Hexagonal boron nitride bio-interfacing the skin: role of shape and size in its safety profile assessed on 2D and 3D epidermal models

Due to its unique physico-chemical properties, hexagonal boron nitride ( h -BN) is one of the most promising two-dimensional materials. Considering its technological potential, its hazard characterization is critical to ensure safety for both consumers and workers. Given that skin contact represents one of the major exposure routes for humans, this study aimed at i ) evaluating h -BN cutaneous effects using two in vitro models with different complexity levels, and ii ) investigating whether key physico-chemical properties (shape and size) can influence h -BN interactions with epidermal cells and its toxicity. h -BN exhibited good biocompatibility with human HaCaT keratinocytes: mild cytotoxic and pro-inflammatory effects were observed only after a long exposure (7 days) at concentration >10 μg/mL, with extremely low impact after a shorter contact (24 h). These effects appeared influenced mostly by shape and size of the h -BN flakes. In fact, compared to rounded h -BN, larger sharp-edged h -BN was internalized to a lesser extent by keratinocytes but exhibits a stronger interaction with plasma membrane, compromising membrane integrity, consequently triggering a higher cellular damage. However, using a more predictive epidermal model, such as a three-dimensional reconstructed human epidermis, and adopting specific test guidelines provided by the Organization for Economic Cooperation and Development, h -BN was classified as non-corrosive and non-irritant for the skin. On this model, h -BN biocompatibility was unaffected by flake morphology, likely due to the protective barrier function of the Stratum corneum of epidermis. Altogether, these findings provide valuable insights for the Safe-by-Design development of h -BN applications involving a direct skin contact.