The use of micro- and nanospheres as functional components for bone tissue regeneration

Abstract

During the last decade, the use of micro- and nanospheres as functional components for bone tissue regeneration has drawn increasing interest. Scaffolds comprising micro- and nanospheres display several advantages compared with traditional monolithic scaffolds that are related to (i) an improved control over sustained delivery of therapeutic agents, signaling biomolecules and even pluripotent stem cells, (ii) the introduction of spheres as stimulus-sensitive delivery vehicles for triggered release, (iii) the use of spheres to introduce porosity and/or improve the mechanical properties of bulk scaffolds by acting as porogen or reinforcement phase, (iv) the use of spheres as compartmentalized microreactors for dedicated biochemical processes, (v) the use of spheres as cell delivery vehicle, and, finally, (vi) the possibility of preparing injectable and/or moldable formulations to be applied by using minimally invasive surgery. This article focuses on recent developments with regard to the use of micro- and nanospheres for bone regeneration by categorizing micro-/nanospheres by material class (polymers, ceramics, and composites) as well as summarizing the main strategies that employ these spheres to improve the functionality of scaffolds for bone tissue engineering.

FIG. 1.

Number of publications on the use of micro-/nanospheres for biomedical applications in the past decade by combining keywords “microspheres and biomedical” or “nanospheres and biomedical,” respectively (PubMed).

FIG. 2.

Schematic representation of the use of micro-/nanospheres for spatiotemporal control over delivery of bioactive molecules. (A) Spatial control of biomolecule delivery by employing a gradient distribution of micro-/nanospheres as delivery vehicles. (B) Temporal control of biomolecule delivery using micro-/nanospheres with differing release characteristics.

FIG. 3.

Experimental design and resulting photographs of two modes of cell delivery using hydrogels: cells were directly encapsulated into hydrogels to form conventional gel construct (top); alternatively, cell-laden microspheres were incorporated into hydrogels to form microsphere/hydrogel composite system (GC) (bottom). The former strategy resulted in cell death, whereas the latter one led to cell survival and proliferation in the hydrogel. Cytoskeleton F-actin (red) was counterstained with nuclei (blue). Reprinted from 22 with permission. Copyright 2011, Elsevier.

FIG. 4.

Schematic representation of using micro-/nanospheres as building blocks for bottom-up design of scaffolds by random packing (A), directed assembly (B), and rapid prototyping (C). Directed assembly can be induced by interparticle forces such as electrostatic (D), magnetic (E), and hydrophobic (F) interactions.

FIG. 5.

Schematic diagram (A) and resulting photographs (B–F) of injectable colloidal gels based on using oppositely charged gelatin nanospheres as building blocks showing the self-assembly (B, C) and gel formation (D–F) of gelatin nanospheres of opposite charge (“+/-” denotes the mixture of oppositely charged particles) as opposed to systems made of similarly charged nanospheres (“+” and “-” denote positive and negatively charged particles, respectively). Adapted from 54 with permission. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.

FIG. 6.

Scaffolds consisting of calcium phosphates/poly(hydroxybutyrate-co-hydroxyvalerate composite microspheres prepared by rapid prototyping using selective lazer sintering technique. (A) Schematic diagram of the scaffold model designed by a computer; microcomputed tomography (B) and scanning electron microscopy (C, D) of the resulting scaffolds after rapid prototyping. Adapted from 170 with reproduction permission. Copyright 2011, Elsevier.