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<!DOCTYPE html> <html lang="en" class="no-js"> <head> <meta charset="UTF-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width, initial-scale=1"> <meta name="robots" content="max-image-preview:large"> <meta name="access" content="Yes"> <meta name="360-site-verification" content="1268d79b5e96aecf3ff2a7dac04ad990" /> <title>An historical perspective on cell mechanics | Pflügers Archiv - European Journal of Physiology</title> <meta name="twitter:site" content="@SpringerLink"/> <meta name="twitter:card" content="summary_large_image"/> <meta name="twitter:image:alt" content="Content cover image"/> <meta name="twitter:title" content="An historical perspective on cell mechanics"/> <meta name="twitter:description" content="Pflügers Archiv - European Journal of Physiology - The physical properties of the protoplasm have long been of interest, and today, several intricate methods, including atomic force..."/> <meta name="twitter:image" content="https://static-content.springer.com/image/art%3A10.1007%2Fs00424-007-0405-1/MediaObjects/424_2007_405_Fig1_HTML.gif"/> <meta name="journal_id" content="424"/> <meta name="dc.title" content="An historical perspective on cell mechanics"/> <meta name="dc.source" content="Pflügers Archiv - European Journal of Physiology 2007 456:1"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="Springer"/> <meta name="dc.date" content="2007-12-07"/> <meta name="dc.type" content="ReviewPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2007 Springer-Verlag"/> <meta name="dc.rights" content="2007 Springer-Verlag"/> <meta name="dc.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="dc.description" content="The physical properties of the protoplasm have long been of interest, and today, several intricate methods, including atomic force microscopy, have been employed in studies of cellular mechanics. However, many current concepts and experimental approaches actually have their beginnings over 300&nbsp;years ago. Unfortunately, these pioneering studies have been all but forgotten. In this paper, we have reviewed some of the early literature on cellular mechanics to place modern work within an historical framework. It is clear that with current nanoscience approaches, modern experiments employing cell indentation, manipulation, particle rheology and micro- or nano-needle poking are now quantifying mechanical properties which were only qualitatively described 100&nbsp;years ago. Aside from the variety of approaches our predecessors have employed to understand cellular mechanics, we feel an understanding of the past will help to propel nanoscience into the future. As nanophysiology and nanomedicine are developing, we as a community should take time to consider the early roots of these fields."/> <meta name="prism.issn" content="1432-2013"/> <meta name="prism.publicationName" content="Pflügers Archiv - European Journal of Physiology"/> <meta name="prism.publicationDate" content="2007-12-07"/> <meta name="prism.volume" content="456"/> <meta name="prism.number" content="1"/> <meta name="prism.section" content="ReviewPaper"/> <meta name="prism.startingPage" content="3"/> <meta name="prism.endingPage" content="12"/> <meta name="prism.copyright" content="2007 Springer-Verlag"/> <meta name="prism.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="prism.url" content="https://link.springer.com/article/10.1007/s00424-007-0405-1"/> <meta name="prism.doi" content="doi:10.1007/s00424-007-0405-1"/> <meta name="citation_pdf_url" content="https://link.springer.com/content/pdf/10.1007/s00424-007-0405-1.pdf"/> <meta name="citation_fulltext_html_url" content="https://link.springer.com/article/10.1007/s00424-007-0405-1"/> <meta name="citation_journal_title" content="Pflügers Archiv - European Journal of Physiology"/> <meta name="citation_journal_abbrev" content="Pflugers Arch - Eur J Physiol"/> <meta name="citation_publisher" content="Springer-Verlag"/> <meta name="citation_issn" content="1432-2013"/> <meta name="citation_title" content="An historical perspective on cell mechanics"/> <meta name="citation_volume" content="456"/> <meta name="citation_issue" content="1"/> <meta name="citation_publication_date" content="2008/04"/> <meta name="citation_online_date" content="2007/12/07"/> <meta name="citation_firstpage" content="3"/> <meta name="citation_lastpage" content="12"/> <meta name="citation_article_type" content="Invited Review"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1007/s00424-007-0405-1"/> <meta name="DOI" content="10.1007/s00424-007-0405-1"/> <meta name="size" content="297519"/> <meta name="citation_doi" content="10.1007/s00424-007-0405-1"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1007/s00424-007-0405-1&api_key="/> <meta name="description" content="The physical properties of the protoplasm have long been of interest, and today, several intricate methods, including atomic force microscopy, have been em"/> <meta name="dc.creator" content="Pelling, Andrew E."/> <meta name="dc.creator" content="Horton, Michael A."/> <meta name="dc.subject" content="Human Physiology"/> <meta name="dc.subject" content="Molecular Medicine"/> <meta name="dc.subject" content="Neurosciences"/> <meta name="dc.subject" content="Cell Biology"/> <meta name="dc.subject" content="Receptors"/> <meta name="citation_reference" content="citation_journal_title=Plant Physiol; citation_title=Methods of research on the physical properties of the protoplasm; citation_author=W Seifriz; citation_volume=12; citation_publication_date=1937; citation_pages=99-116; citation_id=CR1"/> <meta name="citation_reference" content="citation_journal_title=Bull Ecol Soc Am; citation_title=A history of the ecological sciences, Part 19. 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citation_title=Atomic force microscopy can be used to mechanically stimulate osteoblasts and evaluate cellular strain distributions; citation_author=GT Charras, PP Lehenkari, MA Horton; citation_volume=86; citation_publication_date=2001; citation_pages=85-95; citation_id=CR168"/> <meta name="citation_reference" content="citation_journal_title=J Cell Sci; citation_title=Sphingosine 1-phosphate induces cytoskeletal reorganization in C2C12 myoblasts: physiological relevance for stress fibres in the modulation of ion current through stretch-activated channels; citation_author=L Formigli, E Meacci, C Sassoli, F Chellini, R Giannini, F Quercioli, B Tiribilli, R Squecco, P Bruni, F Francini, S Zecchi-Orlandini; citation_volume=118; citation_publication_date=2005; citation_pages=1161-1171; citation_id=CR169"/> <meta name="citation_reference" content="citation_journal_title=Cancer Cell; citation_title=Cell tension, matrix mechanics, and cancer development; citation_author=S Huang, DE Ingber; citation_volume=8; citation_publication_date=2005; citation_pages=175-176; citation_id=CR170"/> <meta name="citation_reference" content="citation_journal_title=Acta Biomater; citation_title=Biomechanics and biophysics of cancer cells; citation_author=S Suresh; citation_volume=3; citation_publication_date=2007; citation_pages=413-438; citation_id=CR171"/> <meta name="citation_reference" content="citation_journal_title=Bull Torrey Bot Club; citation_title=Studies in cell-division; citation_author=DH Campbell; citation_volume=17; citation_publication_date=1890; citation_pages=113-121; citation_id=CR172"/> <meta name="citation_reference" content="citation_journal_title=Proc Am Soc Microsc; citation_title=Cardiac muscle cells in man and certain other mammals; citation_author=BL Oviatt; citation_volume=9; citation_publication_date=1887; citation_pages=283-298; citation_id=CR173"/> <meta name="citation_author" content="Pelling, Andrew E."/> <meta name="citation_author_email" content="a.pelling@ucl.ac.uk"/> <meta name="citation_author_institution" content="The London Centre for Nanotechnology, Centre for Nanomedicine, University College London, London, UK"/> <meta name="citation_author" content="Horton, Michael A."/> <meta name="citation_author_email" content="m.horton@ucl.ac.uk"/> <meta name="citation_author_institution" content="The London Centre for Nanotechnology, Centre for Nanomedicine, University College London, London, UK"/> <meta name="format-detection" content="telephone=no"/> <meta name="citation_cover_date" content="2008/04/01"/> <meta property="og:url" content="https://link.springer.com/article/10.1007/s00424-007-0405-1"/> <meta property="og:type" content="article"/> <meta property="og:site_name" content="SpringerLink"/> <meta property="og:title" content="An historical perspective on cell mechanics - Pflügers Archiv - European Journal of Physiology"/> <meta property="og:description" content="The physical properties of the protoplasm have long been of interest, and today, several intricate methods, including atomic force microscopy, have been employed in studies of cellular mechanics. However, many current concepts and experimental approaches actually have their beginnings over 300 years ago. Unfortunately, these pioneering studies have been all but forgotten. In this paper, we have reviewed some of the early literature on cellular mechanics to place modern work within an historical framework. It is clear that with current nanoscience approaches, modern experiments employing cell indentation, manipulation, particle rheology and micro- or nano-needle poking are now quantifying mechanical properties which were only qualitatively described 100 years ago. Aside from the variety of approaches our predecessors have employed to understand cellular mechanics, we feel an understanding of the past will help to propel nanoscience into the future. As nanophysiology and nanomedicine are developing, we as a community should take time to consider the early roots of these fields."/> <meta property="og:image" content="https://static-content.springer.com/image/art%3A10.1007%2Fs00424-007-0405-1/MediaObjects/424_2007_405_Fig1_HTML.gif"/> <meta name="format-detection" content="telephone=no"> <link rel="apple-touch-icon" sizes="180x180" href=/oscar-static/img/favicons/darwin/apple-touch-icon-92e819bf8a.png> <link rel="icon" type="image/png" sizes="192x192" href=/oscar-static/img/favicons/darwin/android-chrome-192x192-6f081ca7e5.png> <link rel="icon" type="image/png" sizes="32x32" href=/oscar-static/img/favicons/darwin/favicon-32x32-1435da3e82.png> <link rel="icon" type="image/png" sizes="16x16" href=/oscar-static/img/favicons/darwin/favicon-16x16-ed57f42bd2.png> <link rel="shortcut icon" data-test="shortcut-icon" href=/oscar-static/img/favicons/darwin/favicon-c6d59aafac.ico> <meta name="theme-color" content="#e6e6e6">   <link 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However, many current concepts and experimental approaches actually have their beginnings over 300 years ago. Unfortunately, these pioneering studies have been all but forgotten. In this paper, we have reviewed some of the early literature on cellular mechanics to place modern work within an historical framework. It is clear that with current nanoscience approaches, modern experiments employing cell indentation, manipulation, particle rheology and micro- or nano-needle poking are now quantifying mechanical properties which were only qualitatively described 100 years ago. Aside from the variety of approaches our predecessors have employed to understand cellular mechanics, we feel an understanding of the past will help to propel nanoscience into the future. As nanophysiology and nanomedicine are developing, we as a community should take time to consider the early roots of these fields.","datePublished":"2007-12-07T00:00:00Z","dateModified":"2007-12-07T00:00:00Z","pageStart":"3","pageEnd":"12","sameAs":"https://doi.org/10.1007/s00424-007-0405-1","keywords":["Protoplasm","Cell mechanics","Elasticity","Viscoelasticity","Viscosity","Atomic force microscopy","Human Physiology","Molecular Medicine","Neurosciences","Cell Biology","Receptors"],"image":["https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00424-007-0405-1/MediaObjects/424_2007_405_Fig1_HTML.gif","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00424-007-0405-1/MediaObjects/424_2007_405_Fig2_HTML.jpg","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00424-007-0405-1/MediaObjects/424_2007_405_Fig3_HTML.gif"],"isPartOf":{"name":"Pflügers Archiv - European Journal of Physiology","issn":["1432-2013","0031-6768"],"volumeNumber":"456","@type":["Periodical","PublicationVolume"]},"publisher":{"name":"Springer-Verlag","logo":{"url":"https://www.springernature.com/app-sn/public/images/logo-springernature.png","@type":"ImageObject"},"@type":"Organization"},"author":[{"name":"Andrew E. 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European Journal of Physiology</span></a><meta itemprop="position" content="2"> <svg class="c-breadcrumbs__chevron" role="img" aria-hidden="true" focusable="false" width="10" height="10" viewBox="0 0 10 10"> <path d="m5.96738168 4.70639573 2.39518594-2.41447274c.37913917-.38219212.98637524-.38972225 1.35419292-.01894278.37750606.38054586.37784436.99719163-.00013556 1.37821513l-4.03074001 4.06319683c-.37758093.38062133-.98937525.38100976-1.367372-.00003075l-4.03091981-4.06337806c-.37759778-.38063832-.38381821-.99150444-.01600053-1.3622839.37750607-.38054587.98772445-.38240057 1.37006824.00302197l2.39538588 2.4146743.96295325.98624457z" fill-rule="evenodd" transform="matrix(0 -1 1 0 0 10)"/> </svg> </li> <li class="c-breadcrumbs__item" id="breadcrumb2" itemprop="itemListElement" itemscope="" itemtype="https://schema.org/ListItem"> <span itemprop="name">Article</span><meta itemprop="position" content="3"> </li> </ol> </nav> <h1 class="c-article-title" data-test="article-title" data-article-title="">An historical perspective on cell mechanics</h1> <ul class="c-article-identifiers"> <li class="c-article-identifiers__item" data-test="article-category">Invited Review</li> <li class="c-article-identifiers__item"> Published: <time datetime="2007-12-07">07 December 2007</time> </li> </ul> <ul class="c-article-identifiers c-article-identifiers--cite-list"> <li class="c-article-identifiers__item"> <span data-test="journal-volume">Volume 456</span>, pages 3–12, (<span data-test="article-publication-year">2008</span>) </li> <li class="c-article-identifiers__item c-article-identifiers__item--cite"> <a href="#citeas" data-track="click" data-track-action="cite this article" data-track-category="article body" data-track-label="link">Cite this article</a> </li> </ul> <div class="app-article-masthead__buttons" data-test="download-article-link-wrapper" data-track-context="masthead"> <div class="c-pdf-container"> <div class="c-pdf-download u-clear-both u-mb-16"> <a href="/content/pdf/10.1007/s00424-007-0405-1.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="pdf-link" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="button" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-eds-i-download-medium"/></svg> </a> </div> </div> </div> </div> <div class="app-article-masthead__brand"> <a href="/journal/424" class="app-article-masthead__journal-link" data-track="click_journal_home" data-track-action="journal homepage" data-track-context="article page" data-track-label="link"> <picture> <source type="image/webp" media="(min-width: 768px)" width="120" height="159" srcset="https://media.springernature.com/w120/springer-static/cover-hires/journal/424?as=webp, https://media.springernature.com/w316/springer-static/cover-hires/journal/424?as=webp 2x"> <img width="72" height="95" src="https://media.springernature.com/w72/springer-static/cover-hires/journal/424?as=webp" srcset="https://media.springernature.com/w144/springer-static/cover-hires/journal/424?as=webp 2x" alt=""> </picture> <span class="app-article-masthead__journal-title">Pflügers Archiv - European Journal of Physiology</span> </a> <a href="https://link.springer.com/journal/424/aims-and-scope" class="app-article-masthead__submission-link" data-track="click_aims_and_scope" data-track-action="aims and scope" data-track-context="article page" data-track-label="link"> Aims and scope <svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-arrow-right-medium"></use></svg> </a> <a href="https://submission.nature.com/new-submission/424/3" class="app-article-masthead__submission-link" data-track="click_submit_manuscript" data-track-context="article masthead on springerlink article page" data-track-action="submit manuscript" data-track-label="link"> Submit manuscript <svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-arrow-right-medium"></use></svg> </a> </div> </div> </div> </section> <div class="c-article-main u-container u-mt-24 u-mb-32 l-with-sidebar" id="main-content" data-component="article-container"> <main class="u-serif js-main-column" data-track-component="article body"> <div class="c-context-bar u-hide" data-test="context-bar" data-context-bar aria-hidden="true"> <div class="c-context-bar__container u-container"> <div class="c-context-bar__title"> An historical perspective on cell mechanics </div> <div data-test="inCoD" data-track-context="sticky banner"> <div class="c-pdf-container"> <div class="c-pdf-download u-clear-both u-mb-16"> <a href="/content/pdf/10.1007/s00424-007-0405-1.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="pdf-link" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="button" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-eds-i-download-medium"/></svg> </a> </div> </div> </div> </div> </div> <div class="c-article-header"> <header> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Andrew_E_-Pelling-Aff1" data-author-popup="auth-Andrew_E_-Pelling-Aff1" data-author-search="Pelling, Andrew E." data-corresp-id="c1">Andrew E. Pelling<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> & </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Michael_A_-Horton-Aff1" data-author-popup="auth-Michael_A_-Horton-Aff1" data-author-search="Horton, Michael A." data-corresp-id="c2">Michael A. Horton<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> </li></ul> <div data-test="article-metrics"> <ul class="app-article-metrics-bar u-list-reset"> <li class="app-article-metrics-bar__item"> <p class="app-article-metrics-bar__count"><svg class="u-icon app-article-metrics-bar__icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-accesses-medium"></use> </svg>3441 <span class="app-article-metrics-bar__label">Accesses</span></p> </li> <li class="app-article-metrics-bar__item"> <p class="app-article-metrics-bar__count"><svg class="u-icon app-article-metrics-bar__icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-altmetric-medium"></use> </svg>3 <span class="app-article-metrics-bar__label">Altmetric</span></p> </li> <li class="app-article-metrics-bar__item app-article-metrics-bar__item--metrics"> <p class="app-article-metrics-bar__details"><a href="/article/10.1007/s00424-007-0405-1/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Explore all metrics <svg class="u-icon app-article-metrics-bar__arrow-icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-arrow-right-medium"></use> </svg></a></p> </li> </ul> </div> <div class="u-mt-32"> </div> </header> </div> <div data-article-body="true" data-track-component="article body" class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>The physical properties of the protoplasm have long been of interest, and today, several intricate methods, including atomic force microscopy, have been employed in studies of cellular mechanics. However, many current concepts and experimental approaches actually have their beginnings over 300 years ago. Unfortunately, these pioneering studies have been all but forgotten. In this paper, we have reviewed some of the early literature on cellular mechanics to place modern work within an historical framework. It is clear that with current nanoscience approaches, modern experiments employing cell indentation, manipulation, particle rheology and micro- or nano-needle poking are now quantifying mechanical properties which were only qualitatively described 100 years ago. Aside from the variety of approaches our predecessors have employed to understand cellular mechanics, we feel an understanding of the past will help to propel nanoscience into the future. As nanophysiology and nanomedicine are developing, we as a community should take time to consider the early roots of these fields.</p></div></div></section> <div data-test="cobranding-download"> </div> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w92h120/springer-static/cover-hires/book/978-3-662-54357-3?as=webp" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1007/978-3-662-54357-3_31?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1007/978-3-662-54357-3_31">Cellular Nanomechanics </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Chapter</span> <span class="c-article-meta-recommendations__date">© 2017</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1007%2Fs12551-018-0447-y/MediaObjects/12551_2018_447_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1007/s12551-018-0447-y?fromPaywallRec=false" data-track="select_recommendations_2" data-track-context="inline recommendations" data-track-action="click recommendations inline - 2" data-track-label="10.1007/s12551-018-0447-y">Biophysical nanotools for single-molecule dynamics </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__date">18 August 2018</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fnmicrobiol.2016.186/MediaObjects/41564_2016_Article_BFnmicrobiol2016186_Fig1_HTML.jpg" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1038/nmicrobiol.2016.186?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1038/nmicrobiol.2016.186">Optical and force nanoscopy in microbiology </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__date">26 October 2016</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1732704047, embedded_user: 'null' } }); </script> <div class="app-card-service" data-test="article-checklist-banner"> <div> <a class="app-card-service__link" data-track="click_presubmission_checklist" data-track-context="article page top of reading companion" data-track-category="pre-submission-checklist" data-track-action="clicked article page checklist banner test 2 old version" data-track-label="link" href="https://beta.springernature.com/pre-submission?journalId=424" data-test="article-checklist-banner-link"> <span class="app-card-service__link-text">Use our pre-submission checklist</span> <svg class="app-card-service__link-icon" aria-hidden="true" focusable="false"><use xlink:href="#icon-eds-i-arrow-right-small"></use></svg> </a> <p class="app-card-service__description">Avoid common mistakes on your manuscript.</p> </div> <div class="app-card-service__icon-container"> <svg class="app-card-service__icon" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-clipboard-check-medium"></use> </svg> </div> </div> <div class="main-content"> <section data-title="Introduction"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Introduction</h2><div class="c-article-section__content" id="Sec1-content"> <blockquote class="c-blockquote"><div class="c-blockquote__body"> <p>“Much excellent research has been done with a test tube and a Bunsen burner, but certain problems cannot be successfully attacked without the aid of intricate apparatus. It is the latter type of research, in so far as it applies to studies on the physical properties of protoplasm with which this report deals.” (Seifriz, 1937 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Seifriz W (1937) Methods of research on the physical properties of the protoplasm. Plant Physiol 12:99–116" href="/article/10.1007/s00424-007-0405-1#ref-CR1" id="ref-link-section-d7270849e330">1</a>]).</p> </div></blockquote> <p>In the late seventeenth century, the likes of Robert Hooke and Antony van Leeuwenhoek were using simple optical microscopes to peer down into a tiny living universe in which fluid and cellular motion appeared to be extreme. In a letter [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Egerton F (2006) A history of the ecological sciences, Part 19. Leeuwenhoek. Bull Ecol Soc Am 87:47–58" href="/article/10.1007/s00424-007-0405-1#ref-CR2" id="ref-link-section-d7270849e338">2</a>] written on Christmas Day, 1702, van Leeuwenhoek describes what may be the first observations of the ciliate <i>Vorticella</i>, “In structure these little animals were fashioned like a bell, and at the round opening they made such a stir, that the particles in the water thereabout were set in motion thereby…which sight I found mightily diverting.” The appearance of motion in this tiny world was not lost on these early observers. Brownian motion of particles and organelles inside living cells have been commonly reported [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Heilbrunn LV (1926) The physical structure of the protoplasm of sea-urchin eggs. Am Nat 60:143–156" href="/article/10.1007/s00424-007-0405-1#ref-CR3" id="ref-link-section-d7270849e344">3</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Heilbrunn LV (1927) The viscosity of the protoplasm. Q Rev Biol 2:230–248" href="/article/10.1007/s00424-007-0405-1#ref-CR4" id="ref-link-section-d7270849e347">4</a>]. It was also conjectured that it may be possible to estimate viscosity by measuring these quantities. Although the tools were not available in the seventeenth century to perform accurate micro-rheology and nano-indentation experiments, many of the philosophical ideas and concepts we deal with today had their beginnings over 300 years ago. Moreover, the technological basis and understanding of cell and tissue mechanics has its foundation in the rapid industrialisation of the nineteenth century—the need for a thorough understanding of mechanical and structural testing and theory (indentation, beam bending, the Hertz model) of macroscale materials such as engines, boats and bridges [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Thompson DAW (1917) On growth and form, 1st edn. Cambridge University Press, Cambridge, England" href="/article/10.1007/s00424-007-0405-1#ref-CR5" id="ref-link-section-d7270849e350">5</a>]. This in turn reflected an earlier silvan economy—indeed, understanding the adaptation, structure and material properties of different woods (oak versus pine) preceded and defined our concept of tissue adaptation (for example, Wolff’s law as applied to the skeleton) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Thompson DAW (1917) On growth and form, 1st edn. Cambridge University Press, Cambridge, England" href="/article/10.1007/s00424-007-0405-1#ref-CR5" id="ref-link-section-d7270849e354">5</a>]. At the end of the nineteenth century, the mechanical properties of living cells were experimentally examined and analyzed using a variety of techniques based upon these macroscale engineering mechanics. Today, over a century later, our current nanoscale testing and modelling of biological materials is still fundamentally based on nineteenth-century practices [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Wang Y-1, Discher DE (2007) Cell mechanics, 1st edn. Elsevier Academic, Amsterdam" href="/article/10.1007/s00424-007-0405-1#ref-CR6" id="ref-link-section-d7270849e357">6</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Mofrad MRK, Kamm RD (2006) Cytoskeletal mechanics: models and measurements, 1st edn. Cambridge University Press, Cambridge" href="/article/10.1007/s00424-007-0405-1#ref-CR8" id="ref-link-section-d7270849e360">8</a>].</p><p>The living cell is a universe unto itself. It was quickly recognized that the cellular universe is vastly complex and always experiencing turbulent forces and dynamics within the protoplasm which were somehow related to function. In this historical review, we will present work from very early studies involving the mechanical motion and properties of living cells. We will attempt to describe these studies in relation to modern approaches including, but not limited to, atomic force microscopy (AFM) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Binnig G, Quate CF, Gerber C (1986) Atomic force microscope. Phys Rev Lett 56:930–933" href="/article/10.1007/s00424-007-0405-1#ref-CR9" id="ref-link-section-d7270849e366">9</a>]. Although this review hardly covers the entire wealth of scientific literature on the subject, we have attempted to revisit discoveries and philosophical concepts over the past 300 years to fit current work on cellular mechanics into an historical perspective. We hope such perspective will reveal that although we are asking similar questions as early scientists, modern nanoscale approaches are finally providing robust quantitative descriptions of cellular mechanics. These modern approaches are becoming of great importance as the role of nanoscience in physiology and medicine is now emerging.</p><p>The role of mechanical forces in biology is certainly not a new idea but is currently gaining wider acceptance. However, this has not always been the case. In 1850, Carpenter wrote “the degree to which the phenomena of Life are dependent upon Physical agencies has been the subject of inquiry and speculation among scientific investigators of almost every school. That many actions taking place in the living body are conformable to the laws of mechanics, has been hastily assumed as justifying the conclusion that all its actions are mechanical…” In 1917, Thompson discussed the apparent mechanical nature of cellular processes in his classic <i>On Growth and Form</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Thompson DAW (1917) On growth and form, 1st edn. Cambridge University Press, Cambridge, England" href="/article/10.1007/s00424-007-0405-1#ref-CR5" id="ref-link-section-d7270849e375">5</a>], writing that “…though they resemble known physical phenomena, their nature is still the subject of much dubiety and discussion, and neither the forms produced nor the forces at work can yet be satisfactorily and simply explained.” At about this time, many reports were emerging which began to quantify mechanical properties in cells which, until this point, had largely been supported by qualitative, empirical observations. Moreover, early debates about the appropriate theoretical picture one should have about the cell were also emerging [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Heilbrunn LV (1926) The physical structure of the protoplasm of sea-urchin eggs. Am Nat 60:143–156" href="/article/10.1007/s00424-007-0405-1#ref-CR3" id="ref-link-section-d7270849e378">3</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Heilbrunn LV (1927) The viscosity of the protoplasm. Q Rev Biol 2:230–248" href="/article/10.1007/s00424-007-0405-1#ref-CR4" id="ref-link-section-d7270849e381">4</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Bingham EC (1933) Fluidity and plasticity, 1st edn. McGraw-Hill, New York" href="/article/10.1007/s00424-007-0405-1#ref-CR10" id="ref-link-section-d7270849e384">10</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Heilbrunn LV (1924) The surface tension theory of membrane elevation. Bio Bull 46:277–280" href="/article/10.1007/s00424-007-0405-1#ref-CR11" id="ref-link-section-d7270849e388">11</a>]. Cells were initially thought to be of homogeneous gels, sols, viscoelastic and plastic fluids. These lines of thought continue today; however, many models have been developed which describe cellular mechanics in several ways, including a viscoelastic continuum, a combination of discrete mechanical elements, or a combination of viscoelastic fluid within a dense meshwork [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Wang Y-1, Discher DE (2007) Cell mechanics, 1st edn. Elsevier Academic, Amsterdam" href="/article/10.1007/s00424-007-0405-1#ref-CR6" id="ref-link-section-d7270849e391">6</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Mofrad MRK, Kamm RD (2006) Cytoskeletal mechanics: models and measurements, 1st edn. Cambridge University Press, Cambridge" href="/article/10.1007/s00424-007-0405-1#ref-CR8" id="ref-link-section-d7270849e394">8</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Bao G, Suresh S (2003) Cell and molecular mechanics of biological materials. Nat Mater 2:715–725" href="/article/10.1007/s00424-007-0405-1#ref-CR12" id="ref-link-section-d7270849e397">12</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Kasza KE, Rowat AC, Liu J, Angelini TE, Brangwynne CP, Koenderink GH, Weitz DA (2007) The cell as a material. Curr Opin Cell Biol 19:101–107" href="/article/10.1007/s00424-007-0405-1#ref-CR18" id="ref-link-section-d7270849e400">18</a>]. However, for the number of models which exist today, there seem to be just as many experimental proofs which either support or refute each proposed model (for example, recent work on the soft glass rheology phenomenon [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Trepat X, Deng L, An SS, Navajas D, Tschumperlin DJ, Gerthoffer WT, Butler JP, Fredberg JJ (2007) Universal physical responses to stretch in the living cell. Nature 447:592–595" href="/article/10.1007/s00424-007-0405-1#ref-CR19" id="ref-link-section-d7270849e403">19</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Stamenovic D, Rosenblatt N, Montoya-Zavala M, Matthews BD, Hu S, Suki B, Wang N, Ingber DE (2007) Rheological behavior of living cells is timescale-dependent. Biophys. J. 93:L39–L41" href="/article/10.1007/s00424-007-0405-1#ref-CR20" id="ref-link-section-d7270849e407">20</a>]). Through experimental refinement over the past century, highly accurate measurements of viscosity, elasticity, plasticity and motion have been carried out by several techniques. However, this has not led to a complete theoretical description of cell mechanics that is both time-dependent and predictive.</p><p>Importantly, it is not fully understood whether these mechanical phenomena and properties are merely side products of biological processes or if they are intimately controlled at the genetic and physiological level through feedback loops, actuation and/or response pathways. In the past several years, some reports have begun to answer this highly complex question [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Even-Ram S, Artym V, Yamada KM (2006) Matrix control of stem cell fate. Cell 126:645–647" href="/article/10.1007/s00424-007-0405-1#ref-CR21" id="ref-link-section-d7270849e414">21</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Ingber DE (2005) Mechanical control of tissue growth: function follows form. Proc Natl Acad Sci USA 102:11571–11572" href="/article/10.1007/s00424-007-0405-1#ref-CR25" id="ref-link-section-d7270849e417">25</a>]. Here, we will generally limit our discussion towards AFM-based contributions, given the scope and contributors to this special issue on nanophysiology in the <i>Pflügers Archiv European Journal of Physiology</i>. However, contributions from many fields and techniques have been fundamental in the development of our current understanding of cellular mechanics [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Wang Y-1, Discher DE (2007) Cell mechanics, 1st edn. Elsevier Academic, Amsterdam" href="/article/10.1007/s00424-007-0405-1#ref-CR6" id="ref-link-section-d7270849e423">6</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Mofrad MRK, Kamm RD (2006) Cytoskeletal mechanics: models and measurements, 1st edn. Cambridge University Press, Cambridge" href="/article/10.1007/s00424-007-0405-1#ref-CR8" id="ref-link-section-d7270849e426">8</a>]. Clearly, the field of cell mechanics and especially its relation to cell physiology or nanophysiology is vital and growing as many avenues exist to explore the micro- and nano-scopic cellular world. In this review, we will attempt to place modern AFM work side-by-side with studies from the seventeenth century onward to fit our understanding within a fascinating and sometimes surprising historical framework.</p> <h3 class="c-article__sub-heading">The architecture of the protoplasm</h3> <p>In the late nineteenth century, cell doctrine was being generalized and the term protoplasm was used widely as a description of the contents of a cell [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Heilbrunn LV (1926) The physical structure of the protoplasm of sea-urchin eggs. Am Nat 60:143–156" href="/article/10.1007/s00424-007-0405-1#ref-CR3" id="ref-link-section-d7270849e436">3</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Harper RA (1919) The Structure of Protoplasm. Am J Bot 6:273–300" href="/article/10.1007/s00424-007-0405-1#ref-CR26" id="ref-link-section-d7270849e439">26</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Wilson EB (1899) The structure of the protoplasm. Science 237:33–45" href="/article/10.1007/s00424-007-0405-1#ref-CR30" id="ref-link-section-d7270849e442">30</a>]. Early on, the protoplasm was viewed almost spiritually, as it had the ability to self-replicate, and many at the time accepted the idea of so-called vital and physical forces existing within the cell. Vitalists believed that vital forces emanated directly from the “Will of the Omnipotent and Ominpresent Creator” [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Carpenter WB (1850) On the mutual relations of the vital and physical forces. Philos Trans Roy Soc Lond 140:727–757" href="/article/10.1007/s00424-007-0405-1#ref-CR31" id="ref-link-section-d7270849e445">31</a>], and physical forces were a result or the modi operandi of Vital forces. Over time, there emerged a great debate between the “Vitalists” and “Mechanists” about the structure, function and purpose of the protoplasm, where mechanists believed that all processes within the cell could be explained by physical or chemical mechanics [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Osterhout WJV (1914) The chemical dynamics of living protoplasm. Science 39:544–546" href="/article/10.1007/s00424-007-0405-1#ref-CR32" id="ref-link-section-d7270849e448">32</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Seifriz W (1939) A materialistic interpretation of life. Phil Sci 6:266–284" href="/article/10.1007/s00424-007-0405-1#ref-CR33" id="ref-link-section-d7270849e452">33</a>]. Many of these arguments actually continued well into the twentieth century, often arising from the inability of scientists to determine the exact chemical structure of the protoplasm or to explain certain mechanical phenomena [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Myers CS (1900) Vitalism: a brief historical and critical review. Mind 9:319–331" href="/article/10.1007/s00424-007-0405-1#ref-CR34" id="ref-link-section-d7270849e455">34</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Geison GL (1969) The photoplasmic theory of life and the vitalist–mechanist debate. Isis 60:272–292" href="/article/10.1007/s00424-007-0405-1#ref-CR37" id="ref-link-section-d7270849e458">37</a>].</p> <p>The main elements of cellular architecture within the protoplasm were determined in the mid to late 1800s, and up until that point, cells were considered as small compartments containing homogeneous fluids [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="General Notes (1885) Physiology. Am Nat 19:1236–1241" href="/article/10.1007/s00424-007-0405-1#ref-CR38" id="ref-link-section-d7270849e464">38</a>]. With the development of modern microscopic techniques during the eighteenth and nineteenth centuries [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Seifriz W (1937) Methods of research on the physical properties of the protoplasm. Plant Physiol 12:99–116" href="/article/10.1007/s00424-007-0405-1#ref-CR1" id="ref-link-section-d7270849e467">1</a>], including darkfield illumination, oil immersion lenses and high-quality glass optics free from aberrations, together with advances in sample preparation and staining methods (developed by the great European histologists such as Golgi, 1906 Nobel Laureate), the nucleus, nucleoli, chromatin, nuclear membranes, vacuoles, cytoplasmic streaming, filamentous structures (cytoskeleton, reticulum, the mitotic spindle, and actin–myosin striations in muscle) were observed [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Goodale GL (1889) Protoplasm and its history. Bot Gaz 14:235–246" href="/article/10.1007/s00424-007-0405-1#ref-CR28" id="ref-link-section-d7270849e470">28</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Wilson EB (1899) The structure of the protoplasm. Science 237:33–45" href="/article/10.1007/s00424-007-0405-1#ref-CR30" id="ref-link-section-d7270849e473">30</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="General Notes (1885) Physiology. Am Nat 19:1236–1241" href="/article/10.1007/s00424-007-0405-1#ref-CR38" id="ref-link-section-d7270849e476">38</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Lepeschkin WW (1928) The chemical and physical composition of the protoplasm. Science 1928:45–48" href="/article/10.1007/s00424-007-0405-1#ref-CR40" id="ref-link-section-d7270849e480">40</a>] (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00424-007-0405-1#Fig1">1</a>). The granular nature of the protoplasm led to the belief that it was accurately described as a colloidal suspension, giving rise to the early discussions and measurements of viscosity [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Heilbrunn LV (1927) The viscosity of the protoplasm. Q Rev Biol 2:230–248" href="/article/10.1007/s00424-007-0405-1#ref-CR4" id="ref-link-section-d7270849e486">4</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Wilson EB (1899) The structure of the protoplasm. Science 237:33–45" href="/article/10.1007/s00424-007-0405-1#ref-CR30" id="ref-link-section-d7270849e489">30</a>]. As with the development of the optical microscope, the AFM, a new paradigm in microscopy, was utilized early on to visualize some of these cellular structures. </p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Fig. 1"><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 1</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00424-007-0405-1/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00424-007-0405-1/MediaObjects/424_2007_405_Fig1_HTML.gif?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00424-007-0405-1/MediaObjects/424_2007_405_Fig1_HTML.gif" alt="figure 1" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p>Images of living cells from the late nineteenth century. <b>a</b> Detailed studies of mitosis were completed by Campbell in 1890 (image reproduced with permission from the Torrey Botanical Society [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 172" title="Campbell DH (1890) Studies in cell-division. Bull Torrey Bot Club 17:113–121" href="/article/10.1007/s00424-007-0405-1#ref-CR172" id="ref-link-section-d7270849e505">172</a>]). <b>b</b> Striated structures were observed in cardiomyocytes of many species including humans in 1887 (image reproduced with permission from the American Society of Microscopists [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 173" title="Oviatt BL (1887) Cardiac muscle cells in man and certain other mammals. Proc Am Soc Microsc 9:283–298" href="/article/10.1007/s00424-007-0405-1#ref-CR173" id="ref-link-section-d7270849e511">173</a>]). <b>c</b> Modern immuno-fluorescence staining of actin with rhodamine-phalloidin, over a century later, also reveals striated structures in rat cardiomyocytes</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00424-007-0405-1/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <p>Early AFM imaging of live cells quickly revealed the ability to image elements of the cytoskeleton as well as monitoring its dynamics [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Rotsch C, Radmacher M (2000) Drug-induced changes of cytoskeletal structure and mechanics in fibroblasts: an atomic force microscopy study. Biophys J 78:520–535" href="/article/10.1007/s00424-007-0405-1#ref-CR41" id="ref-link-section-d7270849e529">41</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Pesen D, Hoh JH (2005) Micromechanical architecture of the endothelial cell cortex. Biophys J 88:670–679" href="/article/10.1007/s00424-007-0405-1#ref-CR45" id="ref-link-section-d7270849e532">45</a>]. Nuclei were often observed as large structures and contributing significantly to the apparent height of the cells. Due to the nature of AFM imaging, mechanical information was readily inferred and later quantified using various imaging mechanisms [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Rotsch C, Radmacher M (2000) Drug-induced changes of cytoskeletal structure and mechanics in fibroblasts: an atomic force microscopy study. Biophys J 78:520–535" href="/article/10.1007/s00424-007-0405-1#ref-CR41" id="ref-link-section-d7270849e535">41</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Haga H, Nagayama M, Kawabata K, Ito E, Ushiki T, Sambongi T (2000) Time-lapse viscoelastic imaging of living fibroblasts using force modulation mode in AFM. J Electron Microsc (Tokyo) 49:473–481" href="/article/10.1007/s00424-007-0405-1#ref-CR46" id="ref-link-section-d7270849e538">46</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Nagao E, Dvorak JA (1998) An integrated approach to the study of living cells by atomic force microscopy. J Microsc 191:8–19" href="/article/10.1007/s00424-007-0405-1#ref-CR47" id="ref-link-section-d7270849e541">47</a>]. High-resolution AFM imaging has provided detailed information on the structure, function and mechanics of nucleic acids [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 48" title="Sattin BD, Pelling AE, Goh MC (2004) DNA base pair resolution by single molecule force spectroscopy. Nucleic Acids Res 32:4876–4883" href="/article/10.1007/s00424-007-0405-1#ref-CR48" id="ref-link-section-d7270849e545">48</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Weisenhorn AL, Gaub HE, Hansma HG, Sinsheimer RL, Kelderman GL, Hansma PK (1990) Imaging single-stranded DNA, antigen–antibody reaction and polymerized Langmuir–Blodgett films with an atomic force microscope. Scanning Microsc 4:511–516" href="/article/10.1007/s00424-007-0405-1#ref-CR55" id="ref-link-section-d7270849e548">55</a>], several types of membrane proteins [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 56" title="Scheuring S, Sturgis JN, Prima V, Bernadac A, Levy D, Rigaud JL (2004) Watching the photosynthetic apparatus in native membranes. Proc Natl Acad Sci USA 101:11293–11297" href="/article/10.1007/s00424-007-0405-1#ref-CR56" id="ref-link-section-d7270849e551">56</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 61" title="Lehenkari PP, Horton MA (1999) Single integrin molecule adhesion forces in intact cells measured by atomic force microscopy. Biochem Biophys Res Commun 259:645–650" href="/article/10.1007/s00424-007-0405-1#ref-CR61" id="ref-link-section-d7270849e554">61</a>], nuclear pore complexes [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 62" title="Maco B, Fahrenkrog B, Huang NP, Aebi U (2006) Nuclear pore complex structure and plasticity revealed by electron and atomic force microscopy. Methods Mol Biol 322:273–288" href="/article/10.1007/s00424-007-0405-1#ref-CR62" id="ref-link-section-d7270849e557">62</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 67" title="Bustamante JO, Liepins A, Prendergast RA, Hanover JA, Oberleithner H (1995) Patch clamp and atomic force microscopy demonstrate TATA-binding protein (TBP) interactions with the nuclear pore complex. J Membr Biol 146:263–272" href="/article/10.1007/s00424-007-0405-1#ref-CR67" id="ref-link-section-d7270849e560">67</a>], biological filaments [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Friedrichs J, Taubenberger A, Franz CM, Muller DJ (2007) Cellular remodelling of individual collagen fibrils visualized by time-lapse AFM. J Mol Biol 372:594–607" href="/article/10.1007/s00424-007-0405-1#ref-CR68" id="ref-link-section-d7270849e564">68</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 77" title="Wen CK, Goh MC (2004) AFM nanodissection reveals internal structural details of single collagen fibrils. Nano Lett 4:129–132" href="/article/10.1007/s00424-007-0405-1#ref-CR77" id="ref-link-section-d7270849e567">77</a>], molecular motors [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 78" title="Taniguchi M, Matsumoto O, Suzuki S, Nishino Y, Okuda A, Taga T, Yamane T (2003) MgATP-induced conformational changes in a single myosin molecule observed by atomic force microscopy: periodicity of substructures in myosin rods. Scanning 25:223–229" href="/article/10.1007/s00424-007-0405-1#ref-CR78" id="ref-link-section-d7270849e570">78</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 83" title="Sheng S, Gao Y, Khromov AS, Somlyo AV, Somlyo AP, Shao Z (2003) Cryo-atomic force microscopy of unphosphorylated and thiophosphorylated single smooth muscle myosin molecules. J Biol Chem 278:39892–39896" href="/article/10.1007/s00424-007-0405-1#ref-CR83" id="ref-link-section-d7270849e573">83</a>] and cell wall surfaces [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Pelling AE, Li Y, Cross SE, Castaneda S, Shi W, Gimzewski JK (2006) Self-organized and highly ordered domain structures within swarms of Myxococcus xanthus. Cell Motil Cytoskeleton 63:141–148" href="/article/10.1007/s00424-007-0405-1#ref-CR84" id="ref-link-section-d7270849e576">84</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 92" title="Hinterdorfer P, Dufrene YF (2006) Detection and localization of single molecular recognition events using atomic force microscopy. Nat Methods 3:347–355" href="/article/10.1007/s00424-007-0405-1#ref-CR92" id="ref-link-section-d7270849e579">92</a>] which was not accessible with optical microscopy in the 1800s. Although there are many technological differences between both optical and scanning probe microscopy techniques, separated by well over a century, both have intriguingly pointed towards the mechanical nature of the cell.</p> <h3 class="c-article__sub-heading">Protoplasmic mechanics</h3> <p>In a series of three lectures given by Stuart [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 93" title="Stuart A (1738) Three lectures on muscular motion, read before the Royal Society in the Year MDCCXXXVIII: As appointed by the will of Lady Sadleir, pursuant to the design of her first husband William Croone, M. D. Fellow of the College of Physicians, and of the Royal Society: being a supplement to the philosophical transactions for that year. Wherein the elasticity of fluids, and the immediate cause of the cohesion and elasticity of solids, are proved by experiments, &c. and shewn to arise from the same principle as gravity: with a general scheme of muscular motion, founded on anatomy, experiments, etc. Phil Trans (1638–1775) 40:i-liv" href="/article/10.1007/s00424-007-0405-1#ref-CR93" id="ref-link-section-d7270849e590">93</a>] in 1737 and 1738, it was shown that blood, blood vessels and nerves, dissected from a corpse, could all be tested mechanically. Early concepts of hydrostatics, elasticity and viscoelastic fluids were discussed and, apparently, it was observed that nerves were inelastic. In the living organism, mechanical oscillations were studied at length. In his lecture in 1857, Paget [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Paget J (1857) Croonian lecture: on the cause of the rhythmic motion of the heart. Proc Roy Soc London 8:473–488" href="/article/10.1007/s00424-007-0405-1#ref-CR94" id="ref-link-section-d7270849e593">94</a>] discusses the spontaneous contractions of the heart after being removed from a living organism. The mechanical contractions were observed to continue without the need for a functioning nervous system, a property of heart and muscle cells which have been exploited recently in the AFM literature [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 95" title="Domke J, Parak WJ, George M, Gaub HE, Radmacher M (1999) Mapping the mechanical pulse of single cardiomyocytes with the atomic force microscope. Eur Biophys J Biophy 28:179–186" href="/article/10.1007/s00424-007-0405-1#ref-CR95" id="ref-link-section-d7270849e596">95</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 98" title="Haupt BJ, Pelling AE, Horton MA (2006) Integrated confocal and scanning probe microscopy for biomedical research. Sci World J 6:1609–1618" href="/article/10.1007/s00424-007-0405-1#ref-CR98" id="ref-link-section-d7270849e599">98</a>]. Other mechanical oscillations were discussed such as observations on ~3 μm diameter vacuoles in several organisms, cell-wall oscillations in plants and the movement of cilia [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Paget J (1857) Croonian lecture: on the cause of the rhythmic motion of the heart. Proc Roy Soc London 8:473–488" href="/article/10.1007/s00424-007-0405-1#ref-CR94" id="ref-link-section-d7270849e602">94</a>]. In each of these cases, no known muscle structure or nervous system was present. It was not understood how such mechanical oscillations provided an advantage to these organisms. However, the concept of biological mechanics was clearly under development.</p> <p>Early studies on the mechanical properties of the protoplasm were mainly concerned with viscosity. This was partly due to experimental limitations as microscopic methods of observation were not yet well developed (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00424-007-0405-1#Fig2">2</a>). Cytoplasmic streaming (the circular flow of cytoplasm in eukaryotic cells) was observed very early [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Heilbrunn LV (1927) The viscosity of the protoplasm. Q Rev Biol 2:230–248" href="/article/10.1007/s00424-007-0405-1#ref-CR4" id="ref-link-section-d7270849e611">4</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 99" title="Ewart AJ (1901) On the physics and physiology of the protoplasmic streaming in plants. Proc Roy Soc London 69:466–470" href="/article/10.1007/s00424-007-0405-1#ref-CR99" id="ref-link-section-d7270849e614">99</a>] and used as a qualitative measure of the protoplasmic viscosity. It was also clear that the motion of internal granules could also be used as markers for viscosity measurements [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Heilbrunn LV (1926) The physical structure of the protoplasm of sea-urchin eggs. Am Nat 60:143–156" href="/article/10.1007/s00424-007-0405-1#ref-CR3" id="ref-link-section-d7270849e617">3</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Heilbrunn LV (1927) The viscosity of the protoplasm. Q Rev Biol 2:230–248" href="/article/10.1007/s00424-007-0405-1#ref-CR4" id="ref-link-section-d7270849e620">4</a>]. This represents some of the earliest uses of particle tracking in cell mechanics and is essentially a predecessor of modern-particle tracking and micro-rheology measurements [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 100" title="Weihs D, Mason TG, Teitell MA (2006) Bio-microrheology: a frontier in microrheology. Biophys J 91:4296–4305" href="/article/10.1007/s00424-007-0405-1#ref-CR100" id="ref-link-section-d7270849e624">100</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 101" title="Mason TG, Ganesan K, vanZanten JH, Wirtz D, Kuo SC (1997) Particle tracking microrheology of complex fluids. Phys Rev Lett 79:3282–3285" href="/article/10.1007/s00424-007-0405-1#ref-CR101" id="ref-link-section-d7270849e627">101</a>]. Although this early work was carried out in the 1920s and suffers from an obvious lack of appropriate experimental and theoretical considerations, some of the same issues were being discussed as they are today, such as the influence of the size of the granule, the mesh size of the protoplasm, damage to the cell and the influence of temperature [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Heilbrunn LV (1926) The physical structure of the protoplasm of sea-urchin eggs. Am Nat 60:143–156" href="/article/10.1007/s00424-007-0405-1#ref-CR3" id="ref-link-section-d7270849e630">3</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Heilbrunn LV (1927) The viscosity of the protoplasm. Q Rev Biol 2:230–248" href="/article/10.1007/s00424-007-0405-1#ref-CR4" id="ref-link-section-d7270849e633">4</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 102" title="Valentine MT, Perlman ZE, Gardel ML, Shin JH, Matsudaira P, Mitchison TJ, Weitz DA (2004) Colloid surface chemistry critically affects multiple particle tracking measurements of biomaterials. Biophys J 86:4004–4014" href="/article/10.1007/s00424-007-0405-1#ref-CR102" id="ref-link-section-d7270849e636">102</a>]. Similarly, an early magnetic microscope developed in 1923 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 103" title="Seifriz W (1924) An elastic value of protoplasm, with further observations on the viscosity of protoplasm. J Exp Biol 2:1–11" href="/article/10.1007/s00424-007-0405-1#ref-CR103" id="ref-link-section-d7270849e639">103</a>] was used to oscillate nickel particles (~16 μm in diameter) inserted into living cells. Aside from the similarities to modern particle micro-rheology [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Trepat X, Deng L, An SS, Navajas D, Tschumperlin DJ, Gerthoffer WT, Butler JP, Fredberg JJ (2007) Universal physical responses to stretch in the living cell. Nature 447:592–595" href="/article/10.1007/s00424-007-0405-1#ref-CR19" id="ref-link-section-d7270849e643">19</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Stamenovic D, Rosenblatt N, Montoya-Zavala M, Matthews BD, Hu S, Suki B, Wang N, Ingber DE (2007) Rheological behavior of living cells is timescale-dependent. Biophys. J. 93:L39–L41" href="/article/10.1007/s00424-007-0405-1#ref-CR20" id="ref-link-section-d7270849e646">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 100" title="Weihs D, Mason TG, Teitell MA (2006) Bio-microrheology: a frontier in microrheology. Biophys J 91:4296–4305" href="/article/10.1007/s00424-007-0405-1#ref-CR100" id="ref-link-section-d7270849e649">100</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 101" title="Mason TG, Ganesan K, vanZanten JH, Wirtz D, Kuo SC (1997) Particle tracking microrheology of complex fluids. Phys Rev Lett 79:3282–3285" href="/article/10.1007/s00424-007-0405-1#ref-CR101" id="ref-link-section-d7270849e652">101</a>], this approach is similar in concept to magnetic bead-twisting cytometry [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 104" title="Valberg PA, Albertini DF (1985) Cytoplasmic motions, rheology, and structure probed by a novel magnetic particle method. J Cell Biol 101:130–140" href="/article/10.1007/s00424-007-0405-1#ref-CR104" id="ref-link-section-d7270849e655">104</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Massiera G, Van Citters KM, Biancaniello PL, Crocker JC (2007) Mechanics of single cells: rheology, time dependence and fluctuations. Biophys J 93:3703–3713" href="/article/10.1007/s00424-007-0405-1#ref-CR106" id="ref-link-section-d7270849e658">106</a>]. An early example of magnetic manipulation also involved injecting iron particles into bacteria and observing how fast they were attracted to an electromagnet [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Heilbrunn LV (1927) The viscosity of the protoplasm. Q Rev Biol 2:230–248" href="/article/10.1007/s00424-007-0405-1#ref-CR4" id="ref-link-section-d7270849e662">4</a>]. A distinct but very common approach to viscosity measurements at the time involved the centrifugation of cells. Granules would be “thrown to one end of the cell” and slowly migrate back to their original position”, a qualitative estimate of protoplasm viscosity at the time [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Heilbrunn LV (1927) The viscosity of the protoplasm. Q Rev Biol 2:230–248" href="/article/10.1007/s00424-007-0405-1#ref-CR4" id="ref-link-section-d7270849e665">4</a>]. </p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Fig. 2"><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 2</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00424-007-0405-1/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00424-007-0405-1/MediaObjects/424_2007_405_Fig2_HTML.jpg?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00424-007-0405-1/MediaObjects/424_2007_405_Fig2_HTML.jpg" alt="figure 2" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p>Early microscopes used in the study of cellular mechanics. <b>a</b> The Leeuwenhoek microscope from the early 1600s was one of the first utilized in early microscopy (image reproduced with permission from Molecular Expressions images). <b>b</b> The magnetic microscope from the 1920s used in studies which were the predecessors of modern particle microrheology. The microscope incorporated an electromagnet (<i>arrow</i>) into the design to oscillate magnetic micro-particles inserted into living cells (image reproduced with permission from The Company of Biologists [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 103" title="Seifriz W (1924) An elastic value of protoplasm, with further observations on the viscosity of protoplasm. J Exp Biol 2:1–11" href="/article/10.1007/s00424-007-0405-1#ref-CR103" id="ref-link-section-d7270849e687">103</a>]). <b>c</b> The modern AFM, integrated with an inverted laser scanning confocal microscope to allow simultaneous mechanical perturbations and measurements to be performed while imaging cellular structures in three dimensions</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00424-007-0405-1/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <p>Changes in viscosity were measured during sea urchin egg mitosis and fertilization, sometimes by as much as two orders of magnitude [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Heilbrunn LV (1927) The viscosity of the protoplasm. Q Rev Biol 2:230–248" href="/article/10.1007/s00424-007-0405-1#ref-CR4" id="ref-link-section-d7270849e705">4</a>]. Interestingly, it was also observed that preventing changes in viscosity could halt mitosis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 107" title="Heilbrunn LV (1920) The physical effect of anesthetics upon living protoplasm. Bio Bull 39:307–315" href="/article/10.1007/s00424-007-0405-1#ref-CR107" id="ref-link-section-d7270849e708">107</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 108" title="Heilbrunn LV (1920) An experimental study of cell division. I. The physical conditions which determine the appearance of the spindle in sea-urchin eggs. J Exp Zool 30:211–237" href="/article/10.1007/s00424-007-0405-1#ref-CR108" id="ref-link-section-d7270849e711">108</a>]. Furthermore, changes in protoplasmic viscosity in response to the action of temperature, radiation, electric currents and several chemicals (anaesthetics, salt, organic solvents, and even the early chemotherapy agents being developed in the 1940s) have all been measured [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Heilbrunn LV (1926) The physical structure of the protoplasm of sea-urchin eggs. Am Nat 60:143–156" href="/article/10.1007/s00424-007-0405-1#ref-CR3" id="ref-link-section-d7270849e714">3</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Heilbrunn LV (1927) The viscosity of the protoplasm. Q Rev Biol 2:230–248" href="/article/10.1007/s00424-007-0405-1#ref-CR4" id="ref-link-section-d7270849e717">4</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Seifriz W (1931) The structure of protoplasm. Science 1902:648–649" href="/article/10.1007/s00424-007-0405-1#ref-CR29" id="ref-link-section-d7270849e721">29</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 107" title="Heilbrunn LV (1920) The physical effect of anesthetics upon living protoplasm. Bio Bull 39:307–315" href="/article/10.1007/s00424-007-0405-1#ref-CR107" id="ref-link-section-d7270849e724">107</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 109" title="Heilbrunn LV (1925) The electrical charges of living cells. Science 1574:236–237" href="/article/10.1007/s00424-007-0405-1#ref-CR109" id="ref-link-section-d7270849e727">109</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 124" title="Addoms RM (1927) Toxicity as evidenced by changes in the protoplasmic structure of root hairs of wheat. Am J Bot 14:147–165" href="/article/10.1007/s00424-007-0405-1#ref-CR124" id="ref-link-section-d7270849e730">124</a>]. Although the major observable in AFM studies is the Young’s modulus or elasticity (which is a related but fundamentally different parameter from viscosity), similar measurements have been performed in cells over the last two decades with AFM. These include the effects of anti-cytoskeletal drugs [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Rotsch C, Radmacher M (2000) Drug-induced changes of cytoskeletal structure and mechanics in fibroblasts: an atomic force microscopy study. Biophys J 78:520–535" href="/article/10.1007/s00424-007-0405-1#ref-CR41" id="ref-link-section-d7270849e733">41</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 125" title="Pelling AE, Dawson DW, Carreon DM, Christiansen JJ, Shen RR, Teitell MA, Gimzewski JK (2007) Distinct contributions of microtubule subtypes to cell membrane shape and stability. 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Bio Bull 113:388–396" href="/article/10.1007/s00424-007-0405-1#ref-CR114" id="ref-link-section-d7270849e743">114</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 127" title="Lam WA, Rosenbluth MJ, Fletcher DA (2007) Chemotherapy exposure increases leukemia cell stiffness. Blood 109:3505–3508" href="/article/10.1007/s00424-007-0405-1#ref-CR127" id="ref-link-section-d7270849e746">127</a>] and electrical stimulation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Greely AW (1904) Experiments on the physical stucture of the protoplasm of paramœcium and its relation to the reactions of the organism to thermal, chemical and electrical stimuli. Bio Bull 7:3–32" href="/article/10.1007/s00424-007-0405-1#ref-CR27" id="ref-link-section-d7270849e749">27</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 128" title="Zhang PC, Keleshian AM, Sachs F (2001) Voltage-induced membrane movement. Nature 413:428–432" href="/article/10.1007/s00424-007-0405-1#ref-CR128" id="ref-link-section-d7270849e752">128</a>].</p> <p>The majority of AFM mechanical measurements on living cells rely on nano-indentation approaches and extracting mechanical parameters from measured force–displacement curves. Although the main mechanical indicator is taken to be elasticity, rheological parameters have also been extracted from living cells using various approaches [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 129" title="Alcaraz J, Buscemi L, Grabulosa M, Trepat X, Fabry B, Farre R, Navajas D (2003) Microrheology of human lung epithelial cells measured by atomic force microscopy. Biophys J 84:2071–2079" href="/article/10.1007/s00424-007-0405-1#ref-CR129" id="ref-link-section-d7270849e758">129</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 131" title="Smith BA, Tolloczko B, Martin JG, Grutter P (2005) Probing the viscoelastic behavior of cultured airway smooth muscle cells with atomic force microscopy: stiffening induced by contractile agonist. Biophys J 88:2994–3007" href="/article/10.1007/s00424-007-0405-1#ref-CR131" id="ref-link-section-d7270849e761">131</a>]. Indentation approaches have been used in conjunction with scanning to produce force maps [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Rotsch C, Radmacher M (2000) Drug-induced changes of cytoskeletal structure and mechanics in fibroblasts: an atomic force microscopy study. Biophys J 78:520–535" href="/article/10.1007/s00424-007-0405-1#ref-CR41" id="ref-link-section-d7270849e764">41</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Radmacher M (2007) Studying the mechanics of cellular processes by atomic force microscopy. Methods Cell Biol 83:347–372" href="/article/10.1007/s00424-007-0405-1#ref-CR44" id="ref-link-section-d7270849e767">44</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 132" title="Radmacher M (2002) Measuring the elastic properties of living cells by the atomic force microscope. Methods Cell Biol 68:67–90" href="/article/10.1007/s00424-007-0405-1#ref-CR132" id="ref-link-section-d7270849e770">132</a>] or in single spots on living cells to measure time dependence [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 125" title="Pelling AE, Dawson DW, Carreon DM, Christiansen JJ, Shen RR, Teitell MA, Gimzewski JK (2007) Distinct contributions of microtubule subtypes to cell membrane shape and stability. Nanomedicine 3:43–52" href="/article/10.1007/s00424-007-0405-1#ref-CR125" id="ref-link-section-d7270849e774">125</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 127" title="Lam WA, Rosenbluth MJ, Fletcher DA (2007) Chemotherapy exposure increases leukemia cell stiffness. Blood 109:3505–3508" href="/article/10.1007/s00424-007-0405-1#ref-CR127" id="ref-link-section-d7270849e777">127</a>]. Early indentation experiments on living cells almost a century ago employed the use of glass microneedles which were slowly inserted into many cell types to estimate viscosity [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Seifriz W (1918) Observations on the structure of protoplasm by aid of microdissection. Biol Bull 34:307–324" href="/article/10.1007/s00424-007-0405-1#ref-CR39" id="ref-link-section-d7270849e780">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 133" title="Kite GL (1913) Studies on the physical properties of protoplasm. Am J Physiol 32:146–164" href="/article/10.1007/s00424-007-0405-1#ref-CR133" id="ref-link-section-d7270849e783">133</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 135" title="Chambers R, Fell HB (1931) Micro-operations on cells in tissue cultures. Proc Roy Soc London B 109:380–403" href="/article/10.1007/s00424-007-0405-1#ref-CR135" id="ref-link-section-d7270849e786">135</a>]. Although very qualitative, this method and variants of “micro-dissection” became a very common way to estimate the mechanical properties of the protoplasm. In 1931, a “micro-operation” with a microneedle was described in which needles were used to push and penetrate into organelles of living cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 135" title="Chambers R, Fell HB (1931) Micro-operations on cells in tissue cultures. Proc Roy Soc London B 109:380–403" href="/article/10.1007/s00424-007-0405-1#ref-CR135" id="ref-link-section-d7270849e789">135</a>]. Interestingly, in 2005, a “nanoscale operation” was described in which an AFM tip, modified with a nanoneedle, was employed to push and penetrate into the nucleus of living cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 136" title="Obataya I, Nakamura C, Han S, Nakamura N, Miyake J (2005) Nanoscale operation of a living cell using an atomic force microscope with a nanoneedle. Nano Lett 5:27–30" href="/article/10.1007/s00424-007-0405-1#ref-CR136" id="ref-link-section-d7270849e793">136</a>]. Although separated by about three quarters of a century, both reports describe the penetration and deformation of the cell nucleus using very similar approaches (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00424-007-0405-1#Fig3">3</a>). Granted, the AFM measurement provided a quantitative measure of force which was not possible with the early report. Furthermore, simultaneous laser scanning confocal imaging (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00424-007-0405-1#Fig2">2</a>) provides much more detailed three-dimensional information which was also not possible in 1931. </p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Fig. 3"><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 3</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00424-007-0405-1/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00424-007-0405-1/MediaObjects/424_2007_405_Fig3_HTML.gif?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00424-007-0405-1/MediaObjects/424_2007_405_Fig3_HTML.gif" alt="figure 3" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p>Cell indentation as a means of measuring mechanical properties was developed as in the early 1900s. <b>a</b> In 1931, glass microneedles (<i>arrow</i>) were used to “operate” on living cells by indenting and eventually entering the nucleus (image reproduced with permission from the Royal Society [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 135" title="Chambers R, Fell HB (1931) Micro-operations on cells in tissue cultures. Proc Roy Soc London B 109:380–403" href="/article/10.1007/s00424-007-0405-1#ref-CR135" id="ref-link-section-d7270849e818">135</a>]). <b>b</b> Much later, modern techniques using AFM as seen in the phase-contrast micrograph. These similar methods of “nano-indentation” have also been described as “nano-operations” [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 136" title="Obataya I, Nakamura C, Han S, Nakamura N, Miyake J (2005) Nanoscale operation of a living cell using an atomic force microscope with a nanoneedle. Nano Lett 5:27–30" href="/article/10.1007/s00424-007-0405-1#ref-CR136" id="ref-link-section-d7270849e824">136</a>]</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00424-007-0405-1/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <p>Just prior to the development of the AFM in 1986, “cell poking” with calibrated microneedles was developed [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 137" title="Petersen NO, McConnaughey WB, Elson EL (1982) Dependence of locally measured cellular deformability on position on the cell, temperature, and cytochalasin B. Proc Natl Acad Sci USA 79:5327–5331" href="/article/10.1007/s00424-007-0405-1#ref-CR137" id="ref-link-section-d7270849e840">137</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 139" title="Daily B, Elson EL, Zahalak GI (1984) Cell poking. Determination of the elastic area compressibility modulus of the erythrocyte membrane. Biophys J 45:671–682" href="/article/10.1007/s00424-007-0405-1#ref-CR139" id="ref-link-section-d7270849e843">139</a>]. Unlike the early methods which pushed the needle straight through the cell, the needle was indented into the cell membrane to measure cellular deformations and elasticity. Complementary to much older work from the late 1920s, the effect of anti-cytoskeletal drugs were also measured [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 137" title="Petersen NO, McConnaughey WB, Elson EL (1982) Dependence of locally measured cellular deformability on position on the cell, temperature, and cytochalasin B. Proc Natl Acad Sci USA 79:5327–5331" href="/article/10.1007/s00424-007-0405-1#ref-CR137" id="ref-link-section-d7270849e846">137</a>]. Some early examples of whole-cell elasticity were demonstrated using plant cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 140" title="Treitel O (1944) Elasticity of plant tissues. Trans Kans Acad Sci 47:219–239" href="/article/10.1007/s00424-007-0405-1#ref-CR140" id="ref-link-section-d7270849e849">140</a>]. Plant tissue was clamped on either end and stretched using known weights to produce stress–strain curves. Conceptually, this work is related to modern directions towards investigating multi-cellular assemblies, monolayers and tissues [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Huang H, Kamm RD, Lee RT (2004) Cell mechanics and mechanotransduction: pathways, probes, and physiology. Am J Physiol Cell Physiol 287:C1–C11" href="/article/10.1007/s00424-007-0405-1#ref-CR16" id="ref-link-section-d7270849e852">16</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Ingber DE (2006) Mechanical control of tissue morphogenesis during embryological development. Int J Dev Biol 50:255–266" href="/article/10.1007/s00424-007-0405-1#ref-CR24" id="ref-link-section-d7270849e856">24</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Ingber DE (2005) Mechanical control of tissue growth: function follows form. Proc Natl Acad Sci USA 102:11571–11572" href="/article/10.1007/s00424-007-0405-1#ref-CR25" id="ref-link-section-d7270849e859">25</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 141" title="Bray D (1984) Axonal growth in response to experimentally applied mechanical tension. Dev Biol 102:379–389" href="/article/10.1007/s00424-007-0405-1#ref-CR141" id="ref-link-section-d7270849e862">141</a>]. Micropipette aspiration [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 142" title="Waugh R, Evans EA (1979) Thermoelasticity of red blood cell membrane. Biophys J 26:115–131" href="/article/10.1007/s00424-007-0405-1#ref-CR142" id="ref-link-section-d7270849e865">142</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 145" title="Hochmuth RM (2000) Micropipette aspiration of living cells. J Biomech 33:15–22" href="/article/10.1007/s00424-007-0405-1#ref-CR145" id="ref-link-section-d7270849e868">145</a>] has also come into use to study whole-cell mechanics by examining cellular and nuclear deformations in response to suction [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 146" title="Lammerding J, Schulze PC, Takahashi T, Kozlov S, Sullivan T, Kamm RD, Stewart CL, Lee RT (2004) Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Invest 113:370–378" href="/article/10.1007/s00424-007-0405-1#ref-CR146" id="ref-link-section-d7270849e871">146</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 149" title="Rowat AC, Lammerding J, Ipsen JH (2006) Mechanical properties of the cell nucleus and the effect of emerin deficiency. Biophys J 91:4649–4664" href="/article/10.1007/s00424-007-0405-1#ref-CR149" id="ref-link-section-d7270849e875">149</a>]. Microplates [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 150" title="Thoumine O, Ott A, Cardoso O, Meister JJ (1999) Microplates: a new tool for manipulation and mechanical perturbation of individual cells. J Biochem Biophys Methods 39:47–62" href="/article/10.1007/s00424-007-0405-1#ref-CR150" id="ref-link-section-d7270849e878">150</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 151" title="Smith AE, Zhang Z, Thomas CR, Moxham KE, Middelberg AP (2000) The mechanical properties of fs. Proc Natl Acad Sci USA 97:9871–9874" href="/article/10.1007/s00424-007-0405-1#ref-CR151" id="ref-link-section-d7270849e881">151</a>] have been employed to measure cellular deformation and elasticity in response to force. Cells have been either literally “ploughed” from a surface using a cantilever to measure adhesion forces which aid in attachment and motility [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 152" title="Sagvolden G, Giaever I, Pettersen EO, Feder J (1999) Cell adhesion force microscopy. Proc Natl Acad Sci USA 96:471–476" href="/article/10.1007/s00424-007-0405-1#ref-CR152" id="ref-link-section-d7270849e884">152</a>]. There is an extensive literature, dating back to the late 1800s, on wound healing and migration which are also highly mechanical in nature [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 153" title="Herrick EH (1932) Mechanism of movement of epidermis, especially its melanophores, in wound healing, and behavior of skin grafts in frog tadpoles. Bio Bull 63:271–286" href="/article/10.1007/s00424-007-0405-1#ref-CR153" id="ref-link-section-d7270849e887">153</a>]. Recently, AFM has been used to measure the protrusive forces [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Radmacher M (2007) Studying the mechanics of cellular processes by atomic force microscopy. Methods Cell Biol 83:347–372" href="/article/10.1007/s00424-007-0405-1#ref-CR44" id="ref-link-section-d7270849e890">44</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 154" title="Prass M, Jacobson K, Mogilner A, Radmacher M (2006) Direct measurement of the lamellipodial protrusive force in a migrating cell. J Cell Biol 174:767–772" href="/article/10.1007/s00424-007-0405-1#ref-CR154" id="ref-link-section-d7270849e894">154</a>] at the edge of migrating cells in complement to traction force assays [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 155" title="Pelham RJ Jr., Wang Y (1999) High resolution detection of mechanical forces exerted by locomoting fibroblasts on the substrate. Mol Biol Cell 10:935–945" href="/article/10.1007/s00424-007-0405-1#ref-CR155" id="ref-link-section-d7270849e897">155</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 156" title="Jurado C, Haserick JR, Lee J (2005) Slipping or gripping? Fluorescent speckle microscopy in fish keratocytes reveals two different mechanisms for generating a retrograde flow of actin. Mol Biol Cell 16:507–518" href="/article/10.1007/s00424-007-0405-1#ref-CR156" id="ref-link-section-d7270849e900">156</a>], micropipette and laser trap studies [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 157" title="Li S, Guan JL, Chien S (2005) Biochemistry and biomechanics of cell motility. Annu Rev Biomed Eng 7:105–150" href="/article/10.1007/s00424-007-0405-1#ref-CR157" id="ref-link-section-d7270849e903">157</a>]. Migration is a key element in cancer metastasis, and in recent years, cells have been optically trapped and stretched in electromagnetic fields to measure mechanical properties in relation to metastatic potential [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 158" title="Svoboda K, Block SM (1994) Biological applications of optical forces. Annu Rev Biophys Biomol Struct 23:247–285" href="/article/10.1007/s00424-007-0405-1#ref-CR158" id="ref-link-section-d7270849e906">158</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 161" title="Guck J, Schinkinger S, Lincoln B, Wottawah F, Ebert S, Romeyke M, Lenz D, Erickson HM, Ananthakrishnan R, Mitchell D, Kas J, Ulvick S, Bilby C (2005) Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. Biophys J 88:3689–3698" href="/article/10.1007/s00424-007-0405-1#ref-CR161" id="ref-link-section-d7270849e909">161</a>] (complementary to early deformability assays [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 162" title="Ochalek T, Nordt FJ, Tullberg K, Burger MM (1988) Correlation between cell deformability and metastatic potential in B16-F1 melanoma cell variants. Cancer Res 48:5124–5128" href="/article/10.1007/s00424-007-0405-1#ref-CR162" id="ref-link-section-d7270849e913">162</a>]). In addition, magnetic traps have been utilized to perform rheological measurements with magnetic beads [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Stamenovic D, Rosenblatt N, Montoya-Zavala M, Matthews BD, Hu S, Suki B, Wang N, Ingber DE (2007) Rheological behavior of living cells is timescale-dependent. Biophys. J. 93:L39–L41" href="/article/10.1007/s00424-007-0405-1#ref-CR20" id="ref-link-section-d7270849e916">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 163" title="Wang N, Butler JP, Ingber DE (1993) Mechanotransduction across the cell surface and through the cytoskeleton. Science 260:1124–1127" href="/article/10.1007/s00424-007-0405-1#ref-CR163" id="ref-link-section-d7270849e919">163</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 165" title="Puig-De-Morales M, Grabulosa M, Alcaraz J, Mullol J, Maksym GN, Fredberg JJ, Navajas D (2001) Measurement of cell microrheology by magnetic twisting cytometry with frequency domain demodulation. J Appl Physiol 91:1152–1159" href="/article/10.1007/s00424-007-0405-1#ref-CR165" id="ref-link-section-d7270849e922">165</a>]. Measurements of mechanical parameters, organelle deformations and force transmission have all been performed with magnetic bead-twisting cytometry [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 163" title="Wang N, Butler JP, Ingber DE (1993) Mechanotransduction across the cell surface and through the cytoskeleton. Science 260:1124–1127" href="/article/10.1007/s00424-007-0405-1#ref-CR163" id="ref-link-section-d7270849e925">163</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 166" title="Hu S, Eberhard L, Chen J, Love JC, Butler JP, Fredberg JJ, Whitesides GM, Wang N (2004) Mechanical anisotropy of adherent cells probed by a three-dimensional magnetic twisting device. Am J Physiol Cell Physiol 287:C1184–1191" href="/article/10.1007/s00424-007-0405-1#ref-CR166" id="ref-link-section-d7270849e928">166</a>]. These studies are similar in concept to the early studies by Seifriz [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 103" title="Seifriz W (1924) An elastic value of protoplasm, with further observations on the viscosity of protoplasm. J Exp Biol 2:1–11" href="/article/10.1007/s00424-007-0405-1#ref-CR103" id="ref-link-section-d7270849e932">103</a>] and his magnetic microscope as well as early organelle tracking in response to indentations with micropipettes [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 135" title="Chambers R, Fell HB (1931) Micro-operations on cells in tissue cultures. Proc Roy Soc London B 109:380–403" href="/article/10.1007/s00424-007-0405-1#ref-CR135" id="ref-link-section-d7270849e935">135</a>].</p> <p>Obviously, there have been a wide variety of approaches demonstrated over the past 150 years to measure the mechanical properties of living cells. Although the mechanical properties of living cells and organisms was initially very conceptual, we have witnessed a significant growth in the methodologies employed to measure such properties [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Wang Y-1, Discher DE (2007) Cell mechanics, 1st edn. Elsevier Academic, Amsterdam" href="/article/10.1007/s00424-007-0405-1#ref-CR6" id="ref-link-section-d7270849e941">6</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Mofrad MRK, Kamm RD (2006) Cytoskeletal mechanics: models and measurements, 1st edn. Cambridge University Press, Cambridge" href="/article/10.1007/s00424-007-0405-1#ref-CR8" id="ref-link-section-d7270849e944">8</a>]. Many laboratories worldwide have become expert at measuring mechanical properties of cells; however, it is clear from the above literature review that many of the same questions are being asked today that were posed and explored over the past century. Clearly, biological cells and tissues possess mechanical properties, and these properties do appear to change during physiological processes and in disease. Mechanical detection of these states may indeed be a key development important for the future of ‘nanomedicine’ and ‘nanophysiology’. However, these concepts have existed for some time, and it begs the question—Is there more we can do aside from developing very accurate tools to mechanically detect biological processes?</p> <h3 class="c-article__sub-heading">Outlook on cell mechanics and “nanophysiology”</h3> <p>In 1737, Stuart [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 93" title="Stuart A (1738) Three lectures on muscular motion, read before the Royal Society in the Year MDCCXXXVIII: As appointed by the will of Lady Sadleir, pursuant to the design of her first husband William Croone, M. D. Fellow of the College of Physicians, and of the Royal Society: being a supplement to the philosophical transactions for that year. Wherein the elasticity of fluids, and the immediate cause of the cohesion and elasticity of solids, are proved by experiments, &c. and shewn to arise from the same principle as gravity: with a general scheme of muscular motion, founded on anatomy, experiments, etc. Phil Trans (1638–1775) 40:i-liv" href="/article/10.1007/s00424-007-0405-1#ref-CR93" id="ref-link-section-d7270849e955">93</a>] originally discussed the idea of being able to control the heart by stimulating it correctly. Although the measurement of accurate mechanical parameters is of extreme importance, the idea of controlling and altering biological pathways is equally enticing. Previously, it has been shown that mechanical force delivered by the AFM tip can induce various chemo-mechanical responses [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 167" title="Charras GT, Horton MA (2002) Single cell mechanotransduction and its modulation analyzed by atomic force microscope indentation. Biophys J 82:2970–2981" href="/article/10.1007/s00424-007-0405-1#ref-CR167" id="ref-link-section-d7270849e958">167</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 169" title="Formigli L, Meacci E, Sassoli C, Chellini F, Giannini R, Quercioli F, Tiribilli B, Squecco R, Bruni P, Francini F, Zecchi-Orlandini S (2005) Sphingosine 1-phosphate induces cytoskeletal reorganization in C2C12 myoblasts: physiological relevance for stress fibres in the modulation of ion current through stretch-activated channels. J Cell Sci 118:1161–1171" href="/article/10.1007/s00424-007-0405-1#ref-CR169" id="ref-link-section-d7270849e961">169</a>]. In recent work, it has also been shown that the mechanical environment of many cell types (including cancer and stem cells) can be used to control and alter gene expression and differentiation pathways [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Even-Ram S, Artym V, Yamada KM (2006) Matrix control of stem cell fate. Cell 126:645–647" href="/article/10.1007/s00424-007-0405-1#ref-CR21" id="ref-link-section-d7270849e964">21</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Ingber DE (2005) Mechanical control of tissue growth: function follows form. Proc Natl Acad Sci USA 102:11571–11572" href="/article/10.1007/s00424-007-0405-1#ref-CR25" id="ref-link-section-d7270849e967">25</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 164" title="Wang N, Ingber DE (1994) Control of cytoskeletal mechanics by extracellular matrix, cell shape, and mechanical tension. Biophys J 66:2181–2189" href="/article/10.1007/s00424-007-0405-1#ref-CR164" id="ref-link-section-d7270849e971">164</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 170" title="Huang S, Ingber DE (2005) Cell tension, matrix mechanics, and cancer development. Cancer Cell 8:175–176" href="/article/10.1007/s00424-007-0405-1#ref-CR170" id="ref-link-section-d7270849e974">170</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 171" title="Suresh S (2007) Biomechanics and biophysics of cancer cells. Acta Biomater 3:413–438" href="/article/10.1007/s00424-007-0405-1#ref-CR171" id="ref-link-section-d7270849e977">171</a>]. We now have the tools to measure mechanical properties, and we have the tools to alter the mechanical environment of a cell or even deliver well-defined forces to a cell. Therefore, can we now move towards initiating and controlling biological pathways in cell cultures and perhaps, one day, in vivo? Perhaps, the emerging field of nanophysiology will include a branch dedicated to the nanomechanical control of biological pathways. This poorly understood area of pursuit, in concert with ultra-sensitive detection technologies and modern pharmaceutical treatments, may have a significant role to play in the development of nanomedicine and the diagnosis and treatment of diseases.</p> <p>Complementary to the many applications one may envision for nanotechnology in medicine and physiology, it is also becoming clear that the governing physical principles of cell mechanics remain poorly understood and the subject of intense debate. Specifically, the concept of elasticity is ill-defined for a living cell. The cell is heterogeneous, dynamic, undergoes continuous cytoskeletal remodelling and likely highly anisotropic. Therefore, the Hertz model, commonly used in AFM nanoindentation experiments, does not ideally apply. Furthermore, the cellular Poisson ratio is equally ill-defined and has conventionally been taken to be constant, although this may not actually be the case. There is no evidence to show that the Poisson ratio does not itself change during physiological processes, and this may or may not be correlated to changes in Young’s modulus. Therefore, as mentioned above, our theoretical descriptions of cell mechanics still require much further development. However, there is no doubt this will occur as future debates and empirical observations take place.</p> <p>Conclusions regarding cellular mechanics are often drawn from studies carried out on one cell type, under a limited set of conditions, and generalized towards a broad range of cells, if not all cells. However, we suggest that mechanical responses and the biochemical/structural basis for mechanical parameters are likely dependent on the type, physiological and mechanical environment of the cell. Although many cell types contain the same structural components (that is, the cytoplasm, cytoskeleton, nucleus, membranes, etc.), it may be unlikely to utilize them along identical pathways during biological processes. Therefore, rather than searching for a unified theory of cell mechanics, we, as a community, might try to identify heterogeneity in phenotypic mechanical responses and transduction pathways in living cells. Classification might be according to the mechanical model(s) (or combination of models) which describes the cell most appropriately, along the lines of which signalling pathway(s) are activated upon mechanical stimulation, which internal structures are important for mechanotransduction, or the mechanical changes which take place during physiological processes.</p> <p>Regardless of this speculation, the field of cell mechanics is alive and well. The trend towards interdisciplinary research among so-called nanoscientists is an encouraging one and represents one of the major advances in the field of cell mechanics. In the early studies of the protoplasm, there was significant antagonism and territorial fighting between biologists and chemists [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Geison GL (1969) The photoplasmic theory of life and the vitalist–mechanist debate. Isis 60:272–292" href="/article/10.1007/s00424-007-0405-1#ref-CR37" id="ref-link-section-d7270849e987">37</a>]. Today, we see that scientists are becoming ever more able and willing to cross diverse disciplinary lines. As we look back on the history of cell mechanics, we realize that it was only about 100 years ago that a raging debate was taking place about the components of the protoplasm. 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Proc Am Soc Microsc 9:283–298</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 173" href="http://scholar.google.com/scholar_lookup?&title=Cardiac%20muscle%20cells%20in%20man%20and%20certain%20other%20mammals&journal=Proc%20Am%20Soc%20Microsc&volume=9&pages=283-298&publication_year=1887&author=Oviatt%2CBL"> Google Scholar</a> </p></li></ol><p class="c-article-references__download u-hide-print"><a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1007/s00424-007-0405-1?format=refman&flavour=references">Download references<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p></div></div></div></section></div><section data-title="Acknowledgements"><div class="c-article-section" id="Ack1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Ack1">Acknowledgements</h2><div class="c-article-section__content" id="Ack1-content"><p>We gratefully acknowledge the ‘Dr. Mortimer and Mrs. Theresa Sackler Trust’ and the Wellcome Trust for funding this work.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">The London Centre for Nanotechnology, Centre for Nanomedicine, University College London, 17-19 Gordon Street, London, WC1H 0AH, UK</p><p class="c-article-author-affiliation__authors-list">Andrew E. Pelling & Michael A. Horton</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Andrew_E_-Pelling-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Andrew E. Pelling</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Andrew%20E.%20Pelling" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Andrew%20E.%20Pelling" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Andrew%20E.%20Pelling%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Michael_A_-Horton-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Michael A. Horton</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Michael%20A.%20Horton" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Michael%20A.%20Horton" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Michael%20A.%20Horton%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li></ol></div><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding authors</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:a.pelling@ucl.ac.uk">Andrew E. Pelling</a> or <a id="corresp-c2" href="mailto:m.horton@ucl.ac.uk">Michael A. Horton</a>.</p></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" id="rightslink-content"><p class="c-article-rights"><a data-track="click" data-track-action="view rights and permissions" data-track-label="link" href="https://s100.copyright.com/AppDispatchServlet?title=An%20historical%20perspective%20on%20cell%20mechanics&author=Andrew%20E.%20Pelling%20et%20al&contentID=10.1007%2Fs00424-007-0405-1&copyright=Springer-Verlag&publication=0031-6768&publicationDate=2007-12-07&publisherName=SpringerNature&orderBeanReset=true">Reprints and permissions</a></p></div></div></section><section aria-labelledby="article-info" data-title="About this article"><div class="c-article-section" id="article-info-section"><h2 class="c-article-section__title 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