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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
PUBLIC
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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STREAMLINING THE CELL THERAPY WORKFLOW
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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STREAMLINING THE CELL THERAPY WORKFLOW
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
MOVIE
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STREAMLINING THE CELL THERAPY WORKFLOW
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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STREAMLINING THE CELL THERAPY WORKFLOW
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
STREAMLINING THE CELL THERAPY WORKFLOW
▪ 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
54
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
PUBLIC
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