A modular approach for the synthesis of hyaluronic acid hydrogels using orthogonal chemoselective reactions for subsequent enzymatic decomposition to nanoparticles is described.
Functionalization
of hyaluronic acid (HA) with orthogonally reactive aldehyde and thiol
groups permitted simultaneous bioconjugation and networking/nanostructuring
of the HA chains for potential use as local and systemic delivery
vehicles for medical therapies. In one experiment, the thiol–disulfide
exchange reaction and carbazone chemistry were employed to construct
a disulfide hydrogel matrix of HA macromolecules with the carbazone-linked
poly(vinyl alcohol) prodrug of doxorubicin (PVA–DOX). In another
experiment, orthogonal chemoselective reactions were utilized to prepare
nanogel particles through conjugation of the polymeric PVA–DOX
prodrug to HA and simultaneous attachment of hydrophobic fluorescent
groups to the HA chains. The effect of the prodrug nanostructuring
and functionalization with HA on the in vitro drug
release and uptake by cancer cells was preliminary verified.
The precise role and value of incorporating nanoforms in biologically active matrices for medical applications is not known. In our current work, we incorporate two chitin nanoforms (i.e., nanocrystals or nanofibers) into Genipin-chitosan crosslinked matrices. These materials were studied as 2D films and 3D porous scaffolds to assess their potential as primary support and guidance for stem cells in tissue engineering and regenerative medicine applications. The incorporation of either nanoforms in these 2D and 3D materials reveals significantly better swelling properties and robust mechanical performance in contrast to nanoform-free chitosan matrices. Furthermore, our data shows that these materials, in particular, incorporation of low concentration chitin nanoforms provide specific topological cues to guide the survival, adhesion, and proliferation of human adipose-derived stem cells. These findings demonstrate the potential of Genipin-chitosan crosslinked matrices impregnated with chitin nanoforms as value added materials for stem cell-based biomedical applications.
The mucus gel covers the wet epithelia that forms the inner lining of the body. It constitutes our first line of defense protecting the body from infections and other deleterious molecules. Failure of the mucus barrier can lead to the inflammation of the mucosa such as in inflammatory bowel diseases. Unfortunately, there are no effective strategies that reinforce the mucus barrier properties to recover or enhance its ability to protect the epithelium. Herein, we describe a mucus engineering approach that addresses this issue where we physically cross-link the mucus gel with low molar mass chitosan variants to reinforce its barrier functions. We tested the effect of these chitosans on mucus using in-lab purified porcine gastric mucins, which mimic the native properties of mucus, and on mucus-secreting HT29-MTX epithelial cell cultures. We found that the lowest molar mass chitosan variant (degree of polymerization of 8) diffuses deep into the mucus gels while physically cross-linking the mucin polymers, whereas the higher molar mass chitosan variants (degree of polymerization of 52 and 100) interact only superficially. The complexation resulted in a tighter mucin polymer mesh that slowed the diffusion of dextran polymers and of the cholera toxin B subunit protein through the mucus gels. These results uncover a new use for low molar mass mucoadhesive polymers such as chitosans as noncytotoxic mucosal barrier enhancers that could be valuable in the prevention and treatment of mucosal diseases.
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