  Advanced bioactive systems with defined macroscopic properties and
spatio-temporal sequestration of extracellular biomacromolecules are highly
desirable for next generation therapeutics. Here, chitosan hydrogels were
prepared with neutral or negatively-charged crosslinkers in order to promote
selective electrostatic complexation with charged drugs. Chitosan (CT) was
functionalised with varied dicarboxylic acids, such as tartaric acid (TA),
poly(ethylene glycol) bis(carboxymethyl) ether (PEG), 1.4-Phenylenediacetic
acid (4Ph) and 5-Sulfoisophthalic acid monosodium salt (PhS), whereby PhS was
hypothesised to act as a simple mimetic of heparin. ATR FT-IR showed the
presence of C=O amide I, N-H amide II and C=O ester bands, providing evidence
of covalent network formation. The crosslinker content was reversely quantified
by 1H-NMR on partially-degraded network oligomers, so that 18 mol% PhS was
exemplarily determined. Swellability, compressability, material morphology, and
drug-loading capability were successfully adjusted based on the selected
network architecture. Here, hydrogel incubation with model drugs of varied
electrostatic charge, i.e. allura red (AR, --), methyl orange (MO, -) or
methylene blue (MB, +), resulted in direct hydrogel-dye electrostatic
complexation. Importantly, the cationic compound, MB, showed different
incorporation behaviours, depending on the electrostatic character of the
selected crosslinker. In light of this tuneable drug-loading capability, these
CT hydrogels would be highly attractive as drug reservoirs towards e.g. the
fabrication of tissue models in vitro.
