Injectable Polysaccharide Hydrogels Reinforced with Cellulose Nanocrystals: Morphology, Rheology, Degradation, and Cytotoxicity

Injectable hydrogels based on carboxymethyl cellulose and dextran, reinforced with rigid rod-like cellulose nanocrystals (CNCs) and aldehyde-functionalized CNCs (CHO–CNCs), were prepared and characterized. The mechanical properties, internal morphology, and swelling of injectable hydrogels with unmodified and modified CNCs at various loadings were examined. In all cases, gelation occurred within seconds as the hydrogel components were extruded from a double-barrel syringe, and the CNCs were evenly distributed throughout the composite, as observed by scanning and transmission electron microscopy. When immersed in purified water or 10 mM PBS, all CNC-reinforced hydrogels maintained their original shape for more than 60 days. The maximum storage modulus was observed in hydrogels with 0.250 wt % of unmodified CNCs and 0.375 wt % of CHO–CNCs. CHO–CNCs acted as both a filler and a chemical cross-linker, making the CHO–CNC-reinforced hydrogels more elastic, more dimensionally stable, and capable of facilitating higher nanoparticle loadings compared to hydrogels with unmodified CNCs, without sacrificing mechanical strength. No significant cytotoxicity to NIH 3T3 fibroblast cells was observed for the hydrogels or their individual components. These properties make CNC-reinforced injectable hydrogels of potential interest for various biomedical applications such as drug delivery vehicles or tissue engineering matrices

pH-Ionizable <i>in Situ</i> Gelling Poly(oligo ethylene glycol methacrylate)-Based Hydrogels: The Role of Internal Network Structures in Controlling Macroscopic Properties

The incorporation of charge within <i>in situ</i> covalently gelling poly­(oligo ethylene glycol methacrylate) (POEGMA) precursor polymers enables the fabrication of hydrogels that exhibit both pH-responsive swelling and tunable network structures due to multimechanism cross-linking interactions. The gelation times, swelling responses, degradation kinetics, and mechanics of the resulting gels were strongly influenced by both the type of charge(s) incorporated and pH, with both amphoteric gels and anionic gels showing clear evidence of dual network formation. While the amphoteric dual network was anticipated due to charge interactions, the mechanism of the 5-fold enhancement in mechanical properties observed with the anionic gel relative to the neutral gel was revealed by isothermal titration calorimetry and small-angle neutron scattering to relate to the formation of a zippered chain structure based on dipole–dipole interactions. Consequently, rational design of the chemistry and the microscopic network structure results in controllable macroscopic properties amenable to potential biomedical applications

Probing the Internal Morphology of Injectable Poly(oligoethylene glycol methacrylate) Hydrogels by Light and Small-Angle Neutron Scattering

While injectable, <i>in situ</i> gelling hydrogels have attracted increasing attention in the biomedical literature due to their minimally invasive administration potential, little is known about the internal morphology of these hydrogels and thus how to engineer precursor polymer compositions to achieve desired hydrogel properties. In this paper, the internal morphology of injectable <i>in situ</i> gelling hydrogels based on hydrazide and aldehyde-functionalized poly­(oligoethylene glycol methacrylate) precursors with varying lower critical solution temperatures (LCSTs) is investigated using a combination of spectrophotometry, small-angle neutron scattering, and light scattering. If two precursor polymers with similar LCSTs are used to prepare the hydrogel, relatively homogeneous hydrogels are produced (analogous to conventional step-growth polymerized hydrogels); this result is observed provided that gelation is sufficiently slow for diffusional mixing to compensate for any incomplete mechanical mixing in the double-barrel syringe and the volume phase transition temperature (VPTT) of the hydrogel is sufficiently high that phase separation does not occur on the time scale of gelation. Hydrogels prepared from precursor polymers with different LCSTs (1 polymer/barrel) also retain transparency, although their internal morphology is significantly less homogeneous. However, if functionalized polymers with different LCSTs are mixed in each barrel (i.e., 2 polymers/barrel, such that a gelling pair of precursors with both low and high LCSTs is present), opaque hydrogels are produced that contain significant inhomogeneities that are enhanced as the temperature is increased; this suggests phase separation of the hydrogel into lower and higher LCST domains. Based on this work, the internal morphology of injectable hydrogels can be tuned by engineering the gelation time and the physical properties (i.e., miscibility) of the precursor polymers, insight that can be applied to improve the design of such hydrogels for biomedical applications

Injectable and Degradable Poly(Oligoethylene glycol methacrylate) Hydrogels with Tunable Charge Densities as Adhesive Peptide-Free Cell Scaffolds

Injectable, dual-responsive, and degradable poly­(oligo ethylene glycol methacrylate) (POEGMA) hydrogels are demonstrated to offer potential for cell delivery. Charged groups were incorporated into hydrazide and aldehyde-functionalized thermoresponsive POEGMA gel precursor polymers via the copolymerization of N,<i>N</i>′-dimethylaminoethyl methacrylate (DMAEMA) or acrylic acid (AA) to create dual-temperature/pH-responsive in situ gelling hydrogels that can be injected via narrow gauge needles. The incorporation of charge significantly broadens the swelling, degradation, and rheological profiles achievable with injectable POEGMA hydrogels without significantly increasing nonspecific protein adsorption or chronic inflammatory responses following in vivo subcutaneous injection. However, significantly different cell responses are observed upon charge incorporation, with charged gels significantly improving 3T3 mouse fibroblast cell adhesion in 2D and successfully delivering viable and proliferating ARPE-19 human retinal epithelial cells via an “all-synthetic” matrix that does not require the incorporation of cell-adhesive peptides