Multi-Organ-Chip technology

Lush Prize Conference 2018

Ilka Maschmeyer

TissUse – Location
pharma contracts
Manufacturing
iPS cell banking

Oudenarder Strasse 1613347 Berlin

Consumer product industry contracts
organogenesis research“Human-on-a-chip” development

Gustav-Meyer-Allee 2513355 BerlinDrug development today
DRUGSUB
STA
NC
ESlaboratory
animalshuman
2D & 3Dcell culture

preclinics

Marketefficacy

safety~60 volunteers/substance~ 3000 patients/substance

-13.5
-9-11

Discovery

Leadoptimization-8

Preclinics-6,5

Phase I-4

Phase II-1.5

Phase IIIup to $2.5 B, 13.5 years
laboratory animal studies -in vitro testing -clinical trials -Time (years)

0Submission

Patients’
MarketToday

The drug development dilemma

animal models
systemic but not humanstatic 2D & 3D
human cell culture
human but not systemic“Human-on-a-Chip”
human and systemicMulti-Organ-Chip platform development
2011

2010

2012

2013

2-Organ-Chip2014

4-Organ-Chip

2015

2016

Human-on-a-Chip

LiverSkin

Liver- prime metabolic organ- blood protein supplierSkin- target for cosmetics- dermal administration

Intestine

Kidney- target for food additives- oral administration- urine removal- toxicity target

2018Industrial adoption of the skin-liver model
10µM
1 µM
1 nM

Air

7-d skin-liver co-culture

EpiSkin®

“skin”

Retinoic acid

100 nM“liver”

6-d skin-liver co-culture
readouts: gene expression, metabolites
CRABP2 (Day 7)(cellular retinoic acid–binding protein 2)

 Tech transfer
li = liver; sk = skin

Substance administration route matters

Time course of retinoic acid penetration
through the EpiDerm model in transwells
1600.00

RA-CONC. [NM]1400.00
1200.00
1000.00
800.00600.00400.00200.000.0030 min

1h2h4h6h11h24hK 30 min K24 hDMSO
30 minLC/MS Q-Exactive analyses of pooled samples obtained from 2 skin models/time point
Applied: 3 µl of 83,4 µM RA in 0.1% DMSO/H2O. Endvolume 250 µl

Retinoic acid metabolite analyses

Retinoic acid metabolite analyses
induced direct
glucuronidation

repeated systemic exposure
repeated systemic exposure

Repeated application

repeated topical exposure

96012414

Cumulative long-term effects assessable

14472

96

4848

2428242419191499144400

Peak area

M10Systemic vs topical application: permethrin metabolite kinetics

Metabolite peak area
(normalised to nM applied)•Metabolite kinetics of single topical application were different from a single systemic application•Repeat topical application resulted in similar metabolic profile to repeated systemic application –only M2 and M16 were present at lower concentrations

Metabolite peak area
(normalised to nM applied)

Metabolite peak area
(normalised to nM applied)

MOC model lab comparison: permethrin metabolite kinetics

TissUseSystemic: repeat application
80000
60000
40000
2000000123Time (Days)

45

Our 3D organoid engineering
pipeline
primary cells/
tissue explants

iPS-derived

cell lines

Liver 1.

VIntestine 2.
Kidney 3.
Brain 4.
Pancreas 5.

isletsVSkeletal muscles 6.
Adipose tissue 7.

subcutaneous explants

Skin 8.

punch biopsies

Hair 9.

follicular unit extraction

VV

Lung 10.
Bone-marrow 11.

13 single organ
models establishedpunch biopsies

12 multi-organ
combinations
established

Lymph node* 12.
Vasculature 13.

(as of July 2017)

3D Lung tumor*in collaboration with ProBioGen, Germany

V - validated commercially available 3D models

Examples of Established Multi-Organ-Chip Assays
Skin – Liver
Wagner et al. (2013)
Maschmeyer et al. (2015)

Skin – 3D Tumor
Hübner et al. (2018)(accepted)

Intestine – Liver
Maschmeyer et al. (2015)

Bone marrow
Sieber et al. (2017)

Liver – Neuro
Materne et al. (2015)

Intestine – Liver – Skin – Kidney
Maschmeyer et al. (2015)

Liver – Pancreas
Bauer et al. (2017)
Immunocompetent Skin(biopsies) and hair follicles
Atac et al. (2013)
Liver – Lung

14

Intestine – Liver – Neuro – Kidney
Ramme et al. (2018)(submitted)
Optional: add vasculature
Schimek et al. (2013)
Hasenberg et al. (2015)

Outlook: Our Upcoming MOC-Robot Will Further Increase
Efficiency and Cost-Effectiveness of Our End-to-End-Solution

Acknowledgements
Our “Humans” on a shipIlka.maschmeyer@tissuse.com
www.tissuse.com