전누리 서울대학교 기계항공공학부 njeon@snu.ac.kr

인체장기칩

Organ-on-a-chip

mailto:njeon@snu.ac.kr

What is “Organ-on-a-chip”?

What is Organ-on-a-chip?

What is Organ-on-a-chip?

Bioengineering Mechanical engineering

http://www.edutrics.com/wp-content/uploads https://www.wired.com/2015/06/chip-mimics-human-organs-design-year/

Organ-on-a-chip

What is Organ-on-a-chip?

http://home.sogang.ac.kr/sites/nbel/Research/Pages/Cell%20Chip.aspx

Importance of Organ-on-a-chip

http://www.gartner.com/technology/home.jsp

Expecting technologies in July, 2015

The purpose of Organ-on-a-chip

Disease Model

New drug development

Huh, Dongeun, et al. Science (2010)

Chemical Drugs (신약) vs. Biologics (바이오시밀러)

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

Biosimilar (바이오시밀러)

✓ “Highly similar” to an already-approved biological product


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

http://blog.samsung.co.kr/5682http://www.enewstoday.co.kr/news/articleView.html?

idxno=609668

SAMSUNG BIOEPIS

http://news.newsway.co.kr/view.php?tp=1&ud=2016090810312972685&md=20160908103409_AOhttp://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

https://www.retaildetail.eu/en/news/drogmetica/european-ban-animal-testing-cosmetics-upheldhttp://crpc.kist.re.kr/common/attachfile/attachfileNumPdf.do?boardNo=00004944&boardInfoNo=0023&rowNo=1

Pre-clinica

l test

should be

changed

Necessity of the research

Problems of in-vivo experiments

Draize Test

Replacement : Organ-on-a-Chip

Huh et al, 2012. Lab Chip.

• Limited experimental group


• Ethical problems


• Economical inefficiency

• Heterogeneous nature of cell


New drug development

Emerging Trends in Drug Screening

In vivo (animal)

screening

Phenomenological  Low  throughput  

Disease  relevance?

In vitro (biochemical)

screening

Target  based  High  throughput  

Disease  relevance  -‐  low

In vivo (immortalized cells)

screening

Target  based  High  throughput  Disease  relevance?

In vivo (primary cells)

screening

Phenotypically  based  Low  throughput  

Disease  relevance  -‐  high

In vivo (ES and iPS cells)

screening

Phenotypically  based  High  throughput  

Disease  relevance  -‐  high

In vivo (3D tissue assemblies)

screening

Phenotypically  based  Throughput?  

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”

• Micrototal Analysis System (μTAS) • Genomic analysis• Protein analysis• High throughput screening• Cell Biology and Neuroscience

microfluidic gene sequencing LabChip µTAS (Caliper)

manipulation of fluids in small channels

Cell Sorter (Fluidigm)

Microfluidics

Multiscale Control of Cellular Microenvironments

2D Culture

Petri-dish culture

Life is in 3D

✓ 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

2D Culture

3D CultureChristopher S. Chen, Journal of cell science (2012)

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 PlatformFibroblast-HUVEC-Fibroblast

in Fibrin-Collagen matrix Spontaneous network formation

Day 1

Day 3 Day 4

Day 2

100 µm

Day 1 Day 2

Day 3 Day 4

Vasculogenic Vessel Formation

100 um

xz plane

yz plane

*

* *

NucleiF-actin

CD31

xy plane

Lumen-Cross Section for Vasculogenic Vessels

Angiogenesis

Day 0

500 μⅿ

Day

1D

ay 2

Day

3D

ay 4

Aver

age

spro

ut le

ngth

(µm

) 700

525

350

175

0Day 1 Day 2 Day 3 Day 4

Vasc

ular

are

a co

vera

ge (%

) 80

60

40

20

0Day 1 Day 2 Day 3 Day 4

2 million cells/ml 3 million cells/ml

Vasculogenesis Angiogenesis

100 µm

Blood vessel formation

Vasculogenesis-derived network

Nuc

lei

F-a

ctin

C

D31

100 µm

Day 4

~ 88 % success rate (n = 36 chips)

Establishment of Perfusable Vessels

Microbeads flowing through the vascular network

NucleiICAM-1

Collagen IV

Vessel Characterization: Apical-Basal Polarity

FITC-dextran HUVECs

Extravascularfibrin matrix

Vessel Permeability (Fluorescent Dextran 70KD)

NucleusF-actin

Compatible with High Resolution Microscopy

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

Korea University

3D in vitro disease model 3D tissue reconstruction

Translational research

Angiogenesis

Cancer metastasis

Seok Chung

Sungkyunkwan
University

Sungsu Park

Pathogen detection chip

Cell elongation chip

Anticancer chip

Hongik University

3D in vitro gut model Multi organ on a chip

Jong Hwan Sung

Seoul National University

New Fabrication

Vasculature on a Chip Brain on a Chip

Cell Dynamics

Noo Li Jeon

Dan Huh

Gut-on-a-chip

Eye-on-a-chip

University of Pennsylvania

Lung-on-a-chip

Roger Kamm MIT

Biological machines / Microfluidics

Angiogenesis / Vasculogenesis

Cancer

Simulation and modeling

Shoji TakeuchiUniversity of Tokyo

3D tissue construction

Membrane protein chip

Neural interface

Companies 
: Organ-on-a-chip

Field of specification

Emulation 
human biology

Year Founded 2014

Total Funding $40Million

Recent Funding $28Million(March 28, 2016)

Headquarters Cambridge, Massachusetts

Size of corporation 25-50 employees

Website http://emulatebio.com

1. Emulate

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

Field of specification

Microfluidic,Organ on a chip

Year Founded 2013

Total Funding $8.4Million

Recent Funding $1.6Million(January 5, 2016)

Headquarters Leiden,Nederland

Size of corporation 35-50 employees

Website http://ww.mimetas.com

2. Mimetas

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

xxx

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

3. Nortis Bio

Field of specification

Microfluidic,Organ on a chip

Year Founded 2012

Total Funding $2.65Million

Recent Funding $0.41Million(March 19, 2015)

Headquarters Seattle,Washington

Size of corporation 30-40 employees

Website http://ww.nortisbio.com

xxx

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).

4. Hepregen

Field of specification

Liver,In-vitro testing

Year Founded 2007

Total Funding $3Million

Recent Funding $0.5Million(June 27, 2012)

Headquarters Medford,Massachusetts

Size of corporation 10-25 employees

Website http://www.hepregen.com

Summary

Summary1) 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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