Modular self-assembling biomaterials for directing cellular responses

Abstract

Self-assembling biomaterials are promising as cell-interactive matrices because they can be constructed in a modular fashion, which enables the independent and simultaneous tuning of several of their physicochemical and biological properties. Such modularity facilitates the optimization of multi-component matrices for use in complex biological environments such as 3-D cell culture or scaffolds for regenerative medicine. This Highlight will discuss recent strategies for producing modular self-assembling biomaterials, with a particular focus on how ligand presentation and matrix mechanics can be controlled in modular ways. In addition, it will discuss key hurdles that remain for employing these materials as cell-interactive scaffolds in biomedical applications, particularly those that relate to how they may interface with the immune system.

Figure 1

Self-assembly enables a modular approach to biomaterials construction. The co-assembly of chemically defined molecular elements (a) promises to facilitate more systematic optimization and efficient exploration of the large parameter space of cell-biomaterials interactions (b) in order to experimentally identify those combinations of parameters that most effectively drive a desired biological response, for example the formation of a polarized epithelium (c). In panel (c), polarized MDCK epithelial cells are shown with confocal microscopy. The top image shows apical staining (red, gp135), and the bottom image shows basolateral staining (red, E-cadherin). In both images, F-actin is counterstained with phalloidin (green).

Figure 2

Matrix mechanics as a modular aspect of biomaterials. β-sheet forming peptide-thioesters self-assemble into fibrils and undergo native chemical ligation, leading to matrix stiffening (a). Ligated peptides retain the ability to fibrillize (b), and stiffening leads to significantly improved proliferation of human endothelial cells over un-stiffened matrices (c, blue DAPI, green CD31). Reprinted with permission from Jung et. al, Biomaterials, 2008.

Figure 3

Biological mechanisms that can modify self-assembling biomaterials construction in vitro (a–c) and in vivo (a–f). Processes at work in both environments include enzymatic degradation (a), fouling by serum-derived or other soluble proteins (b), and the deposition of new extracellular matrix by cells in contact with the material (c). Processes at work in vivo include phagocytosis of the matrix by antigen-presenting cells (APCs) and presentation in the MHC to potentially stimulate T-cell-dependent immune responses (d, note, many accessory and co-stimulatory proteins are not shown for simplicity), T-independent IgM responses induced by multivalent ligand display and B cell receptor clustering (e), and the binding of low-affinity circulating antibodies or complement proteins (f).