Cell-Based Sensing

Cells on CMOS Chips

In collaboration with Pamela Abshire (ECE) and Ricardo Araneda (Department of Biology), and also with Anita Spetz (at (Linkoping University, Sweden) and the University of Oulu, Finland, we developed a number of cell-based sensors using custom CMOS chips.

The system hardware concept is shown here.  It consists of microfabricated structures on CMOS sensors and circuitry to allow in situ, real-time sensing, and highly parallel, automated measurements.  CMOS technology allows one to realize high density, high-performance arrays for detection combined with sophisticated on-chip signal processing. Vials on the surface of the CMOS chip will enclose different cell types positioned above sensor array.  The vials may require lids that open and close, depending on the type of cell and the type of measurement.  The chip is packaged to expose the center (approx. 2.5 mm x 2.5 mm) to cells and cell medium, but insulate the bond wires that connect the chip to the outside world.

The integrated system comprises:

• electrical or optical sensors
• circuitry for signal processing, control of temperature, lid position
• technology for loading a desired number and type of cell into a particular location
• microfluidics for introducing nutrients and taking away waste, and, for sensing applications, introducing stimulants
• packaging

For our olfactory sensory neuron based odorant work, the motivation was that biological olfactory sensors have, as yet, no equal in human-made devices.

• The binding event is amplified in the cell.
  Odorant binding activates a biochemical amplification that results in an action potential (AP). In mammals, OSNs contain an olfactory-specific G-protein (Golf), tens of which are activated upon odorant binding. In turn, this activates adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) into a neurotransmitter, cyclic AMP (cAMP). A single activated enzyme can convert a large number of ATPs (1000/second). The increase in cAMP opens ion channels that permit Na+ and Ca2+ to enter the cell, depolarizing the neuron and triggering an AP, which can readily be detected extracellularly.

• Use of OSNs provides a large dynamic range due to adaptation.
  OSNs “adapt” and reduce the rate of action potentials in response to the continued presence of an odorant. Adaptation occurs because of: (1) increased Ca2+ binding by the protein calmodulin, decreasing the sensitivity of the channel to cAMP; and (2) the extrusion of Ca2+ through the activation of Na+/Ca2+ exchange proteins that reduce the amplitude of the receptor potential.

• The cells provide the “infrastructure” for maintaining the receptors.
  Cells regulate and repair themselves to maintain normal function (homeostasis).

• OSNs produce an electrical signal (action potential) upon odorant binding.
  These signal can be detected extra-cellularly, and the number of APs is correlated with the odorant concentration.

For further information, see:

• T. Datta-Chaudhuri, P. Abshire, and E. Smela, "Packaging commercial CMOS chips for lab on a chip integration," Lab Chip, 14 (10), 1753 - 1766 (2014).
• T. Datta-Chaudhuri, N. Halonen, A. Hassinen, P. Möller, S. Kellokumpu, P. Abshire, A. Lloyd-Spetz, and E. Smela, "Integration of CMOS chips into LOCs for cell-based sensing" in Biosensors 2014 (Melbourne, Australia, 2014).
• T. Datta-Chaudhuri, P. Abshire, and E. Smela, "System-on-chip considerations for CMOS fluidic and biointerface applications," 2014 IEEE International Symposium on Circuits and Systems (ISCAS 2014), special session Complexity in Heterogeneous Systems on Chip: Analysis and Design Techniques, Melbourne, Australia, vol. ISCAS 2014, p. 2009 - 2012 ( June 1-5, 2014).
• M. Dandin, P. Abshire, and E. Smela, "Polymer filters for ultraviolet-excited integrated fluorescence sensing," J. Micromech. Microeng., 22, 095018 (2012).
• M. Dandin, I. D. Jung, M. Piyasena, J. Gallagher, N. Nelson, M. Urdaneta, C. Artis, P. Abshire, and E. Smela, "Post-CMOS packaging methods for integrated biosensors," 8th IEEE Conference on Sensors (IEEE Sensors), Christchurch, New Zealand, (IEEE), p. 795 - 798 (Oct. 25 - 28, 2009).
• S. B. Prakash, M. Urdaneta, M. Christophersen, E. Smela, and P. Abshire, "In situ electrochemical control of electroactive polymer films on a CMOS chip," Sens. Act. B, 129 (2), 699-704 (2008).
• M. Dandin, P. Abshire, and E. Smela, "Optical filtering technologies for integrated fluorescence sensors," Lab Chip, 7 (8), 955-977 (2007).
  
• N. Reeves, Y. Liu, N. M. Nelson, S. Malhotra, M. Loganathan, J.-M. Lauenstein, J. Chaiyupatumpa, E. Smela, and P. Abshire, "Integrated MEMS structures and CMOS circuitry for bioelectronic interface with single cells," IEEE Int. Symp. Circuits and Systems (ISCAS04), Vancouver, BC, Canada, vol. 3, p. 673-676 (May 23-26, 2004).
• E. Smela, M. Christophersen, S. B. Prakash, M. Urdaneta, M. Dandin, and P. Abshire, "Integrated cell-based sensors and cell clinics utilizing conjugated polymer actuators," SPIE 14th Annual Int'l. Symposium on Smart Structures and Materials, Electroactive Polymer Actuators and Devices (EAPAD), San Diego, CA, (SPIE), vol. 6524, edited by Y. Bar-Cohen, p. 0G 1-10 (2007).
• M. Urdaneta, M. Christophersen, E. Smela, S. B. Prakash, N. Nelson, A. M. Haas, V. Jeng, and P. Abshire, "Cell clinics technology platform for cell sensing," IEEE/NLM Life Science Systems & Applications Workshop, Bethesda, MD (July 13-14, 2006).
• S. B. Prakash, N. M. Nelson, A. M. Haas, V. Jeng, P. Abshire, M. Urdaneta, and E. Smela, "Biolabs-on-a-chip: monitoring cells using CMOS biosensors," Proc. IEEE/NLM Life Science Systems & Applications Workshop, Bethesda, MD (July 13-14, 2006).
• M. Urdaneta, Y. Liu, M. Christophersen, S. Prakash, P. Abshire, and E. Smela, "Integrating conjugated polymer microactuators with CMOS sensing circuitry for studying living cells," SPIE's 12th Annual Int'l. Symp. Smart Structures and Materials, EAPAD, San Diego, CA, vol. 5759, edited by Y. Bar-Cohen, p. 232-240 (March 7-10, 2005).
• N. Reeves, Y. Liu, N. M. Nelson, S. Malhotra, M. Loganathan, J.-M. Lauenstein, J. Chaiyupatumpa, E. Smela, and P. Abshire, "Integrated MEMS structures and CMOS circuitry for bioelectronic interface with single cells," IEEE Int. Symp. Circuits and Systems (ISCAS04), Vancouver, BC, Canada, vol. 3, p. 673-676 (May 23-26, 2004).
• P. Abshire, J.-M. Lauenstein, Y. Liu, and E. Smela, "Cell clinics for bioelectronic interface with single cells," IEEE Int. Symp. Circuits and Systems (ISCAS03), Bangkok, Thailand (May 25-28, 2003).