Mechanomorphology of Colloidal Aggregates and Gels Regulates Cell Fate
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Colloidal gels, unlike monolithic hydrogels, are formed by aggregation of submicron colloidal particles into self-similar space-filling networks due to attractive interparticle interactions. By altering the aggregation mechanism, the particles within the aggregated network of colloidal gels can be organized with distinct microstructure to impart definite spatial morphology. And the bulk elasticity of the colloidal gel can be scaled with particle fraction for a given microstructural morphology. Electrostatic interaction mediated aggregation of ionic colloidal particles can form three-dimensional gel via the electrolytes present in the dispersion media. The mode of aggregation can be varied by altering the electrolyte characteristics as well as by the ionic strength of the electrolytes. Thus, the microstructural morphology of these aggregates and gels are engineered with defined geometry and their mechanical properties are either independently or interdependently controlled by the particle fraction. As a result, the colloidal aggregates and gels, as three-dimensional artificial extracellular matrix, can provide tunable mechanomorphology to guide the spatial organization of cells during morphogenesis. Since cellular morphogenesis is essentially dependent on the local spatial constraints and elasticity of the three-dimensional matrix, it is imperative that the mechanomorphology of the colloidal gels can provide guidance to regulate cell fate. To achieve this, colloidal gels with different mechanomorphological characteristics were developed from cationic colloidal particles, where the colloids particles were developed from cationic polyurethanes (PU). Ionic polyurethanes, as synthetic material, provides a platform to develop ionic aqueous colloids which can be aggregated to form colloidal gels. Specifically, PU based colloidal aggregates and gels were developed by aggregating the colloids using (i) electrolytes from phosphate buffer, i.e. phosphate and chlorides which can neutralize the surface charges of particles and aggregate the colloidal particles into compact microstructure, (ii) polyelectrolytes using sodium-salt of poly-acrylic acid, i.e. carboxylate groups which assemble the ionic particles into branched structures through bridging interactions, and (iii) chondroitin sulfate disaccharide, i.e. multiple sulfate groups which can aggregate the ionic colloids depending on the ionic strength. By using these three platform colloidal gels, mechanomorphological characteristics were tuned over a wide range. Both microstructural morphology and mechanical properties of the aggregates and gels were characterized experimentally to demonstrate that different aggregation modes yield colloidal gels with distinct mechanomorphology. To demonstrate the relevance of mechanomorphology as a matrix guidance for controlling cell fate, two cases were analyzed: (i) endothelial network formation, and (ii) chondrogenesis of mesenchymal stem cell; both of which are known to be dependent on the organization of cells in the three-dimensional matrix. The endothelial network formation by human umbilical vein endothelial cells shows that endothelial cells form capillary-like angiogenic structures in colloidal gels with branched strands of interconnected particles. The endothelial responses were regulated by both cell-cell and cell-matrix interactions and were dependent on the mechanomorphology of the colloidal gels. Similarly, the chondrogenic differentiation of stem cells was dependent on the matrix guidance of colloidal gels where chondrogenesis was favored in colloidal gels with branched strands of interconnected particles. Chondrogenic differentiation was dependent on the organization of cells which was guided by the microstructural morphology and mechanical properties of the colloidal gel. Overall, these two systems demonstrate that the microstructural morphology of three-dimensional matrix in combination with matrix mechanics is an important regulator for cell organization during morphogenesis and colloidal gels can provide this matrix guidance. The unique structural and functional features of colloidal gels enable to regulate the morphology in a controlled manner with respect to the bulk mechanics. This work illustrates that the mechanics and morphology of colloidal aggregates and gels can be decoupled by altering their mechanism of aggregation. The colloidal aggregates and gels can be utilized as a functional cell matrix to regulate the cell-matrix as well as the cell-cell interactions to define the cell fate during morphogenesis. Furthermore, the colloidal gels provide a material engineering opportunity to develop synthetic matrices which can be used for regenerative tissue engineering applications.