Neoproteoglycans in tissue engineering

Abstract

Proteoglycans, comprised of a core protein to which glycosaminoglycan chains are covalently linked, are an important structural and functional family of macromolecules found in the extracellular matrix. Advances in our understanding of biological interactions have lead to a greater appreciation for the need to design tissue engineering scaffolds that incorporate mimetics of key extracellular matrix components. A variety of synthetic and semisynthetic molecules and polymers have been examined by tissue engineers that serve as structural, chemical and biological replacements for proteoglycans. These proteoglycan mimetics have been referred to as neoproteoglycans and serve as functional and therapeutic replacements for natural proteoglycans that are often unavailable for tissue engineering studies. Although neoproteoglycans have important limitations, such as limited signaling ability and biocompatibility, they have shown promise in replacing the natural activity of proteoglycans through cell and protein binding interactions. This review focuses on the recent in vivo and in vitro tissue engineering applications of three basic types of neoproteoglycan structures, protein-glycosaminoglycan conjugates, nano-glycosaminoglycan composites and polymer-glycosaminoglycan complexes.

Fig. 1

Structures of common PGs found in the ECM. Protein backbones are drawn in black, with each different family of GAG chains shown in different colors. Structures of the disaccharide repeating unit of each GAG chain are shown in the Structure Key. Gal, galactose; GlcA, glucuronic acid; IdoA, iduronic acid; GlcNAc, glucosamine; GalNAc, galactosamine. Bold text indicates the locations of possible sulfate groups; X = H or SO₃⁻, Y = COCH₃ or SO₃⁻

Fig. 2

Structure of the three basic neoPG structures and GAG chain attachment orientations. From top to bottom, nano-GAG composites, protein–GAG conjugates, and polymer–GAG complexes. The GAG chain attachment orientation illustrates the asymmetry of GAG chains.GAG chains may be attached through their reducing end (natural orientation on native PGs), their nonreducing end or various attachment points along the chain itself.

Fig. 3

Various functional properties of PGs and neoPGs in native and synthetic scaffolds.PGs and neoPGs may act as (A) signaling molecules, shown here supporting cellular growth; (B) cell adhesion molecules, shown here anchoring cells to the scaffold matrix; (C) sequestering signaling molecules for cellular support, shown here binding growth factors (GF) for slow release and cellular growth; or (D) binding molecules to create gradients and drive cellular responses, shown here establishing a chemokine (interleukin, IL) gradient driving cellular infiltration of the scaffold.

Fig. 4

Example of nanocomposites containing neoPG. Multiwalled carbon nanotubes wrapped with poly(ethyleneimine) to which heparin was covalently attached [72]. Tapping mode-atomic force microscopy phase image of poly(ethyleneimine)-coated and heparinized multiwall nanotube neoPGs. The surface bulges indicated by arrows correspond to heparin.