Biomimetic materials

Biomimetic materials are materials that have been designed such that they elicit specified cellular responses mediated by interactions with scaffold-tethered peptides from extracellular matrix (ECM) proteins; essentially, the incorporation of cell-binding peptides into biomaterials via chemical or physical modification ^[1].

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Such peptides include both native long chains of ECM proteins as well as short peptide sequences derived from intact ECM proteins. The idea is that the biomimetic material will mimic some of the roles that an extracellular matrix plays in neural tissue. In addition to promoting cellular growth and mobilization, the incorporated peptides could also mediate material degradation by specific protease enzymes or initiate cellular responses not present in a local native tissue ^[1]. In the beginning, long chains of ECM proteins including fibronectin (FN), vitronectin (VN), and laminin (LN) were used, but more recently the advantages of using short peptides have been discovered. Short peptides are more advantageous because, unlike the long chains that fold randomly upon adsorption causing the active protein domains to be sterically unavailable, short peptides remain stable and do not hide the receptor binding domains when adsorbed. Another advantage to short peptides is that they can be replicated more economically due to the smaller size. A bi-functional cross-linker with a long spacer arm is used to tether peptides to the substrate surface. If a functional group is not available for attaching the cross-linker, photochemical immobilization may be used ^[1]. In addition to modifying the surface, biomaterials can be modified in bulk, meaning that the cell signaling peptides and recognition sites are present not just on the surface but also throughout the bulk of the material. The strength of cell attachment, cell migration rate, and extent of cytoskeletal organization formation is determined by the receptor biding to the ligand bound to the material; thus, receptor-ligand affinity, the density of the ligand, and the spatial distribution of the ligand must be carefully considered when designing a biomimetic material ^[1].

Extracellular matrix proteins

Many studies utilize laminin-1 when designing a biomimetic material. Laminin is a component of the extracellular matrix that is able to promote neuron attachment and differentiation, in addition to axon growth guidance. It's primary functional site for bioactivity is its core protein domain isoleucine-lysine-valine-alanine-valine (IKVAV), which is located in the α-1 chain of laminin ^[2]. A recent study by Wu, Zheng et al., synthesized a self-assembled IKVAV peptide nanofiber and tested its effect on the adhesion of neuron-like pc12 cells. Early cell adhesion is very important for preventing cell degeneration; the longer cells are suspended in culture, the more likely they are to degenerate. The purpose was to develop a biomaterial with good cell adherence and bioactivity with IKVAV, which is able to inhibit differentiation and adhesion of glial cells in addition to promoting neuronal cell adhesion and differentiation ^[2]. The IKVAV peptide domain is on the surface of the nanofibers so that it is exposed and accessible for promoting cell contact interactions. The IKVAV nanofibers promoted stronger cell adherence than the electrostatic attraction induced by poly-L-lysine, and cell adherence increased with increasing density of IKVAV until the saturation point was reached. IKVAV does not exhibit time dependent effects because the adherence was shown to be the same at 1 hour and at 3 hours ^[2].

Laminin is known to stimulate neurite outgrowth and it plays a role in the developing nervous system. It is known that gradients are critical for the guidance of growth cones to their target tissues in the developing nervous system. There has been much research done on soluble gradients; however, little emphasis has been placed on gradients of substratum bound substances of the extracellular matrix such as laminin ^[3]. Dodla and Bellamkonda, fabricated an anisotropic 3D agarose gel with gradients of coupled laminin-1 (LN-1). Concentration gradients of LN-1 were shown to promote faster neurite extension than the highest neurite growth rate observed with isotropic LN-1 concentrations. Neurites grew both up and down the gradients, but growth was faster at less steep gradients and was faster up the gradients than down the gradients ^[3].

References

1. ^ ^{a b c d} Shin, H., S. Jo, and A.G. Mikos, Biomimetic materials for tissue engineering. Biomaterials, 2003. 24: p. 4353-5364.
2. ^ ^{a b c} Wu, Y., et al., Self-assembled IKVAV peptide nanofibers promote adherence of PC12 cells. Journal of Huazhong University of Science and Technology, 2006. 26(5): p. 594-596.
3. ^ ^{a b} Dodla, M.C. and R.V. Bellamkonda, Anisotropic scaffolds facilitate enhanced neurite extension "in vitro". Journal of Biomedical Materials Research. Part A, 2006. 78: p. 213-221.