Cold-sintered bioceramics for medical applications: State of the art and further perspectives.

Cold sintering has recently emerged as a promising approach for preparing dense ceramic materials and composites at low temperatures. It relies on utilizing transient, typically externally introduced, liquid phases to accelerate material diffusion and densification under applied pressure. Cold-sintered bioceramics, especially those prepared at temperatures below 100°C, may open up numerous possibilities, not only in producing dense ceramics with refined microstructural properties and reduced time/energy costs, but also in developing multifunctional platforms containing bioactive compounds, therapeutics, growth factors, and signaling molecules for enhanced and targeted biological responses. Cold sintering in the presence of liquids inherently involves dissolution and nucleation, which become particularly intricate under applied pressures and elevated temperatures. Pseudo bio-mineralization, an auspicious approach for tailoring synthetic bone grafts toward targeted mechanics, may serve as a viable route for enhancing the densification mechanisms inherent to cold sintering. We have carefully analyzed the current state of the art in cold-sintered bioceramics and the results achieved, with a focus on the chemistry of the employed liquids and the corresponding changes upon sintering, the selection of transient phases, and mineral nucleation, while also addressing the potential for developing new biomaterials. Despite the widely accepted classical dissolution-precipitation strategy, no clear roadmap can yet be defined regarding the type and amount of liquid phase that should be applied, at least in the case of hydroxyapatite (HAp) densification-the most important representative of calcium phosphates. We strongly advocate the use of water as the transient liquid of choice in the cold sintering of HAp-based bioceramics, instead of strong acids/bases, and emphasize the importance of understanding the various processes and parameters that govern and connect solution chemistry to mineral nucleation. This understanding will enable the advancement of cold sintering protocols in a target-oriented manner, and we provide perspectives on future developments, including practical advice.