Constandinou, TG

Georgiou, P

Goh, ZDC

Prodromakis, T

Toumazou, C

English

Spiral - Imperial College Digital Repository

Live Demonstration: A CMOS-based Lab-on-ChipArray for Combined Magnetic Manipulation andOpto-Chemical SensingZheng Da Clinton Goh, Pantelis Georgiou†‡, Timothy G. Constandinou†‡,Themistoklis Prodromakis†‡ and Christofer Toumazou†‡Department of Bioengineering, †Department of Electrical and Electronic Engineering and‡Centre for Bio-Inspired Technology, Institute of Biomedical Engineering, Imperial College London, SW7 2AZ, UKEmail:{zheng.goh06,pantelis,t.constandinou,t.prodromakis,c.toumazou}@imperial.ac.ukAbstract—We demonstrate a CMOS-based lab-on-chip plat-form for combined magnetic manipulation and opto-chemicalsensing. Each pixel of the 8×8 array integrates a ProgrammableGate (PG) ISFET chemical sensor and an active pixel sensor,encompassed within an inductive coil. The system can be usedfor simultaneous optical imaging and pH sensing, and includes anauto-calibration mechanism for eliminating sensor non-idealities.Through a MATLAB-based graphical user interface, the user canprogram a spatiotemporal magnetic field pattern for micro-scalemagnetic manipulation, in addition to visualising chemical andoptical images in real time.I. INTRODUCTIONCurrent advancements in biomedical research are supportedby new frontiers created from integrating CMOS technologywith lab-on-chip platforms. For example, CMOS-based ISFETchemical sensors [1] can be used to acquire a spatiotemporalmap of chemical changes for applications of cell monitoring[2]. Despite these advances in CMOS-based lab-on-chip tech-nology, integration of multiple sensing and actuation modali-ties into a single system has not been achieved, thus drivingefforts in functional integration.We demonstrate the first lab-on-chip array which combinesboth optical and chemical sensing in addition to magneticmanipulation using inductive micro-coils within a single pixel[3]. The platform is controlled via a MATLAB-based graphicaluser interface (GUI) developed for sensor calibration, realtime data acquisition and magnetic field pattern programming.Fabricated in commercially available 0.35μm CMOS process,the system is scaled to form an 8×8 array. This presents aversatile platform for applications requiring magnetic actua-tion of biological samples, such as cell manipulation, DNAhybridisation as well as opto-chemical imaging of ongoingchemical reactions.II. DEMONSTRATION DESCRIPTIONThe demonstration setup shown in Fig 1 consists of powersupplies, a PC for visualisation of real time sensor data, anexternal current sink for biasing the inductive micro-coils anda ADC clock signal generator for polling the sensor array.Integrated on a single PCB, a PIC 18LF4680 microcontrollerexecutes action routines based on commands sent from thePersonal Computer Power SuppliesExternal current sourceExternal ADC ClockSignal GeneratorVeho-004 USBmicroscopeLab-on-Chip Development board with catridgeMATLAB GraphicalUser InterfaceFig. 1. Experimental setup comprising of the lab-on-chip development board,data acquisition system and external biasing devices.MATLAB GUI. A Veho-004 USB microscope is also em-ployed to capture real time images of ongoing biochemicalassays on the chip surface.III. VISITOR EXPERIENCEDuring the demonstration, the visitor will be able to vi-sualise changes to pH and illumination intensity detected bythe lab-on-chip, as well as perform micro-scale magnetic beadmanipulation in real time. The visitor will also be impressedby the high computing efficiency and convergence accuracy ofthe auto-calibration technique developed to eliminate sensornon-idealities, high pH sensitivity and optical detectability, aswell as the versatility of micro-bead manipulation.REFERENCES[1] P. Georgiou and C. Toumazou, “Isfet characteristics in cmos and theirapplication to weak inversion operation,” Sensors and Actuators B:Chemical, vol. In Press, Corrected Proof, pp. –, 2009.[2] P. Georgiou and C. Toumazou, “An adaptive ISFET chemical imagerchip,” Circuits and Systems, 2008. ISCAS 2008. IEEE InternationalSymposium on, pp. 2078–2081, 2008.[3] P. Georgiou, T. Constandinou, T. Prodomakis, and C. Toumazou, “Acmos-based lab-on-chip array for the combined magnetic stimulation andopto-chemical sensing of neural tissue,” in Cellular Nanoscale Networksand Applications, 2010.A CMOS-based Lab-on-Chip Array for CombinedMagnetic Manipulation and Opto-Chemical SensingZheng Da Clinton Goh, Pantelis Georgiou†‡, Timothy G. Constandinou†‡,Themistoklis Prodromakis†‡ and Christofer Toumazou†‡Department of Bioengineering, †Department of Electrical and Electronic Engineering and‡Centre for Bio-Inspired Technology, Institute of Biomedical Engineering, Imperial College London, SW7 2AZ, UKEmail:{zheng.goh06,pantelis,t.constandinou,t.prodromakis,c.toumazou}@imperial.ac.ukAbstract—This paper presents a CMOS-based lab-on-chipplatform for combined magnetic manipulation and opto-chemicalsensing. Within each pixel, a Programmable Gate (PG) ISFETchemical sensor is combined with an active pixel sensor, and isencompassed within an inductive coil. The integrated pixel istesselated to form an 8×8 array. Fabricated in a commerciallyavailable 0.35μm CMOS technology, the system can be used forsimultaneous optical imaging and pH sensing, and includes auto-calibration mechanisms for eliminating sensor non-idealities. Aspatiotemporal magnetic field pattern generator has also beenembedded for micro-scale magnetic manipulation. Controlled viaa MATLAB based graphical user interface, the system achievesreal time data acquisition at 6fps, a pH sensitivity of 57mV/pHand demonstrates magnetic manipulation of micro-beads.I. INTRODUCTIONThe analysis of biological systems and miniaturisation ofanalytical methods are few of the driving forces behindresearch in the field of lab-on-chip. Lab-on-chip is a multi-disciplinary approach to designing integrated micro-scale de-vices for monitoring and performing biochemical assays.Technology miniaturisation allows for controlled transport andmanipulation of biological molecules and cells [1], whilespatiotemporal chemical and optical detection can be achievedby integrating CMOS-based micro-sensors into lab-on-chipdevices [2].Despite technological advances in CMOS-based lab-on-chipdevices, efforts at integrating multiple sensing and acuationmodalities into a single programmable system have beenlimited. Previous designs of CMOS lab-on-chip devices focusmainly on systems which offer a single sensing or actuationmodality [3], [4], contributing only to a small portion of acomplete biochemical ssay.We report the first lab-on-chip array which combines bothoptical and chemical sensing in addition to magnetic manip-ulation using inductive micro-coils within a single pixel. Theplatform is controlled via a MATLAB-based graphical userinterface (GUI) developed for sensor calibration, real timedata acquisition and programming a spatiotemporal magneticfield pattern. Fabricated in commercially available 0.35μmCMOS process, the system is scaled to form an 8×8 array.This presents a versatile platform for applications requiringmagnetic manipulation of biological samples, such as cellmovement, DNA hybridisation as well as opto-chemical imag-ing of ongoing chemical reactions.II. SYSTEM OVERVIEWThe top level system architecture and integrated pixelschematic is shown in Fig. 1. The array combines threesub-systems for sensory acquisition, and generating magneticstimulus. The system uses a common programming/calibrationinterface based on the SPI protocol to load data serially. Thisdata includes 8×8×10-bit words for the chemical imager cal-ibration, 64×10-bit words to define the magnetic field patternand one additional word to control the amplifier gains. Theoutputs are sampled using a 10-bit successive approximationADC by interleaving the chemical and optical image data.A. Magnetic Pattern GeneratorThis is based on a 64×10-bit rolling buffer that cyclesa 10-bit instruction onto the magnetic controller. The 10-bitinstruction is defined as follows: bits 9-7 = x-coordinate, bits6-4 = y-coordinate, bit 3 = polarity and bits 2-0 = magnitude.The current is first generated using a 3-bit DAC (based on abinary-weighted current mirror) and the polarity can then bereversed using an H-bridge configuration. The coordinate bitsare then used to control two demultiplexers (for X and Y) thatcurrent steer the stimulus towards the active pixel.1) Micro-coil: The manipulation of micro-beads isachieved by employing a magnetic trapping force [5]:F =V χμ0· ∇|B|2 (1)where, V and χ are the volume and magnetic susceptibilityof the micro-bead, μ0 is the magnetic permeability in vacuumand B is the magnetic field generated by the micro-coil.B. Sensor arrayA timing generator defines the phases and array controlsignals to poll through the sensor array. The chemical sensorsare sampled during the second half clock period and theoptical sensors are sampled during the first half clock period.Simulated results are reported in [6].1) Chemical sensor: This is based on the PG-ISFET [7]chemical sensor that is biased using a unity-gain buffer atpixel level. The outputs are switched into a shared columnbus, selected at the column header and buffered through aprogrammable gain amplifier for data acquisition. The controlgate input is fed from a DAC that is driven by a lookup table.Sensory Array TimingGenerationDA3-b Current-Out DAC H-BridgeAnalogue1-to-8 DemuxAnalogue1-to-8 DemuxI_REFA BIN OUTCTRLI_OUT10-b3-b3-b3-bGNDCLKSerial to ParallelLoad RegisterSerial_INCLKI_INI_INI1 I8I7I6I5I4I3I2I1I2I3I4I5I6I7I8CTRL(2:0)CTRL(2:0)PGA(x1/5/10)PGA(x1-8)+_AD10-b SA ADCAPS_RAPS_SISFETAPS ArrayAmplifier8-b8-bXres(1:8)Xpix(1:8)Ypix(1:8)X,Yadr(2:0)Vpg AD10-b DAC10bit8x8 RAM3-b 3-bADCCTRLISFETArrayAmplifierCalibrationData InAcquisitionOutSync10-bCorrelatedDoubleSamplingColumnSelectionCLK10bit8x8 RAM5-bRollingBufferYsel(1:8)AddressDataPixel(1,1)Master Reference CircuitsCurrent (PTAT)Voltage (Bandgap)Power on Reset (POR)CpassCCGQ1VDACPBIASROW SELECTISFET BUSRESETAPS BUSNBIASINDUCTOR ROWCOL SELCOL SELCOL SELAPS COL OUTISFET COL OUTINDUCTOR COLM1M2M3M4M5M6M7M8M9M10 M11M12M13D1I1200/1 200/110/10 10/100.8/0.350.8/0.350.8/0.350.6/0.350.8/0.3510/102/0.350.6/0.350.8/0.3510/3(a) (b)Fig. 1. Sytem overview: (a) a schematic of the integrated pixel (left) and (b) a top level architecture of the system (right)When the PG-ISFET is biased, ions in solution bind to thepassivation surface, causing an accumulation of charge whichcreates a pH dependence according to:V ′G = Vref − Vtc − γ +2.3αkTqpH (2)whereby Vtc is the non-ideal effects of trapped charge andpixel mismatch, Vref is the bias voltage of the referenceelectrode, Ut is the thermal voltage of the device, γ is a group-ing of non-chemically related potentials and α is a numberranging from 0-1, describing the reduction in sensitivity fromthe Nernstian response, typically 59mV/pH [8].2) Optical sensor: This implements a standard active pixelsensor utilising a standard 3-transistor pixel. The photodi-ode is based on a n-well/p-substrate parasitic pn-junction ofdimension 16μm×36μm. The shared column bus lines arefed into column-level correlated double sampling buffers anddifferential signal switched into a difference amplifier.III. FABRICATED PLATFORMThe platform shown in Fig. 2 was fabricated in a commer-cially available 0.35μm CMOS technology. Using a four-metallayer process, a multi-layer spiral micro-coil with 5 turns wasimplemented. A split padring was implemented to achieve anisolated power supply for the analogue and digital sections.This allows for planar manipulation of the sensing surface,which is crucial for encapsulating the system [9].IV. TEST PLATFORMA. InstrumentationThe test platform shown in Fig. 3 was developed forprogramming and acquiring data from the lab-on-chip. Actionroutines are executed by a microcontroller, based on com-mands sent via a standard UART interface from MATLAB.InductorControllerSensory Front End(Amplification)Data ConversionInterfaceRAM Bank 2 (offset calibration)8x8Pixel ArrayCDS ColumnBuffersInductorISFETISFET SensorInterfaceAPS CircuitRAM Bank 1(Rolling Buffer)PhotodiodeFig. 2. Microphotograph and overlaid floorplan of: (a) complete system (left)and (b) multimodal pixel (right).An auxiliary catridge was fabricated to providing a platformfor fluidic assays to be conducted on. The chip was encap-sulated using glob-top resin and the cartridge was interfacedto the development board. A 2ml fluidic well was fabricatedand adhered to the catridge using epoxy resin. An externalAg/AgCl reference electrode was also grounded on the PCB.B. User InterfaceA MATLAB-based GUI was developed for sensor calibra-tion, real time visualisation of optical and chemical images,and for programming a magnetic field pattern.1) Magnetic Field Pattern Programming: A GUI was de-veloped for programming the magnetic field pattern, wherebythe user specifies the polarity and magnitude of the biasing cur-rent through each pixel of interest. The current drawn througheach micro-coil during RAM playback can be simulated in a3D plot to visualise regions of peak magnetic field strength.The data is then encoded into a 64×10-bit instruction set andclocked into the lab-on-chip via the microcontroller.Fig. 3. Development board consisting of a microcontroller and peripheralcomponents, interfaced to the lab-on-chip cartridge for fluidic assays.2) Sensor Calibration: A gradient based algorithm wasimplemented to calibrate the PG-ISFET array. The algorithmoptimises the control gate vector through a negative feedbacksystem which adjusts the bias of each pixel based on thedifference between the operating point and actual readout.3) Real Time Data Acquisition: This was achieved bypolling the sensor array with the microcontroller. Each end-of-conversion pulse triggers the sampling of a 10-bit output whichis ordered and stored in memory. Stored bits are streamed toMATLAB after data from each frame is acquired and displayedin the GUI shown in Fig. 4. The cycle is repeated to achievereal time optical sensing and pH detection. A USB microscopewas also used to monitor the lab-on-chip.Software routines were also developed to allow the user tobias the micro-coil of a pixel during real time data acquisition.This is done by temporarily pausing the data acquisitionprocess, clocking the relevant instruction bits into the lab-on-chip and then resuming data acquisition. Through theGUI, real time micro-scale manipulation of micro-beads andsimulaneous opto-chemical sensing is achieved.V. MEASURED RESULTSA. Sensor Calibration and pH SensitivityThe calibration algorithm biases the PG-ISFET array atmid-supply voltage of 1.65V with a pH 7 buffer solution,where it demonstrated a fast rate of convergence (≈500ms periteration) and a convergence accuracy of 45mV (2% pixel-to-pixel variation) on a gain of 10.0 50 100 150 200 250 300 350 4001.51.551.61.651.71.751.81.85Chemical readout for varying pH levelsChemical readout / VPixels (1 to 64) for each pH level, 6 pH levels in totalpH=4.11pH=5.05pH=5.90pH=6.95pH=8.87pH=9.85(a)4 5 6 7 8 9 101.51.551.61.651.71.751.81.85Plot of average readout against pH levelsAverage sensor array readout / VpHEquation: y = 0.057x + 1.243(b)Fig. 5. Chemical readouts for varying pH levels. (a) Recordings from allpixels for each pH level (left) and (b) an averaged array readout for varyingpH levels (right). Data is shown as the mean ± standard deviation(a) (b)Fig. 6. Optical images of a light stimulus on the chip surface: (a) Left toright translation (left) and (b) varying illumination intensity (right).Solutions of varying pH were used to evaluate the pH sensi-tivity of the lab-on-chip. The device was first calibrated and thechemical readout was recorded with solutions of known pH.In all experiments, an Ag/AgCl reference electrode was usedto maintain the fluid potential at 0V. Fig 5 shows the systemresponse to varying pH levels. The system demonstrated achemical sensitivity of 57mV/pH on a gain of 10, which isvery close to the Nernstian sensitivity of 59mV/pH [8].B. Optical DetectionA spot of light was focused onto the chip surface withvarying intensity and at different locations across the chip.Fig. 6 shows the real time system response to a translation inoptical stimulus as well as varying stimulus intensity.C. Magnetic Bead ManipulationMagnetic micro-bead movement is achieved by biasingindividual microcoils with a current of -20mA as shown inFig 7. The period of the current pulse is 3s with a duty cycleof 50%, and the total time required to move beads to the biasedpixel was approximately 180 seconds.VI. CONCLUSIONThis paper has presented the design, fabrication and char-acterisation of a novel lab-on-chip array combining realtime opto-chemical sensing and magnetic field generationfor micro-scale magnetic manipulation. It is the first lab-on-chip device which integrates multiple sensing and actuationmodalities on a single platform.Experimental ParametersAction RoutinesAcquired Opto-chemical ImagesMicroscope Acquired ImagesPixel-basedMagnetic ManipulationFig. 4. Graphical user interface for experimental set up and data acquisition.(a) (b)(c) (d)Fig. 7. Magnetic micro-beads (indicated by the arrow) move towards thebiased pixel (boxed in yellow). Pixel (8,8) is boxed in white to provide areference point.The system demonstrated high pH sensitivity and opticaldetectability in real time, as well as fast and accurate sensorcalibration which eliminates sensor non-idealities such as de-vice mismatch. The motion of micro-beads was also controlledby a user configurable magnetic field pattern. Fabricated inunmodified CMOS, the chip can be combined with microflu-idic platforms for applications such as cell manipulation, DNAhybridisation detection as well as for reaction monitoring.REFERENCES[1] H. Andersson and A. van den Berg, “Microfluidic devices for cellomics:a review,” Sensors and Actuators B: Chemical, vol. 92, no. 3, pp. 315 –325, 2003.[2] P. Georgiou and C. Toumazou, “An adaptive ISFET chemical imagerchip,” Circuits and Systems, 2008. ISCAS 2008. IEEE InternationalSymposium on, pp. 2078–2081, 2008.[3] J.-G. Lee, K. Yun, G.-S. Lim, S. E. Lee, S. Kim, and J.-K. Park, “Dnabiosensor based on the electrochemiluminescence of ru(bpy)32+ withdna-binding intercalators,” Bioelectrochemistry, vol. 70, no. 2, pp. 228– 234, 2007.[4] H. Eltoukhy, “A 0.18um cmos bioluminescence detection lab-on-chip,”IEEE journal of solid-state circuits, vol. 41, no. 3, pp. 651–, 2006.[5] H. Lee, Y. Liu, R. Westervelt, and D. Ham, “IC/microfluidic hybridsystem for magnetic manipulation of biological cells,” IEEE Journal ofSolid-State Circuits, vol. 41, no. 6, pp. 1471–1480, 2006.[6] P. Georgiou, T. Constandinou, T. Prodomakis, and C. Toumazou, “Acmos-based lab-on-chip array for the combined magnetic stimulation andopto-chemical sensing of neural tissue,” in Cellular Nanoscale Networksand Applications, 2010.[7] P. Georgiou and C. Toumazou, “CMOS-based programmable gate ISFET,”Electronics Letters, vol. 44, p. 1289, 2008.[8] P. Bergveld, “Thirty years of isfetology: What happened in the past 30years and what may happen in the next 30 years,” Sensors and ActuatorsB: Chemical, vol. 88, no. 1, pp. 1 – 20, 2003.[9] T. Prodromakis, K. Michelakis, T. Zoumpoulidis, R. Dekker and C.Toumazou, “Biocompatible Encapsulation of CMOS based ChemicalSensors,” in IEEE Sensors, 2009.

A CMOS-Based Lab-on-Chip Array for Combined Magnetic Manipulation and Opto-Chemical Sensing

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A CMOS-Based Lab-on-Chip Array for Combined Magnetic Manipulation and Opto-Chemical Sensing

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