Towards multi-dynamic mechano-biological optimization of 3D-printed scaffolds to foster bone regeneration

Substantial tissue loss, such as in large bone defects, represents a clinical challenge for which regenerative therapies and tissue engineering strategies aim at offering treatment alternatives to conventional replacement approaches by metallic implants. 3D printing technologies provide endless opportunities to shape scaffold structures that could support endogenous regeneration. However, it remains unclear which of the numerous parameters at hand eventually enhance tissue regeneration. In the last decades, a significant effort has been made in the development of computer tools to optimize scaffold designs. Here, we aim at giving a more comprehensive overview summarizing current computer optimization framework technologies. We confront these with the most recent advances in scaffold mechano-biological optimization, discuss their limitations and provide suggestions for future development. We conclude that the field needs to move forward to not only optimize scaffolds to avoid implant failures but to improve their mechano-biological behaviour: providing an initial stimulus for fast tissue organisation and healing and accounting for remodelling, scaffold degradation and consecutive filling with host tissue. So far, modelling approaches fall short in including the various scales of tissue dynamics. With this review, we wish to stimulate a move towards multi-dynamic mechano-biological optimization of 3D-printed scaffolds. STATEMENT OF SIGNIFICANCE: Large bone defects represent a clinical challenge for which tissue engineering strategies aim at offering alternatives to conventional treatment strategies. 3D printing technologies provide endless opportunities to shape scaffold structures that could support endogenous regeneration. However, it remains unclear which of the numerous parameters at hand eventually enhance tissue regeneration. In the last decades, a significant effort has been made in the development of computer tools to optimize scaffold designs. This review summarizes current computer optimization frameworks and most recent advances in mechano-biological optimization of bone scaffolds to better stimulate bone regeneration. We wish to stimulate a move towards multi-dynamic mechano-biological optimization of 3D-printed scaffolds.