The present paper describes an original method to form under physiological conditions homogeneous lactose-modified chitosan (CTL) gels avoiding syneresis. Specifically, combination of boric acidi.e., the crosslinker and mannitoli.e., a polyol competitor for boron bindingwere exploited to reduce the very fast kinetics of CTL/boron self-assembly. Resulting gels were homogeneous as proved by scattering analyses. An indepth rheological characterization was undertaken to identify the correct mannitol-to-boron ratio at which gels showed homogeneity without weakening. Stress sweep and frequency sweep tests were performed to investigate the viscoelastic properties of these dynamic networks, highlighting a marked strain-hardening behavior, which is pivotal in native tissues. Notably, herein we report for the first time that CTL−boric acid gels are multiresponsive systems, whose mechanics can be tailored by different stimuli such as the presence of small molecules like glucose. Moreover, we demonstrate that these networks spontaneously self-heal after breakage. The biocompatibility of such gels was studied under 2D and 3D conditions toward three different cell models, namely, pig primary chondrocytes, human Dental Pulp Stem Cells (hDPSCs), and mouse fibroblasts. Giving the peculiar mechanical performance of selected systems and considering the wellknown bioactivity of the chitosan derivative, CTL−boric acid networks are promising candidates as multiresponsive gels to be used in the field of tissue engineering, especially for articular cartilage regeneration.
