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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Electrochemical Cathodic Polarization, a Simplified Method That Can Modified and Increase the Biological Activity of Titanium Surfaces: A Systematic Review</title><author><name sortKey="Alcazar, Jose Carlos Bernedo" sort="Alcazar, Jose Carlos Bernedo" uniqKey="Alcazar J" first="Jose Carlos Bernedo" last="Alcazar">Jose Carlos Bernedo Alcazar</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Salas, Mabel Miluska Suca" sort="Salas, Mabel Miluska Suca" uniqKey="Salas M" first="Mabel Miluska Suca" last="Salas">Mabel Miluska Suca Salas</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Department of Dentistry, Science Faculty of Tocantins, Tocantins, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Conde, Marcus Cristian Muniz" sort="Conde, Marcus Cristian Muniz" uniqKey="Conde M" first="Marcus Cristian Muniz" last="Conde">Marcus Cristian Muniz Conde</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chisini, Luiz Alexandre" sort="Chisini, Luiz Alexandre" uniqKey="Chisini L" first="Luiz Alexandre" last="Chisini">Luiz Alexandre Chisini</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Demarco, Flavio Fernando" sort="Demarco, Flavio Fernando" uniqKey="Demarco F" first="Flávio Fernando" last="Demarco">Flávio Fernando Demarco</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Department of Public Health, Post-Graduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tarquinio, Sandra Beatriz Chaves" sort="Tarquinio, Sandra Beatriz Chaves" uniqKey="Tarquinio S" first="Sandra Beatriz Chaves" last="Tarquinio">Sandra Beatriz Chaves Tarquinio</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Carre O, Neftali Lenin Villarreal" sort="Carre O, Neftali Lenin Villarreal" uniqKey="Carre O N" first="Neftali Lenin Villarreal" last="Carre O">Neftali Lenin Villarreal Carre O</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff004"><addr-line>Department of Material Science, Post-Graduate Program in Science and Material Engineering, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27441840</idno><idno type="pmc">4956102</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956102</idno><idno type="RBID">PMC:4956102</idno><idno type="doi">10.1371/journal.pone.0155231</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000764</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000764</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Electrochemical Cathodic Polarization, a Simplified Method That Can Modified and Increase the Biological Activity of Titanium Surfaces: A Systematic Review</title><author><name sortKey="Alcazar, Jose Carlos Bernedo" sort="Alcazar, Jose Carlos Bernedo" uniqKey="Alcazar J" first="Jose Carlos Bernedo" last="Alcazar">Jose Carlos Bernedo Alcazar</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Salas, Mabel Miluska Suca" sort="Salas, Mabel Miluska Suca" uniqKey="Salas M" first="Mabel Miluska Suca" last="Salas">Mabel Miluska Suca Salas</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Department of Dentistry, Science Faculty of Tocantins, Tocantins, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Conde, Marcus Cristian Muniz" sort="Conde, Marcus Cristian Muniz" uniqKey="Conde M" first="Marcus Cristian Muniz" last="Conde">Marcus Cristian Muniz Conde</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chisini, Luiz Alexandre" sort="Chisini, Luiz Alexandre" uniqKey="Chisini L" first="Luiz Alexandre" last="Chisini">Luiz Alexandre Chisini</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Demarco, Flavio Fernando" sort="Demarco, Flavio Fernando" uniqKey="Demarco F" first="Flávio Fernando" last="Demarco">Flávio Fernando Demarco</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Department of Public Health, Post-Graduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tarquinio, Sandra Beatriz Chaves" sort="Tarquinio, Sandra Beatriz Chaves" uniqKey="Tarquinio S" first="Sandra Beatriz Chaves" last="Tarquinio">Sandra Beatriz Chaves Tarquinio</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Carre O, Neftali Lenin Villarreal" sort="Carre O, Neftali Lenin Villarreal" uniqKey="Carre O N" first="Neftali Lenin Villarreal" last="Carre O">Neftali Lenin Villarreal Carre O</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff004"><addr-line>Department of Material Science, Post-Graduate Program in Science and Material Engineering, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Background</title><p>The cathodic polarization seems to be an electrochemical method capable of modifying and coat biomolecules on titanium surfaces, improving the surface activity and promoting better biological responses.</p></sec><sec id="sec002"><title>Objective</title><p>The aim of the systematic review is to assess the scientific literature to evaluate the cellular response produced by treatment of titanium surfaces by applying the cathodic polarization technique.</p></sec><sec id="sec003"><title>Data, Sources, and Selection</title><p>The literature search was performed in several databases including PubMed, Web of Science, Scopus, Science Direct, Scielo and EBSCO Host, until June 2016, with no limits used. Eligibility criteria were used and quality assessment was performed following slightly modified ARRIVE and SYRCLE guidelines for cellular studies and animal research.</p></sec><sec id="sec004"><title>Results</title><p>Thirteen studies accomplished the inclusion criteria and were considered in the review. The quality of reporting studies in animal models was low and for the <italic>in vitro</italic> studies it was high. The <italic>in vitro</italic> and <italic>in vivo</italic> results reported that the use of cathodic polarization promoted hydride surfaces, effective deposition, and adhesion of the coated biomolecules. In the experimental groups that used the electrochemical method, cellular viability, proliferation, adhesion, differentiation, or bone growth were better or comparable with the control groups.</p></sec><sec id="sec005"><title>Conclusions</title><p>The use of the cathodic polarization method to modify titanium surfaces seems to be an interesting method that could produce active layers and consequently enhance cellular response, in vitro and in vivo animal model studies.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Van Velzen, Fj" uniqKey="Van Velzen F">FJ Van Velzen</name></author><author><name sortKey="Ofec, R" uniqKey="Ofec R">R Ofec</name></author><author><name sortKey="Schulten, Ea" uniqKey="Schulten E">EA Schulten</name></author><author><name sortKey="Ten Bruggenkate, Cm" uniqKey="Ten Bruggenkate C">CM Ten Bruggenkate</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Becker, St" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27441840</article-id><article-id pub-id-type="pmc">4956102</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0155231</article-id><article-id pub-id-type="publisher-id">PONE-D-15-48286</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Chemistry</subject><subj-group><subject>Chemical Elements</subject><subj-group><subject>Titanium</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Model Organisms</subject><subj-group><subject>Animal Models</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Chemistry</subject><subj-group><subject>Electrochemistry</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Materials Science</subject><subj-group><subject>Materials by Attribute</subject><subj-group><subject>Coatings</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Engineering and Technology</subject><subj-group><subject>Manufacturing Processes</subject><subj-group><subject>Surface Treatments</subject><subj-group><subject>Coatings</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Chemistry</subject><subj-group><subject>Physical Chemistry</subject><subj-group><subject>Chemical Deposition</subject><subj-group><subject>Electrochemical Deposition</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Engineering and Technology</subject><subj-group><subject>Manufacturing Processes</subject><subj-group><subject>Surface Treatments</subject><subj-group><subject>Chemical Deposition</subject><subj-group><subject>Electrochemical Deposition</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Chemistry</subject><subj-group><subject>Chemical Compounds</subject><subj-group><subject>Hydrides</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Engineering and Technology</subject><subj-group><subject>Manufacturing Processes</subject><subj-group><subject>Surface Treatments</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Earth Sciences</subject><subj-group><subject>Atmospheric Science</subject><subj-group><subject>Atmospheric Chemistry</subject><subj-group><subject>Acid Deposition</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Chemistry</subject><subj-group><subject>Environmental Chemistry</subject><subj-group><subject>Atmospheric Chemistry</subject><subj-group><subject>Acid Deposition</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Ecology and Environmental Sciences</subject><subj-group><subject>Environmental Chemistry</subject><subj-group><subject>Atmospheric Chemistry</subject><subj-group><subject>Acid Deposition</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Electrochemical Cathodic Polarization, a Simplified Method That Can Modified and Increase the Biological Activity of Titanium Surfaces: A Systematic Review</article-title><alt-title alt-title-type="running-head">Systematic Review of an Electrochemical Method to Modified Titanium Surface</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Alcazar</surname><given-names>Jose Carlos Bernedo</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Salas</surname><given-names>Mabel Miluska Suca</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Conde</surname><given-names>Marcus Cristian Muniz</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Chisini</surname><given-names>Luiz Alexandre</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Demarco</surname><given-names>Flávio Fernando</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Tarquinio</surname><given-names>Sandra Beatriz Chaves</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-5780-817X</contrib-id><name><surname>Carreño</surname><given-names>Neftali Lenin Villarreal</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Department of Restorative Dentistry, Post-Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Department of Dentistry, Science Faculty of Tocantins, Tocantins, Brazil</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Department of Public Health, Post-Graduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Department of Material Science, Post-Graduate Program in Science and Material Engineering, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Kobeissy</surname><given-names>Firas H</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Florida, UNITED STATES</addr-line></aff><author-notes><fn fn-type="conflict" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: JCBA MMSS MCMC LAC FFD SBCT NLVC. Analyzed the data: JCBA MMSS MCMC LAC FFD SBCT NLVC. Wrote the paper: JCBA MMSS MCMC LAC FFD SBCT NLVC.</p></fn><corresp id="cor001">* E-mail: <email>neftali@ufpel.edu.br</email></corresp></author-notes><pub-date pub-type="epub"><day>21</day><month>7</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>11</volume><issue>7</issue><elocation-id>e0155231</elocation-id><history><date date-type="received"><day>14</day><month>11</month><year>2015</year></date><date date-type="accepted"><day>29</day><month>6</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 Alcazar et al</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Alcazar et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pone.0155231.pdf"></self-uri><abstract><sec id="sec001"><title>Background</title><p>The cathodic polarization seems to be an electrochemical method capable of modifying and coat biomolecules on titanium surfaces, improving the surface activity and promoting better biological responses.</p></sec><sec id="sec002"><title>Objective</title><p>The aim of the systematic review is to assess the scientific literature to evaluate the cellular response produced by treatment of titanium surfaces by applying the cathodic polarization technique.</p></sec><sec id="sec003"><title>Data, Sources, and Selection</title><p>The literature search was performed in several databases including PubMed, Web of Science, Scopus, Science Direct, Scielo and EBSCO Host, until June 2016, with no limits used. Eligibility criteria were used and quality assessment was performed following slightly modified ARRIVE and SYRCLE guidelines for cellular studies and animal research.</p></sec><sec id="sec004"><title>Results</title><p>Thirteen studies accomplished the inclusion criteria and were considered in the review. The quality of reporting studies in animal models was low and for the <italic>in vitro</italic> studies it was high. The <italic>in vitro</italic> and <italic>in vivo</italic> results reported that the use of cathodic polarization promoted hydride surfaces, effective deposition, and adhesion of the coated biomolecules. In the experimental groups that used the electrochemical method, cellular viability, proliferation, adhesion, differentiation, or bone growth were better or comparable with the control groups.</p></sec><sec id="sec005"><title>Conclusions</title><p>The use of the cathodic polarization method to modify titanium surfaces seems to be an interesting method that could produce active layers and consequently enhance cellular response, in vitro and in vivo animal model studies.</p></sec></abstract><funding-group><award-group id="award001"><funding-source><institution>Brazilian National Council for Scientific and Technological Development (CNPQ)</institution></funding-source><award-id>482251/2013-1</award-id></award-group><award-group id="award002"><funding-source><institution>Brazilian coordination for improvement of higher education personnel (CAPES)</institution></funding-source><principal-award-recipient><name><surname>Alcazar</surname><given-names>Jose Carlos Bernedo</given-names></name></principal-award-recipient></award-group><funding-statement>Support was provided by the Brazilian National Council for Scientific and Technological Development (CNPQ), 482251/2013&1 and the Brazilian coordination for improvement of higher education personnel (CAPES).</funding-statement></funding-group><counts><fig-count count="1"></fig-count><table-count count="3"></table-count><page-count count="17"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data are within the paper and its Supporting Information files. All files are available from the PubMed, Web of Science, Scopus, Science Direct, Scielo and EBSCOHost databases until June 2016. Google Scholar.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data are within the paper and its Supporting Information files. All files are available from the PubMed, Web of Science, Scopus, Science Direct, Scielo and EBSCOHost databases until June 2016. Google Scholar.</p></notes></front><body><sec sec-type="intro" id="sec006"><title>Introduction</title><p>The use of dental implants has increased in the last decades and they are currently widely used to provide good clinical results and high survival rates of 94.4% [<xref rid="pone.0155231.ref001" ref-type="bibr">1</xref>, <xref rid="pone.0155231.ref002" ref-type="bibr">2</xref>]. Titanium-based materials are employed for medical purposes in implants for plastic and reconstructive surgeries and orthopaedic and craniofacial reconstructions, and also in dental implantology [<xref rid="pone.0155231.ref003" ref-type="bibr">3</xref>].</p><p>Titanium is a highly biocompatible material, showing adequate mechanical properties, chemical stability and corrosion resistance[<xref rid="pone.0155231.ref004" ref-type="bibr">4</xref>]. The biocompatibility of titanium implants is attributed to the stable oxide layer[<xref rid="pone.0155231.ref003" ref-type="bibr">3</xref>], and together with their excellent mechanical characteristics, allow satisfactory tissue reaction, bone matrix formation, and low immune responses[<xref rid="pone.0155231.ref001" ref-type="bibr">1</xref>]. Even though they have a wide spectrum of advantages implant can fail, especially in patients with poor bone remnants, poor wound healing, or the presence of systemic problems such as osteoporosis and diabetes, which could reduce cellular response [<xref rid="pone.0155231.ref005" ref-type="bibr">5</xref>].</p><p>In order to improve the biological activity of the titanium surfaces and to promote better osteointegration and bone healing, modifications on the titanium implant surface are being used and tested, trying to preserve the titanium mechanical properties and bioinertness[<xref rid="pone.0155231.ref006" ref-type="bibr">6</xref>]. Electrochemical treatment is one of the surface treatments that have been indicated to be relatively simple and cheap, capable of maintaining titanium’s mechanical properties and enhancing cellular responses [<xref rid="pone.0155231.ref006" ref-type="bibr">6</xref>]. Anodic polarization is the electrochemical treatment widely used to deposit molecules on the surfaces, showing the improved biocompatibility of titanium due to the increasing roughness and the oxide layer of the titanium surface [<xref rid="pone.0155231.ref007" ref-type="bibr">7</xref>]. Cathodic polarization is an alternative of electrochemical treatment that has recently been more investigated [<xref rid="pone.0155231.ref006" ref-type="bibr">6</xref>]. This electrochemical treatment is a method that has been reported as a simpler method that does not need higher temperatures to be performed and can activate titanium surfaces promoting roughness and also depositing biomolecules [<xref rid="pone.0155231.ref008" ref-type="bibr">8</xref>]. The cathodic process could produce hydride layers, turning the possible charging of biomolecules [<xref rid="pone.0155231.ref009" ref-type="bibr">9</xref>], including the hydroxyapatite formation, with its capability of inducing a calcium phosphate formation in supersaturated aqueous solutions[<xref rid="pone.0155231.ref010" ref-type="bibr">10</xref>]. Even though the cathodic electrochemical option seems to be an interesting and simplified method to modify titanium surfaces that could enhance cellular activity and bone deposition, the literature is limited and is not consistent regarding the cellular responses.</p><p>The purpose of the present review was to systematically analyze systematically the existing studies that used the cathodic polarization technique to modify titanium surfaces to produce biological active titanium surfaces <italic>in vitro</italic> and <italic>in vivo</italic>.</p></sec><sec sec-type="materials|methods" id="sec007"><title>Methods</title><p>This systematic review followed the PRISMA statement and the ARRIVE statements for reporting animal researches.</p><p>Our research question was formulated using the P.I.C.O. principle to determine if the use of cathodic polarization can produce biologically active medical titanium surfaces in terms of cellular response (proliferation, adhesion, or differentiation) <italic>in vitro</italic> (cells)or <italic>in vivo</italic> (animal model).</p><sec id="sec008"><title>Search Strategy</title><p>The search was conducted in PubMed, Web of Science, Scopus, Science Direct, Scielo and EBSCOHost databases until June 2016. Google Scholar and doctoral theses related to the research questions were also searched and reviewed. No restrictions on publication data or languages were used.</p><p>Mesh terms, commonly used terms, and synonyms were included as part of the search. An extensive combination of keywords was performed, and in order to include all the studies of interest[<xref rid="pone.0155231.ref011" ref-type="bibr">11</xref>], final keywords used included the following terms: <italic>("dental implants" OR implants</italic>, <italic>dental OR dental implant OR medical implants OR implants OR prostheses</italic>, <italic>surgical OR dental prosthesis</italic>, <italic>surgical OR surgical prostheses OR surgical dental prosthesis OR prostheses</italic>, <italic>surgical dental OR prosthesis</italic>, <italic>surgical dental OR discs) AND titanium AND (cathodic polarization OR hydride formation OR "surface deposition" OR "surface modification" OR "surface treatment")</italic></p><p>The sequence of the keywords were adapted according to databases requirements, for instance the Web of Science included “TS = " at the beginning of each item.</p><p>Search results were uploaded to EndNote software (version 7.0, Thompson Reuters, 1988–2013) to facilitate and standardized the literature revision and analysis.</p></sec><sec id="sec009"><title>Study Selection</title><sec id="sec010"><title>Inclusion criteria</title><p>Studies that used medical pure titanium or titanium implants modified by the cathodic polarization treatment, at least in one group, were included. Cathodic polarization method was considered when it was used the experimental titanium as working electrode (cathode) and a platinum electrode as anode, an acidic electrolyte solution, a controlled current density, a controlled temperature, a controlled time and galvanostatic technique.</p><p>Biological response, including cellular proliferation, adhesion, and differentiation; by <italic>in vitro</italic> cellular essays, animal models, or human clinical trials had to be tested to be included in our sample.</p></sec><sec id="sec011"><title>Exclusion criteria</title><p>Researches that evaluated titanium alloys, other material types different from titanium and orthodontic titanium appliances by mechanical or physical tests were excluded. Studies without control groups were also excluded. Modifications of the cathodic polarization standard method, literature reviews, patents, comments, editor letters, abstracts, or posters presentations were also excluded.</p></sec><sec id="sec012"><title>Selecting method</title><p>The selection was performed by two reviewers (MMSS and JCBA) independently and in duplicate, using the same eligibility criteria. The training and calibration process was performed prior to the formal literature analysis. For title and abstract analysis, inter-rater kappa values ranged from 0.88 to 0.93 and from 0.91 to 0.97 respectively. The selection was carried out in four stages. In a first stage, duplicated records were excluded and the titles of the remaining studies were screened to identify studies related to our research question. In the second stage, abstracts were read to localize and include studies that fulfilled the selection criteria. In the third stage, the full text was read and in the fourth stage the quality assessment was done. Differences in data extraction between the reviewers were discussed and consensus was reached.</p><p>Crosschecked bibliographies of the eligible papers for additional references were reviewed according to the eligibility criteria, and newfound studies were added if accomplished the eligibility criteria.</p></sec><sec id="sec013"><title>Data extraction</title><p>Data extracted were sample size; material, design and diameters of the titanium specimens; pre-treatment; studied groups; coating molecule; deposition methods used, characteristics of the cellular essay and/or animal models, cellular responses (proliferation, adhesion, and differentiation) or bone deposition as primary outcome, other mechanical or physical characterization performed, statistical analysis, and other results. Standard deviation and means were also extracted if reported.</p><p>Pre-defined data-collection worksheets were employed for the assessment of the collected records and for each selected publication. Data was organized in tables and categorized to be analyzed for systematic synthesis. Descriptive analysis (absolute and relative numbers) were performed using the software STATA 12.0 (StataCorp, College Station, TX, USA).</p></sec><sec id="sec014"><title>Quality assessment</title><p>Each study was evaluated according to ARRIVE and SYRCLE statements for animal model studies. The ARRIVE criteria was modified to assess the quality of the in vitro studies.</p><p>ARRIVE guidelines for reporting <italic>in vivo</italic> experiments in animal research present a checklist of 20 items to evaluate and have been developed using the CONSORT statement as their foundation. The SYRCLE statement had 10 items and attempted to report if the studies were low bias, high bias, or unclear bias.</p></sec></sec></sec><sec sec-type="results" id="sec015"><title>Results</title><p>The initial search yielded 3,807 records. After the exclusion of duplicate records and the use of the eligibility criteria, 13 studies remained [<xref rid="pone.0155231.ref009" ref-type="bibr">9</xref>, <xref rid="pone.0155231.ref010" ref-type="bibr">10</xref>, <xref rid="pone.0155231.ref012" ref-type="bibr">12</xref>–<xref rid="pone.0155231.ref022" ref-type="bibr">22</xref>]. The identification of the papers and the selection process are presented in <xref ref-type="fig" rid="pone.0155231.g001">Fig 1</xref>. The exclusion of the studies in the last selection phase was mainly due to the use of a modified version of cathodic polarization and the used of other methods different from cathodic polarization as main outcome. Detailed reasons for exclusion are presented in <xref ref-type="supplementary-material" rid="pone.0155231.s003">S1 Table</xref>. The thirteen studies that accomplished the full eligibility criteria, were selected as final sample.</p><fig id="pone.0155231.g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0155231.g001</object-id><label>Fig 1</label><caption><title>Flowchart information of the different phases of papers search and selection.</title></caption><graphic xlink:href="pone.0155231.g001"></graphic></fig><sec id="sec016"><title>Sensitivity analysis</title><p>Quality criteria of the studies are described in <xref ref-type="table" rid="pone.0155231.t001">Table 1</xref>. According to the arrive criteria, 20 items were evaluated in the animal model in vivo studies. The <italic>in vivo</italic> animal model studies presented high or unclear risk of bias. The studies did not report information regarding selection method, sampling and allocation process, randomization, animal allocation and hostelling, blinding and dropouts, or replacement of the animals. Control of any confounders was also not reported. Overall results from seven studies with animal model showed that information was unclear (n = 15(10.7%)) or partially reported (n = 41 (29.3%)). The overall results of “No” (high risk) was 27 (21.0%), and "Yes"(low risk) was 57 (40.7%).</p><table-wrap id="pone.0155231.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0155231.t001</object-id><label>Table 1</label><caption><title>Quality assessment according to ARRIVE and SYRCLE criteria.</title></caption><alternatives><graphic id="pone.0155231.t001g" xlink:href="pone.0155231.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" colspan="3" rowspan="1">Quality Criteria statements</th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" colspan="11" rowspan="1">Authors</th></tr><tr><th align="left" rowspan="1" colspan="1">SYRCLE (Bias)</th><th align="left" colspan="2" rowspan="1"> ARRIVE statements</th><th align="left" rowspan="1" colspan="1">Tao et al., 2016</th><th align="left" rowspan="1" colspan="1">Liang et al., 2014</th><th align="left" rowspan="1" colspan="1">Lamolle et al., 2010</th><th align="left" rowspan="1" colspan="1">Lamolle et al., 2009</th><th align="left" rowspan="1" colspan="1">Zhang et al., 2009</th><th align="left" rowspan="1" colspan="1">Young-Taeg et al., 2009</th><th align="left" rowspan="1" colspan="1">Ban et al., 1996</th><th align="left" rowspan="1" colspan="1">Frank et al., 2014</th><th align="left" rowspan="1" colspan="1">Xing et al., 2014</th><th align="left" rowspan="1" colspan="1">Huang et al., 2013</th><th align="left" rowspan="1" colspan="1">Ou et al., 2008</th><th align="left" rowspan="1" colspan="1">De Giglio et al., 2007</th><th align="left" rowspan="1" colspan="1">Hosaka et al., 2006</th></tr><tr><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1">AM</th><th align="center" rowspan="1" colspan="1">AM and CM</th><th align="center" rowspan="1" colspan="1">AM</th><th align="center" rowspan="1" colspan="1">AM</th><th align="center" rowspan="1" colspan="1">AM</th><th align="center" rowspan="1" colspan="1">AM</th><th align="center" rowspan="1" colspan="1">AM</th><th align="center" rowspan="1" colspan="1">CM</th><th align="center" rowspan="1" colspan="1">CM</th><th align="center" rowspan="1" colspan="1">CM</th><th align="center" rowspan="1" colspan="1">CM</th><th align="center" rowspan="1" colspan="1">CM</th><th align="center" rowspan="1" colspan="1">CM</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>1</bold></td><td align="left" rowspan="1" colspan="1"><bold>TITLE</bold><xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>2</bold></td><td align="left" rowspan="1" colspan="1"><bold>ABSTRACT</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Summary of the background, research objectives<xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Details of the species or strain of animal used</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Key methods, principal findings and conclusions <xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>3</bold></td><td align="left" rowspan="1" colspan="1"><bold>INTRODUCTION</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Background information <xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Experimental approach <xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Relevance to human biology<xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1">4</td><td align="left" rowspan="1" colspan="1"><bold>Objectives</bold><xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1"><bold>METHODS</bold></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>5</bold></td><td align="left" rowspan="1" colspan="1"><bold>Ethical statement/ guidelines for animals care/used</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>6</bold></td><td align="left" rowspan="1" colspan="1"><bold>Study design</bold><xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Experimental and control groups<xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Selection</bold></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Allocation samples<xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Detection</bold></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Randomization samples<xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Performance/ detection</bold></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Blinding (Researchers, caregivers, assessors)</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>7</bold></td><td align="left" rowspan="1" colspan="1"><bold>Experimental procedure</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">in vitro cellular detail method<xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Specimens characteristics and preparations <xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Coating procedures<xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Anesthesia</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Antibiotics</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Analgesia</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Surgical procedure</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>8</bold></td><td align="left" rowspan="1" colspan="1"><bold>Experimental animals</bold></td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Selection</bold></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Species</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">strain, sex, developmental stage, weight</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">source of animals</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Performance</bold></td><td align="right" rowspan="1" colspan="1"><bold>9</bold></td><td align="left" rowspan="1" colspan="1"><bold>Housing and husbandry</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><bold>Housing and husbandry–conditions and welfare-</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Related assessments and interventions</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>10</bold></td><td align="left" rowspan="1" colspan="1"><bold>Sample size</bold><xref ref-type="table-fn" rid="t001fn001">*</xref><bold>–</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Sample size<xref ref-type="table-fn" rid="t001fn001">*</xref> –</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Sample size calculation<xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Number of animals in each experimental group</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Number of samples in each experimental group<xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">2</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"><bold>11</bold></td><td align="left" rowspan="1" colspan="1"><bold>Allocation animals</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Allocation animals to experimental groups</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Randomization or matching</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Order in which animals were treated and assessed</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>12</bold></td><td align="left" rowspan="1" colspan="1"><bold>Experimental outcomes–primary and secondary</bold><xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>13</bold></td><td align="left" rowspan="1" colspan="1"><bold>Statistical methods</bold><xref ref-type="table-fn" rid="t001fn001">*</xref><bold>–details and unit of analysis</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><bold> </bold></td><td align="left" rowspan="1" colspan="1"><bold>RESULTS</bold></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Attrition</bold></td><td align="right" rowspan="1" colspan="1"><bold>14</bold></td><td align="left" rowspan="1" colspan="1"><bold>Baseline data–characteristics /health status of animals</bold></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Attrition</bold></td><td align="right" rowspan="1" colspan="1"><bold>15</bold></td><td align="left" rowspan="1" colspan="1"><bold>Numbers analyzed–</bold></td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Absolute numbers in each group included in each analysis<xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Other</bold></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Explanation for exclusion</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Reporting</bold></td><td align="right" rowspan="1" colspan="1"><bold>16</bold></td><td align="left" rowspan="1" colspan="1"><bold>Outcomes and estimation–results for each analysis with a measure of precision</bold><xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Other</bold></td><td align="right" rowspan="1" colspan="1"><bold>17</bold></td><td align="left" rowspan="1" colspan="1"><bold>Adverse events–details and modifications for reduction</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td><td align="center" rowspan="1" colspan="1"><bold>4</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">DISCUSSION</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>18</bold></td><td align="left" rowspan="1" colspan="1"><bold>Interpretation</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>2</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>3</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><bold>scientific implications</bold><xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Study limitations<xref ref-type="table-fn" rid="t001fn001">*</xref>, bias, limitations of animal model</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"> </td><td align="left" rowspan="1" colspan="1">Implications/ n animal reduction</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>19</bold></td><td align="left" rowspan="1" colspan="1"><bold>Generalisability/translation/ relevance to human biology</bold><xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td></tr><tr><td align="right" rowspan="1" colspan="1"></td><td align="right" rowspan="1" colspan="1"><bold>20</bold></td><td align="left" rowspan="1" colspan="1"><bold>Funding</bold><xref ref-type="table-fn" rid="t001fn001">*</xref></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>0</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td><td align="center" rowspan="1" colspan="1"><bold>1</bold></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p>* <italic>items assess also for in vitro cellular tests</italic> 0 = No (high risk of bias), 1 = Yes (low risk of bias) 2 = Unclear (unclear risk of bias) 3 = partial reported 4 = not applicable; AM = animal model CM = cellular model</p></fn></table-wrap-foot></table-wrap><p>Only 16 items from the ARRIVE criteria fit in the in vitro studies and could be evaluated. According to the criteria, in vitro cellular model studies showed medium bias. Studies presented incomplete (n = 9 (10.7%)) or unclear information (n = 9 (10.7%)). Information that accomplish "Yes" (low risk) criteria was 55 (65.5%) and "No" was 11 (13.1%) in the overall sample of in vitro studies.</p><p>Quantitative assessment according the ARRIVE criteria is presented in <xref ref-type="table" rid="pone.0155231.t002">Table 2</xref> and qualitative data are present in <xref ref-type="supplementary-material" rid="pone.0155231.s002">S1 Fig</xref>.</p><table-wrap id="pone.0155231.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0155231.t002</object-id><label>Table 2</label><caption><title>Quantitative results of ARRIVE according to the 20 evaluated items.</title></caption><alternatives><graphic id="pone.0155231.t002g" xlink:href="pone.0155231.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="center" rowspan="1" colspan="1">Variables/Category</th><th align="center" colspan="2" rowspan="1">No(high)</th><th align="center" colspan="2" rowspan="1">Yes(low)</th><th align="center" colspan="2" rowspan="1">Unclear</th><th align="center" colspan="2" rowspan="1">Partial report</th><th align="center" rowspan="1" colspan="1">Total</th><th align="center" rowspan="1" colspan="1">Risk bias</th></tr><tr><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1">n</th><th align="center" rowspan="1" colspan="1">(%)</th><th align="center" rowspan="1" colspan="1">n</th><th align="center" rowspan="1" colspan="1">(%)</th><th align="center" rowspan="1" colspan="1">n</th><th align="center" rowspan="1" colspan="1">(%)</th><th align="center" rowspan="1" colspan="1">n</th><th align="center" rowspan="1" colspan="1">(%)</th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">1. Tao et al., 2016</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">15.5</td><td align="center" rowspan="1" colspan="1">9</td><td align="center" rowspan="1" colspan="1">45.0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">5.0</td><td align="center" rowspan="1" colspan="1">7</td><td align="center" rowspan="1" colspan="1">35.0</td><td align="center" rowspan="1" colspan="1">20</td><td align="center" rowspan="1" colspan="1">Unclear/high</td></tr><tr><td align="left" rowspan="1" colspan="1">2. Liang et al., 2014</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">20.0</td><td align="center" rowspan="1" colspan="1">9</td><td align="center" rowspan="1" colspan="1">45.0</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">10.0</td><td align="center" rowspan="1" colspan="1">5</td><td align="center" rowspan="1" colspan="1">25.0</td><td align="center" rowspan="1" colspan="1">20</td><td align="center" rowspan="1" colspan="1">Unclear/high</td></tr><tr><td align="left" rowspan="1" colspan="1">3. Lamolle et al., 2010</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">15.0</td><td align="center" rowspan="1" colspan="1">10</td><td align="center" rowspan="1" colspan="1">50.0</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">10.0</td><td align="center" rowspan="1" colspan="1">5</td><td align="center" rowspan="1" colspan="1">25.0</td><td align="center" rowspan="1" colspan="1">20</td><td align="center" rowspan="1" colspan="1">Medium</td></tr><tr><td align="left" rowspan="1" colspan="1">4. Lamolle et al., 2009</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">20.0</td><td align="center" rowspan="1" colspan="1">9</td><td align="center" rowspan="1" colspan="1">45.0</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">10.0</td><td align="center" rowspan="1" colspan="1">5</td><td align="center" rowspan="1" colspan="1">25.0</td><td align="center" rowspan="1" colspan="1">20</td><td align="center" rowspan="1" colspan="1">Unclear/high</td></tr><tr><td align="left" rowspan="1" colspan="1">5. Zhang et al., 2009</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">20.0</td><td align="center" rowspan="1" colspan="1">5</td><td align="center" rowspan="1" colspan="1">25.0</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">20.0</td><td align="center" rowspan="1" colspan="1">7</td><td align="center" rowspan="1" colspan="1">35.0</td><td align="center" rowspan="1" colspan="1">20</td><td align="center" rowspan="1" colspan="1">High</td></tr><tr><td align="left" rowspan="1" colspan="1">6. Young-Taeg et al., 2009</td><td align="center" rowspan="1" colspan="1">5</td><td align="center" rowspan="1" colspan="1">25.0</td><td align="center" rowspan="1" colspan="1">9</td><td align="center" rowspan="1" colspan="1">45.0</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">5.0</td><td align="center" rowspan="1" colspan="1">5</td><td align="center" rowspan="1" colspan="1">25.0</td><td align="center" rowspan="1" colspan="1">20</td><td align="center" rowspan="1" colspan="1">Unclear/high</td></tr><tr><td align="left" rowspan="1" colspan="1">7. Ban et al., 1997</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">20.0</td><td align="center" rowspan="1" colspan="1">6</td><td align="center" rowspan="1" colspan="1">30.0</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">15.0</td><td align="center" rowspan="1" colspan="1">7</td><td align="center" rowspan="1" colspan="1">35.0</td><td align="center" rowspan="1" colspan="1">20</td><td align="center" rowspan="1" colspan="1">High</td></tr><tr><td align="left" rowspan="1" colspan="1">8. Frank et al., 2014<xref ref-type="table-fn" rid="t002fn001">*</xref></td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">14.3</td><td align="center" rowspan="1" colspan="1">10</td><td align="center" rowspan="1" colspan="1">71.4</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">7.1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">7.1</td><td align="center" rowspan="1" colspan="1"><bold>14</bold></td><td align="center" rowspan="1" colspan="1">Medium</td></tr><tr><td align="left" rowspan="1" colspan="1">9. Xing et al., 2014<xref ref-type="table-fn" rid="t002fn001">*</xref></td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">14.3</td><td align="center" rowspan="1" colspan="1">10</td><td align="center" rowspan="1" colspan="1">71.4</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">7.1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">7.1</td><td align="center" rowspan="1" colspan="1"><bold>14</bold></td><td align="center" rowspan="1" colspan="1">Medium</td></tr><tr><td align="left" rowspan="1" colspan="1">10. Huang et al., 2013<xref ref-type="table-fn" rid="t002fn001">*</xref></td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">14.3</td><td align="center" rowspan="1" colspan="1">9</td><td align="center" rowspan="1" colspan="1">64.3</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">7.1</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">14.3</td><td align="center" rowspan="1" colspan="1"><bold>14</bold></td><td align="center" rowspan="1" colspan="1">Medium</td></tr><tr><td align="left" rowspan="1" colspan="1">11. Ou et al., 2008<xref ref-type="table-fn" rid="t002fn001">*</xref></td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">7.1</td><td align="center" rowspan="1" colspan="1">6</td><td align="center" rowspan="1" colspan="1">42.9</td><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">21.4</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">28.6</td><td align="center" rowspan="1" colspan="1"><bold>14</bold></td><td align="center" rowspan="1" colspan="1">Unclear/high</td></tr><tr><td align="left" rowspan="1" colspan="1">12. De Giglio et al., 2007<xref ref-type="table-fn" rid="t002fn001">*</xref></td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">14.3</td><td align="center" rowspan="1" colspan="1">10</td><td align="center" rowspan="1" colspan="1">71.4</td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">14.3</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1"><bold>14</bold></td><td align="center" rowspan="1" colspan="1">Medium</td></tr><tr><td align="left" rowspan="1" colspan="1">13. Hosaka et al., 2006<xref ref-type="table-fn" rid="t002fn001">*</xref></td><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">14.3</td><td align="center" rowspan="1" colspan="1">10</td><td align="center" rowspan="1" colspan="1">71.4</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">7.1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">7.1</td><td align="center" rowspan="1" colspan="1"><bold>14</bold></td><td align="center" rowspan="1" colspan="1">Medium</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t002fn001"><p>* in vitro cellular test</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec017"><title>Data Obtained</title><p>All studies used pure titanium-grade 2 or 4 (100.0%). Pure titanium and also titanium alloys were used in two studies (15.4%). Titanium shapes were used in the studies in the form of coins (53.9%), sheets (15.4%), implants (23.1%), and bars (7.7%).</p><p>To increase the surface energy, eleven studies (84.6%) prepared the experimental titanium surfaces by grinding, polishing, etching, washing, and drying[<xref rid="pone.0155231.ref009" ref-type="bibr">9</xref>, <xref rid="pone.0155231.ref010" ref-type="bibr">10</xref>, <xref rid="pone.0155231.ref013" ref-type="bibr">13</xref>–<xref rid="pone.0155231.ref019" ref-type="bibr">19</xref>, <xref rid="pone.0155231.ref021" ref-type="bibr">21</xref>, <xref rid="pone.0155231.ref022" ref-type="bibr">22</xref>]. Cathodic polarization technique was similar in all studies. It was used platinum as anode, the titanium sample as cathode and the control electrode was calomel (SCE) or silver. The technique included in all cases, the use of acidic solutions as a conduction medium.</p><p>The main results of the studies are presented in <xref ref-type="table" rid="pone.0155231.t003">Table 3</xref>. Cathodic polarization was mainly used to coat biomolecules in eight [<xref rid="pone.0155231.ref009" ref-type="bibr">9</xref>, <xref rid="pone.0155231.ref010" ref-type="bibr">10</xref>, <xref rid="pone.0155231.ref012" ref-type="bibr">12</xref>, <xref rid="pone.0155231.ref014" ref-type="bibr">14</xref>, <xref rid="pone.0155231.ref015" ref-type="bibr">15</xref>, <xref rid="pone.0155231.ref017" ref-type="bibr">17</xref>, <xref rid="pone.0155231.ref020" ref-type="bibr">20</xref>, <xref rid="pone.0155231.ref021" ref-type="bibr">21</xref>]studies (61.6%) three studies (23.1%) used the cathodic polarization for hydration of the titanium surfaces[<xref rid="pone.0155231.ref016" ref-type="bibr">16</xref>, <xref rid="pone.0155231.ref018" ref-type="bibr">18</xref>, <xref rid="pone.0155231.ref022" ref-type="bibr">22</xref>], and two studies (15.4%) used acid electrolytes[<xref rid="pone.0155231.ref013" ref-type="bibr">13</xref>, <xref rid="pone.0155231.ref019" ref-type="bibr">19</xref>]. The deposited biomolecules included calcium phosphate derivate in five studies (38.5%), such as hydroxyapatite and brushite. Other molecules such as enamel matrix derivate, Magnesium, Strontium were also used in three studies (23.1%). Acids such as Pyrrole-3-acetic modified, oxalic acetic or tartaric acids were used to promote surface modifications in five investigations (38.5%).</p><table-wrap id="pone.0155231.t003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0155231.t003</object-id><label>Table 3</label><caption><title>Surface properties and cellular responses from in vitro and in vivo-animal model studies.</title></caption><alternatives><graphic id="pone.0155231.t003g" xlink:href="pone.0155231.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">AUTORS</th><th align="center" rowspan="1" colspan="1">EXPERIMENTAL PROCEDURE</th><th align="left" colspan="2" rowspan="1">SURFACE CHEMISTRY AFTER TREATMENT</th><th align="left" rowspan="1" colspan="1">SURFACE MORPHOLOGY OR FILM COMPOSITION</th><th align="left" rowspan="1" colspan="1">STRENGHT RESISTENCE: PULL-OUT, REMOVAL TORQUE, STABILITY.</th><th align="left" rowspan="1" colspan="1">BONE GROWN /CELL ADHESION</th></tr></thead><tbody><tr><td align="left" colspan="7" rowspan="1"><italic>IN VIVO-ANIMAL MODEL</italic></td></tr><tr><td align="left" rowspan="1" colspan="1">Ban et al. 1997</td><td align="left" rowspan="1" colspan="1">Hydroxyapatite (HA)deposition</td><td align="left" rowspan="1" colspan="1">Basic elements of Apatite were present on the titanium surface.</td><td align="justify" colspan="2" rowspan="1">HA surface only had Spherical particles of HA. Surface with HA electrochemically coated is covered by needle-like precipitates.</td><td align="justify" rowspan="1" colspan="1">Higher strength resistance from pull-out test was observed in the titanium treated by electrochemical methods than the control samples, after 3 and 6 weeks of implantation</td><td align="justify" rowspan="1" colspan="1">The formation of new bone was enhanced in the electrochemical treated surface compared to the control surfaces.</td></tr><tr><td align="left" rowspan="1" colspan="1">Lamolle et al., 2009</td><td align="left" rowspan="1" colspan="1">Hydrofluoric acid (HF)</td><td align="left" rowspan="1" colspan="1">Hydride, Fluoride and Oxide were present.</td><td align="justify" colspan="2" rowspan="1">The oxide concentration was higher in the 0.001% HF at 30nm. Low concentration of HF increased hydrophobicity.</td><td align="justify" rowspan="1" colspan="1">Implants modified by cathodic reduction with 0.01 vol % hydrofluoric acid showed the highest pull out strength (p< 0.05) followed by the 0.1vol%.</td><td align="justify" rowspan="1" colspan="1">The concentrations of the fluoride and hydride in the titanium implant modified surfaces was correlated to the in vivo bone retention(r = 0.94).</td></tr><tr><td align="left" rowspan="1" colspan="1">Lamolle et al., 2010</td><td align="left" rowspan="1" colspan="1">Hydrofluoric acid (HF)</td><td align="left" rowspan="1" colspan="1">Hydride, Fluoride and Oxide were present.</td><td align="justify" colspan="2" rowspan="1">Groups of implants with 0.001% and 0.01% HF showed the highest fluoride content at their surface structure</td><td align="center" rowspan="1" colspan="1">-</td><td align="justify" rowspan="1" colspan="1">All experiment groups showed new peri-implant cortical bone, but implants treated with 0.01% HF showed higher osteocalcin, collagen-I and TRAP, revealing an advanced osseointegration process. Implants modified with 0.001% and 0.01% HF presented a statistically significant increased newly formed bone. Lower presence of blood was observed at the interface after removal of the implant in the groups of implants (0.001% and 0.01% HF). The control group scored higher LDH activity than all the test groups.</td></tr><tr><td align="left" rowspan="1" colspan="1">Liang et al., 2014</td><td align="left" rowspan="1" colspan="1">Pure brushite and modified brushite with 5%, 10%, and 20% Strontium (Sr) deposition</td><td align="left" rowspan="1" colspan="1">Basic elements of Brushite and Strontium were present on the titanium surface.</td><td align="justify" colspan="2" rowspan="1">Brushite coating, presence of crystals, some arranged in clusters. Brushite coating containing 20% Sr showed an irregular surface morphology</td><td align="justify" rowspan="1" colspan="1">Removal torque strength in 5% Sr and 10% Sr groups was significantly increased compared with the other three groups without cathodic treatment (p < 0.01)</td><td align="justify" rowspan="1" colspan="1">After 24, 48, or 72h the number of the proliferating cells on the brushite-coated and Sr-doped brushite groups were higher than in the control group (p < 0.01), especially in the 10% Sr-doped coating. Modified surfaces with 5% and 10% Sr-doped brushite coatings were associated with increased 3D bone volume(p < 0.05), especially around the 10% Sr-doped brushite-coated implants.</td></tr><tr><td align="left" rowspan="1" colspan="1">Tao et al., 2016</td><td align="left" rowspan="1" colspan="1">Electrochemical deposition of Zinc(Zn), Strontium, Magnesium(Mg), and HA.</td><td align="left" rowspan="1" colspan="1">Coatings composed of hydroxyapatite containing 10% Zn, Mg and Sr ions on titanium.</td><td align="center" colspan="2" rowspan="1">-</td><td align="justify" rowspan="1" colspan="1">Push-out force of group Sr-HA was significantly higher than that of groups Zn-HA and Mg-HA. Group Sr-HA showed the strongest effects on all micro-CT parameters (bone volume, trabecular thickness, connective density, trabecular number; trabecular separation) significantly (p<0.05).</td><td align="justify" rowspan="1" colspan="1">After 12 weeks, new bone was formed. Within the circumference of marrow cavities of cortical bone, there were osteoblast-like cells, suggesting the beginning of new bone formation. There was more bone tissue on implant surfaces of Zn-HA, Mg-HA, Sr-HA-coated implants than in those of HA-coated.</td></tr><tr><td align="left" rowspan="1" colspan="1">Young et al.,2009</td><td align="left" rowspan="1" colspan="1">Electrochemical deposition of Magnesium, Phosphate</td><td align="left" rowspan="1" colspan="1">Magnesium, P, and Ti were identified in the composition.</td><td align="justify" colspan="2" rowspan="1">The implants had moderate roughness of 0.7–1.4 mm. Oxidized implants had crystal structures consisting of a mixture of Anatase and rutile phase.</td><td align="justify" rowspan="1" colspan="1">After 6 weeks of healing, all surfaces increased implant stability but it was higher in the modified surfaces than in the control surfaces.</td><td align="justify" rowspan="1" colspan="1">New bone formation occurred in all surfaces, but it was increased in the Mg-MP implant group.</td></tr><tr><td align="left" rowspan="1" colspan="1">Zhang et al., 2009</td><td align="left" rowspan="1" colspan="1">Solution of calcium phosphates as medium</td><td align="left" rowspan="1" colspan="1">Titanium hydride was identified. Calcium and Phosphates were present on the titanium surface.</td><td align="justify" colspan="2" rowspan="1">Metal surface were rough and had fine granular appearance. A thin layer of CaP (100nm thick) was deposited and had higher resistance to displacement.</td><td align="center" rowspan="1" colspan="1"><bold>-</bold></td><td align="justify" rowspan="1" colspan="1">Bone growth was fast in the electrochemical-treated specimens. After 4weeks bone formation and the amount of bone in electrochemical titanium and stainless steel samples were significantly higher than that in control without cathodic treatment (p < 0.01).</td></tr><tr><td align="left" colspan="7" rowspan="1"><bold>IN VITRO STUDIES</bold></td></tr><tr><td align="left" rowspan="1" colspan="1">Franck et al., 2014</td><td align="left" rowspan="1" colspan="1">Enamel Matrix Derivate (EMD) deposition</td><td align="left" rowspan="1" colspan="1">EMD was coated. Characteristic elements were identified in the composition.</td><td align="justify" colspan="2" rowspan="1">Electrochemical EMD coated samples presented larger spherical structures attached to the surface. Sandblasted and acid-etched revealed nano-nodules and small spherical structures on the surface.</td><td align="center" rowspan="1" colspan="1"><bold>-</bold></td><td align="justify" rowspan="1" colspan="1">No cytotoxicity was observed in any group. For Electrochemical treated groups the expression of Coll-1 mRNA levels and the alkaline phosphatase activity was significantly higher compared to control.</td></tr><tr><td align="left" rowspan="1" colspan="1">Xing et al., 2014</td><td align="left" rowspan="1" colspan="1">Acids (oxalic: OA)as medium</td><td align="left" rowspan="1" colspan="1">Presence of Hydride. Characteristic elements were identified in the composition.</td><td align="left" colspan="2" rowspan="1">OA created the roughest surface and thin layers.</td><td align="center" rowspan="1" colspan="1"><bold>-</bold></td><td align="justify" rowspan="1" colspan="1">At day 3, cells grown in all groups faster than in the control. The proliferation rate on acetic acid was significantly higher than others groups. Hydrogen amount on the surfaces was correlated with proliferation rate at day 3 (r 5 0.973, p <0.05). At day 6, proliferation of cells was higher in tartaric and control groups only.</td></tr><tr><td align="left" rowspan="1" colspan="1">Huang et al., 2013</td><td align="left" rowspan="1" colspan="1">Hydroxyapatite (HA) deposition</td><td align="left" rowspan="1" colspan="1">Deposition of HA. HA surface was mainly composed of O, P, Ca, and Si. Si content was 7.77 wt.%±0.39.</td><td align="left" colspan="2" rowspan="1">HA and HA/CS films formed uniform layers on the Ti substrate. The HA/CS coating had a porous structure and the HA coating had a dense surface structure.</td><td align="center" rowspan="1" colspan="1"><bold>-</bold></td><td align="justify" rowspan="1" colspan="1">After 7 days, cell proliferation on the HA/Cathodic coated surfaces was higher (p < 0.05) than those on HA coating.</td></tr><tr><td align="left" rowspan="1" colspan="1">Ou et al., 2008</td><td align="left" rowspan="1" colspan="1">Electrochemical treatment</td><td align="left" rowspan="1" colspan="1">Promote the presence of Hydride. O<sub>2</sub> concentration following electrochemical treatment was higher than in polished Ti.</td><td align="left" colspan="2" rowspan="1">Titania film with cathodic pre-treatment and anodization was thicker than other groups Porosity was higher in ACTi samples</td><td align="center" rowspan="1" colspan="1"><bold>-</bold></td><td align="justify" rowspan="1" colspan="1">Cathodic pre-treatment followed by anodization at 24h significantly more cells attached than controls (cathodic and anodization treatment only). Cells on AC-Ti were more spread out and had more, longer filopods than other groups.</td></tr><tr><td align="left" rowspan="1" colspan="1">De Giglio et al., 2007</td><td align="left" rowspan="1" colspan="1">Pyrrole-3-acetic acid, 4-fluoro-phenylalanine deposition</td><td align="left" rowspan="1" colspan="1">Promote deposition of 4-fluoro-phenylalanine modified PPy-3-acetic film.</td><td align="left" colspan="2" rowspan="1"> </td><td align="left" rowspan="1" colspan="1"> </td><td align="justify" rowspan="1" colspan="1">Cell Adhesion, growth, and viability of osteoblast-like cells onto PPy-3-acetic modified titanium substrates were comparable to the control groups. Cell phenotype was similar in all groups.</td></tr></tbody></table></alternatives></table-wrap><p>Titanium characterization was performed in all studies. The tests included surface morphology by scanning electron microscopy (SEM) or transmission electron microscopy (TEM);surface chemistry by X-ray photoelectron spectroscopy (XPS) or secondary ion mass spectrometry(SIMS),blue light laser profilometer, UV–vis spectroscopy, field emission scanning electron microscopy(FE-SEM), X-ray diffraction, and contact angle measurement.</p><p>Biocompatibility and cellular response tests performed were cytotoxicity, cell proliferation, adhesion and differentiation, cell morphology observation, and RNA isolation-reverse transcriptase (RT)-PCR amplification. For bone growth assessment, Rx and bone mineral density, micro-computed tomography (Micro-CT), confocal laser microscopy, osseointegration histological analysis, and pull-out tests were conducted.</p><p>Studies performed <italic>in vitro</italic> cellular tests (46.2%), six studies opted by the <italic>in vivo</italic> animal model (46.2%) and one study (7.7%) was performed in vitro and in vivo essay.</p><p>The cellular types used were MC3T3-E1osteoblast-like cells (71.4%), human gingival fibroblast (14.3%), NIH3T3, and fibroblasts (14.3%).</p><p>Studies showed that the cathodic polarization method promoted incorporation of the biomolecules, such as phosphate hydroxyapatite derivate, antibiotics, and enamel matrix derivate, on the titanium surfaces.</p><p><italic>In vitro</italic> cellular tests showed significantly higher cellular proliferation [<xref rid="pone.0155231.ref013" ref-type="bibr">13</xref>, <xref rid="pone.0155231.ref015" ref-type="bibr">15</xref>, <xref rid="pone.0155231.ref019" ref-type="bibr">19</xref>]or adhesion[<xref rid="pone.0155231.ref013" ref-type="bibr">13</xref>, <xref rid="pone.0155231.ref014" ref-type="bibr">14</xref>, <xref rid="pone.0155231.ref018" ref-type="bibr">18</xref>] after 3–7 days in the experimental (hydrided or coated) groups than in control groups. Cytotoxicity was similar in all groups [<xref rid="pone.0155231.ref019" ref-type="bibr">19</xref>]and gene expression of Coll-1mRNA and alkaline phosphatase was increased in the coating groups compared to the control groups [<xref rid="pone.0155231.ref009" ref-type="bibr">9</xref>].</p><p><italic>In vivo</italic> animal model studies reported no toxic effect enhancement on bone formation[<xref rid="pone.0155231.ref012" ref-type="bibr">12</xref>, <xref rid="pone.0155231.ref017" ref-type="bibr">17</xref>, <xref rid="pone.0155231.ref021" ref-type="bibr">21</xref>], showing balance in gene expression between some biological factors such as osteocalcin, collagen-I or TRAP[<xref rid="pone.0155231.ref022" ref-type="bibr">22</xref>], and bone retention [<xref rid="pone.0155231.ref016" ref-type="bibr">16</xref>]in the groups of titanium hydrided or with biomolecule coatings[<xref rid="pone.0155231.ref010" ref-type="bibr">10</xref>, <xref rid="pone.0155231.ref020" ref-type="bibr">20</xref>] compared to control groups after 3–12 weeks of experiment.</p></sec></sec><sec sec-type="conclusions" id="sec018"><title>Discussion</title><p>To the best of our knowledge, this review is the first to systematically collect the existing evidence in relation to the cell response to the titanium surfaces modified by the cathodic polarization technique</p><p>Indeed, there are several different techniques of deposition to modify medical titanium surfaces including plasma, sputter-deposition, sol–gel coatings, electrochemical deposition, or biomimetic precipitation. Plasma-spraying is widely used [<xref rid="pone.0155231.ref023" ref-type="bibr">23</xref>], as well as the anodic method to coat molecules. Even though there are advantages of these last two techniques, they present some drawbacks, such as low adhesion and thicker coating, respectively. These problems were attributed to technique issues produced essentially by the temperature used.</p><p>Electrodeposition using titanium as a cathode is usually conducted in acidic electrolytes, organic or inorganic, in order to modify surfaces of titanium for hydridation or deposition of molecules. The techniques make it possible to control the thickness of the coating deposit on all kinds of surfaces and reduce the time required for coating, as the process is highly reproducible and efficient[<xref rid="pone.0155231.ref012" ref-type="bibr">12</xref>].</p><p>Results from our included studies indicated that the use of the cathodic polarization as surface treatment in acid solutions induced the hydride layers’ formation on titanium, increasing positive cellular responses regarding proliferation, adhesion, and differentiation [<xref rid="pone.0155231.ref016" ref-type="bibr">16</xref>, <xref rid="pone.0155231.ref021" ref-type="bibr">21</xref>, <xref rid="pone.0155231.ref022" ref-type="bibr">22</xref>].Other studies that used this technique reported the reduction of the mechanical properties of titanium due to hydrogen embrittlement produced by the hydride layers, which could possible cause implant fractures [<xref rid="pone.0155231.ref024" ref-type="bibr">24</xref>, <xref rid="pone.0155231.ref025" ref-type="bibr">25</xref>]. Recent studies showed that the presence of the hydride layer obtained using cathodic polarization offers the potential for attaching biomolecules, such as antibiotics and hydroxyapatites in ambient temperatures, on pure titanium, titanium alloys [<xref rid="pone.0155231.ref009" ref-type="bibr">9</xref>], or other metal types. In fact, this has been the main advantage of the cathodic polarization so far[<xref rid="pone.0155231.ref012" ref-type="bibr">12</xref>].</p><p>In the present review, most of the investigation have deposited biomolecules on titanium and they observed positive deposition in terms of integrity, adhesion and thickness, also detecting enhanced cell adhesion. Biomolecules deposited on the surface were observed to maintain their integrity, presenting good interaction with the metal surface and having binding strength[<xref rid="pone.0155231.ref017" ref-type="bibr">17</xref>]. The layers generated were mostly thin (100um min) but dense enough to promote good strength of the coatings [<xref rid="pone.0155231.ref010" ref-type="bibr">10</xref>].</p><p>Bioactive molecules can be adsorbed, affecting cell attachment to the surface and tissue response. Several molecules could be deposited to improve titanium surfaces in terms of biological responses such as magnesium, strontium, or bone proteins [<xref rid="pone.0155231.ref009" ref-type="bibr">9</xref>, <xref rid="pone.0155231.ref020" ref-type="bibr">20</xref>, <xref rid="pone.0155231.ref026" ref-type="bibr">26</xref>]. For instance, the electrochemical deposition of calcium-phosphate-derivate molecules can increase fixation of implants to bone tissue, promoting better adhesion and activation of bone cells on the implant surfaces[<xref rid="pone.0155231.ref012" ref-type="bibr">12</xref>]. Another advantage is the possibility to deposit drugs on the active surfaces, which could be released over a period of time, enhancing the cellular responses [<xref rid="pone.0155231.ref027" ref-type="bibr">27</xref>].</p><p>Some factors related to the method of the cathodic technique deposition can influence the film characteristics and consequently cellular response[<xref rid="pone.0155231.ref006" ref-type="bibr">6</xref>]. In this review, the eligibility criteria attempted to include studies presenting similar characteristics regarding the cathodic method used.</p><p>Most of the studies used room temperatures to performed the test in the range of 20°C to 25°C. The technique of deposition is performed at ambient temperatures, being that such characteristics are probably responsible for the good conformability to the shape of the molecules’ components on titanium surfaces, the thickness of the films (less than 1 µm), and the increased resistance to delamination for the coating homogeneity and the stronger adhesion of the coating[<xref rid="pone.0155231.ref006" ref-type="bibr">6</xref>]. Lower temperatures during deposition of the film can decrease the presence of defects or pores on hidroxyapatite crystals [<xref rid="pone.0155231.ref028" ref-type="bibr">28</xref>].</p><p>Cathodic polarization in acid can optimize titanium implant surfaces for improved osseointegration. In the present review, most of the studies opted to use electrolytes with lower pH (2–6). It was reported that baths with pH of 4.11 produce the deposition of hydroxyapatite films on titanium alloy[<xref rid="pone.0155231.ref029" ref-type="bibr">29</xref>]. Studies have observed that increasing the pH to 5 [<xref rid="pone.0155231.ref030" ref-type="bibr">30</xref>]or nearly neutral (7.2)[<xref rid="pone.0155231.ref031" ref-type="bibr">31</xref>] produce mono grain phases. Hydrofluoric acid has been shown to increase the hydride and fluoride amount on Ti surfaces, changing the porosity of the surface and consequently the surface roughness[<xref rid="pone.0155231.ref019" ref-type="bibr">19</xref>]. These alterations were positively correlated within vivo bone retention and peri-implant bone mineralization [<xref rid="pone.0155231.ref016" ref-type="bibr">16</xref>]</p><p>Cell adhesion, growth, and biocompatibility between osteoblast-like cells and treated surfaces have increased, preserving osteoblastic phenotype [<xref rid="pone.0155231.ref013" ref-type="bibr">13</xref>]. The expression of proteins such as Coll-1 mRNA and alkaline phosphatase activity indicated the bone proliferation activity promoted by the modified surface [<xref rid="pone.0155231.ref009" ref-type="bibr">9</xref>].</p><p>The current density is another factor that can influence the films in relation to mechanical, physical and biological characteristics. In our review, studies used current densities in the range of 0.4-20mA/cm2 or -2.0–2.5V during 30 to 60 minutes. The density current determinates the format and the adhesion of the deposit. It has been shown that decreasing the current density produced deposits with needle forms and increasing it can produce blunt forms of the particles of hydroxiapatite[<xref rid="pone.0155231.ref032" ref-type="bibr">32</xref>]. When associate with lower pH and/or with stirrings—ultrasonic or magnetic- the size of the particle could be reduced. The size of the particle is also important since smaller particles were found to enhance the cellular adhesion on the surface [<xref rid="pone.0155231.ref029" ref-type="bibr">29</xref>]. On the other hand, lower current densities in the range of 0.2-15mA/cm<sup>2</sup> increased bond strengths of the coating [<xref rid="pone.0155231.ref033" ref-type="bibr">33</xref>].</p><p>In our study, the sample was composed of investigation using galvanostatic technique. The galvanostatic technique allowed to work in acid or near physiological pH at body temperature and doesn`t require post-treatment, which is required in the pulse electrochemical method where a post-treatment at high temperatures in the range of 300°C-800°C is needed. Higher temperatures could negatively have affected the mechanical properties of the coated surface as aforementioned.</p><p>The studies included were composed of in vitro cellular essays and in vivo animal model experiments that used cathodic polarization method to modified titanium surfaces. In vitro results reported significant higher cellular proliferation, gene expression of bone formation genes and low cytotoxicity. Animal experiments reported no toxic effect, enhancement of bone formation and bone retention in the groups with modified surface of titanium by the cathodic technique. In fact, all the studies with animal models were performed after an in vitro essay. For instance, in vitro observation of titanium surfaces showed needle-like carbonate apatite, this new composite enhance the mechanical bonding strength in early stages of implantation in the animal model, increasing the filling of the gap between the implant and the surface with new bone compared to those without the treatment[<xref rid="pone.0155231.ref012" ref-type="bibr">12</xref>]. The surface modifications, in macro and micro level can efficiently increase biological events in vitro and in vivo[<xref rid="pone.0155231.ref008" ref-type="bibr">8</xref>]. In the study of Young-Taeg et al., 2009, the treatments performed on titanium modified the topographies regarding the roughness and also produce chemistry changes on surfaces. These changes were associated with improvement of osseointegration since the oxidized groups by cathodic polarization presented better stability and bone density[<xref rid="pone.0155231.ref020" ref-type="bibr">20</xref>]. The author also sustained that when implants stability in early stages is low, subsequent resonance values increased rapidly over the time, possibly due to difference in bone properties between the animals and humans[<xref rid="pone.0155231.ref020" ref-type="bibr">20</xref>].</p><p>The hydrophilicity is an important factor in the enhancement of the bone response [<xref rid="pone.0155231.ref006" ref-type="bibr">6</xref>, <xref rid="pone.0155231.ref008" ref-type="bibr">8</xref>, <xref rid="pone.0155231.ref023" ref-type="bibr">23</xref>]. Hydrophilicity was demonstrated to increased osseointegration when using in vitro and in vivo animal models [<xref rid="pone.0155231.ref034" ref-type="bibr">34</xref>]. This situation was also detected by Lamolle et al., 2009, where a positive correlation was found between high bone retention and high amounts of Fluoride and the hydride in the surface in the group with lower concentration of electrolyte. The author explained that this could be due to the aggressive conditions produced by the high electrolyte concentration, once at low hydrofluoric acid concentrations the surfaces were weakly etched, and consequently, kept higher amounts of fluoride, oxide, and hydride.Also a correlation was observed between some roughness parameters regarding positive surface skewness that means elevations on flat surfaces, kurtosis higher than 3 that is rounded peaks and high core fluid retention (more spaces between the peaks) with high bone retention of implants. Studies showed the importance of the roughness and its relation with higher bond strength [<xref rid="pone.0155231.ref035" ref-type="bibr">35</xref>] and the before mention study showed that a conjunct of surface parameters can predict the in vivo performance of bone retention[<xref rid="pone.0155231.ref016" ref-type="bibr">16</xref>].</p><p>It is clear that in vitro controlled methods allowed to obtain more objective results, nevertheless is difficult to extrapolated such findings directly to the in vivo animal models, since several factors cannot be controlled in animal experimentation as opposite to the in vitro condition[<xref rid="pone.0155231.ref036" ref-type="bibr">36</xref>]. The strengths of the animal experiments include the possibility of learning about some biological mechanism in an living organism, turning their results more representative to the clinical situation than those obtained in vitro [<xref rid="pone.0155231.ref037" ref-type="bibr">37</xref>].</p><p>It was suggested that systematic reviews and meta-analyses on animal experiments can be conducted in order to model relevant clinical problems since some treatments are currently being offered to vulnerable groups of patients without much evidence of their beneficial effects [<xref rid="pone.0155231.ref038" ref-type="bibr">38</xref>, <xref rid="pone.0155231.ref039" ref-type="bibr">39</xref>].</p><p>Some limitations should be considered. We did not find any in vivo clinical trials using prosthetic appliances obtained by cathodic polarization, making the clinical effect of this technique unclear. Additionally, systematic reviews including animal experiments or cellular responses are different situations from the in vivo clinical reality; however, it allows a more objective appraisal of the research evidence from the traditional narrative reviews, and also offer a sensible and rational approach to assessing the translational potential of promising experimental interventions before decisions are made to proceed with clinical trials [<xref rid="pone.0155231.ref038" ref-type="bibr">38</xref>, <xref rid="pone.0155231.ref039" ref-type="bibr">39</xref>].</p><p>Our findings should be considered with caution, since according to the ARRIVE quality criteria the studies with animal experiments showed medium or high risk of bias due to the incomplete or lack of data reported. It has been discussed the importance to report information such as the study design, animal characteristics, housing and husbandry, allocation of the animal, eventual exclusions or adverse events in the studies with animal models, which could influence the results, especially when is testing new medicines or drugs[<xref rid="pone.0155231.ref037" ref-type="bibr">37</xref>, <xref rid="pone.0155231.ref040" ref-type="bibr">40</xref>]. However, since there is no evidence testing titanium surfaces modified by cathodic polarization in human clinical trials, the results obtained from our sample of studies using animal experiments can generate contribution firstable with the necessity and importance of a good quality reporting of results when an animal model study is performed, and second, because of the clear necessity of more evidence using animal model before thinking in human clinical trials.</p><p>This systematic review showed that the use of cathodic polarization produced adequate cellular response promoting proliferation, differentiation, and bone development in vitro and in animal experiments. The cathodic polarization seems to be a feasible alternative to successfully modified surfaces, maintaining adequate mechanical and biologic properties, allowing deposit of biomolecules and promoting activity on the surface by hydrided formation.</p></sec><sec sec-type="conclusions" id="sec019"><title>Conclusion</title><p>Cathodic polarization promotes titanium surface modifications, increasing the adhesion of active biomolecules and hydridation of titanium surfaces. Modified surfaces enhance cellular response in vitro and in vivo-animal models.</p></sec><sec sec-type="supplementary-material" id="sec020"><title>Supporting Information</title><supplementary-material content-type="local-data" id="pone.0155231.s001"><label>S1 PRISMA Checklist</label><caption><title>PRISMA Checklist.</title><p>(DOCX)</p></caption><media xlink:href="pone.0155231.s001.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0155231.s002"><label>S1 Fig</label><caption><title>Figure presenting the quantitative results means of the ARRIVE criteria for in vitro and animal model studies.</title><p>(TIF)</p></caption><media xlink:href="pone.0155231.s002.tif"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0155231.s003"><label>S1 Table</label><caption><title>Excluded studies and reasons for exclusion.</title><p>(DOCX)</p></caption><media xlink:href="pone.0155231.s003.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>The authors gratefully acknowledge the Brazilian Coordination for Improvement of Higher Education Personnel (CAPES) and the Brazilian National Council for Scientific and Technological Development (CNPq- process 482251/2013-1).</p><p>Jose Carlos Bernedo Alcázar, Mabel Miluska Suca Salas, Marcus Cristian Muniz Conde, Luiz Alexandre Chisini, Flávio Fernando Demarco, Sandra Beatriz Chaves Tarquinio, and Neftali Lenin Villarreal Carreño analyzed the data, wrote the first draft of the paper, and contributed to the writing of the paper.</p></ack><ref-list><title>References</title><ref id="pone.0155231.ref001"><label>1</label><mixed-citation publication-type="journal"><name><surname>Van Velzen</surname><given-names>FJ</given-names></name>, <name><surname>Ofec</surname><given-names>R</given-names></name>, <name><surname>Schulten</surname><given-names>EA</given-names></name>, <name><surname>Ten Bruggenkate</surname><given-names>CM</given-names></name>. <article-title>10-year survival rate and the incidence of peri-implant disease of 374 titanium dental implants with a SLA surface: a prospective cohort study in 177 fully and partially edentulous patients</article-title>. <source>Clinical oral implants research</source>. <year>2014</year> Epub 2014/11/06. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1111/clr.12499">10.1111/clr.12499</ext-link></comment> .<pub-id pub-id-type="pmid">25370914</pub-id></mixed-citation></ref><ref id="pone.0155231.ref002"><label>2</label><mixed-citation publication-type="journal"><name><surname>Becker</surname><given-names>ST</given-names></name>, <name><surname>Beck-Broichsitter</surname><given-names>BE</given-names></name>, <name><surname>Rossmann</surname><given-names>CM</given-names></name>, <name><surname>Behrens</surname><given-names>E</given-names></name>, <name><surname>Jochens</surname><given-names>A</given-names></name>, <name><surname>Wiltfang</surname><given-names>J</given-names></name>. <article-title>Long-term Survival of Straumann Dental Implants with TPS Surfaces: A Retrospective Study with a Follow-up of 12 to 23 Years</article-title>. <source>Clinical implant dentistry and related research</source>. <year>2015</year> Epub 2015/03/27. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1111/cid.12334">10.1111/cid.12334</ext-link></comment> .<pub-id pub-id-type="pmid">25810237</pub-id></mixed-citation></ref><ref id="pone.0155231.ref003"><label>3</label><mixed-citation publication-type="journal"><name><surname>de Jonge</surname><given-names>L</given-names></name>, <name><surname>Leeuwenburgh</surname><given-names>SG</given-names></name>, <name><surname>Wolke</surname><given-names>JC</given-names></name>, <name><surname>Jansen</surname><given-names>J</given-names></name>. <article-title>Organic–Inorganic Surface Modifications for Titanium Implant Surfaces</article-title>. <source>Pharm Res</source>. <year>2008</year>;<volume>25</volume>(<issue>10</issue>):<fpage>2357</fpage>–<lpage>69</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1007/s11095-008-9617-0">10.1007/s11095-008-9617-0</ext-link></comment><pub-id pub-id-type="pmid">18509601</pub-id></mixed-citation></ref><ref id="pone.0155231.ref004"><label>4</label><mixed-citation publication-type="journal"><name><surname>Niinomi</surname><given-names>M</given-names></name>. <article-title>Mechanical biocompatibilities of titanium alloys for biomedical applications</article-title>. <source>Journal of the mechanical behavior of biomedical materials</source>. <year>2008</year>;<volume>1</volume>(<issue>1</issue>):<fpage>30</fpage>–<lpage>42</lpage>. 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