Blended and Microparticle Composite Hyaluronan Hydrogels with Programmable Degradation through Selective Oxidation

The design space of hydrogels for biomedical applications embraces a wide variety of parameters that can be tuned through chemical modification. Among them, tissue adhesion and viscoelastic properties contribute to the integration of tissue-engineered constructs with native tissues, while the degradation profile determines their temporal evolution and cell invasion. Selective 1,2-diol oxidation is a versatile tool to control all of these properties in polysaccharide-based hydrogels by generating aldehyde groups. A key challenge in implementing this tool is that although aldehyde groups improved adhesion, they also promoted chain fragmentation, demanding a trade-off. To address this, we devised a strategy that leverages the adhesiveness of oxidized biopolymers together with the mechanical stability of their nonoxidized counterparts. Here, we synthesized tyramine-modified hyaluronan (THA) and its oxidized form (oTHA) and evaluated their degradation and adhesion in various combinations and formats, including <i>blended hydrogels</i> and <i>hydrogel microparticle composite</i> networks. As the degree of oxidation increased in oTHA, its molecular weight decreased, the storage modulus of the resulting hydrogels slightly declined, brittleness increased, and physical degradation accelerated. These opposing properties were finely offset in two-component blended hydrogels; increasing the oTHA content proportionally accelerated the degradation rate in both bulk and hydrogel microparticle composite formats while maintaining consistent viscoelastic properties and network topology at a fixed total polymer concentration. By adjusting the oTHA-to-THA ratio, we generated composite hydrogels with two distinct degradation behaviors: (i) <i>collapse-type mode</i>, where <i>blended hydrogels</i> gradually softened and spread without fragmenting; and (ii) <i>fragmentation-type mode</i>, where <i>hydrogel microparticle composites</i> abruptly broke into discrete pieces over degradation time. This tunability enables the design of a new class of composite soft biomaterials with programmable degradation. Such materials show potential for tunable tissue engineering strategies, which could be implemented for controlling cell invasion, migration, and proliferation in biological applications.