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Organ-on-a-chip

전누리
서울대학교
기계항공공학부
[email protected]
What is “Organ-on-a-chip”?
What is Organ-on-a-chip?
What is Organ-on-a-chip?

Bioengineering Mechanical engineering

Organ-on-a-chip http://www.edutrics.com/wp-content/uploads
https://www.wired.com/2015/06/chip-mimics-human-organs-design-year/
What is Organ-on-a-chip?

http://home.sogang.ac.kr/sites/nbel/Research/Pages/Cell%20Chip.aspx
Importance of Organ-on-a-chip
Expecting technologies in July, 2015

http://www.gartner.com/technology/home.jsp
The purpose of Organ-on-a-chip

Disease Model

New drug development

Huh, Dongeun, et al. Science (2010)

Chemical Drugs (신약) vs. Biologics (바이오시밀러)
Biosimilar (바이오시밀러)
✓ “Highly similar” to an already-approved biological product

✓ Can save U.S. $250 billion over the next decade

http://www.hcrnetwork.com/biosimilars-market-in-the-us-2015/
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/
http://www.popsci.com/what-is-biosimilar
SAMSUNG BIOEPIS

http://blog.samsung.co.kr/5682
http://www.enewstoday.co.kr/news/articleView.html?
http://news.newsway.co.kr/view.php?tp=1&ud=2016090810312972685&md=20160908103409_AO
http://news.mtn.co.kr/newscenter/news_viewer.mtn?gidx=2016100409383584361
Drug development process

http://www.ppdi.com/About/About-Drug-Discovery-and-Development
Clinical Trial (임상시험)
New drug development
In pre-clinical research, we should test

✓ Toxicity and Efficacy

✓ Test first on animal models
✓ Whether it is safe to test on human
New drug development

e s t
a l t d
i n i c n g e
- c l h a
P r e e c
l d b
o u
sh

https://www.retaildetail.eu/en/news/drogmetica/european-ban-animal-testing-cosmetics-upheld
http://crpc.kist.re.kr/common/attachfile/attachfileNumPdf.do?boardNo=00004944&boardInfoNo=0023&rowNo=1
Necessity of the research
Problems of in-vivo experiments Replacement : Organ-on-a-Chip

Draize Test

• Limited experimental group

• Ethical problems

• Economical inefficiency

• Heterogeneous nature of cell

Huh et al, 2012. Lab Chip.
New drug development
Emerging Trends in Drug Screening

In vivo In vitro In vivo

(animal) (biochemical) (immortalized cells)
screening screening screening

Phenomenological   Target  based   Target  based  

Low  throughput   High  throughput   High  throughput  
Disease  relevance? Disease  relevance  -­‐  low Disease  relevance?

In vivo In vivo In vivo

(3D tissue assemblies) (ES and iPS cells) (primary cells)
screening screening screening

Phenotypically  based   Phenotypically  based   Phenotypically  based  

Throughput?   High  throughput   Low  throughput  
Disease  relevance  -­‐  high Disease  relevance  -­‐  high Disease  relevance  -­‐  high
The history of Organ-on-a-chip
Neutrophil Chemotaxis
“Old” Tools Still Used in Biology
 No Control Over
Individual Cells, Cell-ECM
and Cell-Cell Interactions
Custom “Apartments for Cells”
and “Communities of Cells”
 Microfluidics
manipulation of fluids in small channels

• Micrototal Analysis System (μTAS)

• Genomic analysis
• Protein analysis
• High throughput screening
• Cell Biology and Neuroscience

microfluidic gene sequencing LabChip µTAS (Caliper) Cell Sorter (Fluidigm)

Multiscale Control of Cellular
Microenvironments
 2D Culture

Petri-dish culture
Life is in 3D
2D Culture

✓ Soluble gradients absent

✓ Forced apical-basal polarity

✓ Continuous layer of matrix

✓ Unconstrained spreading in x-y

plane

✓ Adhesions restricted to x-y plane

✓ High stiffness

Christopher S. Chen, Journal of cell science (2012)

3D Culture
Organ-on-a-chip
Organ-on-a-chip
Organ-on-a-Chip
Lung-on-a-Chip
Lung-on-a-Chip
 Blood Vessel on a Chip:
Toward Vascularized Micro-Tissue Engineered Constructs
 Loading Gelsnad Cells
in Spatially Controlled Manner
Vasculogenesis
Day 0

100 μⅿ
 Vasculogenesis Microfluidic Platform
Fibroblast-HUVEC-Fibroblast
in Fibrin-Collagen matrix Spontaneous network formation

Day 1 Day 2

100 µm

Day 3 Day 4
Vasculogenic Vessel Formation
Day 1 Day 2

Day 3 Day 4

100 um
 Lumen-Cross Section for
Vasculogenic Vessels

Nuclei *
F-actin
CD31

yz plane
xy plane

xz plane

* *
Angiogenesis
Day 0

500 μⅿ
 Blood vessel formation
Vasculogenesis Angiogenesis 80
2 million cells/ml

Vascular area coverage (%)

Day 1

3 million cells/ml
60
100 µm
40

20
Day 2

0
Day 1 Day 2 Day 3 Day 4

700

Average sprout length (µm)

Day 3

525

350

175
Day 4

0
Day 1 Day 2 Day 3 Day 4
Establishment of Perfusable Vessels
Vasculogenesis-derived network
Day 4

~ 88 % success rate
(n = 36 chips)
Nuclei F-actin CD31

100 µm
Microbeads flowing through
the vascular network
 Vessel Characterization:
Apical-Basal Polarity

Nuclei
ICAM-1
Collagen IV
 Vessel Permeability
(Fluorescent Dextran 70KD)

FITC-dextran
HUVECs

Extravascular
fibrin matrix
Compatible with High Resolution Microscopy

F-actin
Nucleus
Live-Cell Imaging of Tip Cell Dynamics
Engineering Functional, Perfusable
3D Microvascular Networks

Kim et al. Lab Chip, 2013

Selected as Top 10% paper, Research highlights
Blood Vessels On-A-Chip

24mm x 24mm coverslip

Organ-on-a Chip
Research Groups
 3D in vitro disease model 3D tissue reconstruction

Seok Chung
Korea University

Angiogenesis

Translational research

Cancer metastasis
 Pathogen detection chip Anticancer chip

Sungsu Park
Sungkyunkwan
University

Cell elongation chip

 3D in vitro gut model Multi organ on a chip

Jong Hwan Sung

Hongik University
 Vasculature on a Chip Brain on a Chip

Noo Li Jeon
Seoul National
University

New Fabrication Cell Dynamics

 Gut-on-a-chip Lung-on-a-chip

Dan Huh
University of
Pennsylvania

Eye-on-a-chip
 Biological machines / Microfluidics

Roger Kamm
MIT
Simulation and modeling

Cancer

Angiogenesis / Vasculogenesis
 3D tissue construction Neural interface

Shoji Takeuchi
University of Tokyo

Membrane protein chip

Companies
: Organ-on-a-chip
1. Emulate

Field of Emulation
specification human biology

Year Founded 2014

Total Funding $40Million

$28Million
Recent Funding
(March 28, 2016)
Cambridge,
Headquarters
Massachusetts

Size of corporation 25-50 employees

Website http://emulatebio.com

https://emulatebio.com/insight/tedmed-2015/
2. Mimetas

Field of Microfluidic,
specification Organ on a chip

Year Founded 2013

Total Funding $8.4Million

$1.6Million
Recent Funding
(January 5, 2016)
Leiden,
Headquarters
Nederland

Size of corporation 35-50 employees

Website http://ww.mimetas.com

3D networks of iPSC-derived neurons and glia for high-throughput neurotoxicity screening,

N.R. Wevers, K.J. Wilschut, R. van Vught, H.L. Lanz, S.J. Trietsch, J. Joore & P. Vulto
3. Nortis Bio

xxx

Field of Microfluidic,
specification Organ on a chip

Year Founded 2012

Total Funding $2.65Million

$0.41Million
Recent Funding
(March 19, 2015)
Seattle,
Headquarters
Washington

Size of corporation 30-40 employees

Website http://ww.nortisbio.com

A human liver microphysiology platform for investigating physiology, drug safety, and
disease models, Lawrence A. Vernetti, Nina Senutovitch, Robert Boltz
4. Hepregen

xxx

Field of Liver,
specification In-vitro testing

Year Founded 2007

Total Funding $3Million

$0.5Million
Recent Funding
(June 27, 2012)
Medford,
Headquarters
Massachusetts

Size of corporation 10-25 employees

Website http://www.hepregen.com

A Micropatterned Hepatocyte Coculture Model for Assessment of Liver Toxicity Using High-Content
Imaging Analysis. Assay Drug Dev Technol., Vol. 12 (1), p 16-27, (2014).
Summary
Summary
1) Petri-dish culture 2) 2D patterned chip

4) Organ-on-a-chip 3) 3D Cell Spheroid

What is Organ-on-a-chip?
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