Robust Biopolymeric Supramolecular “Host−Guest Macromer” Hydrogels Reinforced by <i>in Situ</i> Formed Multivalent Nanoclusters for Cartilage Regeneration

Abstract

Biopolymer-based supramolecular hydrogels cross-linked by host–guest interactions are usually mechanically weak as shown in “inverted vials” instead of freestanding 3D constructs. Herein, we describe a novel host–guest macromer (HGM) approach for preparation of biopolymer-based freestanding supramolecular hydrogels. Host–guest macromers are formed by molecular self-assembly between adamantane-functionalized hyaluronic acid (AD x HA) guest polymers and monoacrylated β-cyclodextrins (mono-Ac-βCD) host monomers. Supramolecular hydrogels are readily prepared by UV-induced polymerization of the preassembled host–guest macromers. Such hydrogels are soely cross-linked by in situ formed multivalent host–guest nanoclusters and show significantly reinforced mechanical properties yet still retain desirable supramolecular features. They can self-heal and be remolded into freestanding 3D constructs which afford effective protection on the encapsulated stem cells during the compression remolding, making them promising carriers for therapeutic cells that can quickly adapt to and integrate with surrounding tissues of the targeted defects. We demonstrate that such hydrogels not only sustain extended release of encapsulated proteinaceous growth factors (TGF-β1) but also support chondrogenesis of the human mesenchymal stem cells (hMSCs) and promote cartilage regeneration in a rat model.