Injectable spontaneously formed asymmetric adhesive hydrogel with controllable removal for wound healing.

Healing large-scale wounds has been a long-standing challenge in the field of biomedicine. Herein, we propose an injectable oxidated sodium alginate/gelatin/3,3'-dithiobis(propionic hydrazide)-aurum (Alg-CHO/gelatin/DTPH-Au) hydrogel filler with asymmetric adhesion ability and removability, which is formed by the Schiff-base reaction between aldehyde-based sodium alginate and multi-amino crosslinkers (gelatin and DTPH), combined with the coordination interaction between Au nanoparticles and disulfide bond of DTPH. Consequently, the prepared Alg-CHO/gelatin/DTPH-Au hydrogel exhibits high mechanical properties and injectable behaviors owing to its multiple-crosslinked interactions. Moreover, because various types of interaction bonding form on the contact side with the tissue, denser crosslinking of the upper layer relative to the lower layer occurs. Combined with the temperature difference between the upper and lower surfaces, this results in asymmetric adhesive properties. Owing to the photothermal effect, the reversible coordination interaction between Au nanoparticles and DTPH and the change in the triple helix structure of gelatin to a coil structure impart the filler-phased removability and antibacterial ability. The choice of all natural polymers also allows for favorable degradability of the wound filler and outstanding biocompatibility. Based on these features, this versatile wound filler can achieve a wide range of applications in the field of all-skin wound repair.

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.

Facile preparation of a thermosensitive and antibiofouling physically crosslinked hydrogel/powder for wound healing.

To improve the therapeutic effect of a hydrogel on damaged tissue, a series of hydroxybutyl chitosan (HBC) and poly(sulfobetaine methacrylate) (PSBMA) composite hydrogels (HBC-PSB) with thermosensitivity, self-healing, antibiofouling, and synergistic antibacterial activity are prepared by mechanical blending. The electrostatic interaction among PSBMA and hydrophobic association among HBC are the main drive force to form a full physically crosslinked hydrogel. HBC can avoid the aggregation and precipitation of PSBMA caused by intermolecular strong association. Meanwhile, the existence of the PSBMA network can promote the sol-gel transition of HBC. Due to the reversible physical crosslinking, the HBC-PSB hydrogel shows excellent self-healing behaviors, and can be stored as dry powder. Intriguingly, the composite hydrogel has good synergistic antibacterial performance via the anti-protein adhesion ability of the PSBMA network and bactericidal ability of the HBC network. Based on these results, a sidewall defect-cecum abrasion model and an infected full-thickness skin defect model are used to investigate the application of the prepared HBC-PSB hydrogel in postoperative anti-adhesion and healing of infected wounds, respectively. The results suggest that the HBC-PSB hydrogel can completely cover the irregular damaged tissue surface, moreover, it can effectively decrease the formation of postoperative adhesion and improve the healing speed of infected wounds via reducing the adhesion and growth of bacteria. Overall, we propose that the HBC-PSB hydrogel is a promising candidate in biomedical applications.

Fully physically crosslinked pectin-based hydrogel with high stretchability and toughness for biomedical application.

Hydrogels derived from natural polymers have been extensively investigated in the biomedical field, while inherent brittleness and poor stability limit their applications. In this study, a tough pectin-Fe3+/poly (acrylamide-co-stearyl methacrylate) (P(AAm-co-SMA)) double physical crosslinking (DPC) network hydrogel is prepared using a three-step method. The first HPAAm network is formed via hydrophobic associations among the PSMA segment in P(AAm-co-SMA), and trivalent ions (Fe3+) crosslinked pectin network as the second network. Due to the reversibility of dual physical cross-linking structures, the pectin-Fe3+/HPAAm hydrogel exhibit excellent toughness (1.04-11.20 MJ m-3). In addition, the pectin-Fe3+/HPAAm DPC hydrogels have tunable mechanical properties (tensile strength: 0.97-1.61 MPa, elongation: 133-1346%, elastic modulus: 0.30-2.20 MPa) via adjusting the ratio of pectin network and HPAAm network. To explore their potential application in tissue engineering, ATDC5 chondrocytes were seeded on the prepared DPC hydrogels. Results suggest that the pectin-Fe3+/HPAAm DPC hydrogels can support the adhesion and proliferation of ATDC5, moreover, the ATDC5 cells can penetrate into the hydrogel. It is concluded that the prepared hydrogels exhibit potential application in the load-bearing tissue repair field.

[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.

Biodegradable and injectable thermoreversible xyloglucan based hydrogel for prevention of postoperative adhesion.

Peritoneal adhesion is very common after abdominal and pelvic surgery, which leads to a variety of severe complications. Although numerous pharmacological treatments and barrier-based devices have been investigated to minimize or prevent postoperative adhesion, the clinical efficacy is not very encouraging. In this work, a biodegradable and thermoreversible galactose modified xyloglucan (mXG) hydrogel was developed and the efficacy of mXG hydrogel in preventing postoperative peritoneal adhesion was investigated. The 4% (w/v) mXG solution was a free flowing sol at low temperature, but could rapidly convert into a physical hydrogel at body temperature without any extra additives or chemical reactions. In vitro cell tests showed that mXG hydrogel was non-toxic and could effectively resist the adhesion of fibroblasts. Moreover, in vitro and in vivo degradation experiments exhibited that mXG hydrogel was degradable and biocompatible. Finally, the rat model of sidewall defect-cecum abrasion was employed to evaluate the anti-adhesion efficacy of the mXG hydrogel. The results demonstrated that mXG hydrogel could effectively prevent postoperative peritoneal adhesion without side effects. The combination of suitable gel temperature, appropriate biodegradation period, and excellent postoperative anti-adhesion efficacy make mXG hydrogel a promising candidate for the prevention of postsurgical peritoneal adhesion. STATEMENT OF SIGNIFICANCE: Despite numerous drugs or barrier-based devices have been developed to prevent postoperative adhesion, few solutions have proven to be uniformly effective in subsequent clinical trials. In the present study, we developed a biodegradable and thermoreversible galactose modified xyloglucan (mXG) hydrogel by green enzymatic reaction without using any organic reagents. The developed physical mXG hydrogel not only showed excellent injectability, appropriate gelation time and temperature, but also exhibited excellent biocompatibility and biodegradability both in vitro and in vivo. In addition, mXG hydrogel was easy to handle and could effectively prevent postoperative adhesion without side effects in a rat model of sidewall defect-bowel abrasion. Our study provide a safe and effective postoperative anti-adhesion material which may have potential applications in clinical practice.