Integrin Clustering Matters: A Review of Biomaterials Functionalized with Multivalent Integrin‐Binding Ligands to Improve Cell Adhesion, Migration, Differentiation, Angiogenesis, and Biomedical Device Integration

Abstract

Material systems that exhibit tailored interactions with cells are a cornerstone of biomaterial and tissue engineering technologies. One method of achieving these tailored interactions is to biofunctionalize materials with peptide ligands that bind integrin receptors present on the cell surface. However, cell biology research has illustrated that both integrin binding and integrin clustering are required to achieve a full adhesion response. This biophysical knowledge has motivated researchers to develop material systems biofunctionalized with nanoscale clusters of ligands that promote both integrin occupancy and clustering of the receptors. These materials have improved a wide variety of biological interactions in vitro including cell adhesion, proliferation, migration speed, gene expression, and stem cell differentiation; and improved in vivo outcomes including increased angiogenesis, tissue healing, and biomedical device integration. This review first introduces the techniques that enable the fabrication of these nanopatterned materials, describes the improved biological effects that have been achieved, and lastly discusses the current limitations of the technology and where future advances may occur. Although this technology is still in its nascency, it will undoubtedly play an important role in the future development of biomaterials and tissue engineering scaffolds for both in vitro and in vivo applications.

Improved ex vivo expansion of mesenchymal stem cells on solubilized acellular fetal membranes

“…All the above studies measured cell size by image analysis of micrographs taken of adherent MSCs during culture. It is well established that variables such as substrate stiffness, ligand presentation, ligand density, and cell motility all impact on the apparent size and shape of adherent cells,, but these confounding factors were not taken into account in these previous studies. To minimize these confounding factors, we used two methods of assessing comparative MSC size for suspended cells.…”

Probing the nanoscale organisation and multivalency of cell surface receptors: DNA origami nanoarrays for cellular studies with single-molecule control

“…Random positioning of peptide functionalised DNA origami demonstrated that a minimum of 12 peptides per DNA origami (~120 36 ligands/µm 2 ) were required to initiate cardiomyocyte ± adhesion and spreading. However, random positioning of DNA origami provides no control over ligand geometry above the level of individual origami (~ 85 nm 2 ) and offers limited information on global and local clustering dynamics, which are key for cell adhesion and spreading 5,21 . To investigate this, DNA origami functionalised with 0, 6 or 12 cRGDfC peptides were bound to EBL nanopatterned substrates at 200 nm and 300 nm intervals ( Figure 5), and this allowed us to further investigate the role of cluster spacing, due to the differences in receptor clustering behaviour between cardiomyocytes and fibroblasts.…”

“…The ECM components serve as anchoring points for the cells, but binding of integrins and other cell surface receptors also induce cellular signalling cascades which regulate fundamental processes from cell growth, to differentiation, motility or cell death 1 . The contact interface between the ECM and cell-binding domains, depends on the receptors' nanoscale spatial organisation 2,3 and clustering [4][5][6][7] . Integrin-ECM interactions are also regulated by cellular (cytoskeletal) and extracellular forces (such as the passive stiffness of the ECM) that affect the stability of the bonds 1,[8][9][10] .…”

Improved efficacy of bio‐mineralization of human mesenchymal stem cells on modified PLLA nanofibers coated with bioactive materials via enhanced expression of integrin α2β1

“…), and through that play an active role in bone formation. 20 Currently, bioactive materials such as hydroxyapatite and collagen are used in bone tissue engineering to modify some of the polymer properties. Hydroxyapatite has properties such as bioactivity, biodegradability and osteo-inductivity that improve bone regeneration.…”