Advancing bioinks for 3D bioprinting using reactive fillers: A review

The growing demand for personalized implants and tissue scaffolds requires advanced biomaterials and processing strategies for the fabrication of three-dimensional (3D) structures mimicking the complexity of the extracellular matrix. During the last years, biofabrication approaches like 3D printing of cell-laden (soft) hydrogels have been gaining increasing attention to design such 3D functional environments which resemble natural tissues (and organs). However, often these polymeric hydrogels show poor stability and low printing fidelity and hence various approaches in terms of multi-material mixtures are being developed to enhance pre- and post-printing features as well as cytocompatibility and post-printing cellular development. Additionally, bioactive properties improve the binding to the surrounding (host) tissue at the implantation site. In this review we focus on the state-of-the-art of a particular type of heterogeneous bioinks, which are composed of polymeric hydrogels incorporating inorganic bioactive fillers. Such systems include isotropic and anisotropic silicates like bioactive glasses and nanoclays or calcium-phosphates like hydroxyapatite (HAp), which provide in-situ crosslinking effects and add extra functionality to the matrix, for example mineralization capability. The present review paper discusses in detail such bioactive composite bioink systems based on the available literature, revealing that a great variety has been developed with substantially improved bioprinting characteristics, in comparison to the pure hydrogel counterparts, and enabling high viability of printed cells. The analysis of the results of the published studies demonstrates that bioactive fillers are a promising addition to hydrogels to print stable 3D constructs for regeneration of tissues. Progress and challenges of the development and applications of such composite bioink approaches are discussed and avenues for future research in the field are presented.