Colloidal Gels with Tunable Mechanomorphology Regulate Endothelial Morphogenesis

Abstract

Endothelial morphogenesis into capillary networks is dependent on the matrix morphology and mechanical properties. In current 3D gels, these two matrix features are interdependent and their distinct roles in endothelial organization are not known. Thus, it is important to decouple these parameters in the matrix design. Colloidal gels can be engineered to regulate the microstructural morphology and mechanics in an independent manner because colloidal gels are formed by the aggregation of particles into a self-similar 3D network. In this work, gelatin based colloidal gels with distinct mechanomorphology were developed by engineering the electrostatic interaction mediated aggregation of particles. By altering the mode of aggregation, colloidal gels showed either compact dense microstructure or tenuous strand-like networks, and the matrix stiffness was controlled independently by varying the particle fraction. Endothelial Cell (EC) networks were favored in tenuous strand-like microstructure through increased cell-matrix and cell-cell interactions, while compact dense microstructure inhibited the networks. For a given microstructure, as the gel stiffness was increased, the extent of EC network was reduced. This result demonstrates that 3D matrix morphology and mechanics provide distinct signals in a bidirectional manner during EC network formation. Colloidal gels can be used to interrogate the angiogenic responses of ECs and can be developed as a biomaterial for vascularization.

Designing Microgels for Cell Culture and Controlled Assembly of Tissue Microenvironments

“…[21] In other instances, an increase in microgel stiffness was observed to increase the rates of cell proliferation and the efficacy of gene transfer [24] and cellular morphogenesis. [134] Another instance demonstrated how collagen content and microgel mechanics could be varied independently to control neuronal cell aggregation. [65] Importantly, these examples demonstrate how scaffold parameters can be decoupled, assessing the influence of mechanics independent from adhesive ligand density and scaffold porosity, respectively.…”

“…The Segura lab also demonstrated this concept in vivo, where stiffness, degradability, and adhesive ligand concentration could all be varied to control the immunogenic response and cell infiltration into the porous scaffold. [135] Microgel scaffold modulus has been varied from several Pascals (Pa) for endothelial cell network formation, [134] several hundred Pascals to match vocal fold tissue strength, [64] several kPa for differentiation of stem cell spheroids, [136] to several MPa in doubly cross-linked networks for supporting degenerated intervertebral discs. [137] The wide range of achievable mechanics, as well as the ability to independently tune multiple parameters, demonstrate how microgel mechanics can be designed to mimic the ECM of specific tissues in order to optimize culture for specific cell types.…”

“…[48,140] This approach can also be used in a layer-by-layer fashion to recreate tissue interfaces (e.g., the osteochondral interface), [62] or to vary network structure to influence cell behavior. [134] Mechanically heterogeneous microgel scaffolds have also been created using a layer-by-layer assembly to control cell spreading and morphology. [46] Other approaches, such as centrifugation and vacuum molding, can also be used to create 3D gradients of specific cell types ( Figure 4A).…”

Additive Manufacturing of Precision Biomaterials

“…While the jammed granular inks form free‐standing solids after extrusion, the materials, in some instances, were reinforced with photoinduced cross‐linking to generate granular elastic solids . In other approaches, injectable granular materials have been engineered exploiting supramolecular or ionic binding interactions between constituent microgels …”

Intermediate structural hierarchy in biological networks modulates the fractal dimension and force distribution of percolating clusters

“…The scientific community have developed many artificial substitutes for biological networks. In addition to the polymeric networks we see in biology, which are artificially reproduced as semi-flexible polymer networks and gels [2], we also have peptide assemblies and gels [17,18], colloidal gels [19,20] and folded protein-based hydrogels [21][22][23]. Each have unique viscoelastic behaviours, finding applications in food science [24], as drug delivery systems [25,26] and as candidates for artificial extra-cellular matrices and scaffolds [27][28][29][30][31].…”