Regenerating large bone defects remains a significant clinical challenge, motivating increased interest in additive manufacturing and 3D bioprinting to engineer superior bone graft substitutes. 3D bioprinting enables different biomaterials, cell types, and growth factors to be combined to develop patientspecific implants capable of directing functional bone regeneration. Current approaches to bioprinting such implants fall into one of two categories, each with their own advantages and limitations. First are those that can be 3D bioprinted and then directly implanted into the body and second those that require further in vitro culture after bioprinting to engineer more mature tissues prior to implantation. This review covers the key concepts, challenges, and applications of both strategies to regenerate damaged and diseased bone.
Current Bioprinting Strategies for Bone RegenerationSince the first US patent was awarded for 3D bioprinting (see Glossary) in 2006 (https://www.google.com/patents/US7051654), there have been significant advances in the field, particularly its application towards bone regeneration. This can be seen in the large number of publications (>600 papers) and reviews [1][2][3][4][5][6][7][8][9][10][11][12] devoted to the topic in the past 4 years alone. Advances in additive manufacturing and 3D bioprinting have had a significant impact on the fields of tissue engineering and regenerative medicine, with microextrusion, inkjet, laser-assisted bioprinting, and more recently melt-electrowriting (MEW) techniques all being used to generate implants for bone repair. In the literature there are a variety of definitions for the terms 'bioprinting' and 'bioinks', with some specifying the presence of cells as a mandatory component of the printing formulation in bioprinting [13]. For the purpose of this review, we define bioprinting as the use of 3D printing technologies to deposit cells and/or other biological factors, specifically genes, growth factors, and/or extracellular matrix (ECM) components, in a spatially controlled pattern to fabricate or regenerate living tissues and organs. Common features of a bone bioprinting strategy include a bioink (typically a hydrogel), laden with cells, genes, and/or growth factors, and a mechanical backbone of a thermopolymer or ceramic to accommodate the challenging loads experienced by the implant in situ. Extensive reviews have been written on the various technologies [1,2,4,5,[9][10][11][12][14][15][16][17] and bioinks [1,3,[6][7][8]10,18,19] under development for bone regeneration. Broadly speaking, putative therapeutics that can be derived from such technologies fall into one of two categories; first, those that can be 3D bioprinted and then directly implanted into the body (herein termed 'print-and-implant' devices), and second, those that require further in vitro culture after bioprinting (e.g., in a bioreactor) to mature the engineered tissue prior to implantation. Both approaches have their own inherent advantages and limitations. Constructs that can be biopri...