Kai Cheng , Yan Deng , Lin Qiu , Shuhang Song , Lei Chen , LinGe Wang , Qianqian Yu
{"title":"Heparin-loaded hierarchical fiber/microsphere scaffolds for anti-inflammatory and promoting wound healing","authors":"Kai Cheng , Yan Deng , Lin Qiu , Shuhang Song , Lei Chen , LinGe Wang , Qianqian Yu","doi":"10.1016/j.smaim.2024.02.002","DOIUrl":"https://doi.org/10.1016/j.smaim.2024.02.002","url":null,"abstract":"<div><p>Chronic non-healing wounds induced by oxidative stress and inflammation can activate inflammatory cells and produce large amounts of inflammatory mediators, which fail to maintain homeostasis in the skin and delay the wound-healing process. To tackle this issue, heparin-loaded hierarchical composite scaffolds comprised of electrospun fibers and electrosprayed microspheres were prepared to act as an effective anti-inflammatory wound dressing. Microspheres with different electrosprayed densities were deposited into the surface of the electrospun fibers for the improvement of surface topographical cues and cellular activities. The results indicated that the electrospun fibers followed by electrosprayed for 3 min to fabricate the composite fiber/microsphere scaffolds contributed to the best performance in terms of promoting cellular activities, with no obvious cytotoxicity, good adhesion morphology, and the fastest cell migration rate. In addition, a suitable amount of heparin was added to the composite scaffolds to alleviate inflammation. The significant adsorption efficiency of heparin-loaded composite scaffolds on inflammatory mediator MCP-1 indicates a favorable anti-inflammation effect <em>in vitro</em>. Furthermore, the heparin-loaded hierarchical scaffolds accelerated the pace of inflammatory wound healing <em>in vivo</em> when compared to commercial 3 M Tegaderm and non-heparin-loaded scaffolds. Our work provided a facile strategy for fabricating heparin-loaded hierarchical fiber/microsphere scaffolds to modulate cellular activities via topographical cues and accelerating the inflammatory wound healing process by electrostatic interactions between heparin and MCP-1. These findings suggested that the heparin-loaded hierarchical scaffold was expected to be a promising dressing for inflammatory wound healing.</p></div>","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"5 2","pages":"Pages 240-250"},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590183424000140/pdfft?md5=87e72f78ab41cd75eeba08006f76f8b3&pid=1-s2.0-S2590183424000140-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140113249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shengxi Jiang , Peiji Yang , Yujia Zheng , Xiong Lu , Chaoming Xie
{"title":"Machine learning for polyphenol-based materials","authors":"Shengxi Jiang , Peiji Yang , Yujia Zheng , Xiong Lu , Chaoming Xie","doi":"10.1016/j.smaim.2024.02.001","DOIUrl":"https://doi.org/10.1016/j.smaim.2024.02.001","url":null,"abstract":"<div><p>Polyphenol-based materials, primarily composed of polyphenolic compounds, have attracted considerable attention due to their unique chemical structures and biological activities. However, there are many derivatives of polyphenols, resulting in the complexity and diversity of polyphenol-based materials. Traditional methods are difficult to meet the rapid development of polyphenol-based materials. Machine learning, known for its proficiency in predicting performance, optimizing synthesis processes, and designing novel materials, offers significant potential in the intelligent design and applications of polyphenol-based materials. In this review, we summarize the recent advancements in the research and development of polyphenol-based materials and machine learning. The intersection of polyphenol-based materials and machine learning is also discussed, including their applications in biomedical, environmental, and energy fields. The challenges and prospects for the future development of polyphenol-based materials based on machine learning are highlighted.</p></div>","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"5 2","pages":"Pages 221-239"},"PeriodicalIF":0.0,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590183424000139/pdfft?md5=7f0ddbde2e40cb18a9a5a75c4e740d78&pid=1-s2.0-S2590183424000139-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139935234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ke Zheng , Muyuan Chai , Bingping Luo , Kezhao Cheng , Zhenxing Wang , Nan Li , Xuetao Shi
{"title":"Recent progress of 3D printed vascularized tissues and organs","authors":"Ke Zheng , Muyuan Chai , Bingping Luo , Kezhao Cheng , Zhenxing Wang , Nan Li , Xuetao Shi","doi":"10.1016/j.smaim.2024.01.001","DOIUrl":"10.1016/j.smaim.2024.01.001","url":null,"abstract":"<div><p>Since the need for vascular networks to supply oxygen and nutrients while expelling metabolic waste, most cells can only survive within 200 μm of blood vessels; thus, the construction of well-developed blood vessel networks is essential for the manufacture of artificial tissues and organs. Three-dimensional (denoted as 3D) printing is a scalable, reproducible and high-precision manufacturing technology. In the past several years, there have been many breakthroughs in building various vascularized tissues, greatly promoting the development of biological tissue engineering. This paper highlights the latest progress of 3D printed vascularized tissues and organs, including the heart, liver, lung, kidney, and penis. We also discuss the application status and potential of the above printed tissues, and prospect the further requirement of 3D printing technology for manufacturing clinically useable vascularized tissues.</p></div>","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"5 2","pages":"Pages 183-195"},"PeriodicalIF":0.0,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590183424000127/pdfft?md5=5687a89e851d648e61c59bd2aa7b3354&pid=1-s2.0-S2590183424000127-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139539770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lihua Li , Yao Lu , Xinyue Lao , Sin-Yi Pang , Menglin Song , Man-Chung Wong , Feng Wang , Mo Yang , Jianhua Hao
{"title":"A magnetic-enhanced FRET biosensor for simultaneous detection of multiple antibodies","authors":"Lihua Li , Yao Lu , Xinyue Lao , Sin-Yi Pang , Menglin Song , Man-Chung Wong , Feng Wang , Mo Yang , Jianhua Hao","doi":"10.1016/j.smaim.2023.12.003","DOIUrl":"10.1016/j.smaim.2023.12.003","url":null,"abstract":"<div><p>Accurate, rapid and sensitive detection of specific immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies in human samples is crucial for preventing and assessing pandemics, especially in the case of recent COVID-19 outbreaks. However, simultaneous and efficient detection of IgG and IgM in a single system remains challenging. Herein, we developed a multicolor nanosystem capable of quantitatively analyzing <em>anti</em>-SARS-CoV-2 IgG and IgM with high sensitivity within 20 min. The detection system consists of core-shell upconversion nanoparticles (csUCNPs), secondary antibodies labeled with fluorescent dyes (sab), and magnetic nanocrystals (PMF). By leveraging the Förster resonance energy transfer (FRET) effect, the photoluminescence (PL) intensity of blue and green regions is restored for IgG and IgM detection, respectively. Inspiringly, owing to the introducing of PMF, the limits of detection (LODs) of IgG and IgM tested are improved to 89 fmol L<sup>−1</sup> and 19.4 fmol L<sup>−1</sup>, representing about 416-folds and 487-folds improvement over only-dye dependent system, respectively. Mechanistic investigations reveal that the high collective effect and surface energy transfer efficiency from csUCNPs to PMF contribute to the enhanced detection sensitivity. The assay enables us to quantify clinical vaccinated samples with high specificity and precision, suggesting our multicolor platform can be a promising alternative for clinical point-of-care serological assay.</p></div>","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"5 2","pages":"Pages 196-206"},"PeriodicalIF":0.0,"publicationDate":"2024-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590183424000024/pdfft?md5=8ffa25f8348644eb2f4cf61236b2ce89&pid=1-s2.0-S2590183424000024-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139393659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhimin Jiang , Shengao Qin , Weiyi Wang , Tianxiang Du , Yaran Zang , Yuzhu He , Xufeng Dong , Huiying Liu , Guowu Ma
{"title":"Investigating the anti-inflammatory and bone repair-promoting effects of an injectable porous hydrogel containing magnesium ions in a rat periodontitis mode","authors":"Zhimin Jiang , Shengao Qin , Weiyi Wang , Tianxiang Du , Yaran Zang , Yuzhu He , Xufeng Dong , Huiying Liu , Guowu Ma","doi":"10.1016/j.smaim.2023.12.002","DOIUrl":"10.1016/j.smaim.2023.12.002","url":null,"abstract":"<div><p>Periodontitis is associated with several systemic diseases, and advanced periodontitis is often linked to an extensive inflammatory microenvironment and irregularly shaped alveolar bone defects. However, eliminating periodontal inflammation in a minimally invasive manner while repairing irregularly shaped bone defects is clinically challenging. In comparison to traditional bone grafts, a thermo-sensitive hydrogel can be injected into deep periodontal pockets, forming and filling the alveolar bone defects <em>in situ</em>. In this study, porous injectable thermo-sensitive hydrogels containing magnesium ions were prepared by adding magnesium particles (MPs) to a glycerophosphate solution and combining this mixture with a chitosan solution. The incorporation of MPs created interconnected pores in the hydrogel, exhibiting high cytocompatibility and maintaining cell viability, proliferation, spreading, and osteogenesis <em>in vitro</em>. Evaluation on an experimental periodontitis rat model, using micro-computed tomography and histological analyses, demonstrated that this Mg<sup>2+</sup>-containing hydrogel effectively reduced periodontal inflammation, inhibited osteoclast activity, and partially repaired inflammation-induced alveolar bone loss. These results suggest that Mg<sup>2+</sup>-containing thermo-sensitive porous hydrogels might be promising candidates for treating periodontitis.</p></div>","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"5 2","pages":"Pages 207-220"},"PeriodicalIF":0.0,"publicationDate":"2024-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590183424000012/pdfft?md5=17e4d62c4bc4c8f24fcdcf40066163a3&pid=1-s2.0-S2590183424000012-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139394237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Erratum for previously published articles","authors":"","doi":"10.1016/j.smaim.2023.12.001","DOIUrl":"https://doi.org/10.1016/j.smaim.2023.12.001","url":null,"abstract":"","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"5 1","pages":"Page 181"},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590183423000479/pdfft?md5=050f5e6744846e9c43f81fc52f83a792&pid=1-s2.0-S2590183423000479-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138839829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shiyu Yao , Hui Yan , Shiyu Tian , Rifang Luo , Yuancong Zhao , Jin Wang
{"title":"Anti-fouling coatings for blood-contacting devices","authors":"Shiyu Yao , Hui Yan , Shiyu Tian , Rifang Luo , Yuancong Zhao , Jin Wang","doi":"10.1016/j.smaim.2023.10.001","DOIUrl":"https://doi.org/10.1016/j.smaim.2023.10.001","url":null,"abstract":"<div><p>Blood-contacting medical devices, such as vascular stents, intravascular catheters, and artificial heart valves, frequently encounter complications in clinical practice, including thrombosis, inflammatory reactions, and infections. These challenges pose significant obstacles in the effective application of blood-contacting medical devices. Given that protein adhesion serves as the primary trigger for detrimental events upon contact with blood, this review focuses on various anti-fouling coating strategies aimed at inhibiting protein adsorption. Currently, surface modification of blood-contacting medical devices primarily involves the construction of active or passive anti-fouling coatings. This review explores the implementation of active and passive anti-fouling coating strategies utilizing chemistry, physics, and biotechnology. Examples of anti-fouling coatings discussed include hydrophilic polymer coatings, zwitterionic polymer coatings, superhydrophobic coatings, and composite coatings. Furthermore, we propose implementation approaches for these coatings to address inflammation and infection challenges associated with blood-contacting devices. The review concludes with a brief overview of current surface modification technologies employed in commercial anti-fouling coatings and offers insights into the future of anti-fouling coating technologies for blood-contacting material surfaces. These advancements are essential for the advancement of design, development, and application of blood-contacting materials.</p></div>","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"5 1","pages":"Pages 166-180"},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590183423000431/pdfft?md5=8ad11314421acec30dc5d25ddd1674c8&pid=1-s2.0-S2590183423000431-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138582430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dan Yang , Hailan Chen , Hua Wei , An Liu , Dai-Xu Wei , Jing Chen
{"title":"Hydrogel wound dressings containing bioactive compounds originated from traditional Chinese herbs: A review","authors":"Dan Yang , Hailan Chen , Hua Wei , An Liu , Dai-Xu Wei , Jing Chen","doi":"10.1016/j.smaim.2023.10.004","DOIUrl":"https://doi.org/10.1016/j.smaim.2023.10.004","url":null,"abstract":"<div><p>Various factors can cause skin defects, resulting in the loss of physiological functions and even death due to severe concurrent infection. Dressings are often clinically used to fully cover the wounds to improve healing. Hydrogel wound dressings can be loaded with therapeutic compounds (<em>e.g.</em>, curcumin) within their three-dimensional networks to enable the in situ delivery of compounds at skin defects for wound healing. In recent decades, natural herbal active components have gradually gained worldwide recognition owing to their safe and diverse therapeutic effects, and an increasing number of bioactive components can be loaded into hydrogels or directly act as hydrogel matrices to enhance safety and achieve the desired therapeutic effects. In this review, twelve bioactive compounds from natural Chinese herbs that can promote wound healing and their mechanism of action are summarized, and the latest research progress in the use of Chinese herbal hydrogels for wound treatment is reviewed.</p></div>","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"5 1","pages":"Pages 153-165"},"PeriodicalIF":0.0,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590183423000467/pdfft?md5=30175c670f61a2af412ea348271066d2&pid=1-s2.0-S2590183423000467-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137116143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yue Zhou , Yumeng Xue , Xubo Lin , Menglong Duan , Weili Hong , Lina Geng , Jin Zhou , Yubo Fan
{"title":"Smartphone-based polydiacetylene colorimetric sensor for point-of-care diagnosis of bacterial infections","authors":"Yue Zhou , Yumeng Xue , Xubo Lin , Menglong Duan , Weili Hong , Lina Geng , Jin Zhou , Yubo Fan","doi":"10.1016/j.smaim.2023.10.002","DOIUrl":"https://doi.org/10.1016/j.smaim.2023.10.002","url":null,"abstract":"<div><p>The rapid progress in point-of-care testing (POCT) has become a promising decentralized patient-centered approach for the control of infectious diseases, especially in resource-limited settings. POCT devices should be inexpensive, rapid, simple operation and preferably require no power supply. Here, we developed a simple bacterial sensing platform that can be operated by a smartphone for bacteria identification and antimicrobial susceptibility testing (AST) based on using a polydiacetylene (PDA) arrayed membrane chip. Each PDA array produced a unique color ‘fingerprint’ pattern for each bacteria based on different modes of action of toxins from bacteria on biomimetic lipid bilayers within PDA-lipid assemblies. We show that the PDA-based device can detect viable cells of bacteria as low as 10<sup>4</sup> CFU/mL within 1.5 h compared with several days of conventional bacterial identification, with the aid of a smartphone app. The device can also be used for an antimicrobial susceptibility test (AST) for at least two broad-spectrum antimicrobials within 4 h and provide identification of antimicrobial susceptibility and resistance, enabling the selection of appropriate therapies. This PDA-based sensing platform provides an alternative way for bacterial detection and could be used as a portable and inexpensive POCT device for the rapid detection of bacterial infection in limited-resource settings.</p></div>","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"5 1","pages":"Pages 140-152"},"PeriodicalIF":0.0,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590183423000443/pdfft?md5=b89fa660f31883a469339ba6e9814a65&pid=1-s2.0-S2590183423000443-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137116142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthew S. Dargusch , Nicolas Soro , Ali Gokhan Demir , Jeffrey Venezuela , Qiang Sun , Yuan Wang , Abdalla Abdal-hay , Aya Q. Alali , Saso Ivanovski , Barbara Previtali , Damon Kent
{"title":"Optimising degradation and mechanical performance of additively manufactured biodegradable Fe–Mn scaffolds using design strategies based on triply periodic minimal surfaces","authors":"Matthew S. Dargusch , Nicolas Soro , Ali Gokhan Demir , Jeffrey Venezuela , Qiang Sun , Yuan Wang , Abdalla Abdal-hay , Aya Q. Alali , Saso Ivanovski , Barbara Previtali , Damon Kent","doi":"10.1016/j.smaim.2023.10.003","DOIUrl":"10.1016/j.smaim.2023.10.003","url":null,"abstract":"<div><p>Additively manufactured lattices based on triply periodic minimal surfaces (TPMS) have attracted significant research interest from the medical industry due to their good mechanical and biomorphic properties. However, most studies have focussed on permanent metallic implants, while very little work has been undertaken on manufacturing biodegradable metal lattices. In this study, the mechanical properties and <em>in vitro</em> corrosion of selective laser melted Fe–35%Mn lattices based on gyroid, diamond and Schwarz primitive unit-cells were comprehensively evaluated to investigate the relationships between lattice type and implant performance. The gyroid-based lattices were the most readily processable scaffold design for controllable porosity and matching the CAD design. Mechanical properties were influenced by lattice geometry and pore volume. The Schwarz lattices were stronger and stiffer than other designs with the 42% porosity scaffold exhibiting the highest combination of strength and ductility, while diamond and gyroid based scaffolds had lower strength and stiffness and were more plastically compliant. The corrosion behaviour was strongly influenced by porosity, and moderately influenced by geometry and geometry-porosity interaction. At 60% porosity, the diamond lattice displayed the highest degradation rate due to an inherently high surface area-to-volume ratio. The biodegradable Fe–35Mn porous scaffolds showed a good cytocompatibility to primary human osteoblasts cells. Additive manufacturing of biodegradable Fe–Mn alloys employing TPMS lattice designs is a viable approach to optimise and customise the mechanical properties and degradation response of resorbable implants toward specific clinical applications for hard tissue orthopaedic repair.</p></div>","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"5 1","pages":"Pages 127-139"},"PeriodicalIF":0.0,"publicationDate":"2023-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590183423000455/pdfft?md5=0cd70ae9e634245f56ae4c18fbc9f38d&pid=1-s2.0-S2590183423000455-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136007631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}