Topography-mediated pH-responsive chitosan blends for scalable continuous cell production: A platform for next-generation cell therapy manufacturing

● Chitosan-based polymeric blends could serve as potent platforms for pH-driven continuous cell production ● The chitosan component dictates cell detachment in response to the pH transition while the pH-nonresponsive component drives cell expansion ● The reduction in the domain distance enclosed by disparate polymer domains increases the efficiency for cells to recognize either growth or detachment under pH transitions With an exponential advancement in the cell therapy industry, stimuli-responsive cell expansion systems have been springing up as an alternative to the conventional batch-type cultures. However, the development of pH-responsive platforms remains significantly underrepresented in this field. This study aims to investigate the application of chitosan-based polymeric blends for pH-driven continuous cell production. Our findings reveal that nylon-6,6/chitosan (NL/CS) blends, characterized by a unique condensed pebble-paving micro-architecture, significantly outperform other sample blends in cell recovery rates, re-expansion efficiency, and overall processing time. The NL/CS surface maintains a highly uniform, isotropic profile with height amplitudes below 100 nm, featuring tightly-packed heterogeneous domains that allow cells to effectively bridge growth-favoring regions. The unique micro-architecture supports robust mechanical sensing and facilitates a seamless transition between cell expansion and detachment cycles. Collectively, this work establishes a design principle based on surface topography and phase distribution for controlling cell fate in dynamic culture systems, offering a scalable platform for cell therapy manufacturing.