Approaches for building bioactive elements into synthetic scaffolds for bone tissue engineering

Abstract

Bone tissue engineering (BTE) is emerging as a possible solution for regeneration of bone in a number of applications. For effective utilization, BTE scaffolds often need modifications to impart biological cues that drive diverse cellular functions such as adhesion, migration, survival, proliferation, differentiation, and biomineralization. This review provides an outline of various approaches for building bioactive elements into synthetic scaffolds for BTE and classifies them broadly under two distinct schemes; namely, the top-down approach and the bottom-up approach. Synthetic and natural routes for top-down approaches to production of bioactive constructs for BTE, such as generation of scaffold-extracellular matrix (ECM) hybrid constructs or decellularized and demineralized scaffolds, are provided. Similarly, traditional scaffold-based bottom-up approaches, including growth factor immobilization or peptide-tethered scaffolds, are provided. Finally, a brief overview of emerging bottom-up approaches for generating biologically active constructs for BTE is given. A discussion of the key areas for further investigation, challenges, and opportunities is also presented.

Keywords: biological modification; biomimetic scaffolds; bone tissue engineering; extracellular matrix; synthetic scaffolds.

Figure 1

Schematic representation of top-down approaches to generation of bioactive constructs for bone tissue engineering. In the natural route for the top-down approaches, a native bone can be decellularized and demineralized to obtain a natural matrix in various forms (e.g., powder, paste, putty, injectable; not shown) devoid of cells that can be utilized for generating engineered bone. For the synthetic route, scaffold-ECM hybrid matrices are developed by culturing of cell-seeded scaffolds for a limited duration of time often under engineered culture conditions and subsequently scaffold-ECM hybrid matrices are obtained after decellularization to produce a biologically active matrix that can be used for engineering bone tissue.

Figure 2

Schematic representation of 3D scaffold-based and alternative bottom-up approaches to bone tissue engineering. In the traditional 3D scaffold-based bottom-up approaches, growth factors, peptides, cytokines and/or cells are utilized as building blocks to create a functionalized 3D scaffold that is ultimately used either with or without pre-seeded cells for engineering bone tissue. In the emerging alternative approaches, cell sheets, cell aggregates, cell laden microgels, or 3D/bioprinting technologies are used for assembling/stacking/layering components to generate 3D constructs.