FMSG: Bio: End-to-End Continuous Manufacture of Cell Therapies Enabled by Robotics and Microfluidic Processing

Georgia Tech Research Corporation, Atlanta GA

Investigators

Abstract

This project will seek to create a more continuous, integrated workflow for cell therapy manufacturing based upon microfluidic technology and robotic cell processing. The transition to a more continuous cell therapy manufacturing workflow from the current batch processing can include a higher purity and yield of potent cells, which has also benefited other conventional manufacturing workstreams such as chemical manufacturing. With the cost of life-saving cell therapies >$100k per dose, innovating new integrated processes and technologies for cell therapy products is essential to expand access and increase the rate of innovation. There are several challenges to cell therapy manufacturing that this study will address. First, cell therapy products are currently produced using a “batch” manufacturing approach that consists of a multi-step process. As a result, the process results in batch-to-batch variation, an inability to use donor-specific variables in the manufacturing, and difficulty in system control of critical quality attributes. Second, the sensors that are used in cell therapy manufacturing that are related to cell function (e.g., molecular) are not real-time and cannot be used in nimble process control. Third, because autologous therapies are derived from a patient-donor, there is substantial variability of the starting material—yet this variability is not incorporated into the manufacturing process. The broader impacts of the project include the training of graduate and undergraduate students in microfluidic approaches to cell therapy manufacturing that may increase the innovation rate and decrease the costs associated with clinical cell manufacturing, while enabling small industry to innovate in the production of therapeutic cells. This project will harness fluid dynamics at the microscale using integrated microfluidic transfection and separation operations, as well as vision- and data analytics-enabled robotics to help automate the cell culture process. As a testbed, the study will apply the technologies to an induced pluripotent stem cell (iPSC) derived retinal organoid manufacturing process. The new technology and process control will be applied to generate functional retinal cell grafts, i.e., 3D engineered retinal constructs from iPSC-derived retinal organoids. The project can improve regenerative strategies through greater integration of iPSC genetic engineering, robotics-based culture, and new label-free cell selection methods to purify desired cell types that are consistent with Good Manufacturing Practices production. The team brings together three core expertises to accomplish the transformation: a current Good Manufacturing Practices process for retinal organoid manufacturing from human induced pluripotent stem cell culture; microfluidics-enabled cell transfection, characterization, and separation unit operations; and a capability for robotics-enabled cell processing and image analysis. The first objective is to apply a cell microfluidic transfection platform that uses choreographed mechanical deformations to convectively deliver large gene-editing CRISPR/Cas9 and DNA cargo to iPSCs. Moreover, because patient-derived specimens vary from donor to donor, the study will also characterize the biomechanical properties of donor cells to optimize the transfection. The second objective is to combine automated cell culture systems and machine learning to develop a robotic platform capable of performing high quality automated iPSC generation, CRISPR-correction, and retinal differentiation. The third objective examines how mixtures of retinal cells can better produce functional retinal grafts using a label-free cell separation microfluidic technology. Together the intellectual merits of this project will be to demonstrate an integrated approach to generate 3D engineered retinal constructs to address inherited blindness. This Future Manufacturing award was supported by Molecular and Cellular Biosciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.