Stem cell-based therapies hold transformative potential for regenerative medicine, yet their progress is constrained by persistent variability in manufacturing and clinical performance. Conventional frameworks such as Quality by Design (QbD), though effective for drugs and biologics, struggle to accommodate the dynamic nature of living cell products, whose quality evolves through donor heterogeneity, culture history, and environmental fluctuations. We propose a new interpretive lens: the fluctuation (yuragi) of cellular "feeling" (kimochi)-a metaphor for how cells sense, interpret, and inscribe their environmental experiences into chromatin and nuclear architecture. This "feeling" reflects the coupling of biochemical and mechanical inputs into cellular memory, which progressively transitions from epigenetic plasticity to mechanically stabilized states during ex vivo culture. Rather than treating variability as noise, we frame it as a designable property of living systems, grounded in measurable memory dynamics. This dual framing-"kimochi" as an operational metaphor, memory as a mechanistic substrate-motivates a next-generation paradigm: fluctuation-aware QbD, or QbD aligned with cellular feeling. Built upon three pillars-standardized memory metrics, multiscale modeling with digital twins, and adaptive process control-and enabled by integrated virtual factory-therapy infrastructures, this framework treats fluctuation not as a problem to suppress but as a feature to harness. In doing so, it charts a path toward reproducible, scalable, and clinically reliable living medicines.
Kim et al. (Sun,) studied this question.