Robust Biopolymeric Supramolecular “Host−Guest\nMacromer” Hydrogels Reinforced by in Situ Formed\nMultivalent Nanoclusters for Cartilage Regeneration

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