Diels−Alder Click Cross-Linked Hyaluronic Acid Hydrogels for Tissue Engineering

TLDR

Hyaluronic acid is a promising polymer for tissue engineering, yet existing cross‑linking chemistries often require toxic coupling agents, catalysts, or multi‑step syntheses that increase system complexity. The study aims to develop a simpler, one‑step, aqueous Diels‑Alder click cross‑linking system for HA hydrogels. Furan‑modified HA was cross‑linked with dimaleimide‑functionalized PEG, and adjusting the furan‑to‑maleimide molar ratio allowed tuning of the hydrogels’ mechanical strength and degradation rate. Rheological and degradation tests confirmed the Diels‑Alder reaction as an effective, cytocompatible cross‑linking method, indicating the hydrogels’ potential for soft tissue engineering.

Abstract

Hyaluronic acid (HA) is a naturally occurring polymer that holds considerable promise for tissue engineering applications. Current cross-linking chemistries often require a coupling agent, catalyst, or photoinitiator, which may be cytotoxic, or involve a multistep synthesis of functionalized-HA, increasing the complexity of the system. With the goal of designing a simpler one-step, aqueous-based cross-linking system, we synthesized HA hydrogels via Diels−Alder "click" chemistry. Furan-modified HA derivatives were synthesized and cross-linked via dimaleimide poly(ethylene glycol). By controlling the furan to maleimide molar ratio, both the mechanical and degradation properties of the resulting Diels−Alder cross-linked hydrogels can be tuned. Rheological and degradation studies demonstrate that the Diels−Alder click reaction is a suitable cross-linking method for HA. These HA cross-linked hydrogels were shown to be cytocompatible and may represent a promising material for soft tissue engineering.