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Laser-cut paper-based device for the detection of dengue non-structural NS1 protein and specific IgM in human samples

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Abstract

The incidence of flavivirus infections has increased dramatically in recent decades in tropical and sub-tropical areas worldwide, affecting hundreds of millions of people each year. Dengue viruses are typically transmitted by mosquitoes and can cause a wide range of symptoms from flu-like fever to organ impairment and death. Although conventional diagnostic tests can provide early diagnosis of acute dengue infections, access to these tests is often limited in developing countries. Consequently, there is an urgent need to develop affordable, simple, rapid, and robust diagnostic tools that can be used at ‘Point of Care’ settings. Early diagnosis is crucial to improve patient management and reduce the risk of complications. In the present study, a novel laser-cut device made of glass-fiber paper was designed and tested for the detection of the dengue Non Structural 1 (NS1) viral protein and specific IgM in blood and plasma. The device, called PAD, was able to detect around 25 ng/mL of NS1 protein in various sample types in 8 minutes, following a few simple steps. The PAD was also able to detect specific IgM in human plasmas in less than 10 minutes. The PAD appears to have all the potential to assist health workers in early diagnosis of dengue fever or other tropical fevers caused by flaviviruses.

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References

  1. Ahmed S, Bui MPN, Abbas A (2016) Paper-based chemical and biological sensors: engineering aspects. Biosens Bioelectron 77:249–263

    Article  PubMed  CAS  Google Scholar 

  2. Alcon S, Talarmin A, Debruyne M, Falconar A, Deubel V, Flamand M (2002) Enzyme-linked immunosorbent assay specific to Dengue virus type 1 nonstructural protein NS1 reveals circulation of the antigen in the blood during the acute phase of disease in patients experiencing primary or secondary infections. J Clin Microbiol 40:376–381

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Althouse BM, Hanley KA, Diallo M, Sall AA, Ba Y, Faye O, Diallo D, Watts DM, Weaver SC, Cummings DA (2015) Impact of climate and mosquito vector abundance on sylvatic arbovirus circulation dynamics in Senegal. Am J Trop Med Hyg 92:88–97

    Article  PubMed  PubMed Central  Google Scholar 

  4. PS-M (2013) CO 2-laser cutting and ablative etching for the fabrication of paper-based devices. J Micromech Microeng 23:067003

    Article  CAS  Google Scholar 

  5. Apilux A, Ukita Y, Chikae M, Chailapakul O, Takamura Y (2013) Development of automated paper-based devices for sequential multistep sandwich enzyme-linked immunosorbent assays using inkjet printing. Lab Chip 13:126–135

    Article  PubMed  CAS  Google Scholar 

  6. Batra G, Nemani SK, Tyagi P, Swaminathan S, Khanna N (2011) Evaluation of envelope domain III-based single chimeric tetravalent antigen and monovalent antigen mixtures for the detection of anti-dengue antibodies in human sera. BMC Infect Dis 11:64

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bedin F, Boulet L, Voilin E, Theillet G, Rubens A, Rozand C (2017) Paper-based point-of-care testing for cost-effective diagnosis of acute flavivirus infections. J Med Virol 89:1520–1527

    Article  PubMed  CAS  Google Scholar 

  8. Carrilho E, Martinez AW, Whitesides GM (2009) Understanding wax printing: a simple micropatterning process for paper-based microfluidics. Anal Chem 81:7091–7095

    Article  PubMed  CAS  Google Scholar 

  9. Cate DM, Adkins JA, Mettakoonpitak J, Henry CS (2015) Recent developments in paper-based microfluidic devices. Anal Chem 87:19–41

    Article  PubMed  CAS  Google Scholar 

  10. Cedillo-Barron L, Garcia-Cordero J, Bustos-Arriaga J, Leon-Juarez M, Gutierrez-Castaneda B (2014) Antibody response to dengue virus. Microbes Infect 16:711–720

    Article  PubMed  CAS  Google Scholar 

  11. Chen J, Wen K, Li XQ, Yi HS, Ding XX, Huang YF, Pan YX, Hu DM, Di B, Che XY, Fu N (2016) Functional properties of DENV EDIIIreactive antibodies in human DENV1infected sera and rabbit antiserum to EDIII. Mol Med Rep 14:1799–1808

    Article  PubMed  CAS  Google Scholar 

  12. Cheung SF, Cheng SK, Kamei DT (2015) Paper-based systems for point-of-care biosensing. J Lab Autom 20:316–333

    Article  PubMed  CAS  Google Scholar 

  13. Chin C, Chin S, Laksanasopin T, Sia S (2013) Low-cost microdevices for point-of-care testing. In: Issadore D, Westervelt RM (eds) Point-of-care diagnostics on a chip. Springer, Berlin, pp 3–21

    Chapter  Google Scholar 

  14. Choi JR, Hu J, Tang R, Gong Y, Feng S, Ren H, Wen T, Li X, Wan Abas WAB, Pingguan-Murphy B, Xu F (2016) An integrated paper-based sample-to-answer biosensor for nucleic acid testing at the point of care. Lab Chip 16:611–621

    Article  PubMed  CAS  Google Scholar 

  15. Combe M, Lacoux X, Martinez J, Mejan O, Luciani F, Daniel S (2017) Expression, refolding and bio-structural analysis of a tetravalent recombinant dengue envelope domain III protein for serological diagnosis. Protein Expr Purif 133:57–65

    Article  PubMed  CAS  Google Scholar 

  16. Cucunawangsih Lugito NP, Kurniawan A (2015) Immunoglobulin G (IgG) to IgM ratio in secondary adult dengue infection using samples from early days of symptoms onset. BMC Infect Dis 15:276

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Dussart P, Petit L, Labeau B, Bremand L, Leduc A, Moua D, Matheus S, Baril L (2008) Evaluation of two new commercial tests for the diagnosis of acute dengue virus infection using NS1 antigen detection in human serum. PLoS Negl Trop Dis 2:e280

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Fang X, Wei S, Kong J (2014) Paper-based microfluidics with high resolution, cut on a glass fiber membrane for bioassays. Lab Chip 14:911–915

    Article  PubMed  CAS  Google Scholar 

  19. Flamand M, Megret F, Mathieu M, Lepault J, Rey FA, Deubel V (1999) Dengue virus type 1 nonstructural glycoprotein NS1 is secreted from mammalian cells as a soluble hexamer in a glycosylation-dependent fashion. J Virol 73:6104–6110

    PubMed  PubMed Central  CAS  Google Scholar 

  20. Fu E, Liang T, Houghtaling J, Ramachandran S, Ramsey SA, Lutz B, Yager P (2011) Enhanced sensitivity of lateral flow tests using a two-dimensional paper network format. Anal Chem 83:7941–7946

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Fu E, Liang T, Spicar-Mihalic P, Houghtaling J, Ramachandran S, Yager P (2012) Two-dimensional paper network format that enables simple multistep assays for use in low-resource settings in the context of malaria antigen detection. Anal Chem 84:4574–4579

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Gan W, Zhuang B, Zhang P, Han J, Li CX, Liu P (2014) A filter paper-based microdevice for low-cost, rapid, and automated DNA extraction and amplification from diverse sample types. Lab Chip 14:3719–3728

    Article  PubMed  CAS  Google Scholar 

  23. Granger D, Leo YS, Lee LK, Theel ES Serodiagnosis of dengue virus infection using commercially available antibody and NS1 antigen ELISAs

  24. Mahato K, Srivastava A, Chandra P (2017) Paper based diagnostics for personalized health care: emerging technologies and commercial aspects. Biosens Bioelectron 96:246–259

    Article  PubMed  CAS  Google Scholar 

  25. Mahmud M, Blondeel EJM, Kaddoura M, MacDonald BD (2016) Creating compact and microscale features in paper-based devices by laser cutting. Analyst 141:6449–6454

    Article  PubMed  CAS  Google Scholar 

  26. Marcondes CB, Ximenes MF (2016) Zika virus in Brazil and the danger of infestation by Aedes (Stegomyia) mosquitoes. Rev Soc Bras Med Trop 49:4–10

    Article  PubMed  Google Scholar 

  27. Martinez AW, Phillips ST, Whitesides GM (2008) Three-dimensional microfluidic devices fabricated in layered paper and tape. Proc Natl Acad Sci USA 105:19606–19611

    Article  PubMed  PubMed Central  Google Scholar 

  28. Martinez AW, Phillips ST, Whitesides GM, Carrilho E (2010) Diagnostics for the developing world: microfluidic paper-based analytical devices. Anal Chem 82:3–10

    Article  PubMed  CAS  Google Scholar 

  29. Mathengtheng L, Burt FJ (2014) Use of envelope domain III protein for detection and differentiation of flaviviruses in the Free State Province, South Africa. Vector Borne Zoonotic Dis (Larchmont, NY) 14:261–271

    Article  Google Scholar 

  30. Niu G, Pang Z, Guan C, Qi J, Li D (2015) Dengue virus envelope domain III protein based on a tetravalent antigen secreted from insect cells: potential use for serological diagnosis. Virus Res 201:73–78

    Article  PubMed  CAS  Google Scholar 

  31. Posthuma-Trumpie GA, Korf J, van Amerongen A (2009) Lateral flow (immuno)assay: its strengths, weaknesses, opportunities and threats. A literature survey. Anal Bioanal Chem 393:569–582

    Article  PubMed  CAS  Google Scholar 

  32. Priyamvada L, Hudson W, Ahmed R, Wrammert J (2017) Humoral cross-reactivity between Zika and dengue viruses: implications for protection and pathology. Emerg Microbes Infect 6:e33

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Pryor MJ, Wright PJ (1993) The effects of site-directed mutagenesis on the dimerization and secretion of the NS1 protein specified by dengue virus. Virology 194:769–780

    Article  PubMed  CAS  Google Scholar 

  34. Rodriguez-Morales AJ, Villamil-Gomez WE, Franco-Paredes C (2016) The arboviral burden of disease caused by co-circulation and co-infection of dengue, chikungunya and Zika in the Americas. Travel Med Infect Dis 14:177–179

    Article  PubMed  Google Scholar 

  35. Saswat T, Kumar A, Kumar S, Mamidi P, Muduli S, Debata NK, Pal NS, Pratheek BM, Chattopadhyay S, Chattopadhyay S (2015) High rates of co-infection of Dengue and Chikungunya virus in Odisha and Maharashtra, India during 2013. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis 35:134–141

    Google Scholar 

  36. Shah P, Zhu X, Li CZ (2013) Development of paper-based analytical kit for point-of-care testing. Expert Rev Mol Diagn 13:83–91

    Article  PubMed  CAS  Google Scholar 

  37. Shukla J, Khan M, Tiwari M, Sannarangaiah S, Sharma S, Rao PV, Parida M (2009) Development and evaluation of antigen capture ELISA for early clinical diagnosis of chikungunya. Diagn Microbiol Infect Dis 65:142–149

    Article  PubMed  CAS  Google Scholar 

  38. dlC-H SI, Flores-Aguilar H, Gonzalez-Mateos S, Lopez-Martinez I, Alpuche-Arand C, Ludert JE, del Angel RM (2013) Determination of viremia and concentration of circulating nonstructural protein 1 in patients infected with dengue virus in Mexico. Am J Trop Med Hyg 88:446–454

    Article  CAS  Google Scholar 

  39. Songjaroen T, Dungchai W, Chailapakul O, Henry CS, Laiwattanapaisal W (2012) Blood separation on microfluidic paper-based analytical devices. Lab Chip 12:3392–3398

    Article  PubMed  CAS  Google Scholar 

  40. Soni A, Jha SK (2015) A paper strip based non-invasive glucose biosensor for salivary analysis. Biosens Bioelectron 67:763–768

    Article  PubMed  CAS  Google Scholar 

  41. Soo KM, Khalid B, Ching SM, Tham CL, Basir R, Chee HY (2017) Meta-analysis of biomarkers for severe dengue infections. PeerJ 5:e3589

    Article  PubMed  PubMed Central  Google Scholar 

  42. Steidel M, Fragnoud R, Guillotte M, Roesch C, Michel S, Meunier T, Paranhos-Baccala G, Gervasi G, Bedin F (2012) Nonstructural protein NS1 immunodominant epitope detected specifically in dengue virus infected material by a SELDI-TOF/MS based assay. J Med Virol 84:490–499

    Article  PubMed  CAS  Google Scholar 

  43. Steinhagen K, Probst C, Radzimski C, Schmidt-Chanasit J, Emmerich P, van EM, Schinkel J, Grobusch MP, Goorhuis A, Warnecke JM, Lattwein E, Komorowski L, Deerberg A, Saschenbrecker S, Stocker W, Schlumberger W (2016) Serodiagnosis of Zika virus (ZIKV) infections by a novel NS1-based ELISA devoid of cross-reactivity with dengue virus antibodies: a multicohort study of assay performance, 2015 to 2016. In: Euro surveillance: bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin. https://doi.org/10.2807/1560-7917.ES.2016.21.50.30426

  44. Tsai WY, Youn HH, Brites C, Tsai JJ, Tyson J, Pedroso C, Drexler JF, Stone M, Simmons G, Busch MP, Lanteri M, Stramer SL, Balmaseda A, Harris E, Wang WK (2017) Distinguishing secondary dengue virus infection from Zika virus infection with previous dengue by a combination of 3 simple serological tests. Clin Infect Dis 65:1829–1836

    Article  PubMed  Google Scholar 

  45. Vazquez S, Ruiz D, Barrero R, Ramirez R, Calzada N, del Rosario PB, Reyes S, Guzman MG (2010) Kinetics of dengue virus NS1 protein in dengue 4-confirmed adult patients. Diagn Microbiol Infect Dis 68:46–49

    Article  PubMed  CAS  Google Scholar 

  46. Vella SJ, Beattie P, Cademartiri R, Laromaine A, Martinez AW, Phillips ST, Mirica KA, Whitesides GM (2012) Measuring markers of liver function using a micropatterned paper device designed for blood from a fingerstick. Anal Chem 84:2883–2891

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Wong SJ, Furuya A, Zou J, Xie X, Dupuis AP 2nd, Kramer LD, Shi PY (2017) A multiplex microsphere immunoassay for Zika virus diagnosis. EBioMedicine 16:136–140

    Article  PubMed  PubMed Central  Google Scholar 

  48. Yen CW, de Puig H, Tam JO, Gomez-Marquez J, Bosch I, Hamad-Schifferli K, Gehrke L (2015) Multicolored silver nanoparticles for multiplexed disease diagnostics: distinguishing dengue, yellow fever, and Ebola viruses. Lab Chip 15:1638–1641

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Yetisen AK, Akram MS, Lowe CR (2013) Paper-based microfluidic point-of-care diagnostic devices. Lab Chip 13:2210–2251

    Article  PubMed  CAS  Google Scholar 

  50. Zhang B, Salieb-Beugelaar GB, Nigo MM, Weidmann M, Hunziker P (2015) Diagnosing dengue virus infection: rapid tests and the role of micro/nanotechnologies. Nanomed Nanotechnol Biol Med 11:1745–1761

    Article  CAS  Google Scholar 

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Acknowledgements

Authors wish to thank Marc Bossus, Celine Roesch, Michèle Guillote (Immunoassays department of bioMérieux) for antibody productions; Florence Bettworth, Blandine Le Levreur and Marie-Claire Cavaud (Immunoassays department of bioMérieux) for antibody purification and labeling. Special thanks to Maxime Combe and Fabien Fulmar for providing various raw materials. The final manuscript has been red and corrected by RWS life science, Lausane, CH.

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Authors and Affiliations

  1. BioMerieux, Innovations New Immuno-Concepts, Chemin de l’Orme, 69280, Marcy-l’Etoile, France

    G. Theillet, A. Rubens, F. Foucault, P. Dalbon, C. Rozand & F. Bedin

  2. ERRIT, HIA Laveran, 34 boulevard Laveran, 13013, Marseille, France

    G. Theillet & I. Leparc-Goffart

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  1. G. Theillet
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  2. A. Rubens
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  3. F. Foucault
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  4. P. Dalbon
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  6. I. Leparc-Goffart
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  7. F. Bedin
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Contributions

All of the authors contributed to the study conception. AR and FF carried out the PAD design and manufacturing. GT, AR and FB performed research. FB, GT and AR wrote the manuscript. All of the authors analyzed data, read, corrected and approved the final manuscript. FB, PD, ILG and CR performed the study coordination and funding.

Corresponding author

Correspondence to F. Bedin.

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Funding

This study was funded by BioMerieux SA and Agence Nationale de la Recherche et de la Technologie (G. Theillet’s grant CIFRE no 2015/0514).

Conflict of Interest

All the authors (except I. Leparc -Goffart) are employed by bioMerieux SA.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Handling Editor: Tim Skern.

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Theillet, G., Rubens, A., Foucault, F. et al. Laser-cut paper-based device for the detection of dengue non-structural NS1 protein and specific IgM in human samples. Arch Virol 163, 1757–1767 (2018). https://doi.org/10.1007/s00705-018-3776-z

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  • DOI: https://doi.org/10.1007/s00705-018-3776-z

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