No abstract

No abstract

Boronic ester hydrogels have been widely used in biomedical fields for their stimuli responsiveness to multiple disease-related triggers. However, the restricted pH for gelation and the poor hydrolysis stability limit their application in variable physiological microenvironments. Here, we report a modular conjugation method for designing internal boron−nitrogen coordinated boronic ester (IBNCB) hydrogels by constructing polymers with phenylboronic acid or N,N-bis(2-hydroxyethyl) moieties based on amides. Eight distinct IBNCB hydrogel models composed of polymer/polymer or polymer/micromolecule were prepared, exhibiting a unique pH responsiveness in the alkaline environment, an enhanced hydrolysis stability, bidirectional pHtunable mechanical properties, and a lowered and tunable pH for gelation. In addition, the IBNCB hydrogels maintained a sol−gel transitional responsiveness to reactive oxygen species (ROS), glucose, and temperature. Especially, we found that the pH required to form an ideal IBNCB hydrogel should be greater than the pK a of phenylboronic acid but lower than the pK a of N,N-bis(2hydroxyethyl), and reducing the pK a of phenylboronic acid could lower the gelation pH. The pK a of the tertiary amine in N,N-bis(2hydroxyethyl) was shown to be important in the creation of the B−N coordination bond, which influenced the formation of the IBNCB bond. Finally, we explored the effect of the main chain's charge on gelability and proposed the dynamic equilibrium mechanism of IBNCB bonds in the hydrogel. We expect that the multi-stimuli-responsive IBNCB hydrogels will provide a new strategy for designing smart materials sensitive to physicochemical signals. Furthermore, the amide-based modular conjugation could be exploited to generate a theoretically limitless number of novel IBNCB materials including microgels, polymer vesicles, and micro−nano particles.

Osteochondral defect (OCD) regeneration remains challenging because of the hierarchy of the native tissue including both the articular cartilage and the subchondral bone. Constructing an osteochondral scaffold with biomimetic composition, structure, and biological functionality is the key to achieve its high-quality repair. In the present study, an injectable and 3D printable bilayered osteochondral hydrogel based on compositional gradient of methacrylated sodium alginate, gelatin methacryloyl, and 𝜷-tricalcium phosphate (𝜷-TCP), as well as the biochemical gradient of kartogenin (KGN) in the two well-integrated zones of chondral layer hydrogel (CLH) and osseous layer hydrogel (OLH) is developed. In vitro and subcutaneous in vivo evaluations reveal that apart from the chondrogenesis of the embedded bone mesenchymal stem cells induced by CLH with a high concentration of KGN, a low concentration of KGN with 𝜷-TCP in the OLH synergistically achieves superior osteogenic differentiation by endochondral ossification, instead of the intramembranous ossification using OLH with only 𝜷-TCP. The biomimetic construct leveraging KGN as the only biochemical inducer can facilitate cartilage and subchondral bone restoration in the in vivo osteochondral defect. This one-stone-two-birds strategy opens up a new facile approach for OCD regeneration by exploiting the biological functions of the bioactive drug molecule KGN.

Partial-thickness cartilage defects (PTCDs) of the articular surface is the most common problem in cartilage degeneration, and also one of the main pathogenesis of osteoarthritis (OA). Due to the lack of a clear diagnosis, the symptoms are often more severe when full-thickness cartilage defect (FTCDs) is present. In contrast to FTCDs and osteochondral defects (OCDs), PTCDs does not injure the subchondral bone, there is no blood supply and bone marrow exudation, and the nearby microenvironment is unsuitable for stem cells adhesion, which completely loses the ability of self-repair. Some clinical studies have shown that partial-thickness cartilage defects is as harmful as full-thickness cartilage defects. Due to the poor effect of conservative treatment, the destructive surgical treatment is not suitable for the treatment of partial-thickness cartilage defects, and the current tissue engineering strategies are not effective, so it is urgent to develop novel strategies or treatment methods to repair PTCDs. In recent years, with the interdisciplinary development of bioscience, mechanics, material science and engineering, many discoveries have been made in the repair of PTCDs. This article reviews the current status and research progress in the treatment of PTCDs from the aspects of diagnosis and modeling of PTCDs, drug therapy, tissue transplantation repair technology and tissue engineering (“bottom-up”).