TOWARDS A PARADIGM CHANGE IN NON-CLINICAL DRUG DEVELOPMENT AND TOXICITY SCREENING - Spectaris
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MICROPHYSIOLOGICAL ORGAN-ON-A-CHIP PLATFORMS:
TOWARDS A PARADIGM CHANGE IN NON-CLINICAL
DRUG DEVELOPMENT AND TOXICITY SCREENING
Jun.-Prof. Dr. Peter Loskill
µOrgano Lab
1) AttractGroup Organ-on-a-Chip, Fraunhofer IGB,
Stuttgart, Germany
of Women’s Health, Faculty of Medicine
2) Dept.
Eberhard Karls University Tübingen
Lab.Vision 2019
Ludwigshafen, DE
May 8th, 2019
© Fraunhofer IGB
Autonomous Blockchain Next
Vehicles Generation
Batteries
Nanosensors
Two- and the
Dimensional Internet of
Materials Nanothings
Open AI Optogenetics Organ-on- Perovskite
Ecosystem a-chip Solar Cells
Systems
Metabolic
Engineering
© Fraunhofer IGB
Why Organ-on-a-chip?
MOORE‘s Law
© Fraunhofer IGB
Why Organ-on-a-chip?
EROOM‘s Law
Scannell et al., Nat Rev
Drug Discovery (2012)
© Fraunhofer IGB
Why Organ-on-a-chip?
➥ The era of
imprecision medicine
Adverse drug events:
Cause of death for more than:
197 000 (Europeans)
180 000 (Americans)
➥ More than colon cancer!
Limited drug efficacy:
(Best grossing) drugs do not help the
majority of the patients
Personalized
SOURCE: U.S. Centers for Disease Control and medicine: Time for
Prevention and Journal of the American Medical one-person trials, N.J.
Association (JAMA) Schork, Nature, 2015.
© Fraunhofer IGB
Why Organ-on-a-chip?
Extremely important transition but Population-based studies
inefficient and ineffective of drugs for individuals
A. Mosig, J. Nawroth, and P. Loskill, DZKF (2017)
© Fraunhofer IGB
Why Organ-on-a-chip?
Cell assays Animal models
Human genetic background Complex tissue architecture
Standardized & automated Circulation
Cost efficient Systemic effects
No perfusion Different physiology
No mechanical forces Different immune system
Cell to media ratio too low Specific environment & diet
2D (mono-)cultures of Strain-specific results due to
(cancer) cells on hard plastic (in)breeding
© Fraunhofer IGB
What defines an Organ-on-a-chip?
Human tissue
In vivo structure & function
Physiological microenvironment
Microfluidic perfusion
… yields microphysiological
The human body … Organ-on-a-chip systems
…as a
structural
blueprint and
as a cell (primary, iPS)
source …
… together with a tailored
microfluidic platform …
A. Mathur, P. Loskill et al., Stem Cell Res & Ther (2013)
“a fit-for-purpose microfluidic device, containing living engineered organ substructures in a controlled microenvironment,
that recapitulates one or more aspects of the organ’s dynamics, functionality and (patho)physiological response in vivo
under real-time monitoring” As defined by the ORCHID Vision Workshop
This project has received funding from the European Union’s
Horizon 2020 research and innovation programme under
© Fraunhofer IGB
grant agreement No 766884
What defines an Organ-on-a-chip?
Cell assays Animal models
Human genetic background Complex tissue architecture
Standardized & automated Circulation
Cost efficient Systemic effects
No perfusion Different physiology
No mechanical forces Different immune system
Microphysiological Systems
Cell to media ratio too low Specific environment & diet
Human engineered tissues
2D (mono-)cultures of Strain-specific results due to
In vivo structure & function
(cancer) cells on hard plastic (in)breeding
Microphysiological environment
© Fraunhofer IGB
What defines an Organ-on-a-chip?
➥ More than „just“ a drug screening tool!
J. Rogal, C. Probst, and P. Loskill, Future Science OA (2017)
© Fraunhofer IGB A. Mosig, J. Nawroth, and P. Loskill, DZKF (2017)The µOrgano Lab
PDMS modul PDMS modul
untreated „barrier coating“
Advanced chip materials &
A. Mathur et al. Sci Rep (2015)
N. Huebsch et al. Sci Rep (2016)
coatings
O. Schneider et al. under review
Heart-on-a- Retina-on-a-
chip chip
O. Schneider et al.
under review Enabling
OoC- K. Achberger et al. under review
J. Haderspeck et al. Expert Opin
technol-
Systems Drug Discov (2019)
ogies
Automation Multi-organ
concepts integration
J. Rogal et al., Future
Science OA (2017)
WAT-on-a- Pancreas-
P. Loskill et al. PLOS
chip on-a-chip ONE (2015)
P. Loskill et al. Lab Chip (2017) A. Zbinden et al. C. Probst et al. COBME (2018)
J. Rogal et al. under review under review
S. Schneider et al. under review
Women‘s
Diabetes
health Applications research
research
Centre for
Women’s Health
Compound & Tox screening
J. Nawroth*, J. Rogal*, M. Weiss, S. Y. Brucker, P.Loskill,
Adv. Healthcare Mater. (2017) (small molecules & biologicals) J. Rogal*, A Zbinden*, K. Schenke-Layland, P.Loskill, ADDR (2018)
© Fraunhofer IGBThe µOrgano Lab
PDMS modul PDMS modul
untreated „barrier coating“
Advanced chip materials &
A. Mathur et al. Sci Rep (2015)
N. Huebsch et al. Sci Rep (2016)
coatings
O. Schneider et al. under review
Heart-on-a- Retina-on-a-
chip chip
O. Schneider et al.
under review Enabling
OoC- K. Achberger et al. under review
J. Haderspeck et al. Expert Opin
technol-
Systems Drug Discov (2019)
ogies
Automation Multi-organ
concepts integration
J. Rogal et al., Future
Science OA (2017)
WAT-on-a- Pancreas-
P. Loskill et al. PLOS
chip on-a-chip ONE (2015)
P. Loskill et al. Lab Chip (2017) A. Zbinden et al. C. Probst et al. COBME (2018)
J. Rogal et al. under review under review
S. Schneider et al. under review
Women‘s
Diabetes
health Applications research
research
Centre for
Women’s Health
Compound & Tox screening
J. Nawroth*, J. Rogal*, M. Weiss, S. Y. Brucker, P.Loskill,
Adv. Healthcare Mater. (2017) (small molecules & biologicals) J. Rogal*, A Zbinden*, K. Schenke-Layland, P.Loskill, ADDR (2018)
© Fraunhofer IGBHeart diseases
Leading cause of death
Few new drugs
2014 FDA Drug Approvals
Mullard, A. Nat Rev Drug discovery (2015) 2014 Data from Center for Disease Control and Prevention CDC
© Fraunhofer IGBHeart diseases Leading cause of death Few new drugs Adverse cardiovascular events are number one cause of drug withdrawal, limitation, or development termination Laverty, H. et al. Br J Pharmacol (2011) © Fraunhofer IGB
Cardiac in vitro systems
Engineered heart tissues Micro heart chambers Micro heart fibers
Zimmermann et al.
Nat Med (2006)
Z. Ma, J. Wang, P. Loskill et al. Nat. Commun.
(2015)
Liau et al. Biomaterials (2011) N. Huebsch, P. Loskill et al. Sci. Rep. (2016)
➥ Need for microscale models featuring vasculature-like perfusion
© Fraunhofer IGBHeart-on-a-chip
➥ Recapitulate the human
heart / myocardium
Strongly aligned
cardiomyocytes between
perimysial collagen fibers
Cell chamber mimics
perimysial fiber spacing
150 µm
150 µm
©Patrick J. Lynch, C. Carl Jaffe Kanzaki et al.,
Circulation 2010
A. Mathur, P. Loskill, et al. Sci. Rep. (2015)
© Fraunhofer IGBHeart-on-a-chip
➥ Recapitulate the human
heart / myocardium
Strongly aligned
cardiomyocytes between
perimysial collagen fibers
Cell chamber mimics Convective transport
perimysial fiber spacing in media channels
Separate media & cell Diffusive transport to
channels connected by µ- the tissue
pores
Tissue protected from
Vasculature-like perfusion shear forces
with endothelial-like barrier
hiPSC based cardiac 3D
tissue with aligned structure
A. Mathur, P. Loskill, et al. Sci. Rep. (2015)
© Fraunhofer IGBHeart-on-a-chip
➥ Recapitulate the human
heart / myocardium
Strongly aligned
cardiomyocytes between
perimysial collagen fibers
Cell chamber mimics
perimysial fiber spacing
Separate media & cell
channels connected by µ-
pores
Vasculature-like perfusion
with endothelial-like barrier
hiPSC based cardiac 3D
tissue with aligned structure
Anisotropic physiological
beating w/o pacing
Functional > 1 month
A. Mathur, P. Loskill, et al. Sci. Rep. (2015)
© Fraunhofer IGB„Next-Gen“ Heart-on-a-chip 2.0
1) Scale-up & parallelization
Multilayer module w/ separated media channels and tissue chambers
Dumbbell structured chambers for highly aligned tissues
Parallelized system featuring 8 individual tissue chambers
O. Schneider, … , P. Loskill Tissue Eng (2019)
© Fraunhofer IGB PCT/EP2018/065723, patent pending.„Next-Gen“ Heart-on-a-chip 2.0
2) Automation & user-friendliness
O. Schneider, … , P. Loskill Tissue Eng (2019)
© Fraunhofer IGB PCT/EP2018/065723, patent pending.„Next-Gen“ Heart-on-a-chip 2.0
2) Automation & user-friendliness
FC
ω
1. Transport of cells into microchannels
FC
a) b)
F||
Centrifugation-based tissue generation
Compatible with standard laboratory centrifuges 1 1
Cell injection via precisely controllable centrifugal force 2 2
Sequential & reproducible dense filling of multiple tissue
chambers 2. Filling of 3D-chambers sequentially
O. Schneider, … , P. Loskill Tissue Eng (2019)
© Fraunhofer IGB PCT/EP2018/065723, patent pending.„Next-Gen“ Heart-on-a-chip 2.0
➥ Highly efficient generation of multiple independent cardiac tissues
Physiological structure
O. Schneider, … , P. Loskill Tissue Eng (2019)
© Fraunhofer IGB PCT/EP2018/065723, patent pending.„Next-Gen“ Heart-on-a-chip 2.0
➥ Highly efficient generation of multiple independent cardiac tissues
Physiological structure
Physiological functionality
O. Schneider, … , P. Loskill Tissue Eng (2019)
© Fraunhofer IGB PCT/EP2018/065723, patent pending.„Next-Gen“ Heart-on-a-chip 2.0
➥ Highly efficient generation of multiple independent cardiac tissues
Physiological structure
Physiological functionality
Long-term stable
O. Schneider, … , P. Loskill Tissue Eng (2019)
© Fraunhofer IGB PCT/EP2018/065723, patent pending.„Next-Gen“ Heart-on-a-chip 2.0
➥ Highly efficient generation of multiple independent cardiac tissues
Physiological structure
Physiological functionality
Long-term stable
Applicable for compound screening
(multiple replicates simultaneously,
repeated dose)
O. Schneider, … , P. Loskill Tissue Eng (2019)
© Fraunhofer IGB PCT/EP2018/065723, patent pending.„Next-Gen“ Heart-on-a-chip 2.0
➥ Integration of motion sensors
(OpenHeartWare)
frame n
frame n+1
Segment image into individual blocks
Block-matching algorithm to determine optical flow
Find best matching block in defined region in subsequent
frame
➥ User-friendly reconstruction of motion vectors
O. Schneider, … , P. Loskill Tissue Eng (2019)
© Fraunhofer IGB PCT/EP2018/065723, patent pending.„Next-Gen“ Heart-on-a-chip 2.0
➥ Integration of motion sensors
(OpenHeartWare)
O. Schneider, … , P. Loskill Tissue Eng (2019)
© Fraunhofer IGB PCT/EP2018/065723, patent pending.„Next-Gen“ Heart-on-a-chip 2.0
Drug development Replace animal testing
Toxicity screening Increase relevance
Disease modeling Increased throughput and
transferability
Personalised medicine
Amenable for automation
Centrifugal Heart-chip
Incorporates cardiac tissue derived from human iPSCs
Vasculature-like perfusion and physiological transport processes
Enables parallelized generation of dense 3D tissues with precisely controlled
stresses
Enables long-term culture (> 1 month)
Validated via functional characterisation and compound screening
Easy to use & compatible with standard lab equipment & prevents bubble
formation
O. Schneider, … , P. Loskill Tissue Eng (2019)
© Fraunhofer IGB PCT/EP2018/065723, patent pending.Thank you for your attention Visit us at www.loskill-lab.com
➥ Funding
Follow us on @OoaCLab
FhG Programs: Attract, Talenta Start,
Dr. Christopher Probst Discover, MAVO, MEF
Dr. Madalena Cipriano MRC: NC3Rs CRACK IT
Dr. med. Martin Weiss EU: FET-Open ORCHID, MSCA ITN
EUROoC
Julia Rogal DFG: LO 2081/1-1
Johanna Chuchuy BW Foundation
Stefan Schneider DAAD PPP
Oliver Schneider
Elena Kromidas
Katharina Schlünder
Silvia Kolbus-Hernandez
Kirstin Linke ➥ Collaborators
Cristhian Rojas
Stefan Liebau, Katja Schenke-Layland
Stefanie Fuchs (University of Tübingen)
Marina Albaladejo Siguan Andreas Stahl, Kevin Healy (UC Berkeley)
Aline Zbinden Alexander Mosig (Jena University)
Silke Keller Joost Overduin Sandra Sturm Frank Sonntag (Fraunhofer IWS)
Lisa Zeifang Alina Grobel Ibrahim Maulana Katherina Sewald (Fraunhofer ITEM)
Lydia Moll Carla Sailer Florian Erdemann Nathanial Huebsch (WashU St. Louis)
Lisa Rebers Annika Foit Eva Forsten Bruce Conklin (Gladstone Institute)
Lejla Strauss Thomas Hutschalik Lisa Michalek Stefan Kustermann (Roche)
Lydia Seelos Esther Richter Carina Binder
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