Microelectronics

Division Nanotechnology & Life-Sciences Division Ins@tute of Bioengineering - CLSE Ins@tute of Electrical Engineering - LSI

Division of Clinical Pharmacology and Toxicology

Intelligent Integrated Systems for Personalized Medicine

ISyPeM
C. Guiducci - ISyPeM AM2013 1

Microelectronics Division Nanotechnology & Life-Sciences Division Ins@tute of Bioengineering - CLSE Ins@tute of Electrical Engineering - LSI

Division of Clinical Pharmacology and Toxicology

Enable and extend the adjustment of the drug dosage to a wider disease spectrum through the development of so5ware and hardware biomedical engineering solu@ons, combining bioanaly:cs, molecular biology, pharmacology, sensor technology, ICs, nanotechnology
C. Guiducci - ISyPeM AM2013 2

Variability in treatment response

IMATINIB Modern anticancer agent

Verena Go)a
C. Guiducci - ISyPeM AM2013 3

Variability in treatment response

2.4 Drug Concentra:on (g/mL) 2.0 1.6 1.2 0.8 0.4 0.0 0 1

Ima:nib 400 mg qd

Risk of adverse eects

Target
T. Buclin, et al. Who is in charge of assessing therapeu5c drug monitoring? The case of ima5nib. Lancet Oncol. 2011;12(1):9-11.

800 mg qd Risk of inecacy

2 3

Pa:ent
10 11 12

4 5 6 7 8 9 Treatment dura:on (days)

C. Guiducci - ISyPeM AM2013

Mo@va@on and aims

Informa:on and Interpreta:on
Missing sta@s@cal popula@on data Need for formal and accessible models of interpreta@on

Safety

Integra@on of the medical protocol in a semi-autonomous plaZorm for dose adjustment with verica@on

Compa:bility/Suitability

Acceptable and suitable se]ng for in-eld drug measurement, considering disease, frequency of monitoring, treatment toxicity, costs Need for stable and specic molecular assay for drug measurement, compa@ble with on eld biosensors
C. Guiducci - ISyPeM AM2013 5

LSI

Missing popula@on data Need for formal and accessible models of interpreta@on

INFORMATION/INTERPRETATION

C. Guiducci - ISyPeM AM2013

Meta-data analysis
to summarize mul@ple studies into a single set of reference parameters
Verena Goda Nicolas Widmer

Range of expected ima:nib concentra:ons

very high/low, un-expected

Therapeu5c Drug Monitoring, 2013

rather high/low but in expected range 50% median 90% predic@on interval

Clinical Pharmacokine5cs, 2012

C. Guiducci - ISyPeM AM2013

the range, he amount ep to give increased

t of data designed al stromal tients and trial[20]), tients and sis, in the mpare the a general

Fig. 3. Comparison between Pharmacokinet Modeling and LS-SVM Methods based on 100% Utilization of the Patients Library, x-axis: Predicted Concentration Values, y -axis: Measured Concentration Values.

Drug concentra@on predic@on

Data Library
Predic@ons Clinical Data Training Samples

d to deterExample-

nds on the oice is to rameter

Fig. 4. Histogram of the Mean Absolute Difference in the Drug Concentration Predictions Among the four Approaches: (a) PK Model, (b) LS-SVM, (c) E-SVM Uniform, (d) E-SVM Discriminatory [bar unit = 200mcg/L]

Support Vector Machine

Nicolas Widmer

rformance meters and of C0 and y growing actice, our fold cross e original our experhe set of are used

6)

sest trained feature

cal to the value of . imated by set before

Histogram of the dierence in the drug of the testing patients. However, to make our system adaptive to each specic patient, we choose a specic concentra@on value that for each data set. Practically, it performs as a predic@ons among the lter to pass only the rst M % closest training data. fd : decides theafeatures to be used in the training four pproaches: data samples and to perform the prediction of drug (a) P mAs odel, (b) LS- of using concentration asK well. the main advantage SVM-based approaches, or removing one feature SVM, (c) Eadding xample- in building up the model is simpler than the classical based SVM Ufeatures niform, (d) pharmacokinetic method. The to be considered as training data are: {Amount of Dosage, Time of MeaExample-based SVM suring, Gender, Age, Body Weight}, which correspond to {A, Discriminatory. B, C, D, E} in Table I. Additionally, we also
compare the inuence of using subsets of these features.

Wenqi You, Nicolas Widmer, Giovanni De Micheli, 'Example-based Support Vector Machine for Drug Concentra@on Analysis', 33rd Annual Interna@onal Conference of the IEEE EMBS, pp.153-157. Wenqi You, Nicolas Widmer, Giovanni De Micheli, 'Personalized modeling for drug concentra@on predic@on using support vector machine', 4th Interna@onal Conference on Biomedical Engineering and Informa@cs (BMEI), pp. 1523-1527. Wenqi You; Widmer, N.; De Micheli, G., "Personalized modeling for drug concentra@on predic@on using Support Vector Machine," Biomedical Engineering and Informa5cs (BMEI), 2011 4th Interna5onal Conference on , vol.3, no., pp. C. Guiducci - IO SyPeM 1505,1509, 15-17 ct. 2011 AM2013

Wenqi You

Figure 3 shows the comparison of drug concentration predictions (x-axis) versus the measured concentration (y -axis)

Benchmarking Therapeu@c Drug Monitoring sonware

Aline Fuchs Nicolas Widmer Chantal Casajka Thierry Buclin

Yann Thoma

C. Guiducci - ISyPeM AM2013

www.ezeCHiel.ch
Pa@ent characteriza@on derived from popula@on data and observed drug concentra@on Op@mize posology (Constraint Sa@sfac@on Problem and Gene@c algorithms)

Aline Fuchs Nicolas Widmer Chantal Casajka Thierry Buclin

Yann Thoma Carlos Pena Miguel Barreto

C. Guiducci - ISyPeM AM2013

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www.ezeCHiel.ch
Dose adjustment sugges@ons based on (a combina@on of: Elimina@on, Intake, Number of compartments) Validated by CHUV with Gentamicin for newborns

C. Guiducci - ISyPeM AM2013

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LSI

Integra@on of the medical protocol in a semi-autonomous plaZorm for dose adjustment

SAFETY

C. Guiducci - ISyPeM AM2013

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Formal Modeling of Medical Protocols

Formal Modeling in Medicine: Arden (1989) Asbru (1998) EON (1996) GLARE (1997) GLIF (1998) GUIDE (1998) Pres@ge (1996) PRODIGY (1996) PROforma (1992 - 2000) SAGE (2002) Stepper (2001 - 2003)

Do not allow or allow only par@ally: Safety analysis Coordina@on or coopera@on analysis Valida@on Real-@me analysis Synthesis

LSI

Alena Simalatsar

T1 = P1 give_dose T1 ! == 0

Romain Bornet
calculate_dos e!

Timed Automata Model Checker

T3 = P3

1
T1 < P1 T2 < P2 T3 < P3

T2 = P2 dose = T2 == 0 new_dose

A. Simalatsar et al., , Time Aware Formal Representa@on of Medical Guidelines: Ima@nib Case-study, CODES+ISSS12 A. Simalatsar et al., TAT-based Formal Representa@on of Medical C. Guiducci - ISyPeM AM2013 Guidelines: Ima@nib Case-study, EMBC12

Nicolas Widmer
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Embedded plaZorm with dose adjustment in real-@me

Serial link Alena Simalatsar Wenqi You Anna Ferre]

Drug Concentra:on measurement and processing

Real-:me control based on @med automata Dosage adjustment calcula@on

Popula:on data update + SVM training Automa@c interac@on with EzeCHiel

Romain Bornet Yann Thoma

Chris@an Enz Alexandre Corbaz

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Towards companion diagnos@cs

2.4 GHz MBAN or MICS 400 MHz

2.4 GHz BT LE

badery powered nodes remote powered nodes

Wireless body area network Connec@ng wearable devices and a smart user interface On-body nodes have to communicate on the 400MHz MICS band or the upcoming 2.36-2.4 GHz MBAN band Ability to talk on Bluetooth Low Energy (BT-LE) with the external monitoring unit
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Aravind Heragu

A Low-Power MEMS-based 2.4-GHz Receiver

0.18-um CMOS process. BAW resonators A rejec:on of 50-dB measured at 15-MHz oset from the center frequency. Can tolerate blocker level up to -9.2-dBm with 8-dB margin.

Aravind Heragu Chris@an Enz

A. Heragu, et al, A Concurrent Quadrature Sub-Sampling Mixer for Mul@band Receivers, European Conference on Circuit Theory and Design (ECCTD 09), 2009, "Best Paper" award A.Heragu, et al. , A Mul@band Concurrent Sampling Based RF Front End for Biotelemetry Applica@ons, IEEE Symposium on Circuits and Systems (ISCAS 2010). A. Heragu, et al. , A MEMS based 2.4-GHz Sub-Sampling RF Frontend for Advanced Healthcare Applica@ons, IEEE Radio-Frequency Integra@on Technology 2011. A. Heragu, et al. ,A Low Power 2.4-GHz Front-end with MEMS La]ce based Channel Filtering at RF, IEEE Symposium on Circuits and Systems (ISCAS 2012). A.Heragu, et al. , A 2.4-GHz MEMS based Sub-Sampling Receiver Front-end with Low Power Channel Selec@on Filtering at RF, IEEE Interna@onal Symposium on Radio Frequency Integrated Circuits (RFIC 2012). A.Heragu, et al. , A 2.4-GHz MEMS-Based PLL-Free Mul:-Channel Receiver with Channel Filtering at RF, European Solid State Circuits Conference (ESSCIRC 2012). A. Heragu, et al. , The design of ultra-low-power MEMS-based radio for WSN and WBAN, 22nd workshop on Advances in Analog Circuit Design, April, 2013. A. Heragu, et al. , A Low Power BAW resonator based 2.4-GHz Receiver with Bandwidth Tunable Channel Selec:on Filter at RF, accepted for publica@on in the Journal of Solid State Circuits (JSSC) publica@on expected in the June, 2013 issue. A.Heraguet al. , A 2.4-GHz MEMS-Based PLL-Free Mul:-Channel Receiver with Channel Filtering at RF, solicited and accepted for publica@on in the Journal of Solid State Circuits (JSSC) special issue (ESSCIRC) publica@on expected in the July, 2013 special issue. C. Guiducci - ISyPeM AM2013 16

Acceptable and suitable se]ng for drug measurement, with respect to the disease, frequency of monitoring, treatment toxicity, costs Need for stable and specic molecular assays for drug measurement, compa@ble with in-eld biosensors

COMPATIBILITY/SUITABILITY
C. Guiducci - ISyPeM AM2013 17

Candidate treatments for therapeu@c drug monitoring

Modern anticancer agents IMATINIB 1000 ng/ml 493.60 Da Immunosuppressant TACROLIMUS 10 ng/ml 804.02 Da

Antiretrovirals EFAVIRENZ 2000 ng/ml 315.70 Da

Antibiotics TOBRAMYCIN 1000 ng/ml 467.5 Da

C. Guiducci - ISyPeM AM2013

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Congura@on and se]ng for drug measurement on pa@ent

Blood sampling Drug concentra:on measurement

hdp://e-sante.futura-sciences.com

Abbod "Architect ci8200"

MDs cabinet or hospital

Central clinical facilities

C. Guiducci - ISyPeM AM2013

cleic acids

Detection through low-density microarray

The In-Check microarray module is used to detect the amplied labeled DNA sequences through hybridization on a low-density microarray composed of 126 spots.

erature sensor the In-Check PCR and cooling cycles t PCR.

eck PCR module is driven by the emperature control CS). This allows fast ammable temperature ether with ent random access for tests simultaneously.

The microarray module is uidically connected to the PCR module and is thermally driven by the temperature control system. After hybridization, the microarray module is read by the In-Check optical reader (OR) in a few seconds.

Congura@on and se]ng for drug measurement on pa@ent

The microarray module includes a set of control probes at xed positions, as well as specic probes located according to customer requirements.

In-Check system

Bench-top stand-alone analy:cal system

Hand-held device for self sampling

CR and hybridization tion does not require y simplies the typical

The In-Check system is extremely userfriendly and allows unskilled operators to perform all steps from sample to result.

In-Check PCR and microarray on chip

Fabio Spiga
C. Guiducci - ISyPeM AM2013 20

Tobramycin detec@on based on Transmission SPR

CLSE Giulia Cappi Fabio Spiga Enrico Accastelli

RNA on surface

Tobramycin 200 M 467 Da

Buer NaCl Buer dissocia@on Surface Return to regenera@on RNA baseline

Nicolas Widmer Laurent Decosterd

G. Cappi, et.al, Peak Shin Measurement of Localized Surface Plasmon Resonance by a Portable Electronic System, Sensors and Actuators B: Chemical, 2012 G. Cappi, et al., A portable setup for molecular detec@on based on transmission LSPR. MRS Proceedings from IMRC 2012.

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Exploring integrated low-noise signal measurement for ultra miniaturized plaZorms

CMOS 0.18m interface Low noise front-end current mode amplier 8 bit asynchronous A/D converter
CLSE Anna Ferre] Yuksel Temiz

Viswa Balasubramanian Chris@an Enz

V. Balasubramanian al, A 0.18 Low Power CMOS Biosensor Interface To be submided to the IEEE Journal of Solid State Circuits (JSSC). V. Balasubramanian, et al, A 0.18 Biosensor Front-end based on 1/f Noise, Distor@on Cancela@on and Chopper Stabiliza@on Techniques (TBioCAS) journal. V. Balasubramanian, et al., Noise Canceling Chopper Stabilized Front-End for Electrochemical Biosensors with Improved Dynamic Range, (ISCAS), 2012. V. Balasubramanian, et.al. , Analysis of Ultralow-Power Asynchronous ADCs, Presented at the Special Session on Ultralow-Power Sensor Interfaces for Biomedical Applica@ons,. (ISCAS), 2010.

C. Guiducci - ISyPeM AM2013

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Robustness and scalability of integrated sensor features

(a) (b)
Fig. 1. SEM images of a SiNR: (a) Top view, (b) Crosssection. When the width is comparable with the thickness, as in this case, we can call the structure a Silicon Nanowire (SiNW). The SiNRs are fabricated on Silicon-On-Insulator (SOI) wafers and defined by means of standard top-down CMOS compatible processes, such as Deep Ultraviolet (DUV) photolithography, e-beam lithography and Reactive Ion Etching (RIE) [1]. SEM pictures courtesy of CEA-LETI (Grenoble, France).

2 cm (a) 2 cm

(b)

Fig. 2. Exploded view of Ithe microfluidic LETI E.Accastelli t a l. EEE NANO setup. 2013 Fig. e 1. SEM images of a The SiNR: (a) Top view, (b) CEA, Crossmicrochannels are realized with a chemical resistant section. is comparable with the double-coated tape, When patterned the by width laser micromachining. The height of the channels is defined thickness, as in this case, we can call the structure a by the thickness of the tape (~190 m). A PMMA cap Silicon Nanowire is placed to seal the channels and host (SiNW). the inlets and The SiNRs are fabricated on outlets tubes. A sealing polymer is used to avoid fluid wafers and defined by means Silicon-On-Insulator (SOI) leakages from the inlets/outlets tubes.

1.5E-7
Drain current (A)

Drain Current (A)

1.0E-7 5.0E-8 0.0E+0 -100 1000

2E-7 1E-7 0E+0 -100 3200

of standard top-down CMOS compatible processes, such as Deep Ultraviolet (DUV) photolithography, CLSE e-beam 5E-7 lithography and Reactive Ion Etching (RIE) [1]. SEM Anna Ferre] pictures courtesy of CEA-LETI (Grenoble, France). 4E-7
3E-7

Enrico Accastelli Yuksel Temiz

Time (s)
Fig. 3. The drain current drift can be modeled by a stretched-exponential time dependence given by the equation above. The red dots show how well the model fit the experimental data (black line). (Inset) When the electrolyte is not polarized by means of proper REs, the drain current doesnt show predictable trend.

Drain current (A)

2100

3200

Current (A)

Y. Temiz, A. Ferre], Y. Leblebici, C. Guiducci, A Compara@ve Study on Fabrica@on Techniques for 2E-7 1.5E-7 On-Chip Micro- electrodes, Lab Chip, 2012, 12, 49204928 1E-7 Y. Temiz, M. Zervas, C. Guiducci and Y. Leblebici, A CMOS Compa@ble Chip-to-Chip 3D Integra@on PlaZorm, 2012 , Page(s): 555 560. 1E+0 1E-6 1E-3 C. Guiducci, Y. 1.0E-7 Temiz, Y. Leblebici, E. Accastelli, A. Ferre], G. Cappi, E. Bianchi, "Integra@ng Bio- Na2SO4 Ionic Strength (M) sensing Func@ons on CMOS Chips," Proc. of Asia Pacic Conference on Circuits and Systems (APCCAS), 2010. surface Fig. 4. The charged of the gate oxide attracts a 2E-7 layer of counter-ions to maintain the overall charge Y. Temiz, E. Accastelli Y. Leblebici and C . Guiducci, "Robust Microelectrodes Developed for Improved neutrality,in forming an Electrical Double Layer (EDL). of Biomolecular 1E-7 Layers," Proc. IEEE Sensors, 2010. 23 Stability Electrochemical Characteriza@on 5.0E-8
Keeping constant the pH, the ionic strength of the solution affects the distribution of ions close to the SiNRs channel, thus affecting the capacitive coupling between the gate and the wire and its drain current as a

Fig. 2. Explod microchannels double-coated micromachinin by the thicknes is placed to se outlets tubes. A leakages from

5E-7 4E-7 3E-7

0E+0 -100 3200

1E-6

2E-7

Sample prepara@on for drug free- frac@on

Molecular transport through nanopores membranes Tuning of pore diameter for size-based ltra@on of small biomolecules
1 nm 5 nm
To be published Montagne, F., Blondiaux, N., Bojko, A. & Pugin, R. Molecular transport through nanoporous silicon nitride membranes produced from self- assembling block copolymers. Nanoscale 4, 58805886 (2012).

Alexandre Bojko Gaelle Andreada Frank Montaigne Raphael Pugin

Laurent Decosterd

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Highly-stable DNA molecular probes for small molecules

CLSE Fabio Spiga Anna Ferre]

Laurent Decosterd Nicolas Widmer unpublished results

C. Guiducci - ISyPeM AM2013 25

Microelectronics Division Nanotechnology & Life-Sciences Division Ins@tute of Bioengineering - CLSE Ins@tute of Electrical Engineering - LSI

Division of Clinical Pharmacology and Toxicology

ISyPeM Drug Dose Adjustment for In-eld Use

C. Guiducci - ISyPeM AM2013

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Thank you!

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