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.

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.

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.

There is considerable interest in the cryopreservation in 3D cell culture, as structurally preserving intact cells and tissues is critical in utilizing these systems to promote cell differentiation and tissue organization. Temperatureresponsive physical gels and zwitterionic polymers are useful materials as 3D scaffolds for cell culture which may also provide cryoprotection to the composite cells. Nevertheless, there has been a lack of relevant data for polymer systems that have both of these properties. In this study, highly biocompatible triblock copolymers were examined for their effectiveness both as gelators and as cryo-protectants. The triblock copolymers were synthesized with 2-methacryloyloxyethyl phosphorylcholine (MPC) and di(ethylene glycol) methyl ether methacrylate (DEGMA) via atom transfer radical polymerization (PDEGMA 113 -b-PMPC 243 -b-PDEGMA 113 ). ABA triblock copolymers composed of hydrophilic "B" block and temperature responsive "A" block could form physical gels above their lower critical solution temperatures (LCST). PDEGMA 113 -b-PMPC 243 -b-PDEGMA 113 triblock copolymer exhibited the LCST derived from DEGMA and assembled in micellar structures forming physical gels above the LCST. The mechanical properties of the physical gels were evaluated by rheological tests, and the low toxicity of PDEGMA 113 -b-PMPC 243 -b-PDEGMA 113 was confirmed by MTT assay. Interestingly, the triblock copolymer showed ice recrystallization inhibition (IRI) activity which was determined to be suitable for the cryopreservation of several cell lines. In vitro studies were conducted to demonstrate the cryo-protectant properties and the formation of two and three-dimensional (2D/3D) cell culture scaffolds with high biocompatibility. This stimuli-responsive gelator polymers can therefore be useful for cryopreservation of different cells models, and a promising material for 3D cell culture.

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.

Biological tissues are capable of stiffening and self-healing as they are strained or damaged in order to preserve their integrity and functionalities. However, mimicking both strain-stiffening and selfhealing functions of biological tissues in biocompatible flexible hydrogels remains a challenge. Here, we report a flexible hydrogel constructed by two biocompatible polymers, which can smartly adopt biological strainstiffening or self-healing strategy to maintain the structural integrity and functionalities in response to mechanical deformation. The hydrogel can be reversibly and repeatedly stiffened up to eight times of its original modulus as it is strained, without showing mechanical hysteresis. Besides, the damaged hydrogel can repeatedly self-heal within seconds and fully retains the strain-stiffening capability. In addition, benefitting from the excellent biocompatibility and dynamic nature, the biomimetic hydrogel can be facilely applied for 3D cell encapsulation. This work provides novel insights into the molecular design of tissue-like self-protective soft materials, which may also inspire the development of biomimetic cell culture matrices, artificial tissues, as well as soft machines and robotics for various biomedical and engineering applications.

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.