Jiamin Liu, Yankun Lu, Yi Tian, Qian Liu, Xinghua Sun, Yi Liu, Yuan Lei
{"title":"A Light-Activatable Nitric Oxide Donor for Targeted Glaucoma Therapy with Real-Time Monitoring Capabilities.","authors":"Jiamin Liu, Yankun Lu, Yi Tian, Qian Liu, Xinghua Sun, Yi Liu, Yuan Lei","doi":"10.1002/adhm.202404221","DOIUrl":"https://doi.org/10.1002/adhm.202404221","url":null,"abstract":"<p><p>Primary open-angle glaucoma (POAG), the most common form of glaucoma, is characterized by a gradual increase in intraocular pressure (IOP). Nitric oxide (NO) donors are promising treatments for POAG, but their effectiveness requires selective NO release triggered by ocular-relevant stimuli. RhNO-Ab, a visible light-activatable NO donor and fluorescent probe is introduced. RhNO-Ab releases NO from its N-nitroso group and transforms from a non-fluorescent spirolactone to fluorescent Rhodamine (Rh) upon NO release. In vitro studies, including in bulk and single molecule level demonstrated a rapid NO release and fluorescence recovery upon light irradiation. Immunofluorescence shows enhanced delivery to target tissues of RhNO-Ab with ABCA1 antibody modification. Administration of RhNO-Ab with light at 30, 20, and 10 µm significantly reduces IOP in NOS3 KO mice by 2.11 mmHg (12.50%, n = 6), 1.77 mmHg (9.88%, n = 6), and 1.55 mmHg (8.23%, n = 6) 3 h post-treatment (<sup>*</sup>p < 0.05). RhNO-Ab with light also reduces transendothelial electrical resistance (TEER) in Schlemm's canal (SC) endothelial cells (n = 3, <sup>*</sup>p < 0.05) and upregulates soluble guanylate cyclase (sGC) mRNA and protein expression in mouse outflow tissues and human trabecular meshwork (HTM) cells. Unlike traditional NO donors, RhNO-Ab offers visible light-triggered therapeutic NO release and real-time monitoring, making it a promising novel strategy for POAG treatment.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2404221"},"PeriodicalIF":10.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rui Chang, Pei Wang, Hongrui Chen, Shih-Jen Chang, Qianyi Chen, Lei Chang, Yajing Qiu, Xiansong Wang, Xiaoxi Lin
{"title":"Multifunctional Hydrogel Integrated Hemangioma Stem Cell-Derived Nanovesicle-Loaded Metal-Polyphenol Network Promotes Diabetic Flap Survival.","authors":"Rui Chang, Pei Wang, Hongrui Chen, Shih-Jen Chang, Qianyi Chen, Lei Chang, Yajing Qiu, Xiansong Wang, Xiaoxi Lin","doi":"10.1002/adhm.202404776","DOIUrl":"https://doi.org/10.1002/adhm.202404776","url":null,"abstract":"<p><p>Diabetes-associated skin defects represent a significant global health challenge. While flap grafts have been a preferred treatment for soft-tissue injuries in diabetic patients, their survival is often compromised by impaired vascularization, infection, and the adverse diabetic pathological microenvironment. To address these limitations, a hybrid photo-crosslinkable hydrogel (HPC) integrated hemangioma stem cell-derived nanovesicle (HemV)-loaded dual-metal-polyphenol network (dMPN) (HemV@dMPN/HPC) is developed. HemVs, derived from highly vascularized infantile hemangioma tissues, play a key role in promoting cell proliferation and angiogenesis. The dMPN facilitates the gradual release of copper (Cu<sup>2+</sup>) and magnesium ions (Mg<sup>2+</sup>), stimulating angiogenesis and mitigating inflammation. The HPC further sustains ion release while preserving the therapeutic efficacy of HemVs. Moreover, both HPC and Cu<sup>2+</sup> act to confer antibacterial properties, further accelerating wound healing. This multifunctional HemV@dMPN/HPC platform offers a promising therapeutic strategy for treating large diabetic skin defects and can potentially improve flap graft survival.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2404776"},"PeriodicalIF":10.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lu Liu, Daiyong Chao, Qing Dong, Xianli Zhang, Kai Zhang, Zhenyu Ju
{"title":"Bimetallic NiCu-MOF Protects DOX-Induced Myocardial Injury and Cardiac Dysfunction by Suppressing Ferroptosis and Inflammation.","authors":"Lu Liu, Daiyong Chao, Qing Dong, Xianli Zhang, Kai Zhang, Zhenyu Ju","doi":"10.1002/adhm.202405175","DOIUrl":"https://doi.org/10.1002/adhm.202405175","url":null,"abstract":"<p><p>Doxorubicin (DOX), a potent anthracycline chemotherapeutic agent, is widely used in cancer treatment but is associated with significant adverse effects, particularly DOX-induced cardiomyopathy (DIC). DIC pathogenesis involves the generation of reactive oxygen species (ROS) and ferroptosis induction. Novel therapeutic strategies targeting antioxidant defenses and ferroptosis inhibition are essential for mitigating DIC. An innovative bimetallic metal-organic framework (MOF), NiCu-MOF (NCM), is developed, exhibiting multifaceted antioxidant enzyme-mimicking activities that effectively scavenge a broad spectrum of ROS. Additionally, the bimetallic NCM exhibits excellent iron-chelating ability. In vitro experiments demonstrate that NCM significantly reduces cardiomyocyte death by attenuating ROS levels and inhibiting ferroptosis. Furthermore, in a mouse model of DIC, NCM treatment results in substantial myocardial protection, evidenced by improved cardiac function and structural integrity. This protective effect is attributed to suppression of ferroptosis, preservation of mitochondrial function, and attenuation of inflammatory responses. Collectively, these findings highlight biocompatible NCM's potential as a novel cardioprotective agent and offer a promising therapeutic strategy for managing DIC.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2405175"},"PeriodicalIF":10.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Near-Infrared Imaging Agent ABSi-148 Alleviates CA IX-Mediated Hypoxic Fibrosis in Inflammation-Cancer Transition.","authors":"Zhi Cao, Jingmin Li, Weibin Hu, Jian Xu, Fengyun Zhao, Yishu Wang, Shuanglin Qin, Ming Liu, Ping Wang, Jingwei Duan, Wensheng Zhou, Zhaowei Ding, Shaohui Tang, Xiaodong Ma, Lisheng Wang","doi":"10.1002/adhm.202404935","DOIUrl":"https://doi.org/10.1002/adhm.202404935","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge due to its late diagnosis and intrinsic treatment resistance, exacerbates by its development from chronic inflammation to cancer transition (ICT). Here, this investigation aims to develop and evaluate ABSi-148, a novel near-infrared (NIR) agent targeting hypoxic carbonic anhydrase IX (CA IX), for its potential applications in ICT imaging and even PDAC treatment. ABSi-148 is synthesized from 4-(2-Aminoethyl) benzene sulfonamide (ABS), a sulfonamide derivative, conjugating with MHI-148 dye with merits of exceptional NIR-emitting traits, high biocompatibility, and deep tissue penetration imaging capability. It selectively accumulates in CoCl<sub>2</sub>-induced pancreatic stellate cells and pancreatic cancer cells via binding with transmembrane CA IX in vitro. Meanwhile, ABSi-148 effectively visualizes the early pancreatic lesion, and its long-term administration inhibits the progression of hypoxia-related fibrosis involved in pancreatic intraepithelial neoplasias (PanINs), and even PDAC progression in vivo. Besides, ABSi-148 monitors treatment efficacy and localizes hypoxic tumor regions, enhancing survival in tamoxifen combined with caerulein-induced KPC mice. Overall, ABSi-148 emerges as a theranostic NIR agent for precise diagnosis and targeted therapy in ICT of PDAC, promising to alleviate tumor progression and enhancing outcomes.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2404935"},"PeriodicalIF":10.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhijie Li, Dan Luo, Yaqian Zhang, Xin Niu, Hao Liu
{"title":"Smart Health Monitoring: Review of Electrochemical Biosensors for Cortisol Monitoring.","authors":"Zhijie Li, Dan Luo, Yaqian Zhang, Xin Niu, Hao Liu","doi":"10.1002/adhm.202404454","DOIUrl":"https://doi.org/10.1002/adhm.202404454","url":null,"abstract":"<p><p>Cortisol, also known as the stress hormone, is a crucial corticosteroid hormone that significantly increases secretion in the human body when facing notable stress. Monitoring cortisol levels is crucial for personal stress management and the diagnosis and treatment of certain diseases. Electrochemical biosensors combine the efficient sensitivity of electrochemical technology with the high specificity of biological recognition processes, making them widely applicable in the analysis of human body fluid components. This work outlines the working mechanism of cortisol electrochemical biosensors, focusing particularly on sensing elements such as antibodies, aptamers, and molecularly imprinted polymers. It provides detailed explanations of the operational principles of these different recognition elements. This work summarizes and evaluates the latest advancements in electrochemical biosensors for detecting cortisol in human body fluids, discussing the influence of different recognition elements on sensor design and electrochemical performance. Subsequently, through a comparative analysis of various sensor performances, the work further discusses the challenges in translating laboratory achievements into practical applications, including enhancing key metrics such as sensor reusability, reproducibility, long-term stability, continuous monitoring capability, and response time. Finally, it offers insights and recommendations for achieving real-time, continuous, and long-term monitoring with cortisol electrochemical biosensors.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2404454"},"PeriodicalIF":10.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An Enhanced Long-Term Wet Adhesion Strategy of Spatial Control the Emergence of Dual Covalent Cross-Linking for Sutureless Cornea Transplant.","authors":"Zhuhao Tan, Wenfang Liu, Siqi Jiang, Jia Liu, Jingjie Shen, Xiaoyun Peng, Baolei Huang, Hailin Zhang, Wenjing Song, Li Ren","doi":"10.1002/adhm.202404557","DOIUrl":"https://doi.org/10.1002/adhm.202404557","url":null,"abstract":"<p><p>Corneal transplantation regeneration requires bioadhesives to perform long-term and stable adhesion functions in a wet environment. However, many current studies focus on the instantaneous or short-term adhesion persistence of bioadhesives, and ignore the evaluation of their long-term wet adhesion behaviors which is urgent for keratoplasty repair process. In view of this situation, a dual covalent cross-linking hydrogel (ASO) bioadhesive is developed. The ASO bioadhesive comprised acrylated gelatin(G-AA), thiolated gelatin(G-SH), and oxidized dextran (OD). Introduction of thiol chemistry made the emergence of ASO dual covalent cross-linking controllable by UV light irradiation. The analysis of this feature revealed an intriguing phenomenon. The ASO bioadhesive demonstrated spatially specific control over cross-linking behavior by first penetrating the tissue and then initiating cross-linking, thereby significantly enhancing its long-term wet adhesion ability. The ASO bioadhesive can maintain more than 50% adhesion after being immersed in wet environment for one month. Subsequently, ASO bioadhesive demonstrated long-term wet adhesive stability once again on corneal lamellar transplantation model through maintaining strong anchorage of corneal donor to recipient bed and promoting their integration. The unprecedented adhesive mechanism presented in this study provided innovated theoretical basis for designing bioadhesives with superior long-term wet adhesion.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2404557"},"PeriodicalIF":10.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"On-Demand Removal of Rapid Hemostatic Sponge for Non-Compressible Hemorrhage Through Disrupting Ionic Bonds.","authors":"Pengcheng Zhang, Chuan Yu, Zhuofan Hu, Yijin Li, Guangming Wan, Keyong Tang, Xialian Fan","doi":"10.1002/adhm.202404894","DOIUrl":"https://doi.org/10.1002/adhm.202404894","url":null,"abstract":"<p><p>Self-expanding hemostatic sponge plays an important role in the control of non-compressible hemorrhage in deep wound. After hemostasis is accomplished, the sponge adheres to the wound via blood clots, posing a considerable challenge in wound debridement. A kind of protocatechualdehyde modified chitosan/sodium alginate composite hemostatic sponge with on-demand removal performance is designed in this study. After absorbing blood, the compression sponge rapidly expands and compresses the damaged blood vessels. The physical compression of the hemostatic sponge and the chemical adhesion of catechol is used to promote rapid hemostasis of the wound. The composite hemostatic sponge demonstrated outstanding hemostasis performance in both mouse liver and rat femoral artery bleeding model. Notably, after complete hemostasis of the rat femoral artery, the composite sponge is rapidly removed from the wound by rinsing it with a suitable concentration of Sodium carbonate (Na<sub>2</sub>CO<sub>3</sub>) solution. This composite hemostatic sponge featuring the on-demand removal capability demonstrates outstanding application potential for non-compressible hemorrhage in deep wounds and provides a novel way for constructing removable hemostatic sponges.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2404894"},"PeriodicalIF":10.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Weikang Lin, Hai Tang, Runfeng Cao, Jiafei Chen, Long Wang, Yunlang She, Lei Zhang, Yi Chen, Ziyin Pan, Qingfeng Bai, Deping Zhao, Minglei Yang, Guofang Zhao, Weiyan Sun, Dong Xie, Chang Chen
{"title":"3D-printed Engineered Trachea Functionalized by Diverse Extracellular Matrix Particles.","authors":"Weikang Lin, Hai Tang, Runfeng Cao, Jiafei Chen, Long Wang, Yunlang She, Lei Zhang, Yi Chen, Ziyin Pan, Qingfeng Bai, Deping Zhao, Minglei Yang, Guofang Zhao, Weiyan Sun, Dong Xie, Chang Chen","doi":"10.1002/adhm.202500124","DOIUrl":"https://doi.org/10.1002/adhm.202500124","url":null,"abstract":"<p><p>It remains a significant challenge to construct a tracheal substitute with both a native-like structure and multiple essential physiological functions. In this study, a combination of 3D printing techniques and a modular strategy is employed to fabricate an engineered trachea, in which the decellularized extracellular matrix particles (DEPs) from diverse sources determined specific regenerative environments in different spatial regions. Costal cartilage-derived DEPs are integrated within the cartilage rings of the engineered trachea. They effectively activated chondrocytes to secrete specific matrix proteins and develop into mature cartilage with a natural pattern of collagen deposition, which provided sufficient mechanical properties to maintain tracheal ventilation. Lung-derived DEPsare strategically placed between the cartilage rings, and are able to accelerate endothelial cell migration to form a transmural vessel network. Additionally, lung-derived DEPs exhibited a great capability to recruit macrophages and facilitate their polarization, which is beneficial for tissue regeneration. The engineered trachea underwent heterotopic vascularization and utilized for long-segmental trachea replacement in a rabbit model, demonstrating a satisfactory physiological function. Through DEP functionalization, the tracheal substitute developed a native-like complex structure with adequate mechanical supply, abundant blood perfusion, and favorable immune conditions, demonstrating significant clinical potential for patients requiring tracheal reconstruction.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2500124"},"PeriodicalIF":10.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Exos-Loaded Gox-Modified Smart-Response Self-Healing Hydrogel Improves the Microenvironment and Promotes Wound Healing in Diabetic Wounds (Adv. Healthcare Mater. 7/2025)","authors":"Pu Yang, Yikun Ju, Naisi Shen, Shuai Zhu, Jiaqian He, Lingxiu Yang, Jiajie Lei, Xiaoli He, Wenjia Shao, Lanjie Lei, Bairong Fang","doi":"10.1002/adhm.202570039","DOIUrl":"https://doi.org/10.1002/adhm.202570039","url":null,"abstract":"<p><b>Smart Response Hydrogel Dressing</b></p><p>In article 2403304, Lanjie Lei, Bairong Fang, and co-workers construct a hydrogel dressing with glucose-responsive properties based on the glucose-catalyzed properties of glucose oxidase and the pH-responsive properties of Schiff base reaction. When the hydrogel dressing senses glucose in the microenvironment, it can intelligently release the exosomes it carries, thus improving the microenvironment of diabetic wounds and achieving better healing.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":"14 7","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/adhm.202570039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"4D printed Stimuli Responsive Scaffold with Tissue Expansion and Photothermal Tumor Ablation Property for Post-Mastectomy Breast Reconstruction.","authors":"Muran Zhou, Guo Zhang, Jinfei Hou, Lifeng Chen, Chao Luo, Shan Mou, Ke Guo, Rongrong Wang, Lingyun Xiong, Zhenxing Wang, Nengqiang Guo, Jiaming Sun","doi":"10.1002/adhm.202404575","DOIUrl":"https://doi.org/10.1002/adhm.202404575","url":null,"abstract":"<p><p>Breast tissue engineering is a promising alternative to post-mastectomy breast reconstruction. However, the high relapse rate (about 20%) of this malignant tumor negatively affects its long-term prognosis. Moreover, the shortage of recipient site volume often hampers the reconstruction of large-sized breast. Here, this work reports on the additive manufacturing of a novel breast tissue engineering scaffold with photothermal shape memory and tumor ablation properties to solve the aforementioned issues. Graphene nanosheets (GN) are used to functionalize the surface of 3D-printed polyurethane scaffolds (GfPU) without compromising the biocompatibility of polyurethane. Subsequently, the GfPU scaffolds are remodeled into temporary shapes using established procedures. After exposure to an 808 nm laser, the GfPU scaffolds are heated to 47.1 °C, and they converted from a temporary shape to their original shape in a light intensity-dependent manner. With an accurate structural design, the shape memory scaffold could act as a stimuli-responsive tissue expander in vivo. Meanwhile, the laser-irradiated GfPU could specifically ablate multiple breast cancer cell lines in vitro and suppress both tumor growth and tumor recurrence in vivo. This dual-functional scaffold has the potential to be used in breast tissue engineering applications to optimize both the oncological and reconstructive effect.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2404575"},"PeriodicalIF":10.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}