Elucidation of Structure–Function Relationships of Hyaluronic Acid-Based Polymers via Combinatorial Approaches

Abstract

Hydrogels have been identified as biomaterials of significant interest owing to their unique properties─hydrophilic structures, high degree of structural flexibility, low toxicity, biocompatibility─that qualify them as ideal candidates in a wide range of biomedical and pharmaceutical applications from wound dressing surface coatings, to drug delivery composites, and tissue scaffolds. However, such desired properties of hydrogels simultaneously endow these materials with inherent shortcomings that have hindered their prolific implementation in even more industrial applications; specifically, hydrogels suffer from low mechanical stability and loss of native function upon exposure to industrial solvents. One proposed technique to overcome these challenges and thus functionalize hydrogels to increased their wider range of industrial applications is their chemical modification to elicit controllable changes in their structure and function to thus fulfill the user-defined end goal. The chemical modification strategy further drives the need for an in-depth understanding of the physical and chemical phenomena that control the assembly of modified biopolymers and thus determine their functionality. We hypothesize that a combinatorial approach employing both molecular dynamics (MD) simulations and analytical techniques could be used to probe the self-assembly of alkyl chain-modified hyaluronic acid (HYA)─model biopolymer chosen for its hydrophilicity, relative abundance, biocompatibility, and periodic carboxylate reactive group─and thus will allow us to control the assembly dynamics and its end structure properties when alkyl-chain-modified HYA networks are to be constructed, especially porosity, average pore aperture size, and accessible surface area. For this purpose, modified HYA chains were synthesized via (1)-ethyl-3-(3-dimethylaminopropyl) carbodiimide chloride (EDC)-mediated amine group attachment of dodecylamine to the periodic carboxylate group onto the HYA backbone. Material characterization including Fourier transform infrared spectroscopy, nuclear magnetic resonance, and thermogravimetric analysis was conducted to confirm the expected EDC reaction chemistry and further assess the water uptake capacity of the resulting modified hydrogels. MD simulations of both unmodified HYA and modified HYA chains─with varied lengths of attached alkyl groups as well as varied degrees of alkyl group substitution on the HYA backbone─were carried out to analyze the self-assembly dynamics of such chains and thus determine how differences in chemical modification eventuate the critical differences in the end structure properties of the resulting networks. Our findings demonstrate that targeted, atomic-level investigation and corroborated analytical analyses of the assembly of chemically modified hydrogels are necessary to develop the next generation of fully optimized biomaterials that have extended applicability in industrial settings.