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

Abstract

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.

FIG. 1.

Simplified representation of the bone microenvironment: from architecture to composition. (a) Long bones have a distinct hierarchical tissue organization. Histologically, bone is subdivided into (1) trabecular bone, (2) bone marrow, (3) cortical bone, (4) periosteum, and (5) cartilage. Differences in their composition, density, and porosity give the bone distinct mechanical and regenerative properties. (b) The bone microenvironment has a dynamic composition characterized by an orchestrated interaction between cellular components (skeletal cells, stem cells, vascular cells, immune cells, and nerve cells) and noncellular components (e.g., extracellular matrix, soluble signals, and vascular networks). ECs (endothelial cells), HSC (hematopoietic stem cells), and MSC (mesenchymal stem cells).

FIG. 2.

Schematic representation of the most common components used to recapitulate the bone microenvironments under in vitro conditions and its potential applications. (a) Simple and complex strategies have been proposed to mimic the bone architecture, the composition, the bone healing mechanisms, the vascular network, and the osteo-immune microenvironment. (b) The strategies combine different elements, i.e., cellular and noncellular components, biomaterials, technologies, and culture systems. (c) The development of bioengineered bone microenvironments can be divided into cell-rich (e.g., scaffold-free and cell-sheets), closed hybrid systems (e.g., scaffolds, hydrogels, and liquefied capsules), and open hybrid systems (e.g., porous scaffolds, particles, fibers, or membranes). (d) Three-dimensional (3D) constructs resembling the in vivo bone complexity can find a wide range of applications. They can be used as platforms for basic biology research, drug screening for bone pathologies, as alternative to minimize animal experimentation, and as potential regenerative therapy.

FIG. 3.

Strategies to mimic the bone vascular networks. The strategies use monoculture of endothelial cells (ECs) or endothelial progenitor cells (EPCs), or coculture of ECs/EPCs with bone resident cells. Different approaches use numerous biomaterials as a biophysical support or as a bioinstructive template. The strategies can also combine different technologies to recapitulate the bone microenvironmental properties [e.g., physiological flow, gradient of nutrients, temperature, oxygen (O₂) tension, and shear stresses], under controlled in vitro conditions. The supplementation of pro-angiogenic factors is also a common practice. MSC (mesenchymal stem cell) and ACS (adipose-derived stem cell).

FIG. 4.

Intrinsic correlation between the process complexity of the bioengineered bone microenvironment and its translational potential. Simple and advanced strategies have been proposed to recapitulate the bone microenvironment. While the first one approach has shown an elevated translation potential, the incorporation of several elements (e.g., biomaterials, cellular and noncellular components, different approaches, technologies, and culture systems) has limited the translational potential of the second approach.