multi-organ-chip developments: towards a paradigm shift in ... · the multi-organ-chip (moc)...
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Multi-Organ-Chip developments: Towards a paradigm shift in drug development
Non-Animal Approaches - The Way Forward
- Brussels 2016 -
Transatlantic Think Tank on Toxicology – Berlin June 2015
17 + 5 + 14
National Center for Safety Evaluation for Drugs
JaCVAM
Biology-inspired microphysiological system approaches to solve the prediction dilemma of drug testing
(Adrian Roth and Uwe Marx)
Leading MPS experts from academia and
SMEs
MPS status report
Marx et al., ALTEX 33 (3) 2016 272-321 (36 authors)
Microphysiological systems (MPS)
are microfluidic cell culture devices
capable of emulating human biology at the smallest biologically acceptable scale.
- Brussels 2016 -
Types of MPS and key players
Marx et al. (2016) ALTEX 33 (3) 272-321
Emulate Inc.
Linda Griffith, Cambridge, USA
Michael Shuler, Ithaka, USA
Donald Ingber, at Harvard Medical School, Boston, USA
Uwe Marx. Berlin, Germany
James Hickman, Orlando, USA
Olivier Frey, Zürich, Switzerland
Seattle, USA
Leiden, The Netherlands
- Brussels 2016 -
The Multi-Organ-Chip (MOC) Technology
Organoid Culture Units Microfluidic
Channel
On-Chip Pump Access Point
Features:
Chip format of a standard microscopic slide
On-chip micro-pump and natural tissue to fluid ratio
Variable physiological shear stresses applicable
Tissue cultures 100,000-fold smaller than original organs
Rapid prototyping of any relevant chip design
Compatible with life tissue imaging - Brussels 2016 -
The Multi-Organ-Chip Platform
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Historical sketch of our Multi-Organ-Chip platform 2012 2015 2010 2011 2013 2014 2016
4-Organ-Chip
Kidney
Intestine
- target for food additives - oral administration
- urine removal - toxicity target
2-Organ-Chip
- prime metabolic organ - blood protein supplier
- target for cosmetics - dermal administration
Liver
2018
Human-on-a-Chip
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Skin
Liver
Skin
Bone marrow* 11.
Lymph node 12.
Vasculature
Pancreas 5.
Skeletal muscles 6.
Adipose tissue 7.
ipSC-derived cells
Liver 1.
Intestine 2.
Kidney* 3.
Brain 4.
Skin 8.
Hair* 9.
Lung 10.
Our organoid engineering pipeline de novo assembly
primary cells
commercial models
cell lines
- Brussels 2016 -
tissue explants
punch biopsies
follicular unit extraction
precision cut tissue slices
islets
subcutaneous explants
punch biopsies
* in collaboration with the TU Berlin, Germany
Human 2-Organ-Chip Assays
In-process controls Viability, e.g. LDH metabolism, e.g. glucose cell morphology others
histology qPCR metabolites microarrays -omics others
exposure regimen
8-40 circuits / exp. (n = 3-5)
Human MoA/AOP data-based informed decision, prior to any use in man (or animals)!
de novo assembly of organ equivalents
1-8 weeks 1-4 weeks at homeostasis (preclinical and clinical safety testing)
tissue explants
Endpoint readouts
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Preparing for ADMET: 28d 4-Organ-Chip feasibility
Increased systemic complexity
intestinal lumen: surrogate blood circuit:
excretory circuit:
250 µl 830 µl 600 µl
2 g/l Gluc
10 % HS
2.5 g/l Gluc
10 % HS 1 g/l
Gluc
The 4-Organ-Chip: Intestine – Liver – Skin - Kidney
CK15 CK10 100 µm
NaK ATPase
Cytokeratin 8/18 Vimentin
NaK-ATPase human RPTEC/TERT cell line
Metabolism
Excretion ADMET-Chip Maschmeyer et al., Lab Chip. 2015, 15(12):2688-99
Skin Liver
Kidney
Cytokeratin 19 SmI 24w format
Adsorption
Intestine
Distribution
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4OC prototype
The 4-Organ-Chip as part of PBPK
modeling
urine
bile
+ O2
food & drugs
feces
urine
bile
food & drugs
feces
H2020-PHC-2015-single-stage_RTD (PHC-33-2015, RIA) “Systemic toxicity testing in vitro” Chemical space, Start: 01.01.2016, ~€30m, 5 years, 41 partners http://www.eu-toxrisk.eu/
PBPK- compliant
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Next Generation „Human-on-a-Chip“
https://www.youtube.com/watch?v=S6t30-abqCY Marx et al., Altern Lab Anim. 2012 Oct;40(5):235-57
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Marx et al., ALTEX 2016 May 15. doi: 10.14573/altex.1603161.
Innovative solutions
Industrial adoption
Regulatory acceptance
2015 2020 2025 2030 2035 2010 2005
none (initial MPS evaluation)
none (MPS-based regulatory
science)
single- and multi-organ MPS tools
MoA assessment,
toxicity testing
validated safety assays
A roadmap towards MPS-based decision-making
Marx et al. (2016) ALTEX 33 (3) 272-321
systemic safety testing, disease modeling,
on-chip clinical trials
human „Body-on-
a-chip” models
validated hazard identification,
systemic efficacy assay
- Brussels 2016 -
Thank you for your attention
- Brussels 2016 -