Automated Manufacturing of Microtissue Based Osteochondral Implants: The »JOINTPROMISE« Platform

Over 300 million cases of osteoarthritis were reported in 2017, stating one of the most prevalent chronic joint diseases worldwide characterized predominantly by long-term progressive cartilage and subchondral bone degeneration. Conventional therapy approaches utilize pharmacotherapy mostly for pain relief and at end stage disease treated by whole joint replacement surgery to retrieve some mobility and function. Novel Regenerative Medicine (RM) strategies employing Tissue Engineered implants could enable cure, more than care, of such life-constraining disabilities to meet the rising demand for medical interventions due to an ageing world population. Engineering joint tissue implants for the regeneration of the cartilage-bone unit of the joints remains a challenge due to the complex structural organization and functionality of native joint tissue. The use of microtissue/spheroid platforms has enabled differentiation and maturation of cartilage intermediates and gives hope for the engineering of efficient large-scale implants for osteochondral regeneration. However, there is still lack of enabling technologies for scaling of these approaches and robust manufacturing with end-to-end automation of such advanced therapeutic medicinal products (ATMPs).
To allow sufficient scaling, overcome risks of contamination as well as inconsistent product quality in manual production procedures, the automated, GMP-compliant manufacturing platform »JointPromise« is developed. By establishing a robust, large-scale manufacturing process, a reliable microtissue-based product for the treatment of deep osteochondral defects can be generated with suitable productivity. The platform concept is based on the translation of Standard Operating Procedures (SOPs) for microtissue production, harvest and condensation into a sequence of automated process steps. Derived process design criteria and technical specifications result in device requirements for an automated production process. After initiating the conceptualizing stage of the platform design by creating a 2D layout according to the material flow of the translated SOPs, the final arrangement of devices was optimized in the overall 3D CAD model. The resulting production platform model combines all required devices for cell cultivation, microtissue harvest and ATMP production in an overall layout consisting of pipetting units, an incubator, centrifuge, bioprinter and housing for a defined hygienic environment. Following the SOPs, about 28,000 microtissue spheroids can be produced within 21 days of culture out of 1 mL cell suspension per tissue culture plate. To reach the required productivity of around 100 tissue culture plates per implant, the production platform will need to process around 70 L of liquids during seeding and harvest processes and 5 L per cell media change to produce around 2.8M microtissue spheroids in 21 days. The build-up of the »JointPromise« platform is followed by the implementation of the control software COPE (Control Operate Plan Execute, Fraunhofer IPT, Aachen, Germany) for process controlling and monitoring during cell seeding, cultivation and harvest.