{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:10:11Z","timestamp":1790737811306,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2017,4,17]],"date-time":"2017-04-17T00:00:00Z","timestamp":1492387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biosensors"],"abstract":"<jats:p>This study demonstrates the rapid and label-free detection of Interleukin-6 (IL-6) using carbon nanotube micro-arrays with aptamer as the molecular recognition element. Single wall carbon nanotubes micro-arrays biosensors were manufactured using photo-lithography, metal deposition, and etching techniques. Nanotube biosensors were functionalized with 1-Pyrenebutanoic Acid Succinimidyl Ester (PASE) conjugated IL-6 aptamers. Real time response of the sensor conductance was monitored with increasing concentration of IL-6 (1 pg\/mL to 10 ng\/mL), exposure to the sensing surface in buffer solution, and clinically relevant spiked blood samples. Non-specific Bovine Serum Albumin (BSA), PBS samples, and anti-IgG functionalized devices gave similar signatures in the real time conductance versus time experiments with no significant change in sensor signal. Exposure of the aptamer functionalized nanotube surface to IL-6 decreased the conductance with increasing concentration of IL-6. Experiments based on field effect transistor arrays suggested shift in drain current versus gate voltage for 1 pg and 1 ng of IL-6 exposure. Non-specific BSA did not produce any appreciable shift in the Ids versus Vg suggesting specific interactions of IL-6 on PASE conjugated aptamer surface gave rise to the change in electrical signal. Both Z axis and phase image in an Atomic Force Microscope (AFM) suggested unambiguous molecular interaction of the IL-6 on the nanotube-aptamer surface at 1 pg\/mL concentration. The concentration of 1 pg falls below the diagnostic gray zone for cancer (2.3 pg-4 ng\/mL), which is an indicator of early stage cancer. Thus, nanotube micro-arrays could potentially be developed for creating multiplexed assays involving cancer biomarker proteins and possibly circulating tumor cells all in a single assay using PASE functionalization protocol.<\/jats:p>","DOI":"10.3390\/bios7020017","type":"journal-article","created":{"date-parts":[[2017,4,18]],"date-time":"2017-04-18T11:22:04Z","timestamp":1492514524000},"page":"17","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Ultrasensitive Label-Free Sensing of IL-6 Based on PASE Functionalized Carbon Nanotube Micro-Arrays with RNA-Aptamers as Molecular Recognition Elements"],"prefix":"10.3390","volume":"7","author":[{"given":"Farhad","family":"Khosravi","sequence":"first","affiliation":[{"name":"Small Systems Laboratory, Department of Mechanical Engineering, Worcester Polytechnic Institute, Worcester, MA 01532, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3496-576X","authenticated-orcid":false,"given":"Seyed","family":"Loeian","sequence":"additional","affiliation":[{"name":"Small Systems Laboratory, Department of Mechanical Engineering, Worcester Polytechnic Institute, Worcester, MA 01532, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0860-3602","authenticated-orcid":false,"given":"Balaji","family":"Panchapakesan","sequence":"additional","affiliation":[{"name":"Small Systems Laboratory, Department of Mechanical Engineering, Worcester Polytechnic Institute, Worcester, MA 01532, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/363603a0","article-title":"Single-shell carbon nanotubes of 1-nm diameter","volume":"363","author":"Iijima","year":"1993","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3838","DOI":"10.1021\/ja010172b","article-title":"Noncovalent sidewall functionalization of single-walled carbon nanotubes for protein immobilization","volume":"123","author":"Chen","year":"2001","journal-title":"J. Am. Chem. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1021\/nl0340172","article-title":"Electronic detection of specific protein binding using nanotube fet devices","volume":"3","author":"Star","year":"2003","journal-title":"Nano Lett."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Khosravi, F., King, B., Panchapakesan, B., Rai, S., Kloecker, G., and Wickstrom, E. (2013). Nanotube devices for digital profiling of cancer biomarkers and circulating tumor cells. IEEE Int. Conf. Nano, 107\u2013112.","DOI":"10.1109\/NANOMED.2013.6766325"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1021\/ja031723w","article-title":"Ultrasensitive electrical biosensing of proteins and DNA: Carbon-nanotube derived amplification of the recognition and transduction events","volume":"126","author":"Wang","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1021\/nl8025604","article-title":"Label-free DNA biosensors based on functionalized carbon nanotube field effect transistors","volume":"9","author":"Martinez","year":"2009","journal-title":"Nano Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1002\/adma.200702798","article-title":"Electrical detection of femtomolar DNA via gold-nanoparticle enhancement in carbon-nanotube-network field-effect transistors","volume":"20","author":"Dong","year":"2008","journal-title":"Adv. Mater."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1039\/b707025j","article-title":"Electrical detection of hepatitis c virus rna on single wall carbon nanotube-field effect transistors","volume":"132","author":"Dastagir","year":"2007","journal-title":"Analyst"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jcv.2008.09.005","article-title":"Diagnosis of human hepatitis b virus in non-treated blood by the bovine igg DNA-linked carbon nanotube biosensor","volume":"44","author":"Ly","year":"2009","journal-title":"J. Clin. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Shao, N., Wickstrom, E., and Panchapakesan, B. (2008). Nanotube-antibody biosensor arrays for the detection of circulating breast cancer cells. Nanotechnology, 19.","DOI":"10.1088\/0957-4484\/19\/46\/465101"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"King, B.C., Clark, M., Burkhead, T., Sethu, P., Rai, S., Kloecker, G., and Panchapakesan, B. (2012). Electrical detection of specific versus non-specific binding events in breast cancer cells. Biosens. Nanomed. V, 8460.","DOI":"10.1117\/12.929875"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13LT02","DOI":"10.1088\/0957-4484\/27\/13\/13LT02","article-title":"Label-free capture of breast cancer cells spiked in buffy coats using carbon nanotube antibody micro-arrays","volume":"27","author":"Khosravi","year":"2016","journal-title":"Nanotechnology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"44LT03","DOI":"10.1088\/0957-4484\/27\/44\/44LT03","article-title":"Static micro-array isolation, dynamic time series classification, capture and enumeration of spiked breast cancer cells in blood: The nanotube\u2013ctc chip","volume":"27","author":"Khosravi","year":"2016","journal-title":"Nanotechnology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Minot, E.D., Janssens, A.M., Heller, I., Heering, H.A., Dekker, C., and Lemay, S.G. (2007). Carbon nanotube biosensors: The critical role of the reference electrode. Appl. Phys. Lett., 91.","DOI":"10.1063\/1.2775090"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1021\/nl072996i","article-title":"Identifying the mechanism of biosensing with carbon nanotube transistors","volume":"8","author":"Heller","year":"2008","journal-title":"Nano Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ab.2008.06.040","article-title":"Ultrasensitive carbon nanotube-based biosensors using antibody-binding fragments","volume":"381","author":"Kim","year":"2008","journal-title":"Anal. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1021\/ac060830g","article-title":"Label-free protein biosensor based on aptamer-modified carbon nanotube field-effect transistors","volume":"79","author":"Maehashi","year":"2007","journal-title":"Anal. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.bios.2012.12.006","article-title":"Label-free electrochemical ige aptasensor based on covalent attachment of aptamer onto multiwalled carbon nanotubes\/ionic liquid\/chitosan nanocomposite modified electrode","volume":"43","author":"Khezrian","year":"2013","journal-title":"Biosens. Bioelectron."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11906","DOI":"10.1021\/ja053094r","article-title":"Single-walled carbon nanotube biosensors using aptamers as molecular recognition elements","volume":"127","author":"So","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4740","DOI":"10.1016\/j.biomaterials.2010.02.040","article-title":"A high-performance vegf aptamer functionalized polypyrrole nanotube biosensor","volume":"31","author":"Kwon","year":"2010","journal-title":"Biomaterials"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.elecom.2009.02.044","article-title":"Electrochemical immunosensors for interleukin-6. Comparison of carbon nanotube forest and gold nanoparticle platforms","volume":"11","author":"Munge","year":"2009","journal-title":"Electrochem. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3118","DOI":"10.1021\/ac902802b","article-title":"Ultrasensitive electrochemical immunosensor for oral cancer biomarker il-6 using carbon nanotube forest electrodes and multilabel amplification","volume":"82","author":"Malhotra","year":"2010","journal-title":"Anal. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.snb.2011.06.035","article-title":"Electrochemical sensor utilizing ferrocene loaded porous polyelectrolyte nanoparticles as label for the detection of protein biomarker il-6","volume":"158","author":"Li","year":"2011","journal-title":"Sens. Actuators B Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.immunol.23.021704.115806","article-title":"Interleukin-6: From basic science to medicine-40 years in immunology","volume":"23","author":"Kishimoto","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1016\/j.ejca.2005.08.016","article-title":"The role of il-6 and stat3 in inflammation and cancer","volume":"41","author":"Hodge","year":"2005","journal-title":"Eur. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1007\/s00262-005-0047-0","article-title":"Cytokine expression profile in human pancreatic carcinoma cells and in surgical specimens: Implications for survival","volume":"55","author":"Bellone","year":"2006","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"35484","DOI":"10.1074\/jbc.M112.367532","article-title":"Tumor microenvironment macrophage inhibitory factor directs the accumulation of interleukin-17-producing tumor-infiltrating lymphocytes and predicts favorable survival in nasopharyngeal carcinoma patients","volume":"287","author":"Li","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.3390\/ijms16011691","article-title":"Mechanisms and \u03b1pplications of \u03b9nterleukins in cancer immunotherapy","volume":"16","author":"Anestakis","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_29","first-page":"1171","article-title":"Il-6-induced epithelial-mesenchymal transition promotes the generation of breast cancer stem-like cells analogous to mammosphere cultures","volume":"40","author":"Xie","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1002\/ijc.25764","article-title":"Interleukin-6 promotes tumorigenesis by altering DNA methylation in oral cancer cells","volume":"129","author":"Gasche","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/(SICI)1097-0045(20000215)42:3<239::AID-PROS10>3.0.CO;2-G","article-title":"Interleukin-6 induces prostate cancer cell growth accompanied by activation of Stat3 signaling pathway","volume":"42","author":"Lou","year":"2000","journal-title":"Prostate"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/(SICI)1097-0045(19990215)38:3<199::AID-PROS4>3.0.CO;2-H","article-title":"Characterization of the role of il-6 in the progression of prostate cancer","volume":"38","author":"Chung","year":"1999","journal-title":"Prostate"},{"key":"ref_33","first-page":"1427","article-title":"Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma","volume":"19","author":"Zhang","year":"1999","journal-title":"Anticancer Res."},{"key":"ref_34","first-page":"3317","article-title":"Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma","volume":"52","author":"Blay","year":"1992","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/jso.10269","article-title":"Serum interleukin-6 levels reflect the disease status of colorectal cancer","volume":"83","author":"Chung","year":"2003","journal-title":"J. Surg. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"165","DOI":"10.3892\/ijo.2014.2422","article-title":"Interleukin-6-induced epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in human cervical carcinoma","volume":"45","author":"Miao","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2627","DOI":"10.1182\/blood-2004-12-4602","article-title":"Humanized anti\u2013interleukin-6 receptor antibody treatment of multicentric castleman disease","volume":"106","author":"Nishimoto","year":"2005","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1136\/ard.2008.092932","article-title":"Il-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: Results from a 24-week multicentre randomised placebo-controlled trial","volume":"67","author":"Emery","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1186\/ar1969","article-title":"Interleukin-6: A new therapeutic target","volume":"8","author":"Smolen","year":"2006","journal-title":"Arthritis Res. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1517\/14728222.9.4.737","article-title":"Interleukin-6 and new strategies for the treatment of cancer, hyperproliferative diseases and paraneoplastic syndromes","volume":"9","author":"Barton","year":"2005","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1002\/ijc.20270","article-title":"Cnto 328, a monoclonal antibody to il-6, inhibits human tumor-induced cachexia in nude mice","volume":"111","author":"Zaki","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1034\/j.1600-0714.2002.310402.x","article-title":"Serum interleukin-6 level is a useful marker in evaluating therapeutic effects of levamisole and chinese medicinal herbs on patients with oral lichen planus","volume":"31","author":"Sun","year":"2002","journal-title":"J. Oral Pathol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1136\/ard.52.3.232","article-title":"Serum interleukin 6 levels in rheumatoid arthritis: Correlations with clinical and laboratory indices of disease activity","volume":"52","author":"Madhok","year":"1993","journal-title":"Ann. Rheum. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3959","DOI":"10.1182\/blood-2008-05-155846","article-title":"Mechanisms and pathologic significances in increase in serum interleukin-6 (il-6) and soluble il-6 receptor after administration of an anti\u2013il-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and castleman disease","volume":"112","author":"Nishimoto","year":"2008","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1182\/blood.V97.1.256","article-title":"Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: Correlation with phenotypic characteristics and outcome","volume":"97","author":"Fayad","year":"2001","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1021\/cr60064a002","article-title":"Dielectric properties of pure liquids","volume":"19","author":"Debye","year":"1936","journal-title":"Chem. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1088\/0957-4484\/25\/17\/175201","article-title":"Vacuum filtration based formation of liquid crystal films of semiconducting carbon nanotubes and high performance transistor devices","volume":"25","author":"King","year":"2014","journal-title":"Nanotechnology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"355501","DOI":"10.1088\/0957-4484\/25\/35\/355501","article-title":"Nanotube liquid crystal elastomers: Photomechanical response and flexible energy conversion of layered polymer composites","volume":"25","author":"Fan","year":"2014","journal-title":"Nanotechnology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/sj.pcan.4501006","article-title":"Hepatocyte growth factor and interleukin-6 in combination with prostate volume are possible prostate cancer tumor markers in patients with gray-zone psa levels","volume":"11","author":"Nishimura","year":"2008","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/jso.10269","article-title":"Serum interleukin-6 levels reflect the disease status of colorectal cancer","volume":"83","author":"Chung","year":"2003","journal-title":"J. Surg. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"9824","DOI":"10.1073\/pnas.171320598","article-title":"An immune response manifested by the common occurrence of annexins i and ii autoantibodies and high circulating levels of il-6 in lung cancer","volume":"98","author":"Brichory","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Biosensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6374\/7\/2\/17\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:32:48Z","timestamp":1760207568000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6374\/7\/2\/17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,17]]},"references-count":51,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,6]]}},"alternative-id":["bios7020017"],"URL":"https:\/\/doi.org\/10.3390\/bios7020017","relation":{},"ISSN":["2079-6374"],"issn-type":[{"value":"2079-6374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,17]]}}}