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.

Identification and characterization of two morphologically distinct stem cell subpopulations from human urine samples

Urine-derived stem cells(USCs)have shown potentials for the treatment of skeletal and urological disorders.Based on published literature and our own data,USCs consist of heterogeneous populations of cells.In this paper,we identify and characterize two morphologically distinct subpopulations of USCs from human urine samples,named as spindle-shaped USCs(SS-USCs)and rice-shaped USCs(RS-USCs)respectively.The two subpopulations showed similar clone-forming efficiency,while SS-USCs featured faster proliferation,higher motility,and greater potential for osteogenic and adipogenic differentiation,RS-USCs showed greater potential for chondrogenic differentiation.POU5F1 was strongly expressed in both subpopulations,but MYC was weakly expressed.Both subpopulations showed similar patterns of CD24,CD29,CD34,CD44,CD73,CD90 and CD105 expression,while a higher percentage of RS-USCs were positive for CD133.SS-USCs were positive for VIM,weakly positive for SLC12A1 and UMOD,and negative for KRT18,NPHS1,AQP1 and AQP2,indicating a renal mesenchyme origin;while RSUSCs are positive for VIM,partially positive for KRT18,NPHS1,AQP1,SLC12A1 and UMOD,and negative for AQP2,indicating a nephron tubule origin.The above results can facilitate understanding of the biological characteristics of subpopulations of USCs,and provide a basis for further research and applications of such cells.

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.

Progress in development of bioderived materials for dermal wound healing

Treatment of acute and chronic wounds is one of the primary challenges faced by doctors.Bioderived materials have significant potential clinical value in tissue injury treatment and defect reconstruction.Various strategies,including drug loading,addition of metallic element(s),crosslinking and combining two or more distinct types of materials with complementary features,have been used to synthesize more suitable materials for wound healing.In this review,we describe the recent developments made in the processing of bioderived materials employed for cutaneous wound healing,including newly developed materials such as keratin and soy protein.The focus was on the key properties of the bioderived materials that have shown great promise in improving wound healing,restoration and reconstruction.With their good biocompatibility,nontoxic catabolites,microinflammation characteristics,as well as their ability to induce tissue regeneration and reparation,the bioderived materials have great potential for skin tissue repair.

Accelerating ESD-induced gastric ulcer healing using a pH-responsive polyurethane/small intestinal submucosa hydrogel delivered by endoscopic catheter

Endoscopic submucosal dissection(ESD)is the standard treatment for early-stage gastric cancer,but the large post-operative ulcers caused by ESD often lead to serious side effects.Post-ESD mu-cosal repair materials provide a new option for the treatment of post-ESD ulcers.In this study,we developed a polyurethane/small intestinal submucosa(PU/SIS)hydrogel and investigated its effi-cacy for accelerating ESD-induced ulcer healing in a canine model.PU/SIS hydrogel possessed great biocompatibility and distinctive pH-sensitive swelling properties and protected GES-1 cells from acid attack through forming a dense film in acidic conditions in vitro.Besides,PU/SIS gels present a strong bio-adhesion to gastric tissues under acidic conditions,thus ensuring the reten-tion time of PU/SIS gels in vivo.In a canine model,PU/SIS hydrogel was easily delivered via endoscopy and adhered to the ulcer sites.PU/SIS hydrogel accelerated gastric ulcer healing at an early stage with more epithelium regeneration and slight inflammation.Our findings reveal PU/SIS hydrogel is a promising and attractive candidate for ESD-induced ulcer repair.

Techniques for increasing the yield of stem cell-derived exosomes:what factors may be involved?

Exosomes are nano-scale extracellular vesicles secreted by cells and constitute an important part in the cell-cell communication.The main contents of the exosomes include proteins,micro RNAs,and lipids.The mechanism and safety of stem cell-derived exosomes have rendered them a promising therapeutic strategy for regenerative medicine.Nevertheless,limited yield has restrained full explication of their functions and clinical applications.To address this,various attempts have been made to explore the up-and down-stream manipulations in a bid to increase the production of exosomes.This review has recapitulated factors which may influence the yield of stem cell-derived exosomes,including selection and culture of stem cells,isolation and preservation of the exosomes,and development of artificial exosomes.

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.

Application of antibody-conjugated small intestine submucosa to capture urine-derived stem cells for bladder repair in a rabbit model

The need for bladder reconstruction and side effects of cystoplasty have spawned the demand for the development of alternative material substitutes.Biomaterials such as submucosa of small intestine(SIS)have been widely used as patches for bladder repair,but the outcomes are not fully satisfactory.To capture stem cells in situ has been considered as a promising strategy to speed up the process of re-cellularization and functionalization.In this study,we have developed an anti-CD29 antibody-conjugated SIS scaffold(AC-SIS)which is capable of specifically capturing urine-derived stem cells(USCs)in situ for tissue repair and regeneration.The scaffold has exhibited effective capture capacity and sound biocompatibility.In vivo experiment proved that the AC-SIS scaffold could promote rapid endothelium healing and smooth muscle regeneration.The endogenous stem cell capturing scaffolds has thereby provided a new revenue for developing effective and safer bladder patches.