We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

Ultrasensitive bioanalysis: current status and future trends

    Stéphanie Simon

    Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, Université Paris-Saclay, F-91191 Gif-sur-Yvette, France

    &
    Eric Ezan

    *Author for correspondence:

    E-mail Address: eric.ezan@cea.fr

    Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, Université Paris-Saclay, F-91191 Gif-sur-Yvette, France

    Published Online:https://doi.org/10.4155/bio-2017-0018

    Ligand-binding techniques such as immunoassays, the reference for clinical diagnosis, offer a wide range of innovative approaches based on signal DNA amplification, nanotechnologies or digital assays, which result in technologies with sensitivities more than 1000-times that of formats used 20 years ago. Providing that these technologies gain acceptance and translate into robust commercial platforms, we expect that several fields will be impacted in the near future, including the clinical diagnosis of cancer markers, the early detection of infectious diseases and the safety of biotherapeutics. Furthermore, the combination of these techniques with microfluidic systems will allow probing of biological diversity at the single cell level and will lead to the discovery of novel and rare biomarkers.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Yalow RS, Berson SA. Immunoassay of endogenous plasma insulin in man. J. Clin. Invest. 39, 1157–1175 (1960).
    • 2 Hawkridge AM, Heublein DM, Bergen HR, Cataliotti A, Burnett JC, Muddiman DC. Quantitative mass spectral evidence for the absence of circulating brain natriuretic peptide (BNP-32) in severe human heart failure. Proc. Natl Acad. Sci. USA 102(48), 17442–17447 (2005).
    • 3 Sapin R. Insulin immunoassays: fast approaching 50 years of existence and still calling for standardization. Clin. Chem. 53(5), 810–812 (2007).
    • 4 Sano T, Smith CL, Cantor CR. Immuno-PCR: very sensitive antigen detection by means of specific antibody–DNA conjugates. Science 258(5079), 120–122 (1992).
    • 5 Piraino F, Volpetti F, Watson C, Maerkl SJ. A digital–analog microfluidic platform for patient-centric multiplexed biomarker diagnostics of ultralow volume samples. ACS Nano 10(1), 1699–1710 (2016). • A review of the potential of microfluidics and digital assays for biomarker diagnostic.
    • 6 Ahn S, Zhang P, Yu H, Lee S, Kang SH. Ultrasensitive detection of α-fetoprotein by total internal reflection scattering-based super-resolution microscopy for superlocalization of nano-immunoplasmonics. Anal. Chem. 88(22), 11070–11076 (2016). •• An extraordinary sensitivity at 10 zM achieved for α-fetoprotein using nanoimmunoplasmonic and microscopy.
    • 7 Spengler M, Adler M, Jonas A, Niemeyer CM. Immuno-PCR assays for immunogenicity testing. Biochem. Biophys. Res. Commun. 387(2), 278–282 (2009). • Describes the potential application of immuno-PCR in the evaluation of drug safety through immunogenicity testing.
    • 8 Khan AH, Sadroddiny E. Application of immuno-PCR for the detection of early stage cancer. Mol. Cell. Probes 30(2), 106–112 (2016).
    • 9 Fischer SK, Joyce A, Spengler M et al. Emerging technologies to increase ligand binding assay sensitivity. AAPS J. 17(1), 93–101 (2015).
    • 10 Cretich M, Daaboul GG, Sola L, Ünlü MS, Chiari M. Digital detection of biomarkers assisted by nanoparticles: application to diagnostics. Trends Biotechnol. 33(6), 343–351 (2015).
    • 11 Anderson NL. The clinical plasma proteome: a survey of clinical assays for proteins in plasma and serum. Clin. Chem. 56(2), 177–185 (2010).
    • 12 Pavlou MP, Diamandis EP, Blasutig IM. The long journey of cancer biomarkers from the bench to the clinic. Clin. Chem. 59(1), 147–157 (2013).
    • 13 Polanski M, Anderson NL. A list of candidate cancer biomarkers for targeted proteomics. Biomark. Insights 1, 1–48 (2007).
    • 14 Rhea JM, Molinaro RJ. Cancer biomarkers: surviving the journey from bench to bedside. MLO Med. Lab. Obs. 43(3), 10–22 (2011).
    • 15 Chang L, Li J, Wang L. Immuno-PCR: an ultrasensitive immunoassay for biomolecular detection. Anal. Chim. Acta 910, 12–24 (2016).
    • 16 Sokoll LJ, Zhang Z, Chan DW et al. Do ultrasensitive prostate specific antigen measurements have a role in predicting long-term biochemical recurrence-free survival in men after radical prostatectomy? J. Urol. 195(2), 330–336 (2016).
    • 17 Ezan E, Bitsch F. Critical comparison of MS and immunoassays for the bioanalysis of therapeutic antibodies. Bioanalysis 1(8), 1375–1388 (2009).
    • 18 Duriez E, Armengaud J, Fenaille F, Ezan E. Mass spectrometry for the detection of bioterrorism agents: from environmental to clinical applications. J. Mass Spectrom. 51(3), 183–199 (2016).
    • 19 Lasne F, de Ceaurriz J. Recombinant erythropoietin in urine. Nature 405(6787), 635 (2000).
    • 20 Grassi J, Créminon C, Frobert Y et al. Two different approaches for developing immunometric assays of haptens. Clin. Chem. 42(9), 1532–1536 (1996). • A description for a sandwich immunoassay for a small-molecular-weight analyte (angiotensin II).
    • 21 Hashida S, Hashinaka K, Ishikawa E. Ultrasensitive enzyme immunoassay. Biotechnol. Annu. Rev. 1, 403–451 (1995).
    • 22 Volland H, Pradelles P, Taran F, Buscarlet L, Creminon C. Recent developments for SPIE-IA, a new sandwich immunoassay format for very small molecules. J. Pharm. Biomed. Anal. 34(4), 737–752 (2004).
    • 23 Du L, Ji W, Zhang Y, Zhang C, Liu G, Wang S. An ultrasensitive detection of 17β-estradiol using a gold nanoparticle-based fluorescence immunoassay. Analyst 140(6), 2001–2007 (2015).
    • 24 Huang X, Zhan S, Xu H, Meng X, Xiong Y, Chen X. Ultrasensitive fluorescence immunoassay for detection of ochratoxin A using catalase-mediated fluorescence quenching of CdTe QDs. Nanoscale 8(17), 9390–9397 (2016).
    • 25 Jackson TM, Ekins RP. Theoretical limitations on immunoassay sensitivity. Current practice and potential advantages of fluorescent Eu3+ chelates as non-radioisotopic tracers. J. Immunol. Methods 87(1), 13–20 (1986).
    • 26 Saiki RK, Scharf S, Faloona F et al. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230(4732), 1350–1354 (1985).
    • 27 Zhang J, Vernes JM, Ni J et al. Real-time immuno-polymerase chain reaction in a 384-well format: detection of vascular endothelial growth factor and epidermal growth factor-like domain 7. Anal. Biochem. 463, 61–66 (2014).
    • 28 Yin H, Jia M, Shi L et al. Evaluation of a novel ultra-sensitive nanoparticle probe-based assay for ricin detection. J. Immunotoxicol. 11(3), 291–295 (2014).
    • 29 Jani D, Savino E, Goyal J. Feasibility of immuno-PCR technology platforms as an ultrasensitive tool for the detection of anti-drug antibodies. Bioanalysis 7(3), 285–294 (2015).
    • 30 Gaudet D, Nilsson D, Lohr T, Sheedy C. Development of a real-time immuno-PCR assay for the quantification of 17β-estradiol in water. J. Environ. Sci. Health B 50(10), 683–690 (2015).
    • 31 Yang GX, Zhuang HS, Chen HY, Ping XY, Bu D. A sensitive immunosorbent bio-barcode assay based on real-time immuno-PCR for detecting 3,4,3′,4′-tetrachlorobiphenyl. Anal. Bioanal. Chem. 406(6), 1693–1700 (2014).
    • 32 Partyka K, Wang S, Zhao P, Cao B, Haab B. Array-based immunoassays with rolling-circle amplification detection. Methods Mol. Biol. 1105, 3–15 (2014).
    • 33 Wang P, Jin B, Xing Y et al. Rolling circle amplification immunoassay combined with gold nanoparticle aggregates for colorimetric detection of protein. J. Nanosci. Nanotechnol. 14(8), 5662–5668 (2014).
    • 34 Yan J, Hu C, Wang P et al. Novel rolling circle amplification and DNA origami-based DNA belt-involved signal amplification assay for highly sensitive detection of prostate-specific antigen (PSA). ACS Appl. Mater. Interfaces 6(22), 20372–20377 (2014).
    • 35 Fredriksson S, Gullberg M, Jarvius J et al. Protein detection using proximity-dependent DNA ligation assays. Nat. Biotechnol. 20(5), 473–477 (2002).
    • 36 Lundberg M, Eriksson A, Tran B, Assarsson E, Fredriksson S. Homogeneous antibody-based proximity extension assays provide sensitive and specific detection of low-abundant proteins in human blood. Nucleic Acids Res. 39(15), e102 (2011).
    • 37 Malhotra R, Patel V, Chikkaveeraiah BV et al. Ultrasensitive detection of cancer biomarkers in the clinic by use of a nanostructured microfluidic array. Anal. Chem. 84(14), 6249–6255 (2012). • A typical example of ultrasensitivity obtained with nanotechnologies.
    • 38 Sanders M, Lin Y, Wei J, Bono T, Lindquist RG. An enhanced LSPR fiber-optic nanoprobe for ultrasensitive detection of protein biomarkers. Biosens. Bioelectron. 61, 95–101 (2014).
    • 39 Rong Z, Wang C, Wang J, Wang D, Xiao R, Wang S. Magnetic immunoassay for cancer biomarker detection based on surface-enhanced resonance Raman scattering from coupled plasmonic nanostructures. Biosens. Bioelectron. 84, 15–21 (2016).
    • 40 Huang X, Xu Z, Mao Y et al. Gold nanoparticle-based dynamic light scattering immunoassay for ultrasensitive detection of Listeria monocytogenes in lettuces. Biosens. Bioelectron. 66, 184–190 (2015).
    • 41 Han JH, Sudheendra L, Kim HJ, Gee SJ, Hammock BD, Kennedy IM. Ultrasensitive on-chip immunoassays with a nanoparticle-assembled photonic crystal. ACS Nano 6(10), 8570–8582 (2012).
    • 42 Zhao Y, Cao M, McClelland JF, Shao Z, Lu M. A photoacoustic immunoassay for biomarker detection. Biosens. Bioelectron. 85, 261–266 (2016).
    • 43 Wen W, Yan X, Zhu C, Du D, Lin Y. Recent advances in electrochemical immunosensors. Anal. Chem. 89(1), 138–156 (2017).
    • 44 Gong L, Dai H, Zhang S, Lin Y. Silver iodide–chitosan nanotag induced biocatalytic precipitation for self-enhanced ultrasensitive photocathodic immunosensor. Anal. Chem. 88(11), 5775–5782 (2016).
    • 45 Ge Y, Wu J, Ju H, Wu S. Ultrasensitive enzyme-free electrochemical immunosensor based on hybridization chain reaction triggered double strand DNA@Au nanoparticle tag. Talanta 120, 218–223 (2014).
    • 46 Han J, Zhuo Y, Chai Y et al. Ultrasensitive electrochemical strategy for trace detection of APE-1 via triple signal amplification strategy. Biosens. Bioelectron. 41, 116–122 (2013).
    • 47 Wang GL, Shu JX, Dong YM, Wu XM, Li ZJ. An ultrasensitive and universal photoelectrochemical immunoassay based on enzyme mimetics enhanced signal amplification. Biosens. Bioelectron. 66, 283–289 (2015).
    • 48 Tong L, Wu J, Li J, Ju H, Yan F. Hybridization chain reaction engineered DNA nanopolylinker for amplified electrochemical sensing of biomarkers. Analyst 138(17), 4870–4876 (2013).
    • 49 Zhong Z, Li M, Qing Y et al. Signal-on electrochemical immunoassay for APE1 using ionic liquid doped Au nanoparticle/graphene as a nanocarrier and alkaline phosphatase as enhancer. Analyst 139(24), 6563–6568 (2014).
    • 50 Liu D, Yang J, Wang HF et al. Glucose oxidase-catalyzed growth of gold nanoparticles enables quantitative detection of attomolar cancer biomarkers. Anal. Chem. 86(12), 5800–5806 (2014).
    • 51 de la Rica R, Stevens MM. Plasmonic ELISA for the ultrasensitive detection of disease biomarkers with the naked eye. Nat. Nanotechnol. 7(12), 821–824 (2012).
    • 52 Lin D, Wu J, Ju H, Yan F. Nanogold/mesoporous carbon foam-mediated silver enhancement for graphene-enhanced electrochemical immunosensing of carcinoembryonic antigen. Biosens. Bioelectron. 52, 153–158 (2014).
    • 53 Zhang H, Li W, Sheng Z, Han H, He Q. Ultrasensitive detection of porcine circovirus type 2 using gold(III) enhanced chemiluminescence immunoassay. Analyst 135(7), 1680–1685 (2010).
    • 54 Wang H, Li G, Zhang Y et al. Nanobody-based electrochemical immunoassay for ultrasensitive determination of apolipoprotein-A1 using silver nanoparticles loaded nanohydroxyapatite as label. Anal. Chem. 87(22), 11209–11214 (2015).
    • 55 Witters D, Sun B, Begolo S, Rodriguez-Manzano J, Robles W, Ismagilov RF. Digital biology and chemistry. Lab Chip 14(17), 3225–3232 (2014).
    • 56 Zhang Y, Noji H. Digital bioassays: theory, applications, and perspectives. Anal. Chem. 89(1), 92–101 (2017). •• An exhaustive review of digital assays.
    • 57 Rissin DM, Kan CW, Campbell TG et al. Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat. Biotechnol. 28(6), 595–599 (2010). •• The first experimental paper describing the digital single-molecule enzyme-linked immunoassay technology.
    • 58 Chang L, Rissin DM, Fournier DR et al. Single molecule enzyme-linked immunosorbent assays: theoretical considerations. J. Immunol. Methods 378(1–2), 102–115 (2012).
    • 59 Schubert SM, Arendt LM, Zhou W et al. Ultra-sensitive protein detection via single molecule arrays towards early stage cancer monitoring. Sci. Rep. 5, 11034 (2015).
    • 60 Song L, Lachno DR, Hanlon D et al. A digital enzyme-linked immunosorbent assay for ultrasensitive measurement of amyloid-β 1–42 peptide in human plasma with utility for studies of Alzheimer’s disease therapeutics. Alzheimers Res. Ther. 8(1), 58 (2016).
    • 61 Pleil JD, Angrish MM, Madden MC. Immunochemistry for high-throughput screening of human exhaled breath condensate (EBC) media: implementation of automated Quanterix SIMOA instrumentation. J. Breath Res. 9(4), 47108 (2015).
    • 62 Leirs K, Tewari Kumar P, Decrop D et al. Bioassay development for ultrasensitive detection of influenza a nucleoprotein using digital ELISA. Anal. Chem. 88(17), 8450–8458 (2016).
    • 63 Gaylord ST, Abdul-Aziz S, Walt DR. Single-molecule arrays for ultrasensitive detection of host immune response to dengue virus infection. J. Clin. Microbiol. 53(5), 1722–1724 (2015).
    • 64 Wilson DH, Rissin DM, Kan CW et al. The Simoa HD-1 analyzer: a novel fully automated digital immunoassay analyzer with single-molecule sensitivity and multiplexing. J. Lab. Autom. 21(4), 533–547 (2016).
    • 65 Gilbert M, Livingston R, Felberg J, Bishop JJ. Multiplex single molecule counting technology used to generate interleukin 4, interleukin 6, and interleukin 10 reference limits. Anal. Biochem. 503, 11–20 (2016).
    • 66 Yang T, O’Malley TT, Kanmert D et al. A highly sensitive novel immunoassay specifically detects low levels of soluble Aβ oligomers in human cerebrospinal fluid. Alzheimers Res. Ther. 7(1), 14 (2015).
    • 67 Schultze AE, Anderson JM, Kern TG et al. Longitudinal studies of cardiac troponin I concentrations in serum from male cynomolgus monkeys: resting values and effects of oral and intravenous dosing on biologic variability. Vet. Clin. Pathol. 44(3), 465–471 (2015).
    • 68 Yeung D, Ciotti S, Purushothama S et al. Evaluation of highly sensitive immunoassay technologies for quantitative measurements of sub-pg/ml levels of cytokines in human serum. J. Immunol. Methods 437, 53–63 (2016).
    • 69 Yang CT, Wu L, Liu X et al. Exploiting surface-plasmon-enhanced light scattering for the design of ultrasensitive biosensing modality. Anal. Chem. 88(23), 11924–11930 (2016).
    • 70 Dudal S, Baltrukonis D, Crisino R et al. Assay formats: recommendation for best practices and harmonization from the global bioanalysis consortium harmonization team. AAPS J. 16(2), 194–205 (2014).
    • 71 Macaulay IC, Ponting CP, Voet T. Single-cell multiomics: multiple measurements from single cells. Trends Genet. 33(2), 155–168 (2017).
    • 72 Rebelo TSCR, Noronha JP, Galésio M et al. Testing the variability of PSA expression by different human prostate cancer cell lines by means of a new potentiometric device employing molecularly antibody assembled on graphene surface. Mater. Sci. Eng. C Mater. Biol. Appl. 59, 1069–1078 (2016).