The Past, Present, and Future Development of Cell Culture Substrates for PSC-Derived Therapies and the Challenges in Meeting the Plethora of Emerging User Requirements.

The evolution of cell culture substrates for pluripotent stem cell (PSC)-derived therapies has transformed from rudimentary feeder-based systems to sophisticated, defined platforms with clinical scalability.The feeder cell- and tissue extract protocols, enabled the first PSC cultures. However, their inherent limitations, including lot-to-lot variability, labour-intensive preparation, and potential xenogeneic contamination, necessitated the transition to defined and scalable substrates. The subsequent advancement of engineered substrates, ranging from recombinant extracellular matrix proteins like laminin and vitronectin to peptide-functionalized and fully synthetic surfaces. These advancements enable controlled microenvironments that enhance self-renewal, lineage specification, and compatibility with emerging bioprocessing technologies.Despite progress, manufacturing challenges for auxiliary materials persist, and the shift from research-grade to clinical applications adds further complexities, requiring stringent documentation, process standardization, and supply chain resilience. Emerging challenges also include adapting to evolving regulatory frameworks and towards environmental sustainability.Looking ahead, PSC culture substrates must adapt to increasingly complex therapeutic applications, including vivo transplantation environments, to improve the survival of transplanted cells. Demanding continued collaboration between researchers, manufacturers, and regulatory bodies to optimize safety, efficacy, efficiency, and accessibility in regenerative medicine.