Biomedical materials (Bristol, England)最新文献

{"title":"Investigation of novel carboxymethyl chitosan-based bioinks for 3D bioprinting of neural tissues.","authors":"Amanda C Juraski, Victor A da Silva, Ruchi Sharma, Adriano R Azzoni, Stephanie M Willerth","doi":"10.1088/1748-605X/add6f9","DOIUrl":"10.1088/1748-605X/add6f9","url":null,"abstract":"<p><p>The formulation of bioinks is critical for successful 3D bioprinting. It influences printability, stability, and cell behavior. One of the main demands in 3D bioprinting is the development of bioink formulations that can balance long-term cell viability and compositional similarities to the extracellular matrix (ECM) with rheological properties for 3D printing. To address this challenge, this study tested new bioinks using carboxymethyl chitosan (N,O-CMCS or O-CMCS), alginate, and fibrin, which are promising biomaterials due to their biocompatibility and likeness to the ECM. 3D bioprinting of neural tissues comes with additional challenges because neural cells are highly sensitive to environmental conditions. Therefore, we optimized our bioink formulations for the 3D bioprinting of neural progenitor cells derived from human induced pluripotent stem cells (hiPSC-NPC). Here we report a neural tissue constructed 3D bioprinted with a hiPSC-NPC-laden 1% N,O-CMCS, 1% alginate, and 20 mg ml^-1fibrin. This formulation exhibited uniform consistency and minimal extrusion force fluctuations (approximately 8 KPa), indicating homogeneity and optimal printability using an extrusion-based bioprinter. In contrast, O-CMCS formulations did not support neural tissue differentiation while higher concentrations of N,O-CMCS or alginate (3% w/v) resulted in increased viscosity and poorly defined scaffolds. The optimized bioink demonstrated significant water retention, swelling up to 15 times its original weight without losing structural integrity, thus providing a conducive environment for cell culture. Live/dead staining revealed over 60% cell viability over 30 d, underscoring its suitability for long-term cell applications. Immunocytochemistry confirmed that the optimized N,O-CMCS-based bioink effectively guided cells toward further differentiation into neurons and astrocytes, thus forming a 3D bioprinted construct that is able to replicate different neural cell types found in the neural tissue. The optimized bioink described in this study lays the groundwork for future works that will focus on detailing how different CMCS groups affect tissue maturation and functionality in 3D bioprinted constructs that can potentially be used for future neural tissue modeling and drug screening.</p>","PeriodicalId":72389,"journal":{"name":"Biomedical materials (Bristol, England)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Red blood cell membrane-camouflaged nanocarriers for the delivery of piperlongumine to treat triple-negative breast cancer.","authors":"Chenxi Li, Jiaxin Zhang, Xianxian Yao, Yuxin Huang, Yichen Zhang, Wuli Yang","doi":"10.1088/1748-605X/add4da","DOIUrl":"10.1088/1748-605X/add4da","url":null,"abstract":"<p><p>The application of the conventional drugs for triple-negative breast cancer (TNBC) treatment in chemotherapy is limited due to their intrinsic drawbacks such as short drug half-life, lack of tumor selectivity and systemic toxicity. Herein, an effective nanoparticle drug delivery system (NDDS) of red blood cell (RBC) membrane-camouflaged piperlongumine (PL)-loaded iron oxide (Fe₃O₄) magnetic nanoparticles (Fe₃O₄-PL@RBC) was rationally designed as an effective drug delivery platform for<i>in vivo</i>TNBC treatment. The Fe₃O₄-PL@RBC showed considerable cytotoxicity against MDA-MB-231 cells, inducing intracellular accumulation of reactive oxygen species, mitochondrial dysfunction and apoptosis. Furthermore, transcriptomic analyses and western blotting analysis demonstrated that the Fe₃O₄-PL@RBC induced apoptosis through the inhibition of PI3K/AKT/mTOR pathway and downregulation of Bcl-2 protein. In MDA-MB-231 tumor models, the RBC membrane coating in Fe₃O₄-PL@RBC effectively prolonged the circulation time and sufficient enrichment at the tumor sites. And the Fe₃O₄-PL@RBC significantly inhibited tumor growth with good biosafety. This study provides guidance for the rational design of effective Fe₃O₄-based NDDS for TNBC treatment.</p>","PeriodicalId":72389,"journal":{"name":"Biomedical materials (Bristol, England)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in anti-tumor mechanisms and biological applications of vanadium compounds.","authors":"Xinhao Dang, Yan Xue, Siying Zhang, Menglan Chen, Kangliang Sheng, Jie Ma, Shan Gao, Yongzhong Wang","doi":"10.1088/1748-605X/add3e5","DOIUrl":"https://doi.org/10.1088/1748-605X/add3e5","url":null,"abstract":"<p><p>Vanadium, a transition metal, has emerged as a promising element in the development of therapeutic drugs. While not an essential element for life, vanadium compounds have demonstrated significant potential as anticancer agents. Current evidence suggests that these compounds exert their anti-tumor effects through multiple mechanisms, including DNA damage, cell cycle regulation, induction of apoptosis and autophagy, inhibition of metastasis and invasion, and disruption of mitochondrial function. Furthermore, vanadium compounds have shown efficacy against a wide range of cancers, such as melanoma, breast, colorectal, pancreatic, liver, and central nervous system tumors, as well as oral squamous cell carcinoma. This review aims to comprehensively examine the anti-tumor properties and underlying mechanisms of various vanadium compounds while also providing an overview of their current biological applications.</p>","PeriodicalId":72389,"journal":{"name":"Biomedical materials (Bristol, England)","volume":"20 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioprosthetic heart valves with zwitterionic copolymer grafting to improve the properties of endothelialization and anti-calcification.","authors":"Daoyang Zhu, Yu Luo, Shenyu Huang, Lie Ma","doi":"10.1088/1748-605X/add3e7","DOIUrl":"https://doi.org/10.1088/1748-605X/add3e7","url":null,"abstract":"<p><p>Heart valve replacement surgery has been the most effective treatment for severe valvular heart disease. Bioprosthetic heart valves (BHVs) crosslinked by glutaraldehyde (GA) have non-negligible advantages in clinical applications. However, structural valve degeneration, calcification, insufficient re-endothelialization and other factors lead to a shortened service life of BHVs. In this study, GA-crosslinked decellularized heart valves (GADHVs) were grafted with zwitterionic copolymer (PSBG) of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide and glycidyl methacrylate, and further treated with Arg-Glu-Asp-Val (REDV) peptide to obtain REDV-PSBG-GADHVs with anti-fouling ability and endothelial cell affinity. REDV-PSBG-GADHVs exhibited good collagen stability, reliable mechanical property and excellent hemocompatibility. Moreover,<i>in vitro</i>and<i>in vivo</i>experiments demonstrated that REDV-PSBG-GADHVs exhibited better endothelialization property, lower immune responses and reduced calcification than GADHVs. This modified strategy for heart valve fabrication, which can improve the effect of anti-calcification and endothelialization while maintaining the original advantages of BHVs, shows great potential for application in heart valve replacement.</p>","PeriodicalId":72389,"journal":{"name":"Biomedical materials (Bristol, England)","volume":"20 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chitosan nanoparticles: a versatile frontier in drug delivery and wound healing across multiple routes.","authors":"Anshul Singh, Sheersha Pramanik, Ammar Kadi, Bassam M Abualsoud, Manisha Singh, Mohammad Javed Ansari, Abdelwahab Omri, A Deepak, Pankaj Nainwal, Stefano Bellucci","doi":"10.1088/1748-605X/add3e6","DOIUrl":"https://doi.org/10.1088/1748-605X/add3e6","url":null,"abstract":"<p><p>The domain of nanoscience has observed significant advancements over the former two decades. Researchers in nanomedicine field have been rigorously exploring the employment of natural biodegradable polymers for targeted drug delivery (TDD). Chitosan (CS), acquired from the deacetylation of chitin, is a naturally occurring amino polysaccharide, whose features of non-toxicity, prolonged retention time, biocompatibility, increased bioavailability, and biodegradability have hastened extensive study into diverse applications. The presence of amino and hydroxyl groups within CS is crucial for its noteworthy characteristics, comprising mucoadhesion, improvement of permeation, drug's-controlled release,<i>in situ</i>gel preparation, and antimicrobial activity. CS nanoparticles (CS NPs) portray a safe and competent class of nanocarrier systems, demonstrating the controlled release of drugs and preciseness in TDD, and are found hopeful for treating wounds. However, safety concerns such as potential toxicity, immune response, and hemocompatibility must be carefully evaluated to ensure their suitability for clinical applications. This article explores the potential of CS NPs as versatile carriers for TDD, reporting essential challenges in both therapeutic domains, and progressing the advancement of innovative treatments. By connecting drug delivery and wound healing, our review addresses a critical convergence, fostering developments that can certainly affect treatment and recovery of patient. The initial part of the review will shed light on the extraction sources and notable attributes of CS. Additionally, we have presented recent research findings on how CS NPs are being utilized for drug delivery via different routes of administration. Further, we have endeavored to represent the latest investigations on the applications of CS NPs in wound healing.</p>","PeriodicalId":72389,"journal":{"name":"Biomedical materials (Bristol, England)","volume":"20 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A preliminary study on the promotion of wound healing by paeoniflorin carbon dots loaded in chitosan hydrogel.","authors":"Ruiming Feng, Feng Tian, Jian Zhou, Yilin Ping, Wenze Han, Xuexue Shi, Xue Bai, Yufeng Sun, Jiali Zhao, Xiuping Wu, Bing Li","doi":"10.1088/1748-605X/add2ba","DOIUrl":"https://doi.org/10.1088/1748-605X/add2ba","url":null,"abstract":"<p><p>Due to poor angiogenesis under the wound bed, wound treatment remains a clinical challenge. Therefore, there is an urgent need for new dressings to combat bacterial infections, accelerate angiogenesis, and accelerate wound healing. In this study, we prepared carbon dots nanomaterial (PF-CDs) derived from traditional Chinese medicine paeoniflorin using a simple green one pot hydrothermal method. The average particle size of the CSs we prepared was 4 nm, and a concentration of 200 μg ml^-1was ultimately selected for experiments. Subsequently, PF-CDs were loaded into the chitosan hydrogel to form a new type of wound dressing CSMA@PF-CDs hydrogel. CSMA@PF-CDs demonstrated positive biocompatibility by promoting a 20% increase in cell proliferation and strong antibacterial activity. In comparison to the control group, CSMA@PF-CDs enhanced the expression level of anti-inflammatory factors by at least 2.5 times and reduces the expression level of pro-inflammatory factors by at least 3 times. Furthermore, CSMA@PF-CDs promoted the migration of Human umbilical vein endothelial cells and increased vascular endothelial growth factor expression by 5 times. The results of<i>in vivo</i>experiments indicate that CSMA@PF-CDs significantly promoted the healing of back wounds in rats. These characteristics make it a promising material for repairing infected wounds and a potential candidate for clinical skin regeneration applications.</p>","PeriodicalId":72389,"journal":{"name":"Biomedical materials (Bristol, England)","volume":"20 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive review of emerging 3D-printing materials against bacterial biofilm growth on the surface of healthcare settings.","authors":"Shristi Panigrahi, Shraavani Konatam, Antara Tandi, Dijendra Nath Roy","doi":"10.1088/1748-605X/add2bb","DOIUrl":"https://doi.org/10.1088/1748-605X/add2bb","url":null,"abstract":"<p><p>A significant burden on the healthcare system, microbial contamination of biomedical surfaces can result in hospital-acquired illnesses. Bacteria, viruses, and fungi may live on surfaces for days or months and spread to patients and medical personnel. This article describes the 3D printing technologies, such as fused deposition modeling, bioprinting, binder jetting/inkjet, poly-jet, electron beam manufacturing, stereolithography, selective laser sintering, and laminated object manufacturing used for manufacturing the healthcare setting's surface to reduce bacterial contamination with exploring anti-biofilm activity against different bacterial species responsible for infections, based on the critical evaluation of published reports. This strategy has immense potential to become an upcoming approach for advancing the coating concept on the material's surface in healthcare settings. Our literature evaluation identifies beneficial 3D printing materials and associated technologies against microorganisms' growth, mainly bacteria involved in implant-based infection, emphasizing the development of anti-biofilm 3D-printed surfaces. Additionally, the authors have identified a few key areas where research and development are critically required to advance 3D-printing technology in healthcare settings.</p>","PeriodicalId":72389,"journal":{"name":"Biomedical materials (Bristol, England)","volume":"20 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fiber-reinforced gelatin-based hydrogel biocomposite tubular scaffolds with programmable mechanical properties.","authors":"Xiong Yu, Zhongfei Zou, Yi Li, Jiachun Li, Yuewei Chen, Wenhai Shi, Xixia Liu, Rui Guo, Xianhui Cai","doi":"10.1088/1748-605X/add2bc","DOIUrl":"https://doi.org/10.1088/1748-605X/add2bc","url":null,"abstract":"<p><p>Tissue-engineered tubular scaffolds (TETS) provide an effective repair solution for human tubular tissue loss and damage caused by congenital defects, disease, or mechanical trauma. However, there are still major challenges to developing TETS with excellent mechanical properties and biocompatibility for human tubular tissue repair. Gelatin-based hydrogels are suitable candidates for tissue-engineered scaffolds because they are hydrolyzed collagen products and have excellent biocompatibility and degradability. However, the mechanical properties of gelatin-based hydrogels are relatively poor and do not align well with the mechanical properties of human tubular tissues. Inspired by the extracellular matrix architecture of human tubular tissues, this study utilizes high-precision 3D printing to fabricate ultrafine fiber network tubular scaffolds (UFNTS) that mimic the arrangement of collagen fibers, which are then embedded in a cell-compatible gelatin-based hydrogel, resulting in the preparation of a fiber/hydrogel biocomposite tubular scaffold (BCTS) with tunable mechanical properties and a J-shaped stress-strain response. Finite element analysis was employed to predict the mechanical behavior of the UFNTS and BCTS. Experimental results indicate that by modifying the structural parameters of the UFNTS, the mechanical properties of the BCTS can be effectively tuned, achieving a programmable range of tensile modulus (0.2-4.35 MPa) and burst pressure (1580-7850 mmHg), which broadly covers the mechanical properties of most human tubular tissues. The design and fabrication of BCTS offer a new approach for the development of TETS while also providing a personalized strategy for such scaffolds in tissue engineering.</p>","PeriodicalId":72389,"journal":{"name":"Biomedical materials (Bristol, England)","volume":"20 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144054622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Custom FDM-based bioprinter with heated nozzle: optimizing slicer settings for precision printing using a print quality index.","authors":"Leif O Meyer, Valérie Jérôme, Ruth Freitag","doi":"10.1088/1748-605X/add230","DOIUrl":"https://doi.org/10.1088/1748-605X/add230","url":null,"abstract":"<p><p>Bioprinting of microtissues has become a standard technique in medical and biotechnological research, offering a more accurate replication of the<i>in vivo</i>setting than conventional 2D cell culture. However, widespread adoption is limited by the absence of a universally accepted printing benchmark-common in standard fused deposition modeling (FDM) printing, as well as the high cost and restricted customizability of commercial bioprinters. This study introduces a method to convert a standard FDM printer into a bioprinter. All cell-contacting components are biocompatible and autoclavable, while the printer body can be UV-sanitized. Using a heated FDM printhead, we used the thermal properties of alginate-gelatin bioinks to achieve high-resolution 3D printing. A key achievement was the developed print quality index (PQI) method, which correlates nozzle temperature with bioink flow behavior, streamlining optimization of slicer settings. Guided by PQI, we reproducibly bioprinted complex alginate-gelatin structures with high quality and dimensional/geometric accuracy. A case study using recombinant HuH7^EGFPcell-laden hydrogels demonstrated long-term cell proliferation, confirming high viability. Given its efficiency, the PQI method has the potential to become the missing printing benchmark for slicer optimization in bioprinting. The presented approach significantly advances the accessibility of sophisticated bioprinting technology to interested research groups worldwide.</p>","PeriodicalId":72389,"journal":{"name":"Biomedical materials (Bristol, England)","volume":"20 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tuneable dissolution profile of tinidazole through thermoplastic polymer composites in low temperature 3D printing settings for pharmaceutical additive manufacturing applications.","authors":"Abhishek Pawar, Tukaram Karanwad, Subham Banerjee","doi":"10.1088/1748-605X/adcd36","DOIUrl":"https://doi.org/10.1088/1748-605X/adcd36","url":null,"abstract":"<p><p>Thermoplastic polymeric materials are crucial for powder bed fusion (PBF) based three-dimensional (3D) printing in pharmaceuticals. However, due to limited availability and printability nature of the used feedstocks (either as powder bed materials or composites), underscoring a pressing demand for alternative solutions in pharmaceutical additive manufacturing applications. In this study, the first-time introduction of Kollidon® 25 (K25) thermoplastic polymer, which was not previously explored in PBF-based 3D printing technology, along with the simultaneous usage of Kollidon® SR (KSR) to form a thermoplastic polymer composite for the development of a tunable solid oral dosage form. In addition to this, a novel laser-absorbing dye, i.e. Pigment Green 7, was also introduced to facilitate the laser sintering process of the used thermoplastic polymer composites. Sintered tablets obtained from the used thermoplastic polymer bed composites were systematically characterized using various analytical tools and<i>in vitro</i>examinations as well. The physicochemical characterization of all sintered tablet batches (B1-B7) was within the acceptable limit. Thermal and chemical analyses revealed no detrimental physical or chemical interactions between the components and sintered tablet batches after exposure to laser and temperature. Powder x-ray diffraction diffractograms suggested a change in the native state of tinidazole (TNZ, used as an active pharmaceutical ingredient) to amorphous due to the exposure to sintering parameters. Scanning electron microscopy micrographs of all batches showed intense fusion of the particles in the polymer composite. The sintered tablet batches B1 to B7 exhibited a drug content ranging from 90.36 ± 4.32% to 99.36 ± 1.24%. TNZ released in an acidic medium for up to 2.0 h from different sintered tablets were around 100% to 12% from B1 to B7 batches, respectively following alkaline medium for up to 12.0 h. TNZ release pattern was fine-tuned in accordance with the changes in the composition ratio of K25 and KSR polymers in order to get immediate release to sustained release. This prepared unique thermoplastic pharmaceutical grade polymer composite might broaden the range of materials accessible for PBF-mediated 3D printing in pharmaceutical industrial applications in near future.</p>","PeriodicalId":72389,"journal":{"name":"Biomedical materials (Bristol, England)","volume":"20 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}