Design, characterization and applications of nanocolloidal hydrogels.

Nanocolloidal gels (NCGs) are an emerging class of soft matter, in which nanoparticles act as building blocks of the colloidal network. Chemical or physical crosslinking enables NCG synthesis and assembly from a broad range of nanoparticles, polymers, and low-molecular weight molecules. The synergistic properties of NCGs are governed by nanoparticle composition, dimensions and shape, the mechanism of nanoparticle bonding, and the NCG architecture, as well as the nature of molecular crosslinkers. Nanocolloidal gels find applications in soft robotics, bioengineering, optically active coatings and sensors, optoelectronic devices, and absorbents. This review summarizes currently scattered aspects of NCG formation, properties, characterization, and applications. We describe the diversity of NCG building blocks, discuss the mechanisms of NCG formation, review characterization techniques, outline NCG fabrication and processing methods, and highlight most common NCG applications. The review is concluded with the discussion of perspectives in the design and development of NCGs.

Matrix Stiffness-Regulated Growth of Breast Tumor Spheroids and Their Response to Chemotherapy.

Interactions between tumor cells and the extracellular matrix (ECM) are an important factor contributing to therapy failure in cancer patients. Current in vitro breast cancer spheroid models examining the role of mechanical properties on spheroid response to chemotherapy are limited by the use of two-dimensional cell culture, as well as simultaneous variation in hydrogel matrix stiffness and other properties, e.g., hydrogel composition, pore size, and cell adhesion ligand density. In addition, currently used hydrogel matrices do not replicate the filamentous ECM architecture in a breast tumor microenvironment. Here, we report a collagen-alginate hydrogel with a filamentous architecture and a 20-fold variation in stiffness, achieved independently of other properties, used for the evaluation of estrogen receptor-positive breast cancer spheroid response to doxorubicin. The variation in hydrogel mechanical properties was achieved by altering the degree of cross-linking of alginate molecules. We show that soft hydrogels promote the growth of larger MCF-7 tumor spheroids with a lower fraction of proliferating cells and enhance spheroid resistance to doxorubicin. Notably, the stiffness-dependent chemotherapeutic response of the spheroids was temporally mediated: it became apparent at sufficiently long cell culture times, when the matrix stiffness has influenced the spheroid growth. These findings highlight the significance of decoupling matrix stiffness from other characteristics in studies of chemotherapeutic resistance of tumor spheroids and in development of drug screening platforms.

Compound droplets derived from a cholesteric suspension of cellulose nanocrystals.

This study reports microfluidic generation of Janus droplets that consist of a liquid crystal component (a cholesteric aqueous suspension of cellulose nanocrystals, Ch-CNC) and a mineral oil (MO) component. The composition of the droplets was controlled by varying the relative flow rates of MO and Ch-CNC suspension. The shape of the Ch-CNC component of the droplets was changed from a truncated sphere to a hemisphere to a crescent moon. For these three Ch-CNC phase shapes, the Ch packing of the CNC pseudolayers was preserved, however the Ch pitch reduced, which was ascribed to the change in CNC orientation at the Ch-CNC/MO interface from perpendicular to parallel. The shape of the compound droplets was tuned from a dumbbell to a sphere by reducing interfacial tension between the Ch-CNC suspension and MO phases. Photopolymerization of the monomer mixture introduced in the Ch-CNC phase of the droplets and the removal of the sacrificial MO phase enabled the generation of Ch microgels. The results of this work can be used for exploring new applications of Janus colloids and the fabrication of programmable active soft matter.

Supramolecular Nanofibrillar Thermoreversible Hydrogel for Growth and Release of Cancer Spheroids.

Growth of three-dimensional cancer spheroids (CSs) in man-made hydrogels mimicking natural extracellular matrix is an important and challenging task. Herein, we report on a supramolecular temperature-responsive hydrogel designed for the growth and subsequent release of CSs. A filamentous hydrogel was formed at 37 °C from an aqueous suspension of cellulose nanocrystals surface-functionalized with temperature-responsive polymer molecules. The encapsulation of cells in the hydrogel enabled effective growth of CSs with dimensions determined by the concentration of cellulose nanocrystals in the hydrogel. On demand release of CSs without loss of cell viability and spheroid integrity was achieved upon hydrogel cooling. The tumorigenic properties of the released CSs were examined by encapsulating and re-growing them in fibrin hydrogel. The results in this work can be used in fundamental cancer research and in cancer drug screening.

Colloidal Clusters and Networks Formed by Oppositely Charged Nanoparticles with Varying Stiffnesses.

Colloidal clusters and gels are ubiquitous in science and technology. Particle softness has a strong effect on interparticle interactions; however, our understanding of the role of this factor in the formation of colloidal clusters and gels is only beginning to evolve. Here, we report the results of experimental and simulation studies of the impact of particle softness on the assembly of clusters and networks from mixtures of oppositely charged polymer nanoparticles (NPs). Experiments were performed below or above the polymer glass transition temperature, at which the interaction potential and adhesive forces between the NPs were significantly varied. Hard NPs assembled in fractal clusters that subsequently organized in a kinetically arrested colloidal gel, while soft NPs formed dense precipitating aggregates, due to the NP deformation and the decreased interparticle distance. Importantly, interactions of hard and soft NPs led to the formation of discrete precipitating NP aggregates at a relatively low volume fraction of soft NPs. A phenomenological model was developed for interactions of oppositely charged NPs with varying softnesses. The experimental results were in agreement with molecular dynamics simulations based on the model. This work provides insight on interparticle interactions before, during, and after the formation of hard-hard, hard-soft, and soft-soft contacts and has impact for numerous applications of reversible colloidal gels, including their use as inks for additive manufacturing.

Microfluidic arrays of dermal spheroids: a screening platform for active ingredients of skincare products.

Organotypic micrometre-size 3D aggregates of skin cells (multicellular spheroids) have emerged as a promising in vitro model that can be utilized as an alternative of animal models to test active ingredients (AIs) of skincare products; however, a reliable dermal spheroid-based microfluidic (MF) model with a goal of in vitro AI screening is yet to be developed. Here, we report a MF platform for the growth of massive arrays of dermal fibroblast spheroids (DFSs) in a biomimetic hydrogel under close-to-physiological flow conditions and with the capability of screening AIs for skincare products. The DFSs formed after two days of on-chip culture and, in a case study, were used in a time-efficient manner for screening the effect of vitamin C on the synthesis of collagen type I and fibronectin. The computational simulation showed that the uptake of vitamin C was dominated by the advection flux. The results of screening the benchmark AI, vitamin C, proved that DFSs can serve as a reliable in vitro dermal model. The proposed DFS-based MF platform offers a high screening capacity for AIs of skincare products, as well as drug discovery and development in dermatology.