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Spheroid culture systems represent a highly beneficial method for tissue regeneration, disease modeling, and therapeutic purposes. However, conventional spheroid cultures are challenged by uncontrollable cellular proliferation and growth rate, size, structural simplicity, and ultimately core apoptosis due to restricted nutrient diffusion. Hence, the objective of this work is to introduce an ultra-small gelatin nanoparticle (GNP)-assisted stem cell culture system that enables the formation of compact spheroids while promoting intra-/intercellular functionality. Exceptionally biocompatible GNPs ranging from 80–150 nm are engineered with distinct characteristics that facilitate cell–cell and cell-ECM interactions, leading to increased functionality in stem cell spheroids. Fabricated GNP-stem cell spheroids exhibit enhanced cell viability, proliferation capacity, and cellular complexity when compared to traditional stem cell spheroid cultures. Additionally, fabricated GNP-stem cell spheroids' time-dependent regeneration efficiency was evaluated at both hard and soft tissue defects. Overall, these discoveries suggest GNP-stem cell spheroids' contribution to expedited bone and skin regeneration. These novel discoveries pave the way towards GNP-enhanced stem cell spheroids as the next step in regenerative medicine beyond traditional 3D stem cell therapeutics and novel tissue engineering/biomedical applications.
Fig. 2 Ultra-tiny GNPs incorporated with MSC spheroids as a therapeutic platform for enhanced tissue regeneration. (Kim D, et al. 2025)
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