how silicon technology can help transform cell and gene

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How silicon technology can help transform cell and gene therapy

ABOUT IMEC

As a world-leading R&D hub, we

aspire the impossible and aim for radical

innovation. We maximize societal impact by

creating smart sustainable solutions that

enhance life.

At imec, we shape the future.

▪ World-leading R&D in nanoelectronics &

digital technology

▪ >4500 international R&D top talents, >90

nationalities

▪ Unique € 2B leading-edge

semiconductor fabs

▪ Delivering industry relevant technology

solutions serving semiconductor, ICT, IoT,

healthcare and energy markets

▪ 2019: € 640M revenues: 70% industry,

20% regional gov’t, 10 % EU & regional

programs

▪ Collaborating with 600+ industrial partners

▪ Created 118 spin-off companies and

incubated 200+ start ups

▪ 8 sites worldwide

300 mm / 12-inch CMOS PILOT LINE

Operated 24/7

Sub-10 nm CMOS

200 mm /8-inch CMOS PILOT LINE

Operated 24/7

Sensor Technologies

About imec

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200mm pilot line

300mm pilot line

Nano bio labs

NERF labs

Silicon solar cell line

Organic solar cell line

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World-class

infrastructure

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SMART

MOBILITY

SMART

HEALTH

SMART

INDUSTRIES

SMART

CITIES

SMART

EDUCATION

SMART

INFOTAINMENT

SMART

AGROFOOD

SMART

ENERGY

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DIGITAL TECHNOLOGIES

Artificial intelligence

Privacy / cybersecurity

5G network technology

SYSTEM PLATFORMS

Neuromorphic computing

Beamforming platform

DNA sequencing

Nanofluidics processor

Cellsorter

RF technologies for 5G

Wireless sensor hub

Quantum computing

Lens free imaging

Hyperspectral imaging

Solid-state batteries

Solar cell systems

…

TECHNOLOGY PLATFORMS

Logic CMOS

Memory

3D heterogeneous integration

Photonics

MEMS & microfluidics

Sensor platform

Flexible technologies

Innovation platform

What we offer

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TRENDS IN HEALTHCARE

Technology Data

The two primary drivers of change in healthcare

source: CB Insights, 2019, How Healthcare Is Disrupted

Transition to value-based care models

source: Deloitte, 2019 Global Health Care Outlook

Technology is helping in this transition

Blockchain

Cloud-based

computing

Robotic process

automation (RPA)

Virtual Reality

AI

Cloud-based

software-as-a-service

Robotics

Virtual

Health

Digital innovation impacting

more than just clinical – also

impacting back-office operations

like supply chain, finance,

revenue cycle, HRExponential increase in pace and scale

with which digital health care

innovations are emerging.

Internet of Medical

Things

source: CB Insights, 2019, How Healthcare Is Disrupted

And that acceleration is coming to healthcare

Transition to value-based care models

> 300 million registered users

Monthly active user accounts in millions

Drug Discovery Recruitment Real World Evidence

Target selection, protein

simulation, lead candidate

selection

Enrollment,

biometric data,

pre-qualification

Synthetic controls,

supplemental approvals,

novel therapeutic areas

Private data transforming healthcare

Healthcare AI patents heat upTechnology development combined with availability of data

source: CB Insights, Global Healthcare Report 2019

Q1

Number of patents

IMEC OFFERING

STREAMLINING THE CELL THERAPY WORKFLOW

WITH SILICON CHIP SOLUTIONS

The gene therapy pipeline is growingPreclinical through pre-registration phase, 1995–2018

source: Pharma Intelligence, 2018, Gene Therapy: A Paradigm Shift in Medicine;

Argus Research & Capstone Headwaters, 2018, Outsourcing Trends in Biopharma and Cell/Gene Therapy

New Cell and Gene Therapies:

▪ Diabetes

▪ Blindness

▪ Sickle-cell

▪ Hemophilia

▪ β-Thalassemia

▪ Spinal cord injury

▪ (MS) Multiple Sclerosis

▪ CAR-T immunotherapy

▪ (ALS) Amyotrophic Lateral Sclerosis

▪ (ADA-SCID) Adenosine deaminase-deficient

severe combined immunodeficiency “baby

bubble disease”

Oncology and rare diseases are focus therapy areas

43% of the rare disease is considered rare oncologic diseases

source: Pharma Intelligence, 2018, Gene Therapy: A Paradigm Shift in Medicine

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Global cell therapy market share by region, in 2017

AMERICAS37.6%

MIDDLE EAST

& AFRICA

ASIA-PACIFICEUROPE

The global cell therapy market

is expected to reach USD

20,217.00 million in 2023

Challenges for gene therapiesMake reimbursement an issue

Long-term benefits

▪ Approval: single-arm

trials and small number of

patients

▪ To prove long term

benefits we need long

term data.

▪ The longer a gene

therapy takes to have a

significant benefit, the

more likely that payers

are not incentivized to

cover it

Adjustment to funding flows

▪ Financial pressure in

the form of mark-ups

from hospitals or

specialized treatment

centers

▪ Payers to purchase the

gene therapies directly

from the manufacturer?

Value

▪ Value is very personal

▪ How to measure a

healthcare intervention

against that value?

▪ Possible metrics: disease

severity, age of disease

onset, lifetime burden,

personal elements, e.g.

returning to work, burden

for family etc.

Cost

▪ Extremely

expensive,

presents a large

burden to the

healthcare system

▪ US cumulative

budget impact: up

to $3tn

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> 20 days needle-to-needle time

Engineered immune cell therapy Today still a complex workflow

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Higher demands on logistics and quality controlNeeds: higher quality, shorter tat, lower cost

Need for

measurement

Selection

transfection

Selection

upscaling

Process

monitoring

Quality

control

Our innovative sensor platforms

Liquid Biopsies

▪ Cytometry

▪ Genetic

predisposition

▪ Physiological

parameters

▪ Compliance

▪ Immune

response

Precise Cell Engineering

▪ Single cell

transfection

▪ High

throughput cell

sorting

Single Use Bioreactors

▪ Environment (pH, T, DO)

▪ Cell purity, cell

morphology, cell

functionality

▪ Ion sensing

▪ Metabolites & VOCs

▪ Protein levels

▪ Gene expression

▪ ....

Connected

▪ Wireless read out

▪ Quality of data

▪ Privacy

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SENSORS FOR BIOPROCESSING AND CELL THERAPY

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TRADITIONAL BIOPROCESSING

DISPOSABLE BAGS

PRECISION MEDICINE

IMMUNOTHERAPY, GENE THERAPY, ATMP

TISSUE ENGINEERING,

REGENERATIVE MEDICINE

Towards single patient bioprocessingTherapies derived from patient material

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Bioburden in bioprocesses

▪ Total bacterial count: bacteria +

fungi

▪ Specific bacteria quantification:

E. Coli (gram +), S. Aureus (gram -), P.

aeruginosa (gram -), C. Albicans

(yeast)

▪ Bacterial endotoxins

Lipopolysaccharides from gram (–)

cell walls (LPS)

Raw

materials

Process analytical technologies

BIOMANUFACTURING

REGENERATIVE

MEDICINE

PERSONALIZED

MEDICINE

FOCUS ON PROCESS +

QUALITY MONITORINGFOCUS ON ASSAY

DEVELOPMENT

= the use of biological

systems to produce

biomaterials, grown in

specialized equipment

= the process of

replacing, engineering or

regenerating human cells,

tissues or organs to

restore or establish

normal function

= medicine tailored to

the individual patient

based on their predicted

response or risk of

disease

CELL THERAPIES

FOCUS ON PROCESS +

CELL QUALITY

MONITORING

Imec sensor application for bioreactorsEnabling in-line monitoring of metabolites for continuous bioprocesses

Non-evasive interface

▪ Chemo optodes

▪ Spectroscopic sensors

▪ Free floating wireless sensors

Sampling Port

▪ Bypass

▪ Off-line analytics

Disposable Sensor

▪ pH

▪ Dissolved Oxygen

▪ ISFET

▪ Biosensors

▪ RFID

Solid state Flexible

Pump Analytics

Disposable

Reactor Port

Disposable bioreactor

Sampling

port

Imec offering for high performance bioprocess controlPARAMETER IMPORTANCE IN BIOPROCESSES IMEC TECHNOLOGY

pH, temperature, ions, DO Process control ISFET, On-chip photonic sensors, miniaturized ISEs

VOC, CO2, O2, NH3Process control, Metabolism monitoring NIR/Raman spectroscopy / Photoacoustic spectroscopy (on-chip

spectrophotometry)

Small molecules: glucose, glutamine, lactate, ... Metabolism monitoring, media/nutrient monitoring Enzymatic, Raman spectroscopy / Photoacoustic spectroscopy

Pressure Flow rate, shear stress Photonic pressure sensor

Cell genomics (DNA detection) Cell differentiation (CAR-T, stem cells,…) Integrated compact PCR

Cell surface biomarkers Cell identification, differentiation, immune cell activationFluorescent Cytometry, Cell sorter

Photonic multiplex protein biosensor

ProteinIdentification, concentration, growth factors, secreted factors

(BMP, cytokines...)

Photonic multiplex protein biosensor

Antibody based / Label / Label free

Protein Purity On-chip HPLC; Label / Label free

Cell morphology: size, shape, viability, number

(biomass)Cell growth, purity, identification, differentiation

On chip lens free microscopy (LFI), impedance chip

Cell functionality Cell product quality monitoring CMOS MEA, impedance chip

Bacteria, Viruses Bioburden & Contaminants Identification – QC/releaseMagnetic Bead based solution with on-chip PCR,

Integrated compact PCR

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▪ Single patient-disposable

▪ Multiparameter and customizable

▪ multiple measurements, multiple assays, multiple channels on one chip

▪ Automated and self-calibrating

▪ reduce operator interaction/accelerate time to operation/reduce cost

▪ Compatible with IVD/GMP Regulations

▪ closed system/biocompatibility/sterilizable

▪ Higher quality

▪ accurate, reproducible, specific

▪ Higher throughput:

▪ parallelization of 128 sensors, 100 cell sorter channels, ...

▪ Low cost sensors

▪ 5-10 cents/mm2 in high-volume CMOS production

▪ Data solution included

▪ smart, connected, distributed, thrusted and easy data access

Most powerful chip platform meets

immunotherapy specs for bioreactors

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MINIATURIZED, PARALLELIZED CELL SORTER FOR PRECISION

MANUFACTURING

Car-T production still has a few issues

Cost Variability in product

specificationsDelicate and complex

manufacturing

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Towards precision manufacturing

Quality AffordableFastPrecise

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Processing of 1 - 2 billion PBMCs

20 days manufacturing cost per patient

T cell manufacturing today

1 patient

2 FACS

machines

4 operators

2 shifts

Equals 32 imec cell sorters

Less than 1 hour processing time

No impact on viability

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Cell sorter for cytometryEasy to parallelize to get a high rate of cell sorting

▪ Current cell sorting systems (glass or plastic based)

▪ Critical components integrated in instrument leading

▪ Low versatility

▪ Very high instrument cost.

▪ Imec cell sorter (Thermal bubble switch actuator

combined with silicon chip technology and

integrated photonics)

▪ Unlimited scope & applicability

▪ Color & morphology based sorting

▪ Multiple holding chambers

▪ Parallelization of channels for increased sample processing

▪ One workflow for cell sorting & molecular measurement

▪ Lens-free images of sorted cells

▪ Fastest cell sorting actuator

Imec’s on-chip cell sorter system

▪ Specifications:

▪ Area: 1 mm2 / channel

▪ 5000 cells/sec/channel achieved

▪ Sorted purity: >98%

▪ 1m/s cell speed

▪ Monolithic microfluidic chip

▪ No moving parts: excellent durability

On-chip

microscopy

Fluorescent

detection

Rapid on chip

sorting

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LENS FREE IMAGING FOR AUTOMATED CELL QUALITY IMAGING

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Key technologyLens free imaging for automated cell quality imaging

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Large field of view = imager size ~ 6.4mm x 4.6mm

High level of detail

(1.23um resolution)

Compact microscopy for cell culture monitoringCompact, large field of view, <1µm resolution

▪ Compared to conventional microscopy:

▪ 10 x field of view

▪ 25 x smaller

▪ Less than 1µm resolution

Osteoblast cell culture -

visible sub-cellular

structures, such as

chromatin aggregates &

nuclei

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Tumor cells

Inte

rnal

gra

nula

rity

(A

.U.)

Eosinophils

Neutrophils

Monocytes

Basophils

LymphocytesT cells

Imec’s approach to examining single cellsLens-free imaging based flow cytometry of white blood cells

▪ Lens-free imaging based flow

cytometry of white blood cells:

▪ Evaluate diameter and internal

complexity

▪ Additional extensive image

feature analysis

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MULTI ELECTRODE ARRAY FOR PRECISE CELL TRANSDUCTION

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Key technologyMulti electrode array for precise cell transduction

High density MEA platform

▪ Functionality:

▪ Extracellular & intracellular recording

▪ Electrical stimulation (current and voltage)

▪ Impedance (imaging and spectroscopy)

▪ Features:

▪ 0.13µm CMOS technology (active pixel design)

▪ 16,384 electrodes (distributed over 16 areas)

▪ Pitch = 15µm (density: 4444 electrodes/mm2)

▪ 1024 simultaneous readout channels

▪ In-house CMOS compatible BEOL processed TiN electrodes

(9um2 -121um2)

▪ Sampling rate: 30kS/s

Precise gene editing through single cell electroporation

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▪ Imec’s MEA platform:

▪ Single cell measurement

▪ Single cell electroporation

▪ Precise transfection

Managing cell modification variability & efficiency

CMOS array Cardiac Cell culture

on CMOS array

Activated single cell Activated single cell

Single cell electroporationPrecise control + small voltage

▪ Lower cost per patient and with higher turnaround times

▪ Sample-to-result in one chip

▪ Full PCR analysis in less than 10 minutes

Packaging: combine low-cost, large

volume plastics with small, high

precision silicon microfluidics

Ultra fast PCR

microreactor:

40 cycles in 3 minutes

Integrated droplet

generator, sorter &

merging and on-chip

digital PCR

Integrated filters for

DNA / protein

purification /

separation

Crossflow filter for

on-chip enrichment

and plasma separation

Micropillar filters for

DNA or RNA

extraction, surface

enhancement

From sample to resultBioburden DNA testing

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Immune sensor arrays and micro-Elisa’s

▪ Standardized silicon chip

▪ 200mm production flow

▪ Multiplexing

▪ E.g. up to 100 sensors to measure

100 proteins at the same time

▪ Customizable

▪ High specificity limits of detection

vs. very fast detection.

▪ Integrated photonic waveguide circuits

▪ detect refraction index or fluorescent

changes induced by affinity reactions.

▪ Limited manual steps (wash free)

▪ No need for large microscopes to analyze tissue

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Fast, sensitive tests supporting mobile diagnostics

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how silicon technology can help transform cell and gene

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