Multifunctional two-component in-situ hydrogel for esophageal submucosal dissection for mucosa uplift,postoperative wound closure and rapid healing

Endoscopic submucosal dissection (ESD) for gastrointestinal tumors and premalignant lesions needs submucosal fluid cushion (SFC) for mucosal uplift before dissection, and wound care including wound closure and rapid healing postoperatively. Current SFC materials as well as materials and/or methods for post-ESD wound care have single treatment effect and hold corresponding drawbacks, such as easy dispersion, short duration, weak hemostasis and insufficient repair function. Thus, designing materials that can serve as both SFC materials and wound care is highly desired, and remains a challenge. Herein, we report a two-component in-situ hydrogel prepared from maleimide-based oxidized sodium alginate and sulfhydryl carboxymethyl-chitosan, which gelated mainly based on "click" chemistry and Schiff base reaction. The hydrogels showed short gelation time, outstanding tissue adhesion, favorable hemostatic properties, and good biocompatibility. A rat subcutaneous ultrasound model confirmed the ability of suitable mucosal uplift height and durable maintenance time of AM solution. The in vivo/in vitro rabbit liver hemorrhage model demonstrated the effects of hydrogel in rapid hemostasis and prevention of delayed bleeding. The canine esophageal ESD model corroborated that the in-situ hydrogel provided good mucosal uplift and wound closure effects, and significantly accelerated wound healing with accelerating re-epithelization and ECM remodeling post-ESD. The two-component in-situ hydrogels exhibited great potential in gastrointestinal tract ESD.

A self-fused hydrogel for the treatment of glottic insufficiency through outstanding durability,extracellular matrix-inducing bioactivity and function preservation

Injection laryngoplasty with biomaterials is an effective technique to treat glottic insufficiency.However,the inadequate durability,deficient pro-secretion of extracellular matrix(ECM)and poor functional preservation of current biomaterials have yielded an unsatisfactory therapeutic effect.Herein,a self-fusing bioactive hydrogel comprising modified carboxymethyl chitosan and sodium alginate is developed through a dual-crosslinking mechanism(photo-triggered and dynamic covalent bonds).Owing to its characteristic networks,the synergistic effect of the hydrogel for vocal folds(VFs)vibration and phonation is adequately demonstrated.Notably,owing to its inherent bioactivity of polysaccharides,the hydrogel could significantly enhance the secretion of major components(type I/III collagen and elastin)in the lamina propria of the VFs both in vivo and in vitro.In a rabbit model for glottic insufficiency,the optimized hydrogel(C1A1)has demonstrated a durability far superior to that of the commercially made hyaluronic acid(HA)Gel.More importantly,owing to the ECM-inducing bioactivity,the physiological functions of the VFs treated with the C1A1 hydrogel also outperformed that of the HA Gel,and were similar to those of the normal VFs.Taken together,through a simple-yet-effective strategy,the novel hydrogel has demonstrated outstanding durability,ECM-inducing bioactivity and physiological function preservation,therefore has an appealing clinical value for treating glottic insufficiency.

Application of metabolomics in urolithiasis:the discovery and usage of succinate

Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events.It has been shown that the occurrence of calcium oxalate monohydrate(COM)during stone formation is regulated by crystal growth modifiers.Although crystallization inhibitors have been recognized as a therapeutic modality for decades,limited progress has been made in the discovery of effective modifiers to intervene with stone disease.In this study,we have used metabolomics technologies,a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model.By in-depth mining and analysis of metabolomics data,we have screened five differential metabolites.Through density functional theory studies and bulk crystallization,we found that three of them(salicyluric,gentisic acid and succinate)could effectively inhibit nucleation in vitro.We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones.Notably,succinate,a key player in the tricarboxylic acid cycle,could decrease kidney calcium deposition and injury in the model.Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation,inhibition of cell adhesion and osteogenic differentiation.These findings indicated that succinate may provide a new therapeutic option for urinary stones.

Procyanidins-crosslinked small intestine submucosa: A bladder patch promotes smooth muscle regeneration and bladder function restoration in a rabbit model

Currently the standard surgical treatment for bladder defects is augmentation cystoplasty with autologous tissues,which has many side effects.Biomaterials such as small intestine submucosa(SIS)can provide an alternative scaffold for the repair as bladder patches.Previous studies have shown that SIS could enhance the capacity and compliance of the bladder,but its application is hindered by issues like limited smooth muscle regeneration and stone formation since the fast degradation and poor mechanical properties of the SIS.Procyanidins(PC),a natural bio-crosslinking agent,has shown anti-calcification,anti-inflammatory and anti-oxidation properties.More importantly,PC and SIS can crosslink through hydrogen bonds,which may endow the material with enhanced mechanical property and stabilized functionalities.In this study,various concentrations of PC-crosslinked SIS(PC-SIS)were prepared to repair the full-thickness bladder defects,with an aim to reduce complications and enhance bladder functions.In vitro assays showed that the crosslinking has conferred the biomaterial with superior mechanical property and anti-calcification property,ability to promote smooth muscle cell adhesion and upregulate functional genes expression.Using a rabbit model with bladder defects,we demonstrated that the PC-SIS scaffold can rapidly promote in situ tissue regrowth and regeneration,in particular smooth muscle remodeling and improvement of urinary functions.The PC-SIS scaffold has therefore provided a promising material for the reconstruction of a functional bladder.

Multi-crosslinking hydrogels with robust bio-adhesion and pro-coagulant activity for first-aid hemostasis and infected wound healing

Bio-adhesive polysaccharide-based hydrogels have attracted much attention in first-aid hemostasis and wound healing for excellent biocompatibility,antibacterial property and pro-healing bioactivity.Yet,the inadequate mechanical properties and bio-adhesion limit their applications.Herein,based on dynamic covalent bonds,photo-triggered covalent bonds and hydrogen bonds,multifunctional bio-adhesive hydrogels comprising modified carboxymethyl chitosan,modified sodium alginate and tannic acid are developed.Multi-crosslinking strategy endows hydrogels with improved strength and flexibility simultaneously.Owing to cohesion enhancement strategy and self-healing ability,considerable bio-adhesion is presented by the hydrogel with a maximal adhesion strength of 162.6 kPa,12.3-fold that of commercial fibrin glue.Based on bio-adhesion and pro-coagulant activity(e.g.,the stimulative aggregation and adhesion of erythrocytes and platelets),the hydrogel reveals superior hemostatic performance in rabbit liver injury model with blood loss of 0.32 g,only 54.2%of that in fibrin glue.The healing efficiency of hydrogel for infected wounds is markedly better than commercial EGF Gel and Ag+Gel due to the enhanced antibacterial and antioxidant properties.Through the multi-crosslinking strategy,the hydrogels show enhanced mechanical properties,fabulous bio-adhesion,superior hemostatic performance and promoting healing ability,thereby have an appealing application value for the first-aid hemostasis and infected wound healing.

Promotion of right ventricular outflow tract reconstruction using a novel cardiac patch incorporated with hypoxia-pretreated urine-derived stem cells

Approximately 25%of patients with congenital heart disease require implantation of patches to repair.However,most of the currently available patches are made of inert materials with unmatched electrical conductivity and mechanical properties,which may lead to an increased risk for arrhythmia and heart failure.In this study,we have developed a novel Polyurethane/Small intestinal submucosa patch(PSP)with mechanical and electrical properties similar to those of the native myocardial tissue,and assessed its feasibility for the reconstruction of right ventricular outflow tract.A right ventricular outflow tract reconstruction model was constructed in 40 rabbits.Compared with commercially available bovine pericardium patch,the PSP patch has shown better histocompatibility and biodegradability,in addition with significantly improved cardiac function.To tackle the significant fibrosis and relatively poor vascularization during tissue remodeling,we have further developed a bioactive patch by incorporating the PSP composites with urine-derived stem cells(USCs)which were pretreated with hypoxia.The results showed that the hypoxia-pretreated bioactive patch could significantly inhibit fibrosis and promote vascularization and muscularization,resulting in better right heart function.Our findings suggested that the PSP patch combined with hypoxia-pretreated USCs may provide a better strategy for the treatment of congenital heart disease.