The potential of nanolectronics in healthcare

MCH 50 jaar viering– 1 oktober 2016

Johan Van Helleputte, Senior Vice-President Strategic Development O.R.

A world of extreme miniaturization

2

SCOPE OF THE TALK

ICT

(health care processes)

NANOTECHNOLOGY

SEMICONDUTORS BIG DATA

Seen from an imec viewpoint as privileged player in nanoelectronics

Outline

1. Some high level challenges in health care

2. Why are semiconductors heavily involved in healthcare 3. A vision on the revolution of healthcare and some concrete examples and impact for first-line medicine

Some major health care challenges

4

Global healthcare spending

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

196019701980199020002009

Totalspendingonhealthcareasa

percentageofGDP

USA

Europe

Japan

Data from EFPIA (http://www.efpia.eu/pharmaceutical-industry-

figures-edition-2012)

17.4%

8.5% 9.6%

$2.6T

$6.5T

$1.9T

$1.2T

=

=

=

US Health Spending Drivers

$2.6T

0 500

Cardiovascular

Diabetes

Lung disease

Alzheimer's

(in $B)

$430B

$150-170B

US

31%

Hospital

care

20%

Physician/

clinical

20%

Other

care Nursing home care

Home health care

Professional services

10%

Drugs

19%

Other

Chronic disease 75% of $2.6T

7/10 deaths

Data from Martin A.B., et al., Health Affairs, 2012.

US Health Spending Drivers

$2.6T

0 500

Cardiovascular

Diabetes

Lung disease

Alzheimer's

(in $B)

$430B

$150-170B

US 2010

31%

Hospital

care

20%

Physician/

clinical

20%

Other

care Nursing home care

Home health care

Professional services

10%

Drugs

19%

Other

Chronic disease 75% of $2.6T

7/10 deaths

Data from Martin A.B., et al., Health Affairs, 2012.

1. Shift: hospital other settings. 2. Efficacy, efficiency to increase AND cost of technology to drop: extreme miniaturization for expensive equipment 3. Optimization of health care processes (ICT-driven) for cost saving

60%

60%

51%

50%

48%

47%

40%

30%

Asthma

Cardiac Arrythmias

Migrane

Rheumatoid arthritis

Osteoporosis

Hepatitis C virus

Incontinence

Alzheimer's

Oncology

Spears et al. TRENDS in Molecular

Medicine Vol. 7 No. 5 May 2001

Therapeutic Area Effective Rate (%)

Pharma Challenge: pressure on block buster model (2001)

25%

EFFICACY OF DRUGS – 10 years later

Sourc

e: “

Pers

onaliz

ed M

edic

ine”

, Jam

es W

eis

and

Lily

Ch

an, A

pri

l 20

10

Need for personalized (precision) medicine (initially driven by Herceptin case).

Decision making in Healthcare requires collecting and analyzing increasingly complex data

Challenge of Big Data

- Unraveling of (multi-factor) disease mechanisms

- Genetic mapping through DNA Sequencing

- Co-morbidity interactions

- Multi-omic approaches - Disease monitoring & management (“zorgplan”)

- Precision/personalized disease models (in a further future)

- …

11

NEW MEDICAL ENTITIES (NME) – some key facts

1) 12 – 14 years from idea to market introduction

2) At a cost of 2 to 5 B$/NME

3) With an attrition rate of >65% at the end of Phase III clinical phase

12

WHY IS THIS?

- Limited data points (budgetary reasons/technology)

- Lack of early abortion

- Transition from animal to human model often problematic

- Quality clinical trials (a lot of drop-outs)

- Logistic nightmare clinical trials (esp. phase III)

- More severe attitude payors & regulators

We are seeing severe changes in health landscape

13

Trends

Low hanging fruit over, patent cliff, blockbuster model under pressure, higher pressure payors & regulators, …

Broken Pipelines Pharma

1

Efficacy of therapies increasingly requested (cDx) on individual cases, … Power shift to

Payors All

2

cDX, disease management, personalized (precision) medicine, preventive medicine, …

Moving Beyond traditional Diagnosis

Pharma/Dx

3

Source: Johns Hopkins Medicine

14

Trends

Better & cheaper tools becoming available for Dx (diagnostics) & Rx (therapy), potential of ICT & semiconductors, better insights in disease mechanisms, …

Shift in Technology

Focus Dx

4

Shift Shift from point-of-care (POC) to point-of-need (PON)

Increasing Push For Near Patient Testing

Patients

5

Reimbursement strategies reconsidered (outcome based)

Reimburse-ment Strategies

Evolving All

6

Source: Johns Hopkins Medicine

We are seeing severe changes in health landscape

Diagnostics trend from central labs to Point-of-Need

PON

Source: Adapted from Roche investor deck

15

16

Right biomarkers Disease

mechanisms

Diagnostics & cDx

Therapy

Precision disease management

- Therapy compliance - Dose optimization (toxicity) - Therapy resistance

Health care cycle

Big Data

17

Right biomarkers Disease

mechanisms Diagnostics

& cDx Therapy

Precision disease management

- Therapy compliance - Dose optimization (toxicity) - Therapy resistance

Health care cycle

Big Data

Role of NanoElectronics in LS (at imec)

= role for nanoelectronics

Semiconductors for Life sciences

Why imec in healthcare?

▸ Total revenue 2014: 360M€ 445 M€ IN 2016

▸ > 1 Billion € infrastructure installed

▸ >1.4 Billion € new investments planned & being

deployed)

▸ Partnerships with > 600 companies & 208

universities on a global scale

▸ 37 spin-off companies

▸ Headcount 2015: 2300 (excl. iMinds = +1000)

- 1613 imec staff

- 385 industrial residents

- 300 PhD students

- 73 nationalities

FACTS & FIGURES

89% contract

R&D

11% subsidy

RESEARCH PROGRAMS

ELECTRONICS FOR HEALTHCARE & LIFE STYLE

W IRELESSCOMMUNICATION

IMAGE SENSORS & VISION SYSTEMS

ENERGY SENSOR SYSTEMS

FLEX IBLE ELECTRONICS

CORE CMOS

LITHOGRAPHY DEVICES INTERCONNECTS

AP

PL

ICA

TIO

N

DR

IVEN

RESE

AR

CH

TE

CH

NO

LO

GY

D

RIV

EN

RESE

AR

CH

HETEROGENEOUS INTEGRATION

MEMS SENSOR PHOTONICS

Imec has grown over the past 30 years into the largest independent research center for nano-electronics

It uses its unique expertise, infrastructure and technology tool box (horizontal layer) to build game changing

application oriented platforms (verticals) deeply rooted in the horizontal backbone.

21

22

Goals & ambitions in health care

Supercomputers run by consumers

1950 $6,000,000

cm-sized switches

5,000 operations/sec

27 tons

2015 $500

14 nm switches

>30,000,000,000 operations/sec

140 grams

x109

History repeats itself in Life Sciences

x109

Dx

Healthcare @ imec

Body Area Networks

External measurements: ECG,

EEG, galvanic skin response, pulse

oximetry, blood pressure, sweat,

accelerometers, etc.

Life Science Technologies

Measurements of molecules and cells:

molecular diagnostics (DNA, proteins,

metabolites), cytometry, point-of-care

diagnostics, bioreactors, DNA sequencing

Applications: Cancer, infectious diseases,

regenerative therapy, neurodegenerative

diseases, pre-natal diagnosis, consumer health

(biomarker-based), companion Dx

Applications: Neurodegenerative diseases,

consumer health (stress, fitness), cardiovascular

health monitoring

JHU/imec confidential information - December 2014 25

Health patch ECG PATCH

▸ Ultra-low power ECG patch

▸ Bluetooth ultra low energy

▸ Embedded algorithms

▸ 30 days autonomy

RISE IN VALUE CHAIN IS PAYING OFF:

5-YEAR PARTNERSHIP WITH CARDIONET/now

Biotelemetry First FDA approval @ imec/BT

27

WIRELESS EEG

Applications:

▸ Improving traffic safety through drowsiness monitoring

▸ E-learning that adapts to the user’s concentration

▸ Accurate EEG monitoring at home, e.g. epilepsy patients

FROM PLATFORM TO PRODUCT FOR CLINICAL RESEARCH - “with imec R&D innovations inside”

http://www2.imec.be/be_en/press/imec-news/neuropro.html

Miniature spectrometer-on-a-chip with the performance of a bench-top instrument at a fraction of the size and cost

Wearable high-performance spectrometer

conventional bench-top instrument with comparable sensitivity

SiNx photonics

30

TOWARDS < 100€ ‘Genome Chip’

31

From: https://www.genome.gov/27541954/dna-sequencing-costs/

OK for clinical targeted seq applications

Pacific Biosciences single molecule real time sequencing instrument

imec confidential information –2015

Goal: democratizing of DNA sequencing and a crucial pillar for precision medicine

Core $500k machine…

on single, disposable chip

NEXT-next-GEN DNA Sequencing instrumentation-on-a-chip

Single molecule

real time DNA

sequencing

imec confidential information - 2015

7x faster 3x smaller 2x cheaper

Grand challenge: biocompatible miniature electronics

that directly interfaces with the body’s control system:

neurons

34

NEUROSCIENCE LAB-ON-A-CHIP

35

100 µm x 50 µm shank

456 electrodes and amplifiers

52 channels

Low noise: 4µV rms

Recording + stimulation

Replacing >100 kg of tools

for a current neuro-science

experiment!

Signal filtering (LFPs , APs)

Analog-to-digital conversion

Digital interface to small PCB

Direct link to PC

Next generation request >1400 electrodes on a shaft

of < 20 micron diameter, sponsored by leading foundations

36

K.U.LeuvenUniversity Hospital

VIBBiotechnology

imecNanoelectronics

NeuroElectronics Research Flanders

Combining very complementary expertise and critical mass in a unique way at a single

site for exploring the dynamics of neuronal connections in our brain.

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circulating tumor cell

38

CYTOMETRIE: measuring characteristics of cells

circulating tumor cell

CTC diagnostic

market will be $7.9B

by 2018 Transparency Market Research

“Circulating Tumor Cells (CTCs) and

Cancer Stem Cells (CSCs) Market –

Global Scenario, Trends, Size, Growth and

Industry Analysis, 2011 – 2018.”

CTC-based diagnostics will require improved cell detection and isolation solutions that combine high throughput, high sensitivity, multi-modal detection (fluorescence + imaging), and the ability to isolate cells of interest for downstream analysis by next-gen sequencing. We are working on a platform cell manipulation technology that supports the required specifications.

CURRENT CYTOMETRY APPROACHES

• Amnis ImageStream • Flow cytometry with microscopic

imaging

• Conventional microscope

• 1000 cells/s

• Research tool, not for clinical use

FACS (Fluorescence-activated cell sorting)

▸ Beckman-Coulter, Sony (iCyt), Applied Biosystems, BD Biosciences

▸ Research tool (complex to operate)

▸ Biomarker based

data rich

fast

on-chip

cell-sorter

imaging

cytometer

FACS

blue ocean

red sea

40

High-throughput imaging flow cytometer

Input

Output stream 1

Output stream 2

Fast microfluidic bubble-jet

cell routing

Aim is to scale to 20,000,000 cells/s

(identification & sorting)

>1000-fold improvement over current system

Allowing for new applications such as detecting

single circulating tumor cells in a blood

sample.

On-chip high-resolution imaging for

cell classification

In-flow cell tomography

MCF-7

cell

In-flow phase contrast

imaging

41

MiLab Moving the needle in Diagnostics

42

Blood cells

Proteins

Lipids

RNA/DNA viruses

BLOOD CONTAINS A TREASURE OF INFORMATION

... and much more

Diagnostic Testing is largely confined to the centralized laboratory

IN VITRO DIAGNOSTICS USING BLOOD SAMPLES

Takes a few minutes

Decentralized (portable)

at point-of-need

Preferably directed towards prevention,

next to supporting therapeutic decisions

& disease management

Takes one to a few hours (hospital) to

a few days (physician)

Centralized

Curative

CURRENT DIAGNOSTICS FUTURE DIAGNOSTICS

INTEGRATE MULTIPLE STEPS ON A SINGLE CHIP

Example : Hepatitis C virus

NUCLEIC ACID AMPLIFICATION (PCR)

LYSIS + NUCLEIC ACID EXTRACTION

PLASMA SEPARATION

BLOOD

Sample prep on chip !

MiLab: Low cost, accurate, cloud-connected, multi-omic

diagnostics that works via open standard on a device you

already own

CRP

Troponin

CK-MB

Triglycerides

HDL

LDL

Neutrophil/Lympho

cyte ratio

Multi-omic

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The Partners: JHM & IMEC

PARTNERSHIPJOHNS HOPKINS UNIV

PRESS RELEASE

Imec and Johns Hopkins University team to expand healthcare applications

for silicon nanotech

Leuven (Belgium) October 24, 2013 - Researchers and physicians at Johns Hopkins University will

collaborate with the nanoelectronics R&D center imec to advance silicon applications in healthcare,

beginning with development of a device to enable a broad range of clinical tests. The corresponding

tests will be performed outside the laboratory. The collaboration, announced today, will combine the

Johns Hopkins clinical and research expertise with imec’s nanoelectronics capabilities. The two

organizations plan to forge strategic ties with additional collaborators in the healthcare and technology

sectors.

“Johns Hopkins has always prioritized innovative and transformative research opportunities,” said

Landon King, MD, the David Marine Professor of Medicine and executive vice dean of the school of

medicine. “Our new collaboration with imec is such an opportunity, and we very much look forward to

leveraging our respective strengths across the university in biomedical and nanotechnology research to

improve patient diagnosis and care throughout the world.”

Imec and Johns Hopkins University hope to develop the next generation of “lab on a chip” concepts

based on imec technology. The idea is that such a disposable chip could be loaded with a sample of

blood, saliva or urine and then quickly analyzed using a smartphone, tablet or computer, making

diagnostic testing faster and easier for applications such as disease monitoring and management, disease

surveillance, rural health care and clinical trials. Compared with the current system of sending samples

to a laboratory for testing, such an advance would be “the healthcare equivalent of transforming a rotary

telephone into the iPhone,” said Drew Pardoll, MD, PhD, the Martin Abeloff Professor of Oncology.

Pardoll leads the advisory board for the Johns Hopkins-imec collaboration, which will work to extend

new applications of silicon nanotechnology into multiple areas of medicine.

“This relationship with Johns Hopkins is an important step toward creating a powerful cross-disciplinary

ecosystem with consumer electronics and mobile companies, medical device manufacturers, research

centers and the broader bio-pharma and semiconductor industries, to create the combined expertise

required to address huge healthcare challenges that lie ahead,” stated Luc Van den Hove, CEO at imec.

“Only through close collaboration will we be able to develop technology solutions for more accurate,

reliable and low-cost diagnostics that pave the way to better, predictive and preventive home-based

personal health care.”

Rudi Cartuyvels, senior vice president of smart systems at imec, added, “The unique combination of

imec’s nanoelectronics expertise with Johns Hopkins’ proven medical sciences and clinical expertise will

disposable micro-fabricated

test

flexible: blood, saliva, urine

smart phone

health tracking

app + web services

Wireless link

<10 grams <1 cm3

~$10 < 15’ TTR

THE PARTNERS IMEC-JHU: A UNIQUE AND GLOBAL ALLIANCE

miLab / miDiagnostics INITIATIVE

60M€ series A (May 2015)

Accurate diagnostics anywhere, anytime for anyone

Low-cost, Si-based disposable

Leveraging standard semiconductor manufacturing:

scalable to low-cost mass production

Small form factor

Use ubiquitous device as interface (e.g. smartphone)

No separate instrument

Quantitative, accurate and clinically relevant

Sensitivity and specificity that matches reference

methods

Multi-omic

Integration of various assay and sensor types on one

platform

Currently 4 different “pathways” planned

Detection chip

~1 cm

2-4 cm

Fluidics chip

PCB with

radio, power,

control

Packagedisposable

microfabricated test

flexible:

blood, saliva, urine

smart phone

health tracking

app + web

services

Wireless link

<10 grams

<1 cm3

~$10

<15 min

Concept

MiLab : Dx for very different disease areas

Disease screening & Disease management &

follow-up

1

Point of Urgent & Critical Care

3

GP aid for distinguishing fever causes in patients

2

Key Analytes

Nucleic Acid Pathway

Antibody/Protein Pathway

Metabolite Pathway

Cell/Cytology Pathway

Key Applications

Consumer application

4

50

Time to result (TTR) in < 15’

Sou

rce:

Jo

hn

s H

op

kin

s M

edic

ine

Unmet medical needs

INFECTIOUS DISEASES in resource limited regions

• Urgent need for Point-of-Need (PON) MDx tests which match the WHO

ASSURED criteria (special focus on HIV, TB & Malaria):

- Affordable (around 2$)

- Sensitive

- Specific

- User-friendly

- Rapid (<15’) & Robust

- Equipment/instrument free

- Deliverable at place of need (not hospital or lab setting)

• Current POC Dx tests, mostly based upon lateral flow technology:

- Lack of sensitivity

- Lack of specificity

- Not instrument-free

- Often not quantitative

- No direct link to health care ITC network 51

PoN Viral load tester: very high need in developing countries

• Strong need for PON viral load tester: this is an unmet need in most of the developing

countries: - Need is very urgent and large (measuring pathogen/viral DNA or RNA concentrations is

crucial for efficient disease management (compliance, dose optimization, therapy resistance)

and for avoiding re-infection

- Only limited number of expensive viral load testers available in those countries and only in lab

environments (need for special infrastructure & medical expertise)

- In rural areas no access viral load testers. By lack of viral load testers, CD4+ count is done,

which is a poor measurement for disease management.

• Many ID are spreading again or need to be contained: - TB

- Dengue fever

- West-Nile Virus

- HIV

- Malaria

- Sleeping sickness

- HCV

Need for easy to use and cheap PON viral load tester: none existing today: iLab is a perfect candidate.

Imec’s view on the FUTURE of MICROSCOPY

Microscope on chip

CMOS processing

SiN Photonics

Bio-sample

Hologram

Image reconstruction

Integrated light source

Traditional microscope

Diffraction pattern

On-Chip microscopy

Traditional phase-

contrast microscope

Lens-free imager @ imec

Intensity Phase

Human induced pluripotent stem cells

170 µm

54

Miniaturization of blood analysis devices

3-part white blood cell differential

Vercruysse et al., Lab on a chip, 2015

Granulocytes

Monocytes Lymphocytes Inte

rnal co

mp

lexity

Cell size (µm)

Ultra-fast PCR: 40 cycles in < 3 minutes

Scroll further

to 35 seconds

Temperature [°C] Time [s]

98.0 32s

96.0 2s

62.0 2s 40 cycles

Standard 30 cycles PCR > 45+ min.

57

NEXT STEPS

Creation platform & IP company: done (60 M€ SERIES A) Integration building blocks: on-going Clinical validation: starting early 2017 at Johns Hopkins Medicine Regulatory approval: planned 2018 Commercialization: planned for early 2019

58

BIG DATA

EXASCIENCE L IFE LAB

HIGH PERFORMANCE COMPUTING IN LIFE SCIENCES FOR BIG DATA

First focus

• 1. Analytics of DNA sequencing

• 2. In-silico modeling for drug development

Thank you so much!

Discussiepunten (cijfers 2012, ITINERA rapport 2014):

- 70 – 80% zorguitgaven voor chronische aandoeningen (staan ook in voor 70-80% mortaliteit) - 27% Belgen heeft chronische aandoening - Preventie in België is bedroevend laag (0.9%) in vergelijking OESO (2.9%) - Administratie is duurder: 5.2% tov 3.1% OESO gemiddelde - Curatieve zorg en revalidatie: 52.2% budget gezondheidszorg - Gezondheidzorg staat wel in voor 12% beroepsbevolking - Iedere 1% gewonnen kwalitatieve levensjaren op totale actieve bevolking = + 6% BBP (creatieve toegevoegde waarde, koopkracht,…) - België zeer hoge werkbelasting met 11 patiënten/verpleegkundige kwalititeitsrisico’s - 2/3 kwaliteitsproblemen gevolg van ondermaats functioneren in teamverband en van gebrekkige communicatie - Nood aan zorgcontinuum (nu sterk acuut probleemoplossend)

Discussiepunten (cijfers 2012, ITINERA rapport 2014):

- Nood aan complementaire, doelgerichte aanpak via integraal zorgplan - Impliceert ander betalingssysteem en verdienmodel (gezondheidswinst gedreven, geen zero sum game): combinatie van prestatiegericht en meerwaardengedreven - Nood aan meer horizontale organisatie ipv verticale specialisatie organisatiestructuur - Absolute nood aan geïntegreerde ICT systemen (intra & extra muros) als basis integrale zorg - Te veel regelgeving op micro-niveau en te hoge administratieve druk - Rol van overheid eerder kwaliteitsbewaking via kwaliteitsboordtabellen op basis van gezondheidswinst & TQM - Volgens Kaiser Permanente: ruimte voor 25% besparing zorgkosten zonder kwaliteitsverlies door: uniformisering, digitalisering en centralisering van gegevens - Quid koppelen van remgeld aan combinatie van:

• Verantwoordelijk gedrag van patiënt (keerzijde van empowerment) • Kwaliteit van de gekozen zorginstelling (concurrentiebevorderend)

Take away messages GPs