Converging functionality: Strategies for 3D hybrid-construct biofabrication and the role of composite biomaterials for skeletal regeneration.

The evolution of additive manufacturing (AM) technologies, biomaterial development and our increasing understanding of cell biology has created enormous potential for the development of personalized regenerative therapies. In the context of skeletal tissue engineering, physical and biological demands play key roles towards successful construct implantation and the achievement of bone, cartilage and blood vessel tissue formation. Nevertheless, meeting such physical and biological demands to mimic the complexity of human tissues and their functionality is still a significant ongoing challenge. Recent studies have demonstrated that combination of AM technologies and advanced biomaterials has great potential towards skeletal tissue engineering. This review aims to analyze how the most prominent technologies and discoveries in the field converge towards the development of advanced constructs for skeletal regeneration. Particular attention is placed on hybrid biofabrication strategies, combining bioinks for cell delivery with biomaterial inks providing physical support. Hybrid biofabrication has been the focus of recent emerging strategies, however there has been limited review and analysis of these techniques and the challenges involved. Furthermore, we have identified that there are multiple hybrid fabrication strategies, here we present a category system where each strategy is reviewed highlighting their distinct advantages, challenges and potential applications. In addition, bioinks and biomaterial inks are the main components of the hybrid biofabrication strategies, where it is recognized that such platforms still lack optimal physical and biological functionality. Thus, this review also explores the development of composite materials specifically targeting the enhancement of physical and biological functionality towards improved skeletal tissue engineering. STATEMENT OF SIGNIFICANCE: Biofabrication strategies capable of recreating the complexity of native tissues could open new clinical possibilities towards patient-specific regenerative therapies and disease models. Several reviews target the existing additive manufacturing (AM) technologies that may be utilised for biomedical purposes. However, this work presents a unique perspective, describing how such AM technologies have been recently translated towards hybrid fabrication strategies, targeting the fabrication of constructs with converging physical and biological properties. Furthermore, we address composite bioinks and biomaterial inks that have been engineered to overcome traditional limitations, and might be applied to the hybrid fabrication strategies outlined. This work offers ample perspectives and insights into the current and future challenges for the fabrication of skeletal tissues aiming towards clinical and biomedical applications.