Boronic ester, one typical example of dynamic covalent bonds, has presented great potential to prepare selfhealing hydrogels. However, most of currently reported hydrogels based on boronic esters are formed at pH > 8, which impeded their further use in physiological conditions. In this study, we designed two kinds of zwitterionic copolymers with benzoxaborole and catechol pendant groups, respectively. Owing to the lower pK a value of benzoxaborole (7.2), gelation can happen easily at pH 7.4 PBS after mixing these two copolymers due to efficient formation of benzoxaborole-catechol complexations. The resulting hydrogels exhibited excellent self-healing property as well as dual pH/sugar responsiveness due to the dynamic nature of boronic ester. Moreover, benefiting from the cell membrane bioinspired 2-methacryloyloxyethyl phosphorylcholine (MPC)based polymeric matrix, the hydrogel was further investigated for 3D cell encapsulation. The combination of biocompatible zwitterionic polymers with dynamic benzoxaborole-catechol complexation makes the hydrogels a promising platform for diverse potential bioapplications like drug delivery and tissue engineering.

The use of click chemistry as a hydrogel cross-linking reaction is often limited by slow reaction rates and harsh conditions, such as exposure to UV light and/or use of nonspecific or toxic reagents. On the other hand, the process of boronic ester formation between arylboronic acids and diols suffers from its intrinsic reversibility and low binding affinity at low pH, which impede its potential in many biomedical applications where a fast and stable click reaction is needed. Herein, we report a new concept of click hydrogel fabrication that combines a traditional sugar-based boronic ester and a novel nopoldiol-based benzoxaborolate as a dual-crosslink network (DCN) system. The cooperation of dynamic and rigid networks and the unique sensitivity of benzoxaborolate cross-links toward stimulus provide an intelligent hydrogel with a set of interesting features: (i) catalyst/light-free nopoldiol–benzoxaborolate bioorthogonal click cross-linking, (ii) rapid in situ formation within 26 s, (iii) wide self-healing pH range from 8.5 to 1.5, (iv) exceptional stability under acidic condition and polyol solutions, (v) reactive oxygen species/pH-responsive degradation, (vi) pH-responsive drug release, and (vii) capability for viable cell encapsulation. The complementary click partners, a rigid diol monomer [1R)-(−)-nopol-methacrylamido-diol (nopoldiol)] and a benzoxaborole-based monomer [5-methacrylamido-1,2-benzoxaborole (MAAmBO)], can be easily incorporated into a variety of synthetic polymers through free-radical polymerization with poly­(ethylene glycol) methyl ether methacrylate (PEGMA) as the backbone component. The shortened gelation time, improved mechanical properties, and excellent self-healing properties of the resulting DCN hydrogel PBNG were evaluated through rheological measurements. The stability/degradation of PBNG under low pH buffer and H2O2 were monitored via hydrogel weight changes, and the potential of PBNG as a drug-releasing carrier was assessed by the pH-responsive release of doxorubicin. Finally, HeLa cells were successfully encapsulated and cultured in the 3D network to confirm the hydrogel’s biocompatibility as a cell culture scaffold. The nontoxic components and their fast click reaction under mild conditions make the nopoldiol–benzoxaborolate click hydrogels promising candidates for future biomedical applications such as gene delivery, cell therapy, and tissue engineering.

Hydrogels that are injectable, self-healing, and multiresponsive are becoming increasingly relevant for a wide range of applications. In this work, we have successfully developed a novel approach in the fabrication of smart hydrogels with all the above properties. A symmetrical ABA triblock copolymer was first synthesized via atom transfer radical polymerization with a temperature responsive middle block and two permanently hydrophilic glycopolymer chains on both ends. Hydrogels were subsequently constructed by mixing the triblock copolymer with another linear hydrophilic copolymer bearing benzoxaborole groups. The interactions of the benzoxaborole groups with the sugar hydroxyl groups allowed the formation of dynamic covalent bonds. The resulting hydrogels exhibited temperature, pH, and sugar responsiveness. Rheological studies confirmed that the mechanical property can be tuned by changing the pH as well as the galactose/ benzoxaborole molar ratio. Furthermore, the hydrogels showed excellent self-healing ability and shear-thinning performance due to the inherent well-known dynamic covalent bonds of boronic esters. Therefore, these types of hydrogels can have excellent biomedical applications.

Developing effective internal wound dressing materials is important for postoperative tissue regeneration while remains a challenge due to the poor biological environment-adaptability of conventional materials. Here, we report an example of injectable self-healing hydrogel based on gastric environment-adaptive supramolecular assembly, and have explored its application for gastric perforation healing. By leveraging the gastric environment-modulated supramolecular interactions, the self-assembled hydrogel network is orchestrated with sensitive thermo-responsibility, injectability, printability and rapid self-healing capability. The hydrogel dressing can effectively inhibit the attachment of microorganisms and demonstrates outstanding antibiofouling property. In vivo rat model further demonstrates the as-prepared hydrogel dressing simplifies the surgical procedures, reduces postoperative complications as well as enhances the healing process of gastric perforation compared with the conventional treatment. This work provides useful insights into the development of biological environment-adaptive functional materials for various biomedical applications.

The capability to slow ice growth and recrystallization is compulsory in the cryopreservation of cells and tissues to avoid injuries associated with the physical and chemical responses of freezing and thawing. Cryoprotective agents (CPAs) have been used to restrain cryoinjury and improve cell survival, but some of these compounds pose greater risks for the clinical application of cryopreserved cells due to their inherent toxicity. Trehalose is known for its unique physicochemical properties and its interaction with the phospholipids of the plasma membrane, which can reduce cell osmotic stress and stabilized the cryopreserved cells. Nonetheless, there has been a shortage of relevant studies on the synthesis of trehalose-based CPAs. We hereby report the synthesis and evaluation of a trehalose-based polymer and hydrogel and its use as a cryoprotectant and three-dimensional (3D) cell scaffold for cell encapsulation and organoid production. In vitro cytotoxicity studies with the trehalose-based polymers (poly­(Tre-ECH)) demonstrated biocompatibility up to 100 mg/mL. High post-thaw cell membrane integrity and post-thaw cell plating efficiencies were achieved after 24 h of incubation with skin fibroblast, HeLa (cervical), and PC3 (prostate) cancer cell lines under both controlled-rate and ultrarapid freezing protocols. Differential scanning calorimetry and a splat cooling assay for the determination of ice recrystallization inhibition activity corroborated the unique properties of these trehalose-based polyethers as cryoprotectants. Furthermore, the ability to form hydrogels as 3D cell scaffolds encourages the use of these novel polymers in the development of cell organoids and cryopreservation platforms.

The development and application of natural antibacterial materials have always been the focus of biomedical research. Borneol as a natural antibacterial compound has received extensive attention. However, the hydrophobicity caused by its unique structure limits its application range to a certain extent. In this study, we combine zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) with a complex bicyclic monoterpene structure borneol compound and prepare an excellent antifouling and antibacterial surface via the Schiff-base bond. The prepared coating has excellent hydrophilicity verified by the contact angle (CA), and its polymer layer is confirmed by X-ray photoelectron spectroscopy (XPS). The zwitterion MPC and borneol moieties in the copolymer play a coordinating role, relying on super hydration and the special stereochemical structure to prevent protein adsorption and inhibit bacterial adhesion, respectively, which are demonstrated by bovine serum albumin (BSA) adsorption and antibacterial activity test. Moreover, the water-soluble borneol derivative as the antibacterial surfaces we designed here was biocompatible toward MRC-5 (lung fibroblasts), as showed by in vitro cytotoxicity assays. Such results indicate the potential application of the as-prepared hydrophilic surfaces in the biomedical materials.

Strong signaling cascades derived from upregulation and overexpression of growth factors such as the EGF-family (epidermal growth factors) have been crucially related to cancer pathogenesis. Gene silencing techniques to modulate the expression of oncogenes and tumor suppresor genes are a strategy that shows great promise for cancer management but still faces some limitations in the design of biocompatible and effective vectors. In this study, we synthesized, by reversible addition-fragmentation chain transfer (RAFT) polymerization, several acid degradable galactose-based hyperbranched cationic polymers with varying molecular weights (10 to 20 kDa) and compositions with 2-lactobioamidoethyl methacrylamide [LAEMA] and 2-aminoethyl methacrylamide hydrochloride [AEMA] at different ratios (2.0, 1.0, and 0.5). These polymers were then evaluated for their ability to enhance Epidermal Growth Factor Receptor (EGFR) knockdown in cervical carcinoma. All the polymer constructs have enhanced capabilities to condensate siRNA (small interfering RNA), showing low toxicity at higher LAEMA:AEMA ratios (1.0 and 2.0). Western blot assays were conducted to quantify the EGFR expression of each treatment group demonstrating superior gene knockdown efficiency for the polymers having a LAEMA:AEMA ratio of 2.0 than the lower ratio counterparts; while maintaining low toxicity levels. Gene silencing of EGFR of up to 60% was achieved with acid degradable polymers having 10 kDa molecular weight and a LAEMA:AEMA ratio of 2.0. The superior stability of the polyplexes under physiological conditions and the low cytotoxicity observed in the 48 h post-transfection demonstrated the high potential of these acid degradable galactose-based hyperbranched cationic polymers for EGFR silencing treatment applications at the clinical level.

Injectable hydrogels have become a promising material for biomedical engineering applications, but microbial infection remains a common challenge in their application. In this study, we presented an injectable antibacterial hydrogel with self-healing property based on a dual cross-linking network structure of dynamic benzoxaborole−sugar and quadruple hydrogen bonds of the 2-ureido-4-pyrimidone (UPy) moieties at physiological pH. Dynamic rheological experiments demonstrated the gelatinous behavior of the double cross-linking network (storage modulus G′ > loss modulus G″), and the modulus showed frequency-dependent behavior. The noncovalent interactions of UPy units in the polymer segment endowed the injectable hydrogels with good mechanical strength. By varying the solid contents, UPy units, as well as the pH, the mechanical properties of hydrogels could be controlled. Additionally, the hydrogels exhibited not only excellent selfhealing and injectable properties but also pH and sugar dual-responsiveness. Moreover, the hydrogels could effectively inhibit the growth of both Escherichia coli and Staphylococcus aureus while exhibiting low toxicity. 3D cell encapsulation experiment results also demonstrated the potential use of these hydrogels as cell culture scaffolds. Taken together, the injectability, self-healing, and antimicrobial properties of the prepared hydrogels showed great promise for translational medicine, such as cell and tissue engineering applications.