New insights into the biomimetic design and biomedical applications of bioengineered bone microenvironments


The bone microenvironment is characterized by an intricate interplay between cellular and noncellular components, which controls bone remodeling and repair. Its highly hierarchical architecture and dynamic composition provide a unique microenvironment as source of inspiration for the design of a wide variety of bone tissue engineering strategies. To overcome current limitations associated with the gold standard for the treatment of bone fractures and defects, bioengineered bone microenvironments have the potential to orchestrate the process of bone regeneration in a self-regulated manner. However, successful approaches require a strategic combination of osteogenic, vasculogenic, and immunomodulatory factors through a synergic coordination between bone cells, bone-forming factors, and biomaterials. Herein, we provide an overview of (i) current three-dimensional strategies that mimic the bone microenvironment and (ii) potential applications of bioengineered microenvironments. These strategies range from simple to highly complex, aiming to recreate the architecture and spatial organization of cell-cell, cell-matrix, and cell-soluble factor interactions resembling the in vivo microenvironment. While several bone microenvironment-mimicking strategies with biophysical and biochemical cues have been proposed, approaches that exploit the ability of the cells to self-organize into microenvironments with a high regenerative capacity should become a top priority in the design of strategies toward bone regeneration. These miniaturized bone platforms may recapitulate key characteristics of the bone regenerative process and hold great promise to provide new treatment concepts for the next generation of bone implants.& nbsp;(C)

2021 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (



subject category

Engineering, Biomedical


Oliveira, CS; Leeuwenburgh, S; Mano, JF

our authors


The authors acknowledge the financial support from the Portuguese Foundation for Science and Technology (FCT) through the projects CIRCUS (No. PTDC/BTM-MAT/31064/2017), CICECO-Aveiro Institute of Materials (Nos. UIDB/50011/2020 and UIDP/50011/2020), and financed by national funds through the FCT/MEC and, when appropriate, co-financed by FEDER under the PT2020 Partnership Agreement. The authors also acknowledge funding from the European Research Council (ERC) through the project ATLAS (No. ERC-2014-ADG-669858). Figs. 1-3 were created using

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