Analytical and Bioanalytical Chemistry

, Volume 398, Issue 4, pp 1591–1603 | Cite as

Digital biosensors with built-in logic for biomedical applications—biosensors based on a biocomputing concept

  • Joseph WangEmail author
  • Evgeny KatzEmail author


This article reviews biomolecular logic systems for bioanalytical applications, specifically concentrating on the prospects and fundamental and practical challenges of designing digitally operating biosensors logically processing multiple biochemical signals. Such digitally processed information produces a final output in the form of a yes/no response through Boolean logic networks composed of biomolecular systems, and hence leads to a high-fidelity biosensing compared with traditional single (or parallel) sensing devices. It also allows direct coupling of the signal processing with chemical actuators to produce integrated “smart” “sense/act” (biosensor-bioactuator) systems. Unlike common biosensing devices based on a single input (analyte), devices based on biochemical logic systems require a fundamentally new approach for the sensor design and operation and careful attention to the interface of biocomputing systems and electronic transducers. As common in conventional biosensors, the success of the enzyme logic biosensor would depend, in part, on the immobilization of the biocomputing reagent layer. Such surface confinement provides a contact between the biocomputing layer and the transducing surface and combines efficiently the individual logic-gate elements. Particular attention should thus be given to the composition, preparation, and immobilization of the biocomputing surface layer, to the role of the system scalability, and to the efficient transduction of the output signals. By processing complex patterns of multiple physiological markers, such multisignal digital biosensors should have a profound impact upon the rapid diagnosis and treatment of diseases, and particularly upon the timely detection and alert of medical emergencies (along with immediate therapeutic intervention). Other fields ranging from biotechnology to homeland security would benefit from these advances in new biocomputing biosensors and the corresponding closed-loop “add/act” operation.


Biochemical computing and logic-gate systems based on biomolecules have the potential to revolutionize the field of biosensors. This article reviews the prospects, fundamental and practical challenges of designing digitally operating biosensors logically processing multiple biochemical signals.


Biosensor Biocomputing Biomolecular computing Logic gate Logic network Enzyme Biomedical application Electrode 



This research was supported by the National Science Foundation (grants DMR-0706209, CCF-0726698), by ONR (grant N00014-08-1-1202), and by the Semiconductor Research Corporation (award 2008-RJ-1839G).


  1. 1.
    De Silva AP, Uchiyama S, Vance TP, Wannalerse B (2007) Coord Chem Rev 251:1623–1632CrossRefGoogle Scholar
  2. 2.
    De Silva AP, Uchiyama S (2007) Nat Nanotechnol 2:399–410CrossRefGoogle Scholar
  3. 3.
    Szacilowski K (2008) Chem Rev 108:3481–3548CrossRefGoogle Scholar
  4. 4.
    Credi A (2007) Angew Chem Int Ed 46:5472–5475CrossRefGoogle Scholar
  5. 5.
    Calude CS, Costa JF, Dershowitz N, Freire E, Rozenberg G (eds) (2009) Unconventional computation. Lecture notes in computer science, vol 5715. Springer, BerlinGoogle Scholar
  6. 6.
    De Silva AP, Gunaratne HQN, McCoy CP (1993) Nature 364:42–44CrossRefGoogle Scholar
  7. 7.
    De Silva AP, Gunaratne HQN, McCoy CP (1997) J Am Chem Soc 119:7891–7892CrossRefGoogle Scholar
  8. 8.
    De Silva AP, Gunaratne HQN, Maguire GEM (1994) J Chem Soc Chem Commun 1213–1214Google Scholar
  9. 9.
    Credi A, Balzani V, Langford SJ, Stoddart JF (1997) J Am Chem Soc 119:2679–2681CrossRefGoogle Scholar
  10. 10.
    De Silva AP, McClenaghan ND (2002) Chem Eur J 8:4935–4945CrossRefGoogle Scholar
  11. 11.
    De Silva AP, Dixon IM, Gunaratne HQN, Gunnlaugsson T, Maxwell PRS, Rice TE (1999) J Am Chem Soc 121:1393–1394CrossRefGoogle Scholar
  12. 12.
    Straight SD, Liddell PA, Terazono Y, Moore TA, Moore AL, Gust D (2007) Adv Funct Mater 17:777–785CrossRefGoogle Scholar
  13. 13.
    Turfan B, Akkaya EU (2002) Org Lett 4:2857–2859CrossRefGoogle Scholar
  14. 14.
    Wang ZX, Zheng GR, Lu P (2005) Org Lett 7:3669–3672CrossRefGoogle Scholar
  15. 15.
    Baytekin HT, Akkaya EU (2000) Org Lett 2:1725–1727CrossRefGoogle Scholar
  16. 16.
    Zong G, Xiana L, Lua G (2007) Tetrahedron Lett 48:3891–3894CrossRefGoogle Scholar
  17. 17.
    Gunnlaugsson T, MacDónaill DA, Parker D (2001) J Am Chem Soc 123:12866–12876CrossRefGoogle Scholar
  18. 18.
    Gunnlaugsson T, MacDónaill DA, Parker D (2000) Chem Commun 93–94Google Scholar
  19. 19.
    De Sousa M, De Castro B, Abad S, Miranda MA, Pischel U (2006) Chem Commun 2051–2053Google Scholar
  20. 20.
    Li L, Yu M-X, Li FY, Yi T, Huang CH (2007) Colloids Surf A 304:49–53CrossRefGoogle Scholar
  21. 21.
    Luxami V, Kumar S (2008) New J Chem 32:2074–2079CrossRefGoogle Scholar
  22. 22.
    Qian JH, Qian XH, Xu YF, Zhang SY (2008) Chem Commun 4141–4143Google Scholar
  23. 23.
    Wagner N, Ashkenasy G (2009) Chem Eur J 15:1765–1775CrossRefGoogle Scholar
  24. 24.
    Pischel U (2007) Angew Chem Int Ed 46:4026–4040CrossRefGoogle Scholar
  25. 25.
    Brown GJ, De Silva AP, Pagliari S (2002) Chem Commun 2461–2463Google Scholar
  26. 26.
    Qu D-H, Wang Q-C, Tian H (2005) Angew Chem Int Ed 44:5296–5299CrossRefGoogle Scholar
  27. 27.
    Andréasson J, Straight SD, Kodis G, Park C-D, Hambourger M, Gervaldo M, Albinsson B, Moore TA, Moore AL, Gust D (2006) J Am Chem Soc 128:16259–16265CrossRefGoogle Scholar
  28. 28.
    Andréasson J, Kodis G, Terazono Y, Liddell PA, Bandyopadhyay S, Mitchell RH, Moore TA, Moore AL, Gust D (2004) J Am Chem Soc 126:15926–15927CrossRefGoogle Scholar
  29. 29.
    Lopez MV, Vazquez ME, Gomez-Reino C, Pedrido R, Bermejo MR (2008) New J Chem 32:1473–1477CrossRefGoogle Scholar
  30. 30.
    Margulies D, Melman G, Shanzer A (2006) J Am Chem Soc 128:4865–4871CrossRefGoogle Scholar
  31. 31.
    Kuznetz O, Salman H, Shakkour N, Eichen Y, Speiser S (2008) Chem Phys Lett 451:63–67CrossRefGoogle Scholar
  32. 32.
    Katz E, Privman V (2010) Chem Soc Rev 39:1835–1857Google Scholar
  33. 33.
    Sivan S, Tuchman S, Lotan N (2003) Biosystems 70:21–33CrossRefGoogle Scholar
  34. 34.
    Unger R, Moult J (2006) Proteins 63:53–64CrossRefGoogle Scholar
  35. 35.
    Stojanovic MN, Stefanovic D, LaBean T, Yan H (2005) In: Willner I, Katz E (eds) Bioelectronics: from theory to applications. Wiley-VCH, Weinheim, pp 427–455Google Scholar
  36. 36.
    Win MN, Smolke CD (2008) Science 322:456–460CrossRefGoogle Scholar
  37. 37.
    Simpson ML, Sayler GS, Fleming JT, Applegate B (2001) Trends Biotechnol 19:317–323CrossRefGoogle Scholar
  38. 38.
    Baron R, Lioubashevski O, Katz E, Niazov T, Willner I (2006) J Phys Chem A 110:8548–8553CrossRefGoogle Scholar
  39. 39.
    Strack G, Pita M, Ornatska M, Katz E (2008) Chembiochem 9:1260–1266CrossRefGoogle Scholar
  40. 40.
    Privman V, Pedrosa V, Melnikov D, Pita M, Simonian A, Katz E (2009) Biosens Bioelectron 25:695–701CrossRefGoogle Scholar
  41. 41.
    Zhou J, Arugula MA, Halámek J, Pita M, Katz E (2009) J Phys Chem B 113:16065–16070CrossRefGoogle Scholar
  42. 42.
    Baron R, Lioubashevski O, Katz E, Niazov T, Willner I (2006) Angew Chem Int Ed 45:1572–1576CrossRefGoogle Scholar
  43. 43.
    Niazov T, Baron R, Katz E, Lioubashevski O, Willner I (2006) Proc Natl Acad Sci USA 103:17160–17163CrossRefGoogle Scholar
  44. 44.
    Privman V, Arugula MA, Halámek J, Pita M, Katz E (2009) J Phys Chem B 113:5301–5310CrossRefGoogle Scholar
  45. 45.
    Tam TK, Pita M, Katz E (2009) Sens Actuators B 140:1–4CrossRefGoogle Scholar
  46. 46.
    Tokarev I, Gopishetty V, Zhou J, Pita M, Motornov M, Katz E, Minko S (2009) ACS Appl Mater Interfaces 1:532–536CrossRefGoogle Scholar
  47. 47.
    Motornov M, Zhou J, Pita M, Tokarev I, Gopishetty V, Katz E, Minko S (2009) Small 5:817–820CrossRefGoogle Scholar
  48. 48.
    Pita M, Minko S, Katz E (2009) J Mater Sci Mater Med 20:457–462CrossRefGoogle Scholar
  49. 49.
    Pita M, Krämer M, Zhou J, Poghossian A, Schöning MJ, Fernández VM, Katz E (2008) ACS Nano 2:2160–2166CrossRefGoogle Scholar
  50. 50.
    Motornov M, Zhou J, Pita M, Gopishetty V, Tokarev I, Katz E, Minko S (2008) Nano Lett 8:2993–2997CrossRefGoogle Scholar
  51. 51.
    Krämer M, Pita M, Zhou J, Ornatska M, Poghossian A, Schöning MJ, Katz E (2009) J Phys Chem C 113:2573–2579CrossRefGoogle Scholar
  52. 52.
    Zhou J, Tam TK, Pita M, Ornatska M, Minko S, Katz E (2009) ACS Appl Mater Interfaces 1:144–149CrossRefGoogle Scholar
  53. 53.
    Privman M, Tam TK, Pita M, Katz E (2009) J Am Chem Soc 131:1314–1321CrossRefGoogle Scholar
  54. 54.
    Wang X, Zhou J, Tam TK, Katz E, Pita M (2009) Bioelectrochemistry 77:69–73CrossRefGoogle Scholar
  55. 55.
    Katz E, Pita M (2009) Chem Eur J 15:12554–12564CrossRefGoogle Scholar
  56. 56.
    Amir L, Tam TK, Pita M, Meijler MM, Alfonta L, Katz E (2009) J Am Chem Soc 131:826–832CrossRefGoogle Scholar
  57. 57.
    Tam TK, Pita M, Ornatska M, Katz E (2009) Bioelectrochemistry 76:4–9CrossRefGoogle Scholar
  58. 58.
    Margulies D, Hamilton AD (2009) J Am Chem Soc 131:9142–9143CrossRefGoogle Scholar
  59. 59.
    Szacilowski K (2007) Biosystems 90:738–749CrossRefGoogle Scholar
  60. 60.
    Ezziane Z (2006) Nanotechnology 17:R27–R39CrossRefGoogle Scholar
  61. 61.
    Adar R, Benenson Y, Linshiz G, Rosner A, Tishby N, Shapiro E (2004) Proc Natl Acad Sci USA 101:9960–9965CrossRefGoogle Scholar
  62. 62.
    Simmel FC (2007) Nanomedicine 2:817–830CrossRefGoogle Scholar
  63. 63.
    May EE, Dolan PL, Crozier PS, Brozik S, Manginell M (2008) IEEE Sens J 8:1011–1019CrossRefGoogle Scholar
  64. 64.
    von Maltzahn G, Harris TJ, Park J-H, Min D-H, Schmidt AJ, Sailor MJ, Bhatia SN (2007) J Am Chem Soc 129:6064–6065CrossRefGoogle Scholar
  65. 65.
    Pita M, Strack G, MacVittie K, Zhou J, Katz E (2009) J Phys Chem B 113:16071–16076CrossRefGoogle Scholar
  66. 66.
    Tomizaki K, Mihara H (2007) J Am Chem Soc 129:8345–8352CrossRefGoogle Scholar
  67. 67.
    Konry T, Walt DR (2009) J Am Chem Soc 131:13232–13233CrossRefGoogle Scholar
  68. 68.
    LaVan DA, McGuire T, Langer R (2003) Nat Biotechnol 21:1184–1191CrossRefGoogle Scholar
  69. 69.
    Wang J (2008) Talanta 75:636–641CrossRefGoogle Scholar
  70. 70.
    Heller A (2005) AIChE J 51:1054–1061CrossRefGoogle Scholar
  71. 71.
    Wang J (2008) Chem Rev 108:814–825CrossRefGoogle Scholar
  72. 72.
    Melnikov D, Strack G, Pita M, Privman V, Katz E (2009) J Phys Chem B 113:10472–10479CrossRefGoogle Scholar
  73. 73.
    Privman V, Strack G, Solenov D, Pita M, Katz E (2008) J Phys Chem B 112:11777–11784CrossRefGoogle Scholar
  74. 74.
    Strack G, Ornatska M, Pita M, Katz E (2008) J Am Chem Soc 130:4234–4235CrossRefGoogle Scholar
  75. 75.
    Pita M, Zhou J, Manesh KM, Halámek J, Katz E, Wang J (2009) Sens Actuators B 139:631–636CrossRefGoogle Scholar
  76. 76.
    Manesh KM, Halámek J, Pita M, Zhou J, Tam TK, Santhosh P, Chuang M-C, Windmiller JR, Abidin D, Katz E, Wang J (2009) Biosens Bioelectron 24:3569–3574CrossRefGoogle Scholar
  77. 77.
    Kline JA, Maiorano PC, Schroeder JD, Grattan RM, Vary TC, Watts JA (1997) J Mol Cell Cardiol 29:2465–2474CrossRefGoogle Scholar
  78. 78.
    Zink BJ, Schultz CH, Wang X, Mertz M, Stern SA, Betz AL (1999) Brain Res 837:1–7CrossRefGoogle Scholar
  79. 79.
    Prasad MR, Ramaiah C, McIntosh TK, Dempsey RJ, Hipkeos S, Yurek D (1994) J Neurochem 63:1086–1094CrossRefGoogle Scholar
  80. 80.
    Rosenberg JC, Lillehei RC, Longerbean J, Zini-Nierinann B (1961) Ann Surg 154:611–627CrossRefGoogle Scholar
  81. 81.
    Katz E, Privman E, Wang J (2010) In: Proceedings of the fourth international conference on quantum, nano and micro technologies (ICQNM 2010), February 10–16, 2010, St. Maarten, Netherlands Antilles, pp 1–9Google Scholar
  82. 82.
    Wang J (2005) Small 1:1063–1068CrossRefGoogle Scholar
  83. 83.
    Scheller FW, Bauer CG, Makower A, Wollenberger U, Warsinke A, Bier FF (2001) Anal Lett 34:1233–1245CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of NanoEngineeringUniversity of California—San DiegoLa JollaUSA
  2. 2.Department of Chemistry and Biomolecular Science, and NanoBio Laboratory (NABLAB)Clarkson UniversityPotsdamUSA

Personalised recommendations