2.3 Classification of Smart Materials in Tissue Engineering
2.3.3 Biologic Materials
2.3.3.1 Protein-Based Materials
a second group of protein-based materials is collagen. Collagen fibers rep- resent the main structural compound of the eCM. Fibrillar collagens are the best example of hierarchically structured materials. at the nm scale, these molecules form triple helices of α-chains that self-assemble in the eCM form- ing an arrangement of microfibrils that are further organized as fibers on the µm scale, providing mechanical strength to the tissues.74,81,82 the tridi- mensional organization of the collagen fibers provides also binding sites for cells and ligands, facilitating cell infiltration, platelet adhesion and activa- tion, and regulating access to growth factors and cytokines.83 the enzymatic degradation of collagen enables the release or exposure of matricryptic pep- tides, small fragments of peptides with biologic activities such as increased cell mobility, angiogenesis, and eCM deposition, among others.1,84 For these reasons, this fibrous protein has been investigated as a scaffold material for tissue engineering approaches. among all the fibrillar collagens, which include type i, ii, and iii,85 type i collagen is the most abundant component of almost all tissues, and therefore is the type most explored for use as a scaffold material.
the hierarchical structure of collagen enables a versatile configuration of this material. hydrogels can be produced by enzymatic solubilization of collagen to produce a biologically active gelatin.86 random or highly orga- nized fiber structures can be produced by extrusion, microfluidic channels,87 and 3d printing techniques.82 taking advantage of the inherent properties of collagen fibers and their utility as smart materials, Chan et al. (2016) have shown the ability of collagen scaffold materials to promote vascularization in pre-clinical studies, a required event for successful tissue regeneration.88 ryan and o’Brien (2015) showed that composites of collagen–elastin accel- erate the differentiation of smooth muscle cells, induce their contractility in vitro, and improve the mechanical properties by the presence of the elastin molecules in the composite,89 with potential for use in cardiovascular repair.
levingstone et al. (2016) evaluated the osteochondral regenerative potential of a multi-layered scaffold in a pre-clinical model. three layers of a collagen type i scaffold were differentially conjugated with hap particles, hyaluronic acid (ha), or collagen type ii and ha, and assembled to form the osteogenic, calcified cartilage, and cartilaginous layers, respectively. Complete degrada- tion of the multi-layered scaffold was seen at six months post-implantation and was replaced by new functional tissue produced by the cells that infil- trated the material.90
While these investigations using collagen scaffolds as smart materials sound promising in the field of tissue engineering, one of the challenges in the fabrication of collagen scaffolds is the maintenance of adequate site-specific mechanical properties while new tissue is being produced.
different chemical,91,92 physical,89 and enzymatic87 cross-linking agents have been used to modify the final structure of the collagen fibers.
although these methods improve the strength of the collagen scaffold, they negatively affect cytocompatibility and decrease enzymatic access to the collagen, delaying/inhibiting scaffold degradation, affecting the release
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00039
of matricryptic peptides, and promoting a foreign body reaction (FBr).93 therefore, the smart properties of collagen are quenched by the application of such techniques.
Fibronectin represents the third group of eCM protein-based materials with potential for tissue engineering applications. Fibronectin is a dimeric eCM glycoprotein that polymerizes and becomes functional when forming a fibrillar network around the cells94 as a consequence of the unfolding of cryptic domains which facilitate interactions with glycosaminoglycans, gelatin, collagen, as well as cell adhesion through integrins.95 as a result of these interactions and the flexibility of fibronectin fibrils, the fibronectin network regulates the activity of the cells, providing mechanotransductory signals which help regulate eCM deposition.96 the fabrication of fibronec- tin scaffolds is challenging, as changes in the tridimensional structure of the glycoproteins are required to form the network. these problems, however, are being addressed with the use of a surface-initiated assembly (Sia) method. Using this technique, the glycoprotein dimers are adsorbed onto a temporary scaffold of polydimethylsiloxane (pdMS), allowing the polymerization of the fibronectin and exposing the cryptic domains.97 the application of this technique has great potential in the generation of sta- ble structures that trigger the deposition of native eCM in wound repair applications.
From the group of protein-based materials, elastin is the last protein that will be discussed. elastin forms the second group of fibrillar and structural proteins in the eCM. Being more abundant in tissues like lungs, blood vessels, and the dermis, these proteins provide elasticity to the interstitial matrix structure.98 the elastic fibers are long-lived proteins assembled during development. elastin fibers are self-assembled from the tropoelastin precursor, forming a highly hydrophobic protein. the elastin fibers are crosslinked to other glycoproteins or microfibrils that provide the binding domains for interactions with cells and heparin molecules.95 elastin fibers are also an excellent source of matrikines, called elastokines, and matricryptic peptides84 regulating cell behavior and differentiation.89
the natural properties and composition of the elastin fibers make them difficult to isolate for biomedical applications; for this reason, more recent approaches make use of recombinant technologies to express structural and functional domains of tropoelastin in bacterial,99 yeast, or plant set- tings. the advantages of these genetic engineering approaches include the tailoring of specific properties in the construct by the assembly of hybrid modules of different proteins, as well as the control of the composition of the final product, eliminating the variability between batches.100 For example, the generation of silk-elastin-like proteins has been investigated to capture in a single construct the elastic properties of elastin and the tensile strength of silk101,102 while preserving biocompatibility and bio- degradability. likewise, recombinant elastin peptides have been used to improve the biomechanical properties of collagen scaffolds for vascular applications.103
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00039