Multi-Organ-Chip developments: Towards a paradigm shift in drug development

Non-Animal Approaches - The Way Forward

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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.

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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

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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

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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

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uwe.marx@tissuse.com;

reyk.horland@tissuse.com

Thank you for your attention

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