System-on-Chip Considerations for Heterogeneous Integration of CMOS and Fluidic Bio-Interfaces

CMOS chips are increasingly used for direct sensing and interfacing with fluidic and biological systems. While many biosensing systems have successfully combined CMOS chips for readout and signal processing with passive sensing arrays, systems that co-locate sensing with active circuits on a single chip offer significant advantages in size and performance but increase the complexity of multi-domain design and heterogeneous integration. This emerging class of lab-on-CMOS systems also poses distinct and vexing technical challenges that arise from the disparate requirements of biosensors and integrated circuits (ICs). Modeling these systems must address not only circuit design, but also the behavior of biological components on the surface of the IC and any physical structures. Existing tools do not support the cross-domain simulation of heterogeneous lab-on-CMOS systems, so we recommend a two-step modeling approach: using circuit simulation to inform physics-based simulation, and vice versa. We review the primary lab-on-CMOS implementation challenges and discuss practical approaches to overcome them. Issues include new versions of classical challenges in system-on-chip integration, such as thermal effects, floor-planning, and signal coupling, as well as new challenges that are specifically attributable to biological and fluidic domains, such as electrochemical effects, non-standard packaging, surface treatments, sterilization, microfabrication of surface structures, and microfluidic integration. We describe these concerns as they arise in lab-on-CMOS systems and discuss solutions that have been experimentally demonstrated.

[1]  N. Grassie,et al.  The thermal degradation of polysiloxanes—I. Poly(dimethylsiloxane) , 1978 .

[2]  Kevin J. Otto,et al.  Poly(3,4-ethylenedioxythiophene) as a Micro-Neural Interface Material for Electrostimulation , 2009, Front. Neuroeng..

[3]  Ritu Raj Singh,et al.  A hybrid CMOS-microfluidic contact imaging microsystem , 2009, NanoScience + Engineering.

[4]  David Sander,et al.  Mismatch reduction for dark current suppression , 2010, 2010 IEEE Sensors.

[5]  Yong Liu,et al.  Integrated cell manipulation system--CMOS/microfluidic hybrid. , 2007, Lab on a chip.

[6]  Yufu Zhang,et al.  Statistical Framework for Designing On-Chip Thermal Sensing Infrastructure in Nanoscale Systems , 2010, IEEE Transactions on Very Large Scale Integration (VLSI) Systems.

[7]  Pamela Abshire,et al.  Packaging commercial CMOS chips for lab on a chip integration. , 2014, Lab on a chip.

[8]  F. Roy,et al.  New mechanism of plasma induced damage on CMOS image sensor: Analysis and process optimization , 2010, 2010 Proceedings of the European Solid State Device Research Conference.

[9]  R. R. Harrison,et al.  A low-power low-noise CMOS amplifier for neural recording applications , 2003, IEEE J. Solid State Circuits.

[10]  L. Berdondinia,et al.  High-density electrode array for imaging in vitro electrophysiological activity , 2005 .

[11]  R P GEYER,et al.  Bicarbonate as an essential for human cells in vitro. , 1958, Archives of biochemistry and biophysics.

[12]  Teresa H. Y. Meng,et al.  HermesB: A Continuous Neural Recording System for Freely Behaving Primates , 2007, IEEE Transactions on Biomedical Engineering.

[13]  H. Eltoukhy,et al.  A 0.18-/spl mu/m CMOS bioluminescence detection lab-on-chip , 2006, IEEE Journal of Solid-State Circuits.

[14]  H. Bender,et al.  Experimental determination of the maximum post-process annealing temperature for standard CMOS wafers , 2001 .

[15]  J.C. Chen,et al.  An on-chip, attofarad interconnect charge-based capacitance measurement (CBCM) technique , 1996, International Electron Devices Meeting. Technical Digest.

[16]  Michael D Joseph,et al.  Poly(3,4-ethylenedioxythiophene) (PEDOT) polymer coatings facilitate smaller neural recording electrodes , 2011, Journal of neural engineering.

[17]  Jonathan W. Song,et al.  Characterization and resolution of evaporation-mediated osmolality shifts that constrain microfluidic cell culture in poly(dimethylsiloxane) devices. , 2007, Analytical chemistry.

[18]  Antonio Baldi,et al.  Integration of microelectronic chips in microfluidic systems on printed circuit board , 2012 .

[19]  J. Davis,et al.  Basic cell culture :a practical approach , 1994 .

[20]  Igor M. Filanovsky,et al.  Temperature sensor applications of diode-connected MOS transistors , 2002, 2002 IEEE International Symposium on Circuits and Systems. Proceedings (Cat. No.02CH37353).

[21]  Sandro Carrara,et al.  Bio/CMOS Interfaces and Co-Design , 2012 .

[22]  Pamela Abshire,et al.  Detection of on-chip temperature gradient using a 1.5V low power CMOS temperature sensor , 2006, 2006 IEEE International Symposium on Circuits and Systems.

[23]  Ebrahim Ghafar-Zadeh,et al.  A Hybrid Microfluidic/CMOS Capacitive Sensor Dedicated to Lab-on-Chip Applications , 2007, IEEE Transactions on Biomedical Circuits and Systems.

[24]  S. Franssila.  Introduction to microfabrication , 2004 .

[25]  Paul Hasler,et al.  An Autozeroing Floating-Gate Amplifier , 2001 .

[26]  F. Oerlemans,et al.  Phototoxicity of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered culture media for human leukemic cell lines. , 1984, Cancer research.

[27]  S. D. Senturia.  CAD For Microelectromechanical Systems , 1995, Proceedings of the International Solid-State Sensors and Actuators Conference - TRANSDUCERS '95.

[28]  H. Eagle,et al.  Buffer Combinations for Mammalian Cell Culture , 1971, Science.

[29]  G J Brewer,et al.  Viable cultured neurons in ambient carbon dioxide and hibernation storage for a month. , 1996, Neuroreport.

[30]  Jayantha Senawiratne,et al.  Silicon Nitride Surface Conversion into Oxide to Enable Hydrophilic Bonding , 2010 .

[31]  Francois Roy,et al.  New mechanism of plasma induced damage on CMOS image sensor: Analysis and process optimization , 2010, 2010 Proceedings of the European Solid State Device Research Conference.

[32]  B. Eversmann,et al.  A 128 × 128 CMOS bio-sensor array for extracellular recording of neural activity , 2003 .

[33]  P. Abshire,et al.  A CMOS capacitance sensor that monitors cell viability , 2005, IEEE Sensors, 2005..

[34]  Daryl R. Kipke,et al.  Wireless implantable microsystems: high-density electronic interfaces to the nervous system , 2004, Proceedings of the IEEE.

[35]  Mohamad Sawan,et al.  Novel direct-write CMOS-based laboratory-on-chip: Design, assembly and experimental results , 2007 .

[36]  S. Hafizovic,et al.  CMOS microelectrode array for bidirectional interaction with neuronal networks , 2006, IEEE Journal of Solid-State Circuits.

[37]  Steve M. Potter,et al.  A new approach to neural cell culture for long-term studies , 2001, Journal of Neuroscience Methods.

[38]  Peter Schwarz,et al.  Electro-thermal circuit simulation using simulator coupling , 1997, IEEE Trans. Very Large Scale Integr. Syst..

[39]  W. Janke,et al.  Simulation of power dissipation in semiconductor devices of power electronic circuits , 1996, Proceedings of Third International Conference on Electronics, Circuits, and Systems.

[40]  W. H. Teh,et al.  Effect of low numerical-aperture femtosecond two-photon absorption on (SU-8) resist for ultrahigh-aspect-ratio microstereolithography , 2005 .

[41]  L. McIntire,et al.  Effect of shear stress on86Rb+ efflux from calf pulmonary artery endothelial cells , 2006, Annals of Biomedical Engineering.

[42]  Teodor Gotszalk,et al.  The integration of CMOS with plasma-enhanced micromachining , 1997 .

[43]  A. Hierlemann,et al.  CMOS microelectrode array for the monitoring of electrogenic cells. , 2004, Biosensors & bioelectronics.

[44]  Mohamad Sawan,et al.  A Low-Power Integrated Bioamplifier With Active Low-Frequency Suppression , 2007, IEEE Transactions on Biomedical Circuits and Systems.

[45]  K. Wise,et al.  An implantable multielectrode array with on-chip signal processing , 1986 .

[46]  Brian N. Johnson,et al.  An integrated nanoliter DNA analysis device. , 1998, Science.

[47]  Maribel González-García,et al.  Use of polyethyleneimine polymer in cell culture as attachment factor and lipofection enhancer , 2004, BMC biotechnology.

[48]  Graham A. Jullien,et al.  A Low-Light CMOS Contact Imager With an Emission Filter for Biosensing Applications , 2008, IEEE Transactions on Biomedical Circuits and Systems.

[49]  Rahul Sarpeshkar,et al.  An Energy-Efficient Micropower Neural Recording Amplifier , 2007, IEEE Transactions on Biomedical Circuits and Systems.

[50]  Sami Franssila,et al.  Introduction to Microfabrication: Franssila/Introduction to Microfabrication , 2010 .

[51]  Mona E. Zaghloul,et al.  Flexible packaging of solid-state integrated circuit chips with elastomeric microfluidics , 2013, Scientific Reports.

[52]  Lin Li,et al.  Die-level photolithography and etchless parylene packaging processes for on-CMOS electrochemical biosensors , 2012, 2012 IEEE International Symposium on Circuits and Systems.

[53]  Andrew J. Mason,et al.  A Robust Flexible Electrochemical Gas Sensor Using Room Temperature Ionic Liquid , 2013, IEEE Sensors Journal.

[54]  Axel Blau,et al.  Cell adhesion promotion strategies for signal transduction enhancement in microelectrode array in vitro electrophysiology: An introductory overview and critical discussion , 2013 .

[55]  L. Theogarajan,et al.  Wafer Scale Integration of CMOS Chips for Biomedical Applications via Self-Aligned Masking , 2011, IEEE Transactions on Components, Packaging and Manufacturing Technology.

[56]  Eric R. Fossum,et al.  Active pixel sensors: are CCDs dinosaurs? , 1993, Electronic Imaging.

[57]  F. Kudo,et al.  Differential effects of orbital and laminar shear stress on endothelial cells. , 2005, Journal of vascular surgery.

[58]  Lin Li,et al.  CMOS Amperometric Instrumentation and Packaging for Biosensor Array Applications , 2011, IEEE Transactions on Biomedical Circuits and Systems.

[59]  Artur Dybko,et al.  LTCC based microfluidic system with optical detection , 2005 .

[60]  Karan V. I. S. Kaler,et al.  Hybrid Integration of an Active Pixel Sensor and Microfluidics for Cytometry on a Chip , 2007, IEEE Transactions on Circuits and Systems I: Regular Papers.

[61]  Pedram Mohseni,et al.  A fully integrated neural recording amplifier with DC input stabilization , 2004, IEEE Transactions on Biomedical Engineering.

[62]  M. Christophersen,et al.  A CMOS potentiostat for control of integrated MEMS actuators , 2006, 2006 IEEE International Symposium on Circuits and Systems.

[63]  G. Gross.  Simultaneous Single Unit Recording in vitro with a Photoetched Laser Deinsulated Gold Multimicroelectrode Surface , 1979, IEEE Transactions on Biomedical Engineering.

[64]  J. McVittie,et al.  Thin-oxide damage from gate charging during plasma processing , 1992, IEEE Electron Device Letters.

[65]  David Sander,et al.  A CMOS contact imager for locating individual cells , 2006, 2006 IEEE International Symposium on Circuits and Systems.

[66]  Shantanu Chakrabartty,et al.  A Multichannel Femtoampere-Sensitivity Potentiostat Array for Biosensing Applications , 2006, IEEE Transactions on Circuits and Systems I: Regular Papers.

[67]  Y. Tsividis.  Operation and modeling of the MOS transistor , 1987 .

[68]  Andreas G. Andreou,et al.  Design, Fabrication, and Testing of a Hybrid CMOS/PDMS Microsystem for Cell Culture and Incubation , 2007, IEEE Transactions on Biomedical Circuits and Systems.

[69]  Pamela Abshire,et al.  An active micro-electrode array with spike detection and asynchronous readout , 2014, 2014 IEEE Biomedical Circuits and Systems Conference (BioCAS) Proceedings.

[70]  David C. Martin,et al.  Chronic neural recordings using silicon microelectrode arrays electrochemically deposited with a poly(3,4-ethylenedioxythiophene) (PEDOT) film , 2006, Journal of neural engineering.

[71]  C. Toumazou,et al.  A CMOS-Based ISFET Chemical Imager With Auto-Calibration Capability , 2011, IEEE Sensors Journal.

[72]  D. Schmitt-Landsiedel,et al.  A 128 /spl times/ 128 CMOS bio-sensor array for extracellular recording of neural activity , 2003, 2003 IEEE International Solid-State Circuits Conference, 2003. Digest of Technical Papers. ISSCC..

[73]  Pamela Abshire,et al.  A Fully Differential Rail-to-Rail CMOS Capacitance Sensor With Floating-Gate Trimming for Mismatch Compensation , 2009, IEEE Transactions on Circuits and Systems I: Regular Papers.

[74]  L. Geddes,et al.  Criteria for the Selection of Materials for Implanted Electrodes , 2003, Annals of Biomedical Engineering.

[75]  Rebecca S. Shawgo,et al.  Biocompatibility and biofouling of MEMS drug delivery devices. , 2003, Biomaterials.

[76]  David R. S. Cumming,et al.  The development of scalable sensor arrays using standard CMOS technology , 2004 .

[77]  K R Robinson,et al.  The responses of cells to electrical fields: a review , 1985, The Journal of cell biology.

[78]  I. Filanovsky,et al.  Mutual compensation of mobility and threshold voltage temperature effects with applications in CMOS circuits , 2001 .

[79]  J. Christopher Grimaldi,et al.  Introduction to Cell and Tissue Culture: Theory And Technique , 1998 .

[80]  C. Grimbergen,et al.  Investigation into the origin of the noise of surface electrodes , 2002, Medical and Biological Engineering and Computing.

[81]  Ali Hajimiri,et al.  A magnetic cell-based sensor. , 2012, Lab on a chip.

[82]  T. Seese,et al.  Characterization of tissue morphology, angiogenesis, and temperature in the adaptive response of muscle tissue to chronic heating. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[83]  A. Mason,et al.  Lab-on-CMOS integration of microfluidics and electrochemical sensors. , 2013, Lab on a chip.

[84]  Gregory T. A. Kovacs,et al.  Electronic sensors with living cellular components , 2003, Proc. IEEE.

[85]  N. Gavish,et al.  Dependence of the dielectric constant of electrolyte solutions on ionic concentration: A microfield approach. , 2012, Physical review. E.

[86]  P. Wolf.  Thermal Considerations for the Design of an Implanted Cortical Brain–Machine Interface (BMI) , 2008 .

[87]  Barjor Gimi,et al.  In vitro and in vivo evaluation of SU-8 biocompatibility. , 2013, Materials science & engineering. C, Materials for biological applications.

[88]  Yufu Zhang,et al.  Statistical Framework for Designing On-Chip Thermal Sensing Infrastructure in Nanoscale Systems , 2014, IEEE Trans. Very Large Scale Integr. Syst..

[89]  Mohamad Sawan,et al.  A direct-write microfluidic fabrication process for CMOS-based Lab-on-Chip applications , 2009 .

[90]  Pamela Abshire,et al.  Optical filtering technologies for integrated fluorescence sensors. , 2007, Lab on a chip.

[91]  Jan Wouters,et al.  Single-cell recording and stimulation with a 16k micro-nail electrode array integrated on a 0.18 μm CMOS chip. , 2012, Lab on a chip.

[92]  Yan Liu,et al.  Exploiting CMOS Technology to Enhance the Performance of ISFET Sensors , 2010, IEEE Electron Device Letters.

[93]  Jacopo Iannacci,et al.  Experimental Validation of Mixed Electromechanical and Electromagnetic Modeling of RF-MEMS Devices Within a Standard IC Simulation Environment , 2010, Journal of Microelectromechanical Systems.