Artificial Matrices With High-Sulfated Glycosaminoglycans and Collagen Are Anti-Inflammatory and Pro-Osteogenic for Human Mesenchymal Stromal Cells

ABSTRACT Bone healing has been described to be most efficient if the early inflammatory phase is resolved timely. When the inflammation elevates or is permanently established, bone healing becomes impaired and, moreover, bone destruction often takes place. Systemic disorders such as diabetes and bon...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of cellular biochemistry 2014-09, Vol.115 (9), p.1561-1571
Hauptverfasser: Hempel, Ute, Matthäus, Claudia, Preissler, Carolin, Möller, Stephanie, Hintze, Vera, Dieter, Peter
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1571
container_issue 9
container_start_page 1561
container_title Journal of cellular biochemistry
container_volume 115
creator Hempel, Ute
Matthäus, Claudia
Preissler, Carolin
Möller, Stephanie
Hintze, Vera
Dieter, Peter
description ABSTRACT Bone healing has been described to be most efficient if the early inflammatory phase is resolved timely. When the inflammation elevates or is permanently established, bone healing becomes impaired and, moreover, bone destruction often takes place. Systemic disorders such as diabetes and bone diseases like arthritis and osteoporosis are associated with sustained inflammation and delayed bone healing. One goal of biomaterial research is the development of materials/surface modifications which support the healing process by inhibiting the inflammatory bone erosion and suppressing pro‐inflammatory mediators and by that promoting the bone repair process. In the present study, the influence of artificial extracellular matrices (aECM) on the interleukin (IL)‐1β‐induced pro‐inflammatory response of human mesenchymal stromal cells (hMSC) was studied. hMSC cultured on aECM composed of collagen I and high‐sulfated glycosaminoglycan (GAG) derivatives did not secrete IL‐6, IL‐8, monocyte chemoattractant protein‐1, and prostaglandin E2 in response to IL‐1β. The activation and nuclear translocation of nuclear factor κBp65 induced by IL‐1β, tumor necrosis factor‐α or lipopolysaccharide was abrogated. Furthermore, these aECM promoted the osteogenic differentiation of hMSC as determined by an increased activity of tissue non‐specific alkaline phosphatase (TNAP); however, the aECM had no effect on the IL‐1β‐induced TNAP activity. These data suggest that aECM with high‐sulfated GAG derivatives suppress the formation of pro‐inflammatory mediators and simultaneously promote the osteogenic differentiation of hMSC. Therefore, these aECM might offer an interesting approach as material/surface modification supporting the bone healing process. J. Cell. Biochem. 115: 1561–1571, 2014. © 2014 Wiley Periodicals, Inc.
doi_str_mv 10.1002/jcb.24814
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1611620492</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1611620492</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4244-30ab5f41dec701b8565c409b62d737ea68b39380dafa26107d0b2d64db38333a3</originalsourceid><addsrcrecordid>eNqF0ctu1DAYBWALgei0sOAFkCU2sEjrW5zxchrBTKteEAV1aTmOM-PBsVs7Uclz8MK4nbYLJMTKXnz_8eUA8A6jQ4wQOdrq5pCwOWYvwAwjURWMM_YSzFBFUUEoJntgP6UtQkgISl6DPcIqxKngM_B7EQfbWW2Vg-dqiFabBK_tsIEru94UV6Pr1GBauHSTDkn11od13iqfoPItrINzam08XEQDF36wxYnvnOp7NYQ4PZCvMRSXaTAhM6thFyJcjb3y8Nwk4_Vm6vPRV0MM92ttnEtvwKtOuWTePq4H4MeXz9_rVXF2uTypF2eFZoSxgiLVlB3DrdEVws285KVmSDSctBWtjOLzhgo6R63qFOEYVS1qSMtZ29A5pVTRA_Bxl3sTw-1o0iB7m3S-gfImjElijjEniAnyf1qyqqSEYZzph7_oNozR54dkVVJclQKLrD7tlI4hpWg6eRNtr-IkMZL3pcpcqnwoNdv3j4lj05v2WT61mMHRDtxZZ6Z_J8nT-vgpsthN2NzMr-cJFX9Knj-vlNcXS3nB6fEpXQr5jf4BG2O6Mg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1553175919</pqid></control><display><type>article</type><title>Artificial Matrices With High-Sulfated Glycosaminoglycans and Collagen Are Anti-Inflammatory and Pro-Osteogenic for Human Mesenchymal Stromal Cells</title><source>MEDLINE</source><source>Wiley Online Library All Journals</source><creator>Hempel, Ute ; Matthäus, Claudia ; Preissler, Carolin ; Möller, Stephanie ; Hintze, Vera ; Dieter, Peter</creator><creatorcontrib>Hempel, Ute ; Matthäus, Claudia ; Preissler, Carolin ; Möller, Stephanie ; Hintze, Vera ; Dieter, Peter</creatorcontrib><description>ABSTRACT Bone healing has been described to be most efficient if the early inflammatory phase is resolved timely. When the inflammation elevates or is permanently established, bone healing becomes impaired and, moreover, bone destruction often takes place. Systemic disorders such as diabetes and bone diseases like arthritis and osteoporosis are associated with sustained inflammation and delayed bone healing. One goal of biomaterial research is the development of materials/surface modifications which support the healing process by inhibiting the inflammatory bone erosion and suppressing pro‐inflammatory mediators and by that promoting the bone repair process. In the present study, the influence of artificial extracellular matrices (aECM) on the interleukin (IL)‐1β‐induced pro‐inflammatory response of human mesenchymal stromal cells (hMSC) was studied. hMSC cultured on aECM composed of collagen I and high‐sulfated glycosaminoglycan (GAG) derivatives did not secrete IL‐6, IL‐8, monocyte chemoattractant protein‐1, and prostaglandin E2 in response to IL‐1β. The activation and nuclear translocation of nuclear factor κBp65 induced by IL‐1β, tumor necrosis factor‐α or lipopolysaccharide was abrogated. Furthermore, these aECM promoted the osteogenic differentiation of hMSC as determined by an increased activity of tissue non‐specific alkaline phosphatase (TNAP); however, the aECM had no effect on the IL‐1β‐induced TNAP activity. These data suggest that aECM with high‐sulfated GAG derivatives suppress the formation of pro‐inflammatory mediators and simultaneously promote the osteogenic differentiation of hMSC. Therefore, these aECM might offer an interesting approach as material/surface modification supporting the bone healing process. J. Cell. Biochem. 115: 1561–1571, 2014. © 2014 Wiley Periodicals, Inc.</description><identifier>ISSN: 0730-2312</identifier><identifier>EISSN: 1097-4644</identifier><identifier>DOI: 10.1002/jcb.24814</identifier><identifier>PMID: 24706396</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>Adult ; Anti-Inflammatory Agents - chemistry ; Anti-Inflammatory Agents - pharmacology ; Cell Culture Techniques ; Cell Differentiation - drug effects ; Collagen Type I - pharmacology ; EXTRACELLULAR MATRIX ; Extracellular Matrix - chemistry ; Extracellular Matrix - immunology ; Female ; Gene Expression Regulation - drug effects ; GLYCOSAMINOGLYCANS ; Glycosaminoglycans - chemistry ; Glycosaminoglycans - pharmacology ; Humans ; INFLAMMATION ; Interleukin-1beta - genetics ; Interleukin-1beta - metabolism ; Male ; MESENCHYMAL STROMAL CELLS ; Mesenchymal Stromal Cells - cytology ; Mesenchymal Stromal Cells - drug effects ; Mesenchymal Stromal Cells - immunology ; Osteogenesis - drug effects ; OSTEOGENIC DIFFERENTIATION ; PROSTAGLANDINS ; Sulfates - pharmacology</subject><ispartof>Journal of cellular biochemistry, 2014-09, Vol.115 (9), p.1561-1571</ispartof><rights>2014 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4244-30ab5f41dec701b8565c409b62d737ea68b39380dafa26107d0b2d64db38333a3</citedby><cites>FETCH-LOGICAL-c4244-30ab5f41dec701b8565c409b62d737ea68b39380dafa26107d0b2d64db38333a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcb.24814$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcb.24814$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1416,27915,27916,45565,45566</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24706396$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hempel, Ute</creatorcontrib><creatorcontrib>Matthäus, Claudia</creatorcontrib><creatorcontrib>Preissler, Carolin</creatorcontrib><creatorcontrib>Möller, Stephanie</creatorcontrib><creatorcontrib>Hintze, Vera</creatorcontrib><creatorcontrib>Dieter, Peter</creatorcontrib><title>Artificial Matrices With High-Sulfated Glycosaminoglycans and Collagen Are Anti-Inflammatory and Pro-Osteogenic for Human Mesenchymal Stromal Cells</title><title>Journal of cellular biochemistry</title><addtitle>J. Cell. Biochem</addtitle><description>ABSTRACT Bone healing has been described to be most efficient if the early inflammatory phase is resolved timely. When the inflammation elevates or is permanently established, bone healing becomes impaired and, moreover, bone destruction often takes place. Systemic disorders such as diabetes and bone diseases like arthritis and osteoporosis are associated with sustained inflammation and delayed bone healing. One goal of biomaterial research is the development of materials/surface modifications which support the healing process by inhibiting the inflammatory bone erosion and suppressing pro‐inflammatory mediators and by that promoting the bone repair process. In the present study, the influence of artificial extracellular matrices (aECM) on the interleukin (IL)‐1β‐induced pro‐inflammatory response of human mesenchymal stromal cells (hMSC) was studied. hMSC cultured on aECM composed of collagen I and high‐sulfated glycosaminoglycan (GAG) derivatives did not secrete IL‐6, IL‐8, monocyte chemoattractant protein‐1, and prostaglandin E2 in response to IL‐1β. The activation and nuclear translocation of nuclear factor κBp65 induced by IL‐1β, tumor necrosis factor‐α or lipopolysaccharide was abrogated. Furthermore, these aECM promoted the osteogenic differentiation of hMSC as determined by an increased activity of tissue non‐specific alkaline phosphatase (TNAP); however, the aECM had no effect on the IL‐1β‐induced TNAP activity. These data suggest that aECM with high‐sulfated GAG derivatives suppress the formation of pro‐inflammatory mediators and simultaneously promote the osteogenic differentiation of hMSC. Therefore, these aECM might offer an interesting approach as material/surface modification supporting the bone healing process. J. Cell. Biochem. 115: 1561–1571, 2014. © 2014 Wiley Periodicals, Inc.</description><subject>Adult</subject><subject>Anti-Inflammatory Agents - chemistry</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Cell Culture Techniques</subject><subject>Cell Differentiation - drug effects</subject><subject>Collagen Type I - pharmacology</subject><subject>EXTRACELLULAR MATRIX</subject><subject>Extracellular Matrix - chemistry</subject><subject>Extracellular Matrix - immunology</subject><subject>Female</subject><subject>Gene Expression Regulation - drug effects</subject><subject>GLYCOSAMINOGLYCANS</subject><subject>Glycosaminoglycans - chemistry</subject><subject>Glycosaminoglycans - pharmacology</subject><subject>Humans</subject><subject>INFLAMMATION</subject><subject>Interleukin-1beta - genetics</subject><subject>Interleukin-1beta - metabolism</subject><subject>Male</subject><subject>MESENCHYMAL STROMAL CELLS</subject><subject>Mesenchymal Stromal Cells - cytology</subject><subject>Mesenchymal Stromal Cells - drug effects</subject><subject>Mesenchymal Stromal Cells - immunology</subject><subject>Osteogenesis - drug effects</subject><subject>OSTEOGENIC DIFFERENTIATION</subject><subject>PROSTAGLANDINS</subject><subject>Sulfates - pharmacology</subject><issn>0730-2312</issn><issn>1097-4644</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0ctu1DAYBWALgei0sOAFkCU2sEjrW5zxchrBTKteEAV1aTmOM-PBsVs7Uclz8MK4nbYLJMTKXnz_8eUA8A6jQ4wQOdrq5pCwOWYvwAwjURWMM_YSzFBFUUEoJntgP6UtQkgISl6DPcIqxKngM_B7EQfbWW2Vg-dqiFabBK_tsIEru94UV6Pr1GBauHSTDkn11od13iqfoPItrINzam08XEQDF36wxYnvnOp7NYQ4PZCvMRSXaTAhM6thFyJcjb3y8Nwk4_Vm6vPRV0MM92ttnEtvwKtOuWTePq4H4MeXz9_rVXF2uTypF2eFZoSxgiLVlB3DrdEVws285KVmSDSctBWtjOLzhgo6R63qFOEYVS1qSMtZ29A5pVTRA_Bxl3sTw-1o0iB7m3S-gfImjElijjEniAnyf1qyqqSEYZzph7_oNozR54dkVVJclQKLrD7tlI4hpWg6eRNtr-IkMZL3pcpcqnwoNdv3j4lj05v2WT61mMHRDtxZZ6Z_J8nT-vgpsthN2NzMr-cJFX9Knj-vlNcXS3nB6fEpXQr5jf4BG2O6Mg</recordid><startdate>201409</startdate><enddate>201409</enddate><creator>Hempel, Ute</creator><creator>Matthäus, Claudia</creator><creator>Preissler, Carolin</creator><creator>Möller, Stephanie</creator><creator>Hintze, Vera</creator><creator>Dieter, Peter</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T7</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>201409</creationdate><title>Artificial Matrices With High-Sulfated Glycosaminoglycans and Collagen Are Anti-Inflammatory and Pro-Osteogenic for Human Mesenchymal Stromal Cells</title><author>Hempel, Ute ; Matthäus, Claudia ; Preissler, Carolin ; Möller, Stephanie ; Hintze, Vera ; Dieter, Peter</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4244-30ab5f41dec701b8565c409b62d737ea68b39380dafa26107d0b2d64db38333a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Anti-Inflammatory Agents - chemistry</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Cell Culture Techniques</topic><topic>Cell Differentiation - drug effects</topic><topic>Collagen Type I - pharmacology</topic><topic>EXTRACELLULAR MATRIX</topic><topic>Extracellular Matrix - chemistry</topic><topic>Extracellular Matrix - immunology</topic><topic>Female</topic><topic>Gene Expression Regulation - drug effects</topic><topic>GLYCOSAMINOGLYCANS</topic><topic>Glycosaminoglycans - chemistry</topic><topic>Glycosaminoglycans - pharmacology</topic><topic>Humans</topic><topic>INFLAMMATION</topic><topic>Interleukin-1beta - genetics</topic><topic>Interleukin-1beta - metabolism</topic><topic>Male</topic><topic>MESENCHYMAL STROMAL CELLS</topic><topic>Mesenchymal Stromal Cells - cytology</topic><topic>Mesenchymal Stromal Cells - drug effects</topic><topic>Mesenchymal Stromal Cells - immunology</topic><topic>Osteogenesis - drug effects</topic><topic>OSTEOGENIC DIFFERENTIATION</topic><topic>PROSTAGLANDINS</topic><topic>Sulfates - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hempel, Ute</creatorcontrib><creatorcontrib>Matthäus, Claudia</creatorcontrib><creatorcontrib>Preissler, Carolin</creatorcontrib><creatorcontrib>Möller, Stephanie</creatorcontrib><creatorcontrib>Hintze, Vera</creatorcontrib><creatorcontrib>Dieter, Peter</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of cellular biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hempel, Ute</au><au>Matthäus, Claudia</au><au>Preissler, Carolin</au><au>Möller, Stephanie</au><au>Hintze, Vera</au><au>Dieter, Peter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Artificial Matrices With High-Sulfated Glycosaminoglycans and Collagen Are Anti-Inflammatory and Pro-Osteogenic for Human Mesenchymal Stromal Cells</atitle><jtitle>Journal of cellular biochemistry</jtitle><addtitle>J. Cell. Biochem</addtitle><date>2014-09</date><risdate>2014</risdate><volume>115</volume><issue>9</issue><spage>1561</spage><epage>1571</epage><pages>1561-1571</pages><issn>0730-2312</issn><eissn>1097-4644</eissn><abstract>ABSTRACT Bone healing has been described to be most efficient if the early inflammatory phase is resolved timely. When the inflammation elevates or is permanently established, bone healing becomes impaired and, moreover, bone destruction often takes place. Systemic disorders such as diabetes and bone diseases like arthritis and osteoporosis are associated with sustained inflammation and delayed bone healing. One goal of biomaterial research is the development of materials/surface modifications which support the healing process by inhibiting the inflammatory bone erosion and suppressing pro‐inflammatory mediators and by that promoting the bone repair process. In the present study, the influence of artificial extracellular matrices (aECM) on the interleukin (IL)‐1β‐induced pro‐inflammatory response of human mesenchymal stromal cells (hMSC) was studied. hMSC cultured on aECM composed of collagen I and high‐sulfated glycosaminoglycan (GAG) derivatives did not secrete IL‐6, IL‐8, monocyte chemoattractant protein‐1, and prostaglandin E2 in response to IL‐1β. The activation and nuclear translocation of nuclear factor κBp65 induced by IL‐1β, tumor necrosis factor‐α or lipopolysaccharide was abrogated. Furthermore, these aECM promoted the osteogenic differentiation of hMSC as determined by an increased activity of tissue non‐specific alkaline phosphatase (TNAP); however, the aECM had no effect on the IL‐1β‐induced TNAP activity. These data suggest that aECM with high‐sulfated GAG derivatives suppress the formation of pro‐inflammatory mediators and simultaneously promote the osteogenic differentiation of hMSC. Therefore, these aECM might offer an interesting approach as material/surface modification supporting the bone healing process. J. Cell. Biochem. 115: 1561–1571, 2014. © 2014 Wiley Periodicals, Inc.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>24706396</pmid><doi>10.1002/jcb.24814</doi><tpages>11</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0730-2312
ispartof Journal of cellular biochemistry, 2014-09, Vol.115 (9), p.1561-1571
issn 0730-2312
1097-4644
language eng
recordid cdi_proquest_miscellaneous_1611620492
source MEDLINE; Wiley Online Library All Journals
subjects Adult
Anti-Inflammatory Agents - chemistry
Anti-Inflammatory Agents - pharmacology
Cell Culture Techniques
Cell Differentiation - drug effects
Collagen Type I - pharmacology
EXTRACELLULAR MATRIX
Extracellular Matrix - chemistry
Extracellular Matrix - immunology
Female
Gene Expression Regulation - drug effects
GLYCOSAMINOGLYCANS
Glycosaminoglycans - chemistry
Glycosaminoglycans - pharmacology
Humans
INFLAMMATION
Interleukin-1beta - genetics
Interleukin-1beta - metabolism
Male
MESENCHYMAL STROMAL CELLS
Mesenchymal Stromal Cells - cytology
Mesenchymal Stromal Cells - drug effects
Mesenchymal Stromal Cells - immunology
Osteogenesis - drug effects
OSTEOGENIC DIFFERENTIATION
PROSTAGLANDINS
Sulfates - pharmacology
title Artificial Matrices With High-Sulfated Glycosaminoglycans and Collagen Are Anti-Inflammatory and Pro-Osteogenic for Human Mesenchymal Stromal Cells
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-15T00%3A00%3A06IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Artificial%20Matrices%20With%20High-Sulfated%20Glycosaminoglycans%20and%20Collagen%20Are%20Anti-Inflammatory%20and%20Pro-Osteogenic%20for%20Human%20Mesenchymal%20Stromal%20Cells&rft.jtitle=Journal%20of%20cellular%20biochemistry&rft.au=Hempel,%20Ute&rft.date=2014-09&rft.volume=115&rft.issue=9&rft.spage=1561&rft.epage=1571&rft.pages=1561-1571&rft.issn=0730-2312&rft.eissn=1097-4644&rft_id=info:doi/10.1002/jcb.24814&rft_dat=%3Cproquest_cross%3E1611620492%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1553175919&rft_id=info:pmid/24706396&rfr_iscdi=true