Zwitterionic Hydrogel Coating with Antisediment Properties for Marine Antifouling Applications.

Biofouling is a serious issue affecting the marine industry because the attached micro- and macrocontaminants can increase fuel consumption and damage ship hulls. A hydrophilic hydrogel-based coating is considered a promising antifouling material because it is environmentally friendly and the dense hydration layer can protect the substrate from microbial attachment. However, sediment adsorption can be an issue for hydrogel-based coatings. Their natural soft and porous structures can trap sediment from the marine environment and weaken the antifouling capability. There is still little research on the antisediment properties of hydrogels, and none of them deal with this problem. Here, we report on optimizing zwitterionic hydrogel-based coatings to improve their antisediment properties and achieve comparable performance to commercial biocidal coatings, which are the gold standard in the antifouling coating area. After 1 week of sediment contamination and 2 weeks of diatom coculturing, this optimized zwitterionic hydrogel coating maintained its antifouling properties with a few diatoms on the surface. Its large-scale samples also achieved antifouling performance similar to that of biocidal coatings in the Atlantic Ocean for 1.5 months. More importantly, our research provides a universal strategy to improve the antisediment properties of soft hydrogel-based coatings. For the first time, we report that the introduction of interfacial electrostatic interactions enhanced the antisediment properties of hydrogels.

Exploring immune evasion of SARS-CoV-2 variants using a pseudotyped system.

In the United States, coronavirus disease 2019 (COVID-19) cases have consistently been linked to the prevailing variant XBB.1.5 of SARS-CoV-2 since late 2022. A system has been developed for producing and infecting cells with a pseudovirus (PsV) of SARS-CoV-2 to investigate the infection in a Biosafety Level 2 (BSL-2) laboratory. This system utilizes a lentiviral vector carrying ZsGreen1 and Firefly luciferase (Fluc) dual reporter genes, facilitating the analysis of experimental results. In addition, we have created a panel of PsV variants that depict both previous and presently circulating mutations found in circulating SARS-CoV-2 strains. A series of PsVs includes the prototype SARS-CoV-2, Delta B.1.617.2, BA.5, XBB.1, and XBB.1.5. To facilitate the study of infections caused by different variants of SARS-CoV-2 PsV, we have developed a HEK-293T cell line expressing mCherry and human angiotensin converting enzyme 2 (ACE2). To validate whether different SARS-CoV-2 PsV variants can be used for neutralization assays, we employed serum from rats immunized with the PF-D-Trimer protein vaccine to investigate its inhibitory effect on the infectivity of various SARS-CoV-2 PsV variants. According to our observations, the XBB variant, particularly XBB.1.5, exhibits stronger immune evasion capabilities than the prototype SARS-CoV-2, Delta B.1.617.2, and BA.5 PsV variants. Hence, utilizing the neutralization test, this study has the capability to forecast the effectiveness in preventing future SARS-CoV-2 variants infections.

Recent advances in oral insulin delivery technologies.

With the rise in diabetes mellitus cases worldwide, oral delivery of insulin is preferred over subcutaneous insulin administration due to its good patient compliance and non-invasiveness, simplicity, and versatility. However, oral insulin delivery is hampered by various gastrointestinal barriers that result in low drug bioavailability and insufficient therapeutic efficiency. Numerous strategies have been developed to overcome these barriers and increase the bioavailability of oral insulin. Yet, no commercial oral insulin product is available to address all clinical hurdles because of various substantial obstacles related to the structural organization and physiological function of the gastrointestinal tract. Herein, we discussed the significant physiological barriers (including chemical, enzymatic, and physical barriers) that hinder the transportation and absorption of orally delivered insulin. Then, we showcased recent significant and innovative advances in oral insulin delivery technologies. Finally, we concluded the review with remarks on future perspectives on oral insulin delivery technologies and potential challenges for forthcoming clinical translation of oral insulin delivery technologies.

An injectable and biodegradable zwitterionic gel for extending the longevity and performance of insulin infusion catheters.

Continuous subcutaneous insulin infusion (CSII) is an essential insulin replacement therapy in the management of diabetes. However, the longevity of clinical CSII is limited by skin complications, by impaired insulin absorption and by occlusions associated with the subcutaneous insertion of CSII catheters, which require replacement and rotation of the insertion site every few days. Here we show that a biodegradable zwitterionic gel covering the tip end of commercial off-the-shelf CSII catheters fully resolves early skin irritations, extends the longevity of catheters and improves the rate of insulin absorption (also with respect to conventional syringe-based subcutaneous injection) for longer than 6 months in diabetic mice, and by 11 days in diabetic minipigs (from 2 to 13 days, under standard CSII-wearing conditions of insulin pump therapy and in a continuous basal-plus-bolus-infusion setting). The implanted gel displayed anti-inflammatory and anti-foreign-body-reaction properties and promoted the local formation of new blood vessels. The gel is subcutaneously injected before the tip of catheter is inserted into it, and should be generally applicable to CSII catheters and other implantable devices.

Applications of cryostructures in the chromatographic separation of biomacromolecules.

Macroporous-interconnected cryostructures are prepared via cryoprocess approaches, where polymerization, crosslinking-polymerization, or even chain aggregation is primarily conducted at the sub-freezing temperature of the medium followed by thawing. Given their unique desirable properties, cryostructures have been studied as a stationary phase in chromatography to purify and separate proteins. The macroporous cryostructures with their highly interconnected large (10-100 µm) pores have various advantages, including the high surface area, sponge-like morphology, high elasticity, low-pressure drop, short diffusion path, and a temporary residence. In this review, we elaborate on the methods used in the preparation of cryostructures and the factors affecting their properties. We also highlight the underlying progress in chromatography techniques that take advantage of cryostructures as stationary phases for separating multiple biomacromolecules.

Seismic Performance of Precast Concrete Frame Beam-Column Connections with High-Strength Bars.

As the construction industry is striding towards the industrialization of green buildings, a precast concrete frame beam-column joint with high-strength reinforcement was proposed. Simulate reversed cyclic loading was carried out on two precast connections and one cast-in-place connection to examine the seismic behavior of the proposed new precast connection. The main test variables between the two precast connections were the strength of the reinforcement at the bottom of the beam. The failure shape, hysteresis curve, skeleton curve, strength, deformation ability, stiffness degradation, and energy dissipation were monitored and compared with the cast-in-place connection. The findings of this paper showed that the precast joints had good strength reserve, and the seismic performance in the later stage of loading even exceeds the cast-in-place joints. It was also found that the plastic hinge zone of the beam could be moved away from the column surface via reinforcement method. Additionally, based on the experiment, a detailed nonlinear finite element analysis (FEA) method was developed to reproduce the test response of specific types of bending moment-resistant precast concrete beam-column connections under a reversed loading test, which provided a theoretical reference for further research of the connections.

Combined treatment of xyloglucan derivative hydrogel and anti-C5a receptor antibody in preventing peritoneal adhesion.

Postoperative peritoneal adhesion is a common complication after surgery with high morbidity. In addition to improving surgical operations, medical therapy and physical barriers are the two main ways to prevent postoperative peritoneal adhesion. Satisfactory efficacy is not often obtained by the single antiadhesion method, and the combination of barrier therapy and antiadhesion drugs has attracted more attention. In this study, we first demonstrated that aberrant complement activation was associated with peritoneal injury and inflammatory responses. Correspondingly, blocking the C5a-C5aR axis reaction effectively reduced inflammatory reactions. Therefore, we creatively developed an integrated treatment of xyloglucan derivative (mXG) hydrogel and intravenous anti-C5a receptor antibody (anti-C5aRab) aimed at peritoneal adhesion, and then systematically evaluated the therapeutic efficacy using a sidewall defect-cecum abrasion model in mice. In vitro and in vivo experiments showed that the mXG hydrogel had good biocompatibility and degradability and could serve as a safe anti-adhesion barrier. The results showed that anti-C5aRab treatment could significantly inhibit peritoneal adhesions by reducing neutrophil infiltration and the expression of phosphorylated Smad2. Taken together, the mXG hydrogel integrated with anti-C5aRab showed superior antiadhesion performance and holds promising clinical applications in preventing peritoneal adhesion. STATEMENT OF SIGNIFICANCE: Postoperative peritoneal adhesion is an urgent problem to be solved after surgery. Previously, a biodegradable and thermoreversible xyloglucan derivative (mXG) hydrogel was developed that effectively prevented postoperative peritoneal adhesions, but obvious inflammatory responses and proliferation could still be observed. In addition, aberrant complement activation is associated with a variety of inflammatory diseases. We demonstrated that aberrant complement activation is involved in peritoneal adhesion. In this work, mXG hydrogel and intravenous anti-C5a receptor antibody (anti-C5aRab) were integrated to address peritoneal adhesions. The anti-C5aRab reduced the inflammatory responses. In addition, the mXG hydrogel was easy to use and effectively isolated the wound surface at the local injury site. Overall, this integrated treatment significantly improved the antiadhesion effect.

Biodegradable Zwitterionic Cream Gel for Effective Prevention of Postoperative Adhesion.

Postoperative peritoneal adhesions were frequent complications for almost any types of abdominal and pelvic surgery. This led to numerous medical problems and huge financial burden to the patients. Current anti-adhesion strategies focused mostly on physical barriers including films and hydrogels. However, they can only alleviate or reduce adhesions to certain level and their applying processes were far from ideal. This work reported the development of a biodegradable zwitterionic cream gel presenting a series of characters for an idea anti-adhesion material, including unique injectable yet malleable and self-supporting properties, which enabled an instant topical application, no curing, waiting or suturing, no hemostasis requirement, protein/cell resistance and biodegradability. The cream gel showed a major advancement in anti-adhesion efficacy by completely and reliably preventing a primary and a more severe recurrent adhesion in rat models.

Fouling-resistant zwitterionic polymers for complete prevention of postoperative adhesion.

Postoperative adhesions are most common issues for almost any types of abdominal and pelvic surgery, leading to adverse consequences. Pharmacological treatments and physical barrier devices are two main approaches to address postoperative adhesions but can only alleviate or reduce adhesions to some extent. There is an urgent need for a reliable approach to completely prevent postoperative adhesions and to significantly improve the clinical outcomes, which, however, is unmet with current technologies. Here we report that by applying a viscous, cream-like yet injectable zwitterionic polymer solution to the traumatized surface, postoperative adhesion was completely and reliably prevented in three clinically relevant but increasingly challenging models in rats. The success rate of full prevention is over 93% among 42 animals tested, which is a major leap in antiadhesion performance. Clinically used Interceed film can hardly prevent the adhesion in any of these models. Unlike current antiadhesion materials serving solely as physical barriers, the "nonfouling" zwitterionic polymer functioned as a protective layer for antiadhesion applications with the inherent benefit of resisting protein/cell adhesions. The nonfouling nature of the polymer prevented the absorption of fibronectins and fibroblasts, which contribute to the initial and late-stage development of the adhesion, respectively. This is the key working mechanism that differentiated our "complete prevention" approach from current underperforming antiadhesion materials. This work implies a safe, effective, and convenient way to fully prevent postoperative adhesions suffered by current surgical patients.

Zwitterionic micelles efficiently deliver oral insulin without opening tight junctions.

Oral delivery of protein drugs is considered a life-changing solution for patients who require regular needle injections. However, clinical translation of oral protein formulations has been hampered by inefficient penetration of drugs through the intestinal mucus and epithelial cell layer, leading to low absorption and bioavailability, and safety concerns owing to tight junction openings. Here we report a zwitterionic micelle platform featuring a virus-mimetic zwitterionic surface, a betaine side chain and an ultralow critical micelle concentration, enabling drug penetration through the mucus and efficient transporter-mediated epithelial absorption without the need for tight junction opening. This micelle platform was used to fabricate a prototype oral insulin formulation by encapsulating a freeze-dried powder of zwitterionic micelle insulin into an enteric-coated capsule. The biocompatible oral insulin formulation shows a high oral bioavailability of >40%, offers the possibility to fine tune insulin acting profiles and provides long-term safety, enabling the oral delivery of protein drugs.

Engineering and Application Perspectives on Designing an Antimicrobial Surface.

Infections, contaminations, and biofouling resulting from micro- and/or macro-organisms remained a prominent threat to the public health, food industry, and aqua-/marine-related applications. Considering environmental and drug resistance concerns as well as insufficient efficacy on biofilms associated with conventional disinfecting reagents, developing an antimicrobial surface potentially improved antimicrobial performance by directly working on the microbes surrounding the surface area. Here we provide an engineering perspective on the logic of choosing materials and strategies for designing antimicrobial surfaces, as well as an application perspective on their potential impacts. In particular, we analyze and discuss requirements and expectations for specific applications and provide insights on potential misconnection between the antimicrobial solution and its targeted applications. Given the high translational barrier for antimicrobial surfaces, future research would benefit from a comprehensive understanding of working mechanisms for potential materials/strategies, and challenges/requirements for a targeted application.

Tissue Response to Subcutaneous Infusion Catheter.

Insulin infusion pump, continuous glucose monitoring (CGM), and insulin infusion set (IIS) have been developed to be increasingly feasible for people with type 1 diabetes (T1D). Several recently approved CGMs are transitioning from 7-day to 10-day wear time without the need for fingerprick recalibration. Nevertheless, studies and improvements on IIS, a critical part of insulin pump therapy, have been limited. In particular, the recommended wear time of IIS is still 2-3 days, which can hardly match the current duration of CGM for potential closed-loop system development. It is generally believed that both the inserted catheter and the subsequent infused insulin drug could induce particular subcutaneous tissue response and skin-related complications at the infusion site. In certain cases, poor glycaemic control, increased risk of hypoglycemia, and serious cosmetic impact on people with diabetes were observed. Skin complication has also been attributed as an important factor resulting users to discontinue insulin pump therapy. This article provides the rare systematic review of IIS induced subcutaneous tissue responses and skin complications, including the impacts from the inserted catheters, the subcutaneous infused insulin, and the adhesive or tape used to immobilize the catheter. The FDA's recommendation for the frequency of IIS change was further discussed. Future studies on this topic are required to further understand the IIS-related problems, and future strategies could be developed accordingly to significantly reduce the incidence of these problems, extend the wear time, and increase the acceptance of insulin pump based therapy.

[Modeling of Abdominal Wall-Cecum Injury Adhesion and the Anti-adhesion Mechanism of mXG].

OBJECTIVE: To construct the adhesion model of abdominal wall-cecum injury and explore the prevention and treatment effect of modified xyloglucan (mXG) thermosensitive hydrogel on abdominal wall-cecal injury adhesion. METHODS: SD rats were used to construct the abdominal wall-cecal injury adhesion model. Model mice were randomly divided into blank control group (Control), commercial chitosan membrane Control group (Film) and mXG thermosensitive hydrogel group (Hydrogel), each group contained 16 rats.In the Hydrogel group, 1 mL 4% (m/V) mXG solution was smeared on the wound surface of abdominal wall and the cecum, then closed the abdomen after gel was formed (3 min).In the Film group, 2 cm×3 cm chitosan anti-adhesion Film was applied onto the wound surface of the abdominal wall before abdominal closure.In the Control group, 1 mL normal saline was applied onto the wound surface of abdominal wall and the cecum before abdominal closure.On 7 and 14 d after the operation, rats'abdominal cavity was opened by surgery to examine and score the adhesion grade between the abdominal wall and the cecum, with double-blind design.Meanwhile, the adhesion tissue or wound tissue was taken and stained by HE, Masson and Van Gieson to histological evaluate the anti-adhesion effect.The expression of transforming growth factor-ß1 (TGF-ß1) and connective tissue growth factor (CTGF) was determined by immunohistochemical staining as well. Another group of 12 SD rat models were subjected to mXG thermosensitive hydrogel intervention.At the 1 and 6 weeks postoperation, rats main organs such as heart, liver, spleen, lung and kidney were taken for histological examination with HE staining for the purpose of evaluation the toxicity of mXG in vivo. RESULTS: Adhesion grade evaluation results showed that Film group rats occurred mild adhesion, Control group rats occurred severe adhesion, while in Hydrogel group hardly rats occured adhesion, and the differences were statistically significant(P < 0.05). Histological results showed that the Hydrogel group rats recovered well at 7 d after surgery.In healing wound tissue, no mutated tissue was observed, but a certain degree of inflammatory cell infiltration was still existed. At 14 d after surgery, the inflammation cells in the wound were significantly reduced, and the healing tissue containing only a small amount of collagen fibers under the neonatal mesothelial layer.But the other two groups showed different degrees of adhesion at the 7 and 14 d post surgery.Immunohistochemical staining showed that the expression of TGF-ß1 and CTGF in the Hydrogel group were both weaker than those in the other groups, and the difference was statistically significant (P < 0.05). In vivo toxicity tests did not show significant changes in the structure of the organs of mXG gel intervention rats at different time points. CONCLUSION: mXG thermosensitive hydrogel plays a good role in physical isolation during the key period of adhesion formation and effectively prevent the occurrence of cecum-abdominal adhesion.

Biomaterial-tight junction interaction and potential impacts.

The active pharmaceutical ingredients (APIs) have to cross the natural barriers and get into the blood to impart the pharmacological effects. The tight junctions (TJs) between the epithelial cells serve as the major selectively permeable barriers and control the paracellular transport of the majority of hydrophilic drugs, in particular, peptides and proteins. TJs perfectly balance the targeted transport and the exclusion of other unexpected pathogens under the normal conditions. Many biomaterials have shown the capability to open the TJs and improve the oral bioavailability and targeting efficacy of the APIs. Nevertheless, there is limited understanding of the biomaterial-TJ interactions. The opening of the TJs further poses the risk of autoimmune diseases and infections. This review article summarizes the most updated literature and presents insights into the TJ structure, the biomaterial-TJ interaction mechanism, the benefits and drawbacks of TJ disruption, and methods for evaluating such interactions.

Strategies to improve micelle stability for drug delivery.

Micelles have been studied as drug delivery carriers for decades. Their use can potentially result in high drug accumulation at the target site through the enhanced permeability and retention effect. Nevertheless, the lack of stability of micelles in the physiological environment limits their efficacy as a drug carrier. In particular, micelles tend to disassociate and prematurely release the encapsulated drugs, lowering delivery efficacy and creating toxicity concerns. Many efforts to enhance the stability of micelles have focused mainly on decreasing the critical micelle forming concentration and improving blood circulation. Herein, we review different strategies including crosslinking and non-crosslinking approaches designed to stabilize micelles and offer perspectives on future research directions.

Thermoresponsive polysaccharide-based composite hydrogel with antibacterial and healing-promoting activities for preventing recurrent adhesion after adhesiolysis.

Postoperative adhesions are very common complications after general abdominal surgery. Although adhesiolysis has been proven effective in eliminating the preexisting adhesions, the new trauma caused by surgical lysis can induce recurrent adhesion. The prevention of recurrent adhesion after adhesiolysis is more difficult because the injury is more severe and adhesion mechanism is more complicated compared with the primary adhesion. In this study, a thermoresponsive hydrogel contained galactose modified xyloglucan (mXG) and hydroxybutyl chitosan (HBC) was developed as a barrier device for recurrent adhesion prevention after adhesiolysis due to its injectability and spontaneous gelling behaviors at the body temperature without any chemical reactions or extra driving factors. First, mXG and HBC were synthesized via enzymatic modification and etherification reaction, respectively. Rheological measurements indicated that the mXG/HBC composite system showed excellent thermosensitivity properties, and their gelation temperature and time can be modulated via adjusting the mXG/HBC ratio. Moreover, the mXG/HBC hydrogel exhibited excellent cytocompatibility and hemocompatibility in vitro. Furthermore, the mXG/HBC hydrogel could promote wound healing in the rat skin wound model. Finally, the efficacy of the mXG/HBC composite hydrogel in the prevention of recurrent adhesion was evaluated in a more rigorous rat repeated-injury adhesion model. The results demonstrated that the composite hydrogel could not only effectively prevent recurrent adhesion after adhesiolysis, but also promote wound healing and reduce scare formation. These results suggested that the mXG/HBC composite hydrogel may be a promising candidate as an injectable anti-adhesion system for clinical applications. STATEMENT OF SIGNIFICANCE: Although adhesiolysis has been proven effective in eliminating the preexisting adhesions, the new trauma caused by surgical lysis can induce recurrent adhesion. So far, most of the existing barrier systems and pharmacological approaches were developed for primary adhesion prevention while few attention has paid on prevention of recurrent adhesion after adhesiolysis. In the present study, we developed a thermoresponsive polysaccharide-based composite hydrogel by simple mixing galactose modified xyloglucan (mXG) and hydroxybutyl chitosan (HBC). The resulting mXG/HBC composite hydrogel not only was easy to handle and highly effective in preventing the recurrent adhesion after adhesiolysis, but also could promote wound healing and reduce scare formation. Our study provide an effective anti-adhesion system for preventing recurrent adhesion after adhesiolysis.

Engineering Polyzwitterion and Polydopamine Decorated Doxorubicin-Loaded Mesoporous Silica Nanoparticles as a pH-Sensitive Drug Delivery.

Multifunctional drug carriers have great applications in biomedical field. In this study, we introduced both polydopamine (PDA) and zwitterionic polymer of poly(3-(3-methacrylamidopropyl-(dimethyl)-ammonio)propane-1-sulfonate) (PSPP) onto the surface of mesoporous silica nanoparticles (MSNs) to develop a novel nanoparticle (MSNs@PDA-PSPP), which was employed as a new kind of drug carrier for the delivery of doxorubicin (DOX). The PDA coating, as a gatekeeper, could endow the drug carrier with pH-sensitive drug release performance. The outermost PSPP layer would make the drug carrier possess protein resistance performance. The chemical structure and properties were characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), dynamic light scattering (DLS) and thermogravimetric analysis (TGA). MSNs@PDA-PSPP could keep good colloidal stability within 72 h in phosphate buffered saline (PBS) and protein solutions. Meanwhile, MSNs@PDA-PSPP exhibited a high drug loading for DOX. In vitro drug release experiments suggested MSNs-DOX@PDA-PSPP exhibited pH-dependent drug release behaviors. Besides, MSNs@PDA-PSPP had no cytotoxicity to human hepatocellular carcinoma cells (HepG2 cells) even at a concentration of 125 µg/mL. More importantly, cellular uptake and in vitro anticancer activity tests suggested that MSNs-DOX@PDA-PSPP could be taken up by HepG2 cells and DOX could be successfully released and delivered into the cell nuclei. Taken together, MSNs@PDA-PSPP have great potential in the biomedical field.

Micelles with ultralow critical micelle concentration as carriers for drug delivery.

Conventional micellar carriers disassemble into free surfactants when diluted at concentrations below the critical micelle concentration (CMC). This limits the bioavailability in vivo of injected hydrophobic drugs encapsulated in micellar systems. Here, we show that a micelle comprising a superhydrophilic zwitterionic polymer domain and a superhydrophobic lipid domain has an undetectable CMC below 10-6 mM-a value that is orders of magnitude lower than the CMCs (>10-3 mM) of typical micellar systems. We also show that zwitterionic moieties or zwitterionic polymers added to a micelle solution stabilize the micelles at concentrations below their inherent CMC. In a mouse model of melanoma, ultralow-CMC micelles encapsulating docetaxel led to the complete eradication of tumours, whereas conventional docetaxel micellar formulations did not reverse tumour growth. Ultralow-CMC micelles might become next-generation carriers for drug delivery.

Engineering pectin-based hollow nanocapsules for delivery of anticancer drug.

Multifunctional capsules have great applications in biomedical fields. In this study, novel polysaccharide-based nanocapsules were prepared via a layer-by-layer technique using silica as the templates. The shell was constructed based on the electrostatic interactions between pectin and chitosan. The pectin-chitosan nanocapsules ((Pec/Cs)3Pec) could keep good colloidal stability within 96h in PBS solution and 48h in BSA solution. Meanwhile, the nanocapsules exhibited a high drug loading and pH-sensitive release property for doxorubicin hydrochloride. Moreover, (Pec/Cs)3Pec nanocapsules had no cytotoxicity to both human hepatocellular carcinoma cells (HepG2 cells) and mouse fibroblast cells (L929 cells). More importantly, (Pec/Cs)3Pec nanocapsules could be more easily uptaken by HepG2 cells when compared with L929 cells. In vitro anticancer activity tests indicated the carriers could effectively kill HepG2 cells. Overall, (Pec/Cs)3Pec nanocapsules have great potential as a novel anticancer drug carrier as a result of their pH-sensitivity, good colloidal stability and anticancer activity.