Loading…

Repair of bone defects using synthetic mimetics of collagenous extracellular matrices

We have engineered synthetic poly(ethylene glycol) (PEG)–based hydrogels as cell-ingrowth matrices for in situ bone regeneration. These networks contain a combination of pendant oligopeptide ligands for cell adhesion (RGDSP) and substrates for matrix metalloproteinase (MMP) as linkers between PEG ch...

Full description

Saved in:
Bibliographic Details
Published in:Nature biotechnology 2003-05, Vol.21 (5), p.513-518
Main Authors: Hubbell, Jeffrey A, Lutolf, Matthias P, Weber, Franz E, Schmoekel, Hugo G, Schense, Jason C, Kohler, Thomas, Müller, Ralph
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c589t-f8f59fc33ceefe75521a72df912fc017eb3c31ec247f27fc4d6d60321bee109d3
cites cdi_FETCH-LOGICAL-c589t-f8f59fc33ceefe75521a72df912fc017eb3c31ec247f27fc4d6d60321bee109d3
container_end_page 518
container_issue 5
container_start_page 513
container_title Nature biotechnology
container_volume 21
creator Hubbell, Jeffrey A
Lutolf, Matthias P
Weber, Franz E
Schmoekel, Hugo G
Schense, Jason C
Kohler, Thomas
Müller, Ralph
description We have engineered synthetic poly(ethylene glycol) (PEG)–based hydrogels as cell-ingrowth matrices for in situ bone regeneration. These networks contain a combination of pendant oligopeptide ligands for cell adhesion (RGDSP) and substrates for matrix metalloproteinase (MMP) as linkers between PEG chains. Primary human fibroblasts were shown to migrate within these matrices by integrin- and MMP-dependent mechanisms. Gels used to deliver recombinant human bone morphogenetic protein-2 (rhBMP-2) to the site of critical- sized defects in rat crania were completely infiltrated by cells and were remodeled into bony tissue within five weeks. Bone regeneration was dependent on the proteolytic sensitivity of the matrices and their architecture. The cell-mediated proteolytic invasiveness of the gels and entrapment of rhBMP-2 resulted in efficient and highly localized bone regeneration.
doi_str_mv 10.1038/nbt818
format article
fullrecord <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_73229561</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A190182689</galeid><sourcerecordid>A190182689</sourcerecordid><originalsourceid>FETCH-LOGICAL-c589t-f8f59fc33ceefe75521a72df912fc017eb3c31ec247f27fc4d6d60321bee109d3</originalsourceid><addsrcrecordid>eNqN0l1r1jAUAOAiiptTf4FIEVS86MxJ2nxcjuHHYDCYztuSpievGW36mqTg_r0pLb5MLzS5SEiefJzDKYrnQE6BMPned0mCfFAcQ1PzCrjiD_OcSFERaPhR8STGW0IIrzl_XBwBFaRmih8XN9e41y6Uky27yWPZo0WTYjlH53dlvPPpOyZnytGNyxgXaKZh0Dv00xxL_JmCNjgM86BDOeoUnMH4tHhk9RDx2TaeFDcfP3w9_1xdXn26OD-7rEwjVaqstI2yhjGD-VnRNBS0oL1VQK0hILBjhgEaWgtLhTV1z3tOGIUOEYjq2UnxZr13H6YfM8bUji4uv9Ee8-9awShVDYd_QpCCk5rSDF_9AW-nOfgcREtzY7KWJKPTFe30gK3zdlqSkHuPozM5jdbl9TNQBCTlUuUD7-4dyCblzO30HGN78eX6_-3Vt_t2C8uEKcaAtt0HN-pw1wJpl7po17rI8OUW1tyN2B_YVggZvN6AjkYPNmhvXDy4WlIloMnu7epi3vI7DIf8_PXki1V6neaAv6_atn8BZxnViQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>222238480</pqid></control><display><type>article</type><title>Repair of bone defects using synthetic mimetics of collagenous extracellular matrices</title><source>Nature</source><creator>Hubbell, Jeffrey A ; Lutolf, Matthias P ; Weber, Franz E ; Schmoekel, Hugo G ; Schense, Jason C ; Kohler, Thomas ; Müller, Ralph</creator><creatorcontrib>Hubbell, Jeffrey A ; Lutolf, Matthias P ; Weber, Franz E ; Schmoekel, Hugo G ; Schense, Jason C ; Kohler, Thomas ; Müller, Ralph</creatorcontrib><description>We have engineered synthetic poly(ethylene glycol) (PEG)–based hydrogels as cell-ingrowth matrices for in situ bone regeneration. These networks contain a combination of pendant oligopeptide ligands for cell adhesion (RGDSP) and substrates for matrix metalloproteinase (MMP) as linkers between PEG chains. Primary human fibroblasts were shown to migrate within these matrices by integrin- and MMP-dependent mechanisms. Gels used to deliver recombinant human bone morphogenetic protein-2 (rhBMP-2) to the site of critical- sized defects in rat crania were completely infiltrated by cells and were remodeled into bony tissue within five weeks. Bone regeneration was dependent on the proteolytic sensitivity of the matrices and their architecture. The cell-mediated proteolytic invasiveness of the gels and entrapment of rhBMP-2 resulted in efficient and highly localized bone regeneration.</description><identifier>ISSN: 1087-0156</identifier><identifier>EISSN: 1546-1696</identifier><identifier>DOI: 10.1038/nbt818</identifier><identifier>PMID: 12704396</identifier><identifier>CODEN: NABIF9</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Adhesion ; Agriculture ; Animals ; Bioinformatics ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedical Engineering/Biotechnology ; Biomedicine ; Biomimetic Materials - chemical synthesis ; Biotechnology ; Bone Morphogenetic Protein 2 ; Bone Morphogenetic Proteins - pharmacology ; Bone Regeneration - drug effects ; Bone Substitutes - chemical synthesis ; Bone Substitutes - pharmacology ; Coated Materials, Biocompatible - chemical synthesis ; Collagen - chemistry ; Collagen - metabolism ; Culture Techniques - instrumentation ; Culture Techniques - methods ; Extracellular Matrix ; Fundamental and applied biological sciences. Psychology ; Gels ; Infusion Pumps, Implantable ; Invasiveness ; Life Sciences ; Prostheses and Implants ; Rats ; Skull Fractures - pathology ; Skull Fractures - surgery ; Tissue Engineering - instrumentation ; Tissue Engineering - methods ; Transforming Growth Factor beta ; Treatment Outcome</subject><ispartof>Nature biotechnology, 2003-05, Vol.21 (5), p.513-518</ispartof><rights>Springer Nature America, Inc. 2003</rights><rights>2004 INIST-CNRS</rights><rights>COPYRIGHT 2003 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 2003</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c589t-f8f59fc33ceefe75521a72df912fc017eb3c31ec247f27fc4d6d60321bee109d3</citedby><cites>FETCH-LOGICAL-c589t-f8f59fc33ceefe75521a72df912fc017eb3c31ec247f27fc4d6d60321bee109d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2725,27922,27923</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=14829715$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12704396$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hubbell, Jeffrey A</creatorcontrib><creatorcontrib>Lutolf, Matthias P</creatorcontrib><creatorcontrib>Weber, Franz E</creatorcontrib><creatorcontrib>Schmoekel, Hugo G</creatorcontrib><creatorcontrib>Schense, Jason C</creatorcontrib><creatorcontrib>Kohler, Thomas</creatorcontrib><creatorcontrib>Müller, Ralph</creatorcontrib><title>Repair of bone defects using synthetic mimetics of collagenous extracellular matrices</title><title>Nature biotechnology</title><addtitle>Nat Biotechnol</addtitle><addtitle>Nat Biotechnol</addtitle><description>We have engineered synthetic poly(ethylene glycol) (PEG)–based hydrogels as cell-ingrowth matrices for in situ bone regeneration. These networks contain a combination of pendant oligopeptide ligands for cell adhesion (RGDSP) and substrates for matrix metalloproteinase (MMP) as linkers between PEG chains. Primary human fibroblasts were shown to migrate within these matrices by integrin- and MMP-dependent mechanisms. Gels used to deliver recombinant human bone morphogenetic protein-2 (rhBMP-2) to the site of critical- sized defects in rat crania were completely infiltrated by cells and were remodeled into bony tissue within five weeks. Bone regeneration was dependent on the proteolytic sensitivity of the matrices and their architecture. The cell-mediated proteolytic invasiveness of the gels and entrapment of rhBMP-2 resulted in efficient and highly localized bone regeneration.</description><subject>Adhesion</subject><subject>Agriculture</subject><subject>Animals</subject><subject>Bioinformatics</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering/Biotechnology</subject><subject>Biomedicine</subject><subject>Biomimetic Materials - chemical synthesis</subject><subject>Biotechnology</subject><subject>Bone Morphogenetic Protein 2</subject><subject>Bone Morphogenetic Proteins - pharmacology</subject><subject>Bone Regeneration - drug effects</subject><subject>Bone Substitutes - chemical synthesis</subject><subject>Bone Substitutes - pharmacology</subject><subject>Coated Materials, Biocompatible - chemical synthesis</subject><subject>Collagen - chemistry</subject><subject>Collagen - metabolism</subject><subject>Culture Techniques - instrumentation</subject><subject>Culture Techniques - methods</subject><subject>Extracellular Matrix</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gels</subject><subject>Infusion Pumps, Implantable</subject><subject>Invasiveness</subject><subject>Life Sciences</subject><subject>Prostheses and Implants</subject><subject>Rats</subject><subject>Skull Fractures - pathology</subject><subject>Skull Fractures - surgery</subject><subject>Tissue Engineering - instrumentation</subject><subject>Tissue Engineering - methods</subject><subject>Transforming Growth Factor beta</subject><subject>Treatment Outcome</subject><issn>1087-0156</issn><issn>1546-1696</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><recordid>eNqN0l1r1jAUAOAiiptTf4FIEVS86MxJ2nxcjuHHYDCYztuSpievGW36mqTg_r0pLb5MLzS5SEiefJzDKYrnQE6BMPned0mCfFAcQ1PzCrjiD_OcSFERaPhR8STGW0IIrzl_XBwBFaRmih8XN9e41y6Uky27yWPZo0WTYjlH53dlvPPpOyZnytGNyxgXaKZh0Dv00xxL_JmCNjgM86BDOeoUnMH4tHhk9RDx2TaeFDcfP3w9_1xdXn26OD-7rEwjVaqstI2yhjGD-VnRNBS0oL1VQK0hILBjhgEaWgtLhTV1z3tOGIUOEYjq2UnxZr13H6YfM8bUji4uv9Ee8-9awShVDYd_QpCCk5rSDF_9AW-nOfgcREtzY7KWJKPTFe30gK3zdlqSkHuPozM5jdbl9TNQBCTlUuUD7-4dyCblzO30HGN78eX6_-3Vt_t2C8uEKcaAtt0HN-pw1wJpl7po17rI8OUW1tyN2B_YVggZvN6AjkYPNmhvXDy4WlIloMnu7epi3vI7DIf8_PXki1V6neaAv6_atn8BZxnViQ</recordid><startdate>20030501</startdate><enddate>20030501</enddate><creator>Hubbell, Jeffrey A</creator><creator>Lutolf, Matthias P</creator><creator>Weber, Franz E</creator><creator>Schmoekel, Hugo G</creator><creator>Schense, Jason C</creator><creator>Kohler, Thomas</creator><creator>Müller, Ralph</creator><general>Nature Publishing Group US</general><general>Nature</general><general>Nature Publishing Group</general><scope>IQODW</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20030501</creationdate><title>Repair of bone defects using synthetic mimetics of collagenous extracellular matrices</title><author>Hubbell, Jeffrey A ; Lutolf, Matthias P ; Weber, Franz E ; Schmoekel, Hugo G ; Schense, Jason C ; Kohler, Thomas ; Müller, Ralph</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c589t-f8f59fc33ceefe75521a72df912fc017eb3c31ec247f27fc4d6d60321bee109d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Adhesion</topic><topic>Agriculture</topic><topic>Animals</topic><topic>Bioinformatics</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering/Biotechnology</topic><topic>Biomedicine</topic><topic>Biomimetic Materials - chemical synthesis</topic><topic>Biotechnology</topic><topic>Bone Morphogenetic Protein 2</topic><topic>Bone Morphogenetic Proteins - pharmacology</topic><topic>Bone Regeneration - drug effects</topic><topic>Bone Substitutes - chemical synthesis</topic><topic>Bone Substitutes - pharmacology</topic><topic>Coated Materials, Biocompatible - chemical synthesis</topic><topic>Collagen - chemistry</topic><topic>Collagen - metabolism</topic><topic>Culture Techniques - instrumentation</topic><topic>Culture Techniques - methods</topic><topic>Extracellular Matrix</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gels</topic><topic>Infusion Pumps, Implantable</topic><topic>Invasiveness</topic><topic>Life Sciences</topic><topic>Prostheses and Implants</topic><topic>Rats</topic><topic>Skull Fractures - pathology</topic><topic>Skull Fractures - surgery</topic><topic>Tissue Engineering - instrumentation</topic><topic>Tissue Engineering - methods</topic><topic>Transforming Growth Factor beta</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hubbell, Jeffrey A</creatorcontrib><creatorcontrib>Lutolf, Matthias P</creatorcontrib><creatorcontrib>Weber, Franz E</creatorcontrib><creatorcontrib>Schmoekel, Hugo G</creatorcontrib><creatorcontrib>Schense, Jason C</creatorcontrib><creatorcontrib>Kohler, Thomas</creatorcontrib><creatorcontrib>Müller, Ralph</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Biotechnology Research Abstracts</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>Nucleic Acids Abstracts</collection><collection>ProQuest_Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>Materials Science &amp; Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest_Research Library</collection><collection>ProQuest Science Journals</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature biotechnology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hubbell, Jeffrey A</au><au>Lutolf, Matthias P</au><au>Weber, Franz E</au><au>Schmoekel, Hugo G</au><au>Schense, Jason C</au><au>Kohler, Thomas</au><au>Müller, Ralph</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Repair of bone defects using synthetic mimetics of collagenous extracellular matrices</atitle><jtitle>Nature biotechnology</jtitle><stitle>Nat Biotechnol</stitle><addtitle>Nat Biotechnol</addtitle><date>2003-05-01</date><risdate>2003</risdate><volume>21</volume><issue>5</issue><spage>513</spage><epage>518</epage><pages>513-518</pages><issn>1087-0156</issn><eissn>1546-1696</eissn><coden>NABIF9</coden><abstract>We have engineered synthetic poly(ethylene glycol) (PEG)–based hydrogels as cell-ingrowth matrices for in situ bone regeneration. These networks contain a combination of pendant oligopeptide ligands for cell adhesion (RGDSP) and substrates for matrix metalloproteinase (MMP) as linkers between PEG chains. Primary human fibroblasts were shown to migrate within these matrices by integrin- and MMP-dependent mechanisms. Gels used to deliver recombinant human bone morphogenetic protein-2 (rhBMP-2) to the site of critical- sized defects in rat crania were completely infiltrated by cells and were remodeled into bony tissue within five weeks. Bone regeneration was dependent on the proteolytic sensitivity of the matrices and their architecture. The cell-mediated proteolytic invasiveness of the gels and entrapment of rhBMP-2 resulted in efficient and highly localized bone regeneration.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>12704396</pmid><doi>10.1038/nbt818</doi><tpages>6</tpages></addata></record>
fulltext fulltext
identifier ISSN: 1087-0156
ispartof Nature biotechnology, 2003-05, Vol.21 (5), p.513-518
issn 1087-0156
1546-1696
language eng
recordid cdi_proquest_miscellaneous_73229561
source Nature
subjects Adhesion
Agriculture
Animals
Bioinformatics
Biological and medical sciences
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biomedicine
Biomimetic Materials - chemical synthesis
Biotechnology
Bone Morphogenetic Protein 2
Bone Morphogenetic Proteins - pharmacology
Bone Regeneration - drug effects
Bone Substitutes - chemical synthesis
Bone Substitutes - pharmacology
Coated Materials, Biocompatible - chemical synthesis
Collagen - chemistry
Collagen - metabolism
Culture Techniques - instrumentation
Culture Techniques - methods
Extracellular Matrix
Fundamental and applied biological sciences. Psychology
Gels
Infusion Pumps, Implantable
Invasiveness
Life Sciences
Prostheses and Implants
Rats
Skull Fractures - pathology
Skull Fractures - surgery
Tissue Engineering - instrumentation
Tissue Engineering - methods
Transforming Growth Factor beta
Treatment Outcome
title Repair of bone defects using synthetic mimetics of collagenous extracellular matrices
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-14T12%3A26%3A50IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Repair%20of%20bone%20defects%20using%20synthetic%20mimetics%20of%20collagenous%20extracellular%20matrices&rft.jtitle=Nature%20biotechnology&rft.au=Hubbell,%20Jeffrey%20A&rft.date=2003-05-01&rft.volume=21&rft.issue=5&rft.spage=513&rft.epage=518&rft.pages=513-518&rft.issn=1087-0156&rft.eissn=1546-1696&rft.coden=NABIF9&rft_id=info:doi/10.1038/nbt818&rft_dat=%3Cgale_proqu%3EA190182689%3C/gale_proqu%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c589t-f8f59fc33ceefe75521a72df912fc017eb3c31ec247f27fc4d6d60321bee109d3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=222238480&rft_id=info:pmid/12704396&rft_galeid=A190182689&rfr_iscdi=true