.