European Journal of Pharmaceutics and Biopharmaceutics最新文献

{"title":"Molecular effects of paclitaxel-elacridar nanoemulsions in breast cancer cells: impact on uptake, cell cycle and signaling pathways","authors":"Giovanna C. Salata,&nbsp;Isabella D. Malagó,&nbsp;Giovanna Barros de Melo,&nbsp;João Agostinho Machado-Neto,&nbsp;Luciana B. Lopes","doi":"10.1016/j.ejpb.2025.114837","DOIUrl":"10.1016/j.ejpb.2025.114837","url":null,"abstract":"<div><div>In this study, we investigated how paclitaxel incorporation in a bioadhesive, hyaluronic acid-modified nanoemulsion (NE) containing the P-glycoprotein inhibitor elacridar influenced its molecular effects and mechanism of action in breast cancer cells. Incorporation of paclitaxel with elacridar in the nanoemulsion resulted in a 2.5-fold increase in cellular uptake compared to the drug solution. Clathrin-mediated endocytosis contributed to nanoemulsion-mediated cell internalization, with both paclitaxel and NBD-phosphatidylcholine (nanoemulsion surfactant) partially co-localizing with transferrin. The nanoemulsion amplified paclitaxel-mediated chromatin condensation and expression of proteins involved in apoptosis, with a 2.5-fold increase in PARP1 (Poly (ADP-ribose) polymerase 1) cleavage and a 1.7-fold downregulation of BCL2 (B-cell lymphoma protein 2) expression. Apoptosis was maintained as the main mechanism of cell death. The formulation also reduced cell migration (3-fold) compared to the solution at concentrations lower than IC₅₀, while the clonogenic effect (17-fold) was not hindered, supporting a broader impact on tumorigenesis.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"215 ","pages":"Article 114837"},"PeriodicalIF":4.3,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820971","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":"Advances in auricular drug delivery for the management of different otitic conditions","authors":"Niloy Barman ,&nbsp;Sunil Kumar Sah ,&nbsp;Subhadeep Roy ,&nbsp;Santanu Kaity","doi":"10.1016/j.ejpb.2025.114836","DOIUrl":"10.1016/j.ejpb.2025.114836","url":null,"abstract":"<div><div>Millions of people suffer greatly from ear diseases, yet finding effective treatments for these conditions is a constant but frequently disregarded task, especially regarding product development and formulation design. While considerable research has focused on understanding the pathophysiology and treatment of otic diseases, relatively less attention has been paid to innovating targeted and efficient drug delivery systems. This review provides a comprehensive overview of the anatomical and physiological barriers of the ear, the spectrum of otic diseases, and currently available therapeutic approaches. Special emphasis is placed on the evolving landscape of otic drug delivery, including topical, intratympanic, and intracochlear administration routes. The manuscript critically discusses the role of advanced materials such as hydrogels, nanoparticles, and biodegradable polymers in enhancing drug residence time, permeability, and site-specific targeting within the complex inner ear environment. Furthermore, it highlights recent innovations, key challenges, such as limited drug diffusion, pharmacokinetic variability, and emerging strategies, including thermoresponsive systems and bioresponsive platforms. The review concludes by outlining future perspectives in the field, pointing toward developing minimally invasive, precisely controlled, and patient-friendly delivery systems that may revolutionize the treatment of otic diseases in the coming decades.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"215 ","pages":"Article 114836"},"PeriodicalIF":4.3,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798537","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":"Effects of antimicrobial preservatives on protein folding stability and subvisible particle formation in monoclonal antibody trastuzumab","authors":"Ravi Maharjan ,&nbsp;Shavron Hada ,&nbsp;I. Jeong Shin ,&nbsp;Ki Hyun Kim ,&nbsp;Nam Ah Kim ,&nbsp;Seong Hoon Jeong","doi":"10.1016/j.ejpb.2025.114835","DOIUrl":"10.1016/j.ejpb.2025.114835","url":null,"abstract":"<div><div>To prevent microbial contamination, antimicrobial preservatives need to be added in multi-dose biopharmaceuticals; however, it often introduces risks to protein stability, potentially compromising therapeutic efficacy. In this study, we investigated the effects of different preservatives (benzyl alcohol, m-cresol, phenoxyethanol, and benzalkonium chloride) on the biophysical stability of trastuzumab, a monoclonal antibody widely used for treatment of HER2 receptor-positive cancers. Among the preservatives tested, benzyl alcohol (1.0 % v/v) and m-cresol (0.3 % w/v) significantly reduced the monomeric content after 5 days of end-over-end agitation stress. Benzyl alcohol was associated with a surge in nano- to micro-sized particles (21-fold increase) and decreased thermal stability (Δ<em>T_m</em>: −5.39 °C). m-Cresol uniquely triggered visible particle formation (&gt;100 µm) within 72 h, raising concerns for injectable biologics. Benzalkonium chloride (0.01 %–0.04 % w/v) exhibited inconsistent concentration-dependent behavior, initially showing increase in subvisible aggregates before stabilizing through micelle formation at higher concentrations, albeit with irreversible secondary structural shifts toward β-sheet motifs. Conversely, phenoxyethanol (0.5 % v/v) exhibited higher compatibility, preserved the monomeric content, and suppressed particle generation to baseline levels. These findings underscore the necessity of preservative-specific compatibility assessments in formulation design for therapeutic biologics, positioning phenoxyethanol as a promising candidate for trastuzumab preservation owing to the balance between its antimicrobial efficacy and minimal destabilization.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"215 ","pages":"Article 114835"},"PeriodicalIF":4.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774972","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":"Non-invasive detection of protein aggregation in biopharmaceuticals using TD-NMR and MRI","authors":"Gozde Ozesme Taylan ,&nbsp;Hani Alam ,&nbsp;Erdem Mercan ,&nbsp;Ece Erkan ,&nbsp;Cem Yamali ,&nbsp;Mecit Halil Oztop","doi":"10.1016/j.ejpb.2025.114830","DOIUrl":"10.1016/j.ejpb.2025.114830","url":null,"abstract":"<div><div>With the rapid expansion of biotechnological drugs, ensuring their quality has become essential. Proper storage and transportation are critical to maintaining drug stability and efficacy. This study investigates protein aggregation, a major quality concern in biopharmaceuticals, using low-field NMR, Time Domain NMR and Magnetic Resonance Imaging (MRI), as a non-invasive, rapid alternative to conventional analytical methods. For the first time, MRI, T₂ relaxation times, and T₂ relaxation spectra were applied to detect aggregation in Humulin R, a low-concentration subcutaneous insulin. Aggregation was induced by heat and agitation to simulate improper handling. MRI effectively distinguished control and stressed samples, while T₂ relaxation measurements differentiated stress conditions. Additionally, T₂-Inverse Laplace Transform (<em>ILT</em>) indicated aggregate size, aligning with particle size analysis and validating the novel approach. These findings highlight the potential of low-field NMR for biopharmaceutical quality assessment.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"215 ","pages":"Article 114830"},"PeriodicalIF":4.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772695","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":"Cryoconcentration modeling and experimental measurements for freezing and thawing of a biologic bulk drug substance","authors":"Nirajan Adhikari ,&nbsp;Evgeniia Vorozhbit ,&nbsp;Petr Kazarin ,&nbsp;Gayathri Shivkumar ,&nbsp;Darryl Drake ,&nbsp;Jie Wang ,&nbsp;Mrinal Shah ,&nbsp;Sherwin Shang ,&nbsp;Alina A. Alexeenko","doi":"10.1016/j.ejpb.2025.114812","DOIUrl":"10.1016/j.ejpb.2025.114812","url":null,"abstract":"<div><div>The freezing and thawing process is a key determinant of the cryoconcentration distribution in pharmaceutical and biological bulk drug substances (BDS), which has a direct and inevitable impact on protein stability. Due to the critical influence of cryoconcentration — either stabilizing or destabilizing the protein depending on its distribution — understanding the specific mechanisms and changes occurring during freezing and thawing is essential for ensuring the stability of the BDS and, by extension, the drug product (DP). This work presents computational modeling of protein cryoconcentration induced by freezing and thawing in a two-liter plastic container. The study utilized fixed-grid modeling with a species segregation model to investigate freezing and thawing dynamics that lead to a shift in protein concentration distribution inside the container, simulating typical processing for pharmaceutical bulk drug substance. The model incorporates a partition coefficient to represent protein distribution between the BDS solution phase and the frozen ice phase. The solute (such as protein) partitioning during ice formation and gravity settlement of protein-rich liquid from the ice–liquid interface towards the bottom of a container creates cryoconcentration during freezing in an ultra-low temperature freezer. Simulations of previously frozen solution subjected to water-bath thawing at <span><math><mrow><mo>+</mo><mn>23</mn><mspace></mspace><mo>°</mo><mi>C</mi></mrow></math></span> showed a further increase of protein concentration at the bottom of the container due to the inability of the free convective currents set up during the thawing process to overcome the density based segregation. The modeling results were consistent with experimental measurements of freezing and thawing of Human serum albumin solution at 60 mg/mL in 2 L bottles, showing promise for the utilization of computational techniques to design process and equipment that reduces protein cryoconcentration and segregation gradients during freeze–thaw operation improving pharmaceutical manufacturing and product quality.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"215 ","pages":"Article 114812"},"PeriodicalIF":4.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793829","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":"Advancements in drug delivery systems for women’s reproductive health: Vaginal microbiome as a target for innovative drug delivery systems","authors":"Peace-OfonAbasi O. Bassey ,&nbsp;Margaret O. Ilomuanya ,&nbsp;Bukola A. Oseni ,&nbsp;Deborah A. Ogundemuren ,&nbsp;Karamot O. Oyediran ,&nbsp;Evans N. Ekeji ,&nbsp;Peter Abia","doi":"10.1016/j.ejpb.2025.114831","DOIUrl":"10.1016/j.ejpb.2025.114831","url":null,"abstract":"<div><div>The vaginal microbiome, predominantly made up of <em>Lactobacillus spp</em>., plays a pivotal role in women’s reproductive health, especially in dysbiosis associated with various gynecological disorders. In this comprehensive review, we discussed the current advancements in drug delivery systems targeting the vaginal microbiome, the limitations of traditional approaches, as well as explored innovative strategies in drug delivery with the vaginal microbiome as the focal point. The composition and functions of the vaginal microbiome were critically evaluated, emphasizing its significance in maintaining reproductive health. Conventional drug delivery methods, including oral, parenteral, and topical routes are faced with pharmacokinetic challenges such as poor bioavailability and limited targeted delivery. The emergence of vaginal drug delivery systems such as gels, films, rings, nanoparticulate formulations and electrospun fibers show the potential to enhance therapeutic efficacy through localized and sustained drug release. We highlighted the findings on crucial formulation considerations including physicochemical properties of drugs, excipient selection, and targeting strategies. Furthermore, we analyzed pre-clinical studies utilizing <em>in vitro</em> models including organ-on-a-chip and cell cultures, as well as <em>in vivo</em> animal models to assess the safety, efficacy, and pharmacokinetics of these innovative systems. Additionally, the review revealed that cutting-edge technologies such as electrospun fibers and 3D bioprinted scaffolds show promise for precise control over drug release kinetics and probiotic delivery. Future directions should focus on personalized approaches, ethical considerations, and patient education to fully leverage these technologies for improving women’s reproductive health outcomes globally.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"215 ","pages":"Article 114831"},"PeriodicalIF":4.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774971","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":"Controlled release of curcumin and gemcitabine from mucoadhesive chitosan-gelatin polymeric ovules: Cytotoxic effects on cervical cancer cells","authors":"Oscar Alberto Alvarez-Quezada ,&nbsp;Yaresli Edaly Espino-Núñez ,&nbsp;Laura Elizabeth Valencia-Gómez ,&nbsp;Santos Adriana Martel-Estrada ,&nbsp;Norma Cesilia Arellano-Rodríguez ,&nbsp;Pablo Zapata-Benavides ,&nbsp;Claudia Lucía Vargas-Requena","doi":"10.1016/j.ejpb.2025.114834","DOIUrl":"10.1016/j.ejpb.2025.114834","url":null,"abstract":"<div><div>Cervical cancer (CxCa) is the fourth most common type of neoplasm affecting the global female population. Treatment for CxCa typically involves the systemic administration of chemotherapeutic agents. However, these treatments often result in fatigue, increased risk of infection, nausea, vomiting, hair loss, loss of appetite, and diarrhea. Therefore, it is crucial to explore new drugs and site-specific drug delivery strategies to combat cervical neoplasia. This study aimed to design vaginal suppositories based on chitosan–gelatin that enable mucoadhesion and the release of curcumin and gemcitabine and to evaluate their effects on HeLa cells. Gelatin-chitosan ovules loaded with curcumin and gemcitabine were successfully formulated. The uptake of simulated vaginal fluid (SVF) resulted in an increase in weight ranging from 40 % to 80 %. The ovules exhibited porosity<!--> <!-->and hydrophilicity and demonstrated mucoadhesive properties on porcine vaginal tissue. After 8 h of incubation at 37 °C, ovules containing 10 % gelatin released more curcumin, while those with 10 % and 20 % released more gemcitabine. Curcumin and gemcitabine exhibited cytotoxic effects on HeLa cells, with IC₅₀ values of 13.47 µM and 0.15 µM, respectively. Furthermore, it was observed that curcumin reversed gemcitabine-induced necrosis and promoted a mechanism like apoptosis or necroptosis. These findings suggest that ovules loaded with curcumin and gemcitabine can potentially serve as a site-specific treatment for CxCa.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"215 ","pages":"Article 114834"},"PeriodicalIF":4.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772696","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":"Better GRAS than sorry: Excipient toxicity in pulmonary formulations","authors":"Eleonore Fröhlich","doi":"10.1016/j.ejpb.2025.114814","DOIUrl":"10.1016/j.ejpb.2025.114814","url":null,"abstract":"<div><div>Similar to other routes of administration, pulmonary formulations typically contain excipients. The panel of substances that can be used in pulmonary formulations is limited compared to other routes of administration, and most of them have the generally regarded as safe (GRAS) status. New excipients must undergo in vitro and complete in vivo testing to be approved by regulatory authorities. The toxic effects induced by excipients contained in the most common pulmonary formulations (dry powder inhalers, pressurized metered dose inhalers, and nebulizers) were summarized to compare the cytotoxic effects to the approved concentrations. The hypothesis was that a concentration much higher than the approved one could serve as an indicator of the safety of the compound. While the cytotoxic concentration of many excipients was higher than the approved concentration, the opposite was found for some of them. For most of these compounds, adverse lung effects were reported with long-term administration or in specific populations. This suggests that concentrations lower than the cytotoxic threshold are unlikely to cause adverse respiratory effects. Combining excipients can increase toxic effects, but few studies address this. Since neither cytotoxicity testing nor animal testing can reliably identify toxic concentrations of excipients, additional in vitro tests have been proposed.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"215 ","pages":"Article 114814"},"PeriodicalIF":4.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717758","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":"HDL and LDL-bioinspired nanocarriers in acellular targeted delivery of Icariin for cardiac repair post myocardial infarction","authors":"Nermeen H. Kamal ,&nbsp;Lamia A. Heikal ,&nbsp;Basant A. Bakr ,&nbsp;Maged W. Helmy ,&nbsp;Ossama Y. Abdallah","doi":"10.1016/j.ejpb.2025.114816","DOIUrl":"10.1016/j.ejpb.2025.114816","url":null,"abstract":"<div><div>Myocardial infarction (MI) is a major ischemic heart condition that leads to the loss of billions of cardiomyocytes, triggering adverse ventricular remodeling and fibrotic tissue formation, which can ultimately result in heart failure. Current treatments fail to address cardiomyocyte loss, prompting interest in cardiac regeneration strategies. Although cell-based therapies have gained attention, they face limitations such as poor cell survival and engraftment. Acellular nanoformulations represent a promising alternative. In this study, protein-free bioinspired lipid nanoparticles mimicking low- and high-density lipoprotein; LDL and HDL—namely LDE and HDA—were developed and loaded with the phytomedicine Icariin. Both systems demonstrated high encapsulation efficiency (&gt;90 %), favorable drug release profiles, and good serum stability. In vitro, LDE and HDA exhibited superior cellular uptake in H9c2 cells and significantly improved cell viability in doxorubicin-treated cultures compared to free Icariin. Pretreatment with LDE-Icariin effectively reduced cardiomyocyte apoptosis following doxorubicin exposure. Biodistribution analysis revealed enhanced targeting of infarcted myocardium by HDA over LDE in a rat MI model. Moreover, HDA markedly reduced cardiac damage and promoted regeneration more effectively than LDE. These findings highlight HDA and LDE as cost-effective, bioinspired nanoformulations for cardiac repair, with HDA showing superior targeting and therapeutic performance.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"214 ","pages":"Article 114816"},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703676","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":"Age-dependent oral drug absorption in children: Assessment of a bottom-up modelling approach","authors":"Fabian Winter,&nbsp;Jonas Lange,&nbsp;Sandra Klein","doi":"10.1016/j.ejpb.2025.114815","DOIUrl":"10.1016/j.ejpb.2025.114815","url":null,"abstract":"<div><div>Paediatric drug development poses significant challenges due to the unique physiological and ethical considerations in children. Physiologically Based Pharmacokinetic (PBPK) modelling has emerged as a valuable tool for predicting paediatric drug absorption and optimising dosing strategies. This study aimed to refine PBPK modelling for paediatric applications by developing a customised PK-Sim-based paediatric PBPK (pPBPK) model for four drugs that are part of the Model List of Essential Medicines for Children by the World Health Organisation: paracetamol, ibuprofen, darunavir, and itraconazole. The model incorporated age-specific gastrointestinal parameters for four paediatric age groups, minimising the need for parameter interpolation or scaling. The effect of food on drug absorption was investigated by extending the absorption model to account for bile and excipient solubilisation. A literature review identified gaps in the understanding of paediatric intestinal parameters necessary for pPBPK modelling. Biorelevant <em>in vitro</em> dissolution and solubility data were integrated to enhance prediction accuracy. Validation with clinical pharmacokinetic data demonstrated the model’s reliability across different paediatric age groups. Sensitivity analyses highlighted the influence of gastric emptying time, small intestinal transit, and bile salt concentration on drug pharmacokinetics. This research underscores the potential of pPBPK modelling to inform paediatric dosing strategies while addressing current gaps and challenges.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"214 ","pages":"Article 114815"},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706872","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}