The development, maintenance of healthy bone and regeneration of injured tissue in the human body comprise a set of intricate and finely coordinated processes. However, an analysis of current bone regeneration strategies shows that only a small fraction of well-reported bone biology aspects has been used as inspiration and transposed into the development of therapeutic products. Specific topics that include inter-scale bone structural organization, developmental aspects of bone morphogenesis, bone repair mechanisms, role of specific cells and heterotypic cell contact in the bone niche (including vascularization networks and immune system cells), cell-cell direct and soluble-mediated contact, extracellular matrix composition (with particular focus on the non-soluble fraction of proteins), as well as mechanical aspects of native bone will be the main reviewed topics. In this Review we suggest a systematic parallelization of (i) fundamental well-established biology of bone, (ii) updated and recent advances on the understanding of biological phenomena occurring in native and injured tissue, and (iii) critical discussion of how those individual aspects have been translated into tissue regeneration strategies using biomaterials and other tissue engineering approaches. We aim at presenting a perspective on unexplored aspects of bone physiology and how they could be translated into innovative regeneration-driven concepts.

A hanging drop system that allows the multiconfigurational coculture of 3D microtissues is suggested as a versatile platform to promote the formation of functional preconditioned spheroids/microtissues, namely stem‐cell‐derived tissue engineering microtissues, with potential to be applied as scaffold‐free building blocks. Here, superhydrophobic (SH) platforms patterned with wettable regions are adapted for the production and culture of human adipose‐derived stem‐cell spheroids under indirect coculture with 2D layers of different cell types and direct coculture setups. The versatile indirect and direct coculture setups allow the use of cell lines as soluble biomolecules “factories” to continuously modulate microtissues response aspects, including their viability, cell number, and protein expression. This novel application of patterned SH platforms may find application in the massive production of modulated spheroids for the biomedical and pharmaceutical fields, with specific added value in the biofabrication of 3D constructs for tissue regeneration, as disease models, or even for organoids preparation.

Cellular aggregates are used as relevant regenerative building blocks, tissue models, and cell delivery platforms. Biomaterial‐free structures are often assembled either as 2D cell sheets or spherical microaggregates, both incompatible with free‐form deposition, and dependent on challenging processes for macroscale 3D upscaling. The continuous and elongated nature of fiber‐shaped materials enables their deposition in unrestricted multiple directions. Cellular fiber fabrication has often required exogenously provided support proteins and/or the use of biomaterial‐based sacrificial templates. Here, the rapid (<24 h) assembly of fiberoids is reported: living centimeter‐long scaffold‐free fibers of cells produced in the absence of exogenous materials or supplements. Adipose‐derived mesenchymal stem cell fiberoids can be easily modulated into complex multidimensional geometries and show tissue‐invasive properties while keeping the secretion of trophic factors. Proangiogenic properties studied on a chick chorioallantoic membrane in an ovo model are observed for heterotypic fiberoids containing endothelial cells. These micro‐to‐macrotissues may find application as morphogenic therapeutic and tissue‐mimetic building blocks, with the ability to integrate 3D and 4D full biological materials.