ISyPeM 1

ISyPeMIntelligent Integrated Systems for Personalized Medicine

Microelectronics DivisionNanotechnology & Life-Sciences Division

Division of Clinical Pharmacology and Toxicology

Institute of BioengineeringInstitute of Electrical Engineering

Reconfigurable and Embedded Digital Systems

ISyPeM 2

Long-term/highly critical drug therapiesA Personalized Medicine Approach

Life-saving drug agents requiring careful monitoring Medical applications identified in the short term:

HIV therapies Immunosuppression for organ transplant maintenance Anticancer therapies with tyrosine kinase inhibitors

Development of a platform for computer-assisted real-time dose adjustment

3

Long-term/highly critical drug therapiesA Personalized Medicine Approach

ISyPeM

Spread Therapeutic Drug Monitoring culture

ACTI

ON

STE

CHN

OLO

GIE

S

Provide a seamless connection with databases and patient records

Point-of-care pharmacokinetics monitoring

0

500

1000

1500

2000

2500

3000

3500

5:00 8:52 12:44 16:36 20:28 0:20 4:12 8:4

SW for dosing adjustment

Provide fully automated drug monitoring and delivery

Low power circuits for sensing and biotelemetry

Model building and personalization

Automated in vivo delivery

Localized and remote processing BT_LE

MICS

SHORT TERM MEDIUM TERM LONG TERM

ISyPeM 4

Technologies in the framework of ISyPeMBio and

NanotechnologiesWP1 and 4

ICT and algorithmsWP3 and 5

Low power circuits and system architecture

WP2

Miniaturized biosensors for drug and biomarker concentration measurement (STMicroelectronics)

Advanced surface functionalization (Arrayon Biotech.)

Drug delivery by nanoporous membranes

Bayesian algorithms implemented on portable platforms

Formal modeling of the therapeutic protocol for correctness verification

Low power CMOS biosensor interface

Low power radio for WBAN node

Distribution and management of computing power on embedded platforms

ISyPeM 5

Bio and nanotechnologies

Biosensing techniques for drug concentration measurements

ISyPeM 6No drug

No signalDrugSignal

Analyte

No drugNo signal

DrugNo signal

DrugSignal

Analyte

Label

No drugNo signal

DrugSignal

Analyte

Tag-Label

Label-free

Label-based

Quasi Label-freeBio and nanotechnologies

04/08/2023 ISyPeM Plenary Meeting 7

OligoLibrary

Bindingto

beads

Binding totarget,

releasefrom beads

PCRamplificationofselected

Analyte

Bio and nanotechnologiesAptamers that change conformation

ISyPeM 8

Bio and nanotechnologiesLabel-based sensing on miniaturized electrodes on silicon

Institute of Bioengineering

Temiz, IEEE Sensors, 2010Guiducci, APCCAS, 2010Guiducci, ISSCC 2010

50µm

ISyPeM 9

Bio and nanotechnologiesLabel-free sensing on miniaturized electrodes on silicon

Institute of Bioengineering

ISyPeM 10

Bio and nanotechnologiesLabel-free sensing on miniaturized electrodes on silicon

Institute of Bioengineering

Cappi et al, SPP 2011

ISyPeM 11

Bio and nanotechnologiesNanoporous membrane for controlled delivery

Ultrathin (100 nm) nanoporous SiN membranes are produced by combining Block-copolymers lithography and standard microfabrication processes (photolithography, wet/dry etching) – diffusion through nanopores has been demonstrated.

Silicon-based materials

Biocompatible

Electrically driven, integrable with actuation circuitry

Nanotechnology & Life-Sciences

Popa, Nanotechnology, 2009

ISyPeM 12

Bio and nanotechnologiesNanoporous membrane for controlled delivery

Nanotechnology & Life-Sciences

unpublished

Grafting of poly(NIPAM) brushes inside SiN nanoporesPermeability control by varying T below and above LCST, using pelletier element or electrical actuator.

Surface modification with poly(NIPAM) hydrogel containing gold NPs. Permeability control by external light inducing local heating of gold NPs (optical-to-thermal energy conversion)

hydrogel

ISyPeM 13

ICT and algorithms

Other prediction strategies under investigation: Example-based learning algorithm

Bayesian algorithms for Therapeutic Drug Monitoring

Institute of Electrical Engineering

Imatinib.tyrosine kinase inhibitor

Unpublished results

ISyPeM 14

Low Power Circuits and System ArchitectureReconfigurable low-Power CMOS Biosensor Interface

CMOS Interface to the biosensor is: Reconfigurable (Synchronous and Asynchronous Mode). Versatile (Cyclic Voltammetry, Impedance Spectroscopy, Capacitive

Sensing).

Microelectronics Division

Institute of Bioengineering

Balasubramanian, ISCAS 2010

ISyPeM 15

Low Power Circuits and System ArchitectureLow-power Radio for WBAN node

Microelectronics DivisionAbility to communicate on MICS (Medical Implant Communication Services) band (400MHz)AND on Bluetooth Low Energy Extension (BT-LE at 2.4GHz) with the monitoring unit.

Heragu, ISCAS 2010

Reconfigurable and Embedded Digital Systems

Prefilter

LNAS

S/H mixer

I

Q

I

Q

To ADC

Sampling clock fs

RF input fc1,fc2

fBB

(Antialias)

fs

I

Q

S I

Q

I

QfIF fs

I

Q

fBBTo

ADC

fC,1

fC,2

Decimation

Decimation,downconversion

0

0

fBB

Sampling RF front-end

ISyPeM 16

Low Power Circuits and System Architectureicyflex embedded programming

Microelectronics Division

Reconfigurable and Embedded Digital Systems

ISSCC 2010

Definition of drug management policies Management of the control loop Safe and secure transmission of data Integration and miniaturization

ISyPeM 17

Industrial contribution

STMicroelectronics Development of a prototype of a point-of-care in vitro drug measurement system

• fully automated measurement system equipped with sample preparation functionalities

Arrayon Biotechnologies Functionalization of surfaces based on a polysaccharide photolinkers called Optodex® to overcome the phenomenon of non-specific interactions