human organ-like three-dimensional test systems ... · rization. due to the lack of equivalent...
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F R A U N H O F E R I N S T I T U T E F O R I N T E R F A C I A L E N G I N E E R I N G A N D B I O T E C H N O L O G Y I G B
HUMAN ORGAN-LIKE THREE-DIMENSIONAL TEST SYSTEMSALTERNATIVES TO ANIMAL TESTING
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3D TEST SYSTEMS
NEW OPPORTUNITIES FOR DRUG DEVELOPMENT AND SUBSTANCE TESTING IN VITRO
New drugs and substances are required to be tes ted for qual i t y, safet y and ef f icac y before market autho -
r izat ion. Due to the lack of equivalent a l ternat ive methods, animal exper iments are an impor tant s tandard
ins t rument in drug research. Due to spec ies - spec i f i c d i f ferences , however, animal exper iment s are not
always sui table for the author izat ion of new substances or the adaptat ion of new therapies to humans.
Therefore, the Fraunhofer IGB has been increasingly engaged
in the development of alternative human test systems that
mimic the complex characteristics of the body and permit the
investigation of materials according to the ADMET criteria
(absorption, distribution, metabolism, excretion and toxicity).
These test systems are based on in vitro cultured human pri-
mary cells, cell lines, induced-pluripotent stem cells or adult
stem cells. In order to ensure cell functionality in vitro, culture
conditions are created that are similar to the natural microen-
vironment of the cell in the body. For specific applications,
co-cultures with other cell types and custom-designed carrier
substrates must be employed.
The Department of Cell and Tissue Engineering is specialized
in constructing human three-dimensional (3D) tissues. The 3D
nature of the scaffolds considerably affect parameters such
as metabolic activity, viability, division, morphology and dif-
ferentiation status and thus, ultimately, the function of the
tissue as a test model.
3D test systems for various applications for substance testing
or stem cell differentiation tests have already been devel-
oped:
3D test systems
� Skin equivalent
� Skin cancer model
� Caco-2 intestine model
� Trachea model
� Cardiac muscle model
� Blood vessel model
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Basic drug discovery research can identify chemical com-
pounds as effective drug candidates. However, questions
regarding compound safety must be answered. ADMET is
an acronym in pharmacokinetics and pharmacology for ab-
sorption, distribution, metabolism, excretion and toxicolo-
gy. These criteria are important for describing the proper-
ties of a drug candidate.
With the investigation of ADMET parameters, it is possible
to describe the disposition of pharmaceutical compounds
within an organism, e.g. their absorption in the digestive
tract or their distribution over the bloodstream. In the
body, substances are subject to biochemical conversions
that can lead to ineffective or toxic degradation products.
Therefore, if and how a substance is metabolized and ex-
creted is also subject to investigation.
With our 3D test systems, we can examine various ADMET
criteria in vitro at an earlier stage of active substance de-
velopment to make relevant projections on the in vivo ef-
fects that are to be expected. Such early and cost-effective
indications can play a major role in a company’s decision to
pursue a drug candidate, saving millions in R&D costs.
Why ADMET?
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After many years of development, the Fraunhofer IGB has a
patented three-dimensional two-layer human skin equivalent
(patent ID: EP 1 290 145B1 and US8 222 031B2), which very
closely matches natural skin. The dermis layer of the model is
composed of dermal fibroblasts. They are embedded into a
biomatrix consisting of tissue-typical matrix proteins and serve
as a scaffold for the epidermal keratinocytes seeded on them.
During a three-week culture in special culture conditions, the
keratinocytes differentiate into a multilevel epidermis with
Stratum basale, Stratum spinosum, Stratum granulosum and
Stratum corneum. The horny layer plays an important barrier
function for substance penetration. Due to the interaction of
fibroblasts and keratinocytes between dermal and epidermal
sections of the skin model, a functional basal membrane con-
sisting of matrix proteins develops in the model.
The defined two-layered structure of the skin equivalent
permits the analysis of a wide variety of interactions between
epidermal and cutaneous cells. The skin model is certified for
the examination of the biocompatibility of medical devices
(DIN ISO 10993-5) and can be extended – as required – by
other cells such as melanocytes, skin tumor cells or micro-
vascular endothelial cells. Like the skin equivalent, these ex-
tended models can be applied as a preliminary stage to animal
experiments for investigations of functional parameters such
as the penetration, distribution and metabolization of test
substances in various tissue layers. Additionally, effects con-
cerning the proliferation, differentiation, cell death (necrosis,
apoptosis) and the initiation and graduation of tumors of the
applied cell types can be examined.
In vitro model for human squamous cell carcinoma
With 400,000–600,000 new cases per year worldwide,
human squamous cell carcinoma (SCC) is one of the most
common types of skin cancer. SCC has its origin in the
development of atypical epidermal keratinocytes and may
result from so-called precancerous tissue changes associated
with an increased risk of cancer, such as actinic keratosis or
Bowen’s disease. Caused by chronic photo damage, white
skin cancer occurs mainly in fair-skinned people with light-
sensitive skin after years of exposure to UV. Despite high cure
rates, the early treatment of superficial skin cancer is recom-
mended because the formation of cancer metastases is still
a potential threat. A promising new therapeutic approach is
photodynamic therapy (PDT), in which a chemical compound
accumulates selectively in the tumor cells and makes them
more sensitive to light. Subsequently, the tumor and the
healthy tissue surrounding it are irradiated with light of a suit-
able wavelength. This photochemical process generates toxic
substances, leading to cell death.
At the Fraunhofer IGB, we have developed a white skin cancer
model for the testing of new photosensitizers that allow for
the optimization of novel therapy approaches [1]. We intro-
duced white skin cancer cells (cell line SCC-25) into our well-
established three-dimensional skin model creating the first
in vitro model for squamous cell carcinoma. When the SCC
cells are simultaneously introduced with healthy keratinocytes
in defined ratios, both cell types can be co-cultured in the
skin model producing a test system that is morphologically
comparable to the early stage of squamous cell carcinoma
in humans. For late stages of the disease, full-thickness skin
models were developed where the epidermis is composed
solely of SCC cells. In addition, SCC cells were integrated into
the dermal part of the model to allow the development of
1 3D skin model.
2 Skin model with tumor nests.
SKIN EQUIVALENT
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tumor nests, which is similar to nests found in the very late
stage of squamous cell carcinoma. Using Raman spectroscopy,
we were able to non-destructively distinguish healthy kera-
tinocytes from tumor cells in non-fixed models without the
need to use of cell-specific markers.
Our model allows the investigation of new photosensitizing
substances and their effects on healthy and sick cells. We can
further use the model to test different irradiation protocols
for photodynamic therapy and develop comparative studies
of various radiation sources to apply to the tumor cells more
effectively. Furthermore, the model can be used for the devel-
opment of new photosensitizer formulations that reach tumor
cells located in the deep layers of the skin. In collaboration
with the University of Stuttgart, we have also developed a
skin model for skin melanoma.
In vitro pigmented skin model
Skin color is determined by a pigment known as melanin
which is made by melanocytes. A person’s skin color is
determined by the amount and type of melanin. Melanin
levels depend on race and amount of sunlight exposure, as
well as hormonal changes. Exposure to sunlight increases
melanin production to protect the skin against ultraviolet
rays. Skin pigmentation disorders such as postinflamma-
tory hyperpigmentation, melasma and vitiligo affect a great
number of people. Pharmaceuticals to treat skin disorders
are typically tested on animal models. At the Fraunhofer IGB,
we have developed a pigmented in vitro skin model for the
characterization of cosmetic and pharmaceutical substances
that modulate the pigmentation of the skin, as well as mela-
nogenic self-tanning agents used to increase the natural sun
protection of the skin.
In this project, human melanocytes and keratinocytes were
successfully combined to establish the test system. The
melanocyte cell markers melan-a and hmb-45 were positively
identified in the skin model and Fontana-Masson staining
showed that the tissue morphology of the epidermis models
was comparable with that of native human skin. Further-
more, a spectrometric melanin quantification method and a
L-dihydroxyphenylalanine (DOPA) test procedure for topically
applied melanogenic substances was successfully established
and validated. The melanin content of pigmented epidermis
models was significantly increased in a dose-dependent
manner by treatment with DOPA. The effect of melanogenic
sun protection agents was analyzed with a newly developed
parameter used to describe the UV radiation sensitivity of in
vitro epidermis models.
ArtiVasc – Vascularized and standardized artificial skin
equivalent
As part of the circulatory system, vascularization is one of the
most important and highly challenging issues in the develop-
ment of soft tissue [2]. The role of the circulatory system is to
transport nutrients, oxygen, carbon dioxide and blood cells
to and from cells throughout the body and within multilayer
tissues, such as the skin. Without this transport, tissues would
become ischemic and die. As part of the twenty-partner
collaboration within the EU FP7 funded project “ArtiVasc”,
engineers, physicists, chemists, biologists and physicians are
working on developing standardized processes for producing
vascularized scaffolds as well as processes to culture cells
within the scaffolds in order to rapidly and inexpensively pro-
duce standardized and vascularized artificial skin.
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The two main applications for the research into vascularized
artificial skin are in the fields of regenerative medicine and
pharmaceutical testing. For patients requiring major soft tissue
implants after traumatic injury, our scaffolds represent a safe,
fast and inexpensive tissue substitute. In the pharmaceutical
industry, our scaffold will be used as a substitute for expensive
and ethically disputed pharmaceutical tests on animals. The
synthetic vascularized test beds will be used to simulate the
uptake of the pharmaceuticals into the blood. The advantage
of an artificial mass produced test system is a significant in-
crease in standardization and decrease in cost and production
time when compared to animal based vascularized substrates.
Importantly, an animal does not need to be sacrificed to pro-
duce these test systems.
The main objective of the work package at the Fraunhofer IGB
is the development of a vascularized composite graft that is
comparable to native vascularized skin. It will consist of three
layers: subcutaneous fatty tissue, dermis and epidermis. We
have established standard operating procedures (SOPs) for the
isolation and culture of primary preadipocytes and adipocytes
from subcutaneous fat. The human primary adipocytes and
fibroblasts were seeded on synthetic and biological scaffolds
to develop an in vitro fatty tissue. This fatty tissue will be com-
bined with a dermal and an epidermal layer to create a 3D
skin equivalent. Finally, the vascular system will be integrated
in the fatty tissue to supply the artificial skin with nutrients.
When complete, the vascularized 3D scaffolds will be a
cutting-edge component based product for both patients and
industry, with the foundation vascularized construct allowing
for the creation of many different organs and tissues.
The Skin Factory – Mass produced organ replicates:
tissue engineering on demand
The production of artificial skin is extremely complex. In
order to meet the growing demand for in vitro test systems
that are produced at an efficient cost and constant quality,
scientists from the Fraunhofer IGB, IPT, IPA and IZI, in a project
financed by the Fraunhofer Zukunftsstiftung (Fraunhofer
Future Foundation), set out to automate this manufacturing
process. Scientists and engineers were able to fully automate
the continuous process chain from cell extraction and cell pro-
liferation, up to the creation of a complete three-dimensional
tissue structure. The Fraunhofer IGB and colleagues have
demonstrated for the first time world-wide, the ability to fully
automate the production of two-layer skin models in a single
system.
www.tissue-factory.com
Contact
Dipl.-Biol. (t.o.) Sibylle Thude
Phone +49 711 970-4152
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2D accredited test model
The standardized in vitro model for the investigation of absorp-
tion mechanisms at the intestinal barrier is based on a 2D test
system with Caco-2 cells (colon carcinoma cell line), which is
cultured on an artificial PET insert membrane. This test system
was considerably improved in the Department of Cell and Tis-
sue Engineering by modifying the cell culture conditions. It is
currently accredited for transport studies across the intestinal
barrier.
3D test system
We developed a dynamic 3D cell co-culture of human Caco-2
cells with primary-isolated human microvascular endothelial
cells (hMECs) on decellularized porcine jejunal segments within
a custom-made dynamic bioreactor system resembling the
apical and basolateral side of the intestine. After 14 days,
histological analyses revealed that the Caco-2 cells resembled
normal primary enterocytes within their native environ-
ment, with a high-prismatic morphology. In comparison to
dynamic cultures, cells cultured under static conditions are
flattened. We further evaluated the transport of low perme-
able substances, such as fluorescein and desmopressin, which
increased within the dynamic bioreactor cultures. Immunohis-
tochemical staining showed a significantly higher expression
of the efflux transport p-glycoprotein (p-gp) under dynamic
culture conditions in comparison to static cultures [4].
Applications
The 3D intestine test system allows the investigation of resorp-
tion, toxicity and bioavailability of orally applied active sub-
stances and targeted improvement of formulations. It is also
a novel model for the exploration of basic science questions
regarding intestinal development and intestinal crypts.
INTESTINE TEST MODEL
1+2 Tissue factory.
3 Human intestinal villus.
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Treatments for the diseases and injuries of the musculoskeletal
system are currently focused on the development of new
composite materials. Many of these material developments
are aimed at improving the biodegradability and mechanical
properties of the load-bearing areas of the implants. To ensure
the utility of the new material, the establishment of biological
test systems for the analysis of ingrowth into the bone and
the degradation behavior of implant materials are of particular
relevance. However, there are no standardized systems for the
appropriate analysis of material resorption and osteoinduction,
which is the material’s ability to stimulate the formation of new
bone, analyzing both osteoblast and osteoclast function. The
establishment of such systems is part of the Fraunhofer joint
project “DegraLast” as an alternative or supplement to animal
experiments.
Standardized in vitro test systems with bone-forming
and bone-degrading cells
The standardization of cell-based test systems using osteo-
blasts and their precursor cells to simulate bone formation, as
well as bone-resorbing cells, the osteoclasts, to mimic bone
loss, is the goal of the work package at the Fraunhofer IGB. To
assess the ingrowth and the osteoinductive properties of a ma-
terial, we investigate the differentiation of human mesenchy-
mal stem cells (hMSCs) into osteoblasts by analyzing specific
differentiation markers on standard materials, as well as newly
developed materials and coatings. Cell adhesion, proliferation
and differentiation are characterized by the qualitative analysis
of type I collagen as well as the quantitative examination of
alkaline phosphatase and calcium, which showed a significant
increase in differentiated cells relative to control cells.
Loss of bone substance
Osteoclasts are largely responsible for the resorption of
bone. For the osteodegradation test system, monocytes
were isolated from human peripheral blood and successfully
differentiated into osteoclasts. The characterization of dif-
ferentiated osteoclasts was demonstrated by polynuclear size,
the restructuring of the cytoskeleton and the expression of
specific marker proteins. Furthermore, the activity of the cells
was determined by the absorption of a bovine bone substitute
material.
IN VITRO TEST SYSTEMS FOR NOVEL BONE IMPLANTS
1 Histological staining of the vitronectin receptor and
the cell nuclei of human mesenchymal stem cells
and monocytes. In co-culture, the cells develop an
osteoclast phenotype.
2 Actin cytoskeleton (red) and cell nuclei (blue)
of undifferentiated (A) and differentiated (B)
monocytes.
3 Embryonic stem cell derived cardiomyocytes. F-actin
is represented in blue, DAPI in yellow, and cardiac
troponin in green.
1 2 A 2 B
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Advanced model by the co-culture of osteoblasts and
osteoclasts
The recapitulation of the physiological process of bone remod-
eling is an effective method to obtain the desired properties
for bone replacement materials. While osteoclasts resorb the
material, osteoblasts form new bone. Current in vitro studies
focus only on one type of cell and investigate either bone re-
sorption or bone formation. Therefore, we aimed to establish a
co-culture of both cell types to simulate the bone remodeling
process and to develop as an extended test system. In the
development of in vitro co-culture system, we first identified
optimal culture conditions for the two cell types. We then
developed a method that leads to osteoclast differentiation
without addition of differentiation factors, which allowed for
the co-culture of both cell types.
Applications
Our multipotent stem cell bone test system is designed for
the investigation of material resorption and osteoinduction,
analyzing both osteoblast and osteoclast function.
Contact
Dipl.-Biol. Claudia Kleinhans
Phone +49 711 970-4073
Cardiovascular disease remains one of the leading causes of
death in the world. In Europe alone, an estimated 10 million
people are affected each year. New pharmaceutical and
regenerative therapies are being developed all over the world.
The Fraunhofer IGB is developing both a cardiac muscle and
blood vessel test systems based on human primary, embry-
onic, or induced-pluripotent stem cells (iPSC).
Depending on the application, we can create systems based
on natural or synthetic scaffolds using custom designed
bioreactor systems to mimic the biomechanical properties of
the heart and vessels, including electronic stimulation. We
can successfully culture embryonic or iPSC-derived and fetal
cardiomyocytes as well as other cell types of the cardiovascu-
lar system. Our numerous non-contact diagnosis techniques
allow for the continuous monitoring of the cardiovascular test
systems.
For more information, please read our cardiovascular
and non-invasive diagnostics brochures.
CARDIOVASCULAR TEST SYSTEMS
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achieve in culture. Moreover, interactions of the electrospun
scaffolds with immune-mediated mechanisms showed low
immunogenicity [5, 6].
Applications
With our trachea model, various issues concerning the
absorption, biocompatibility and toxicity of a wide variety of
materials can be examined. Cellular reactions after introduc-
tion of aerosols or solids into the reactor can be investigated
using different methods. Penetrated particles can be
demonstrated with histological methods, while quantitative
methods for the analysis of inflammation markers or other
metabolic enzymes in the medium permit conclusions on
toxicity and biocompatibility.
Natural matrices
The airway is a substantial barrier for inhaled materi-
als such as fine dust, nanoparticles and also pathogenic
microorganisms. It has a special cleaning mechanism, with
which the foreign particles are trapped by means of mucus
and transported out of the respiratory pathway by specific
movements of the cilia. A trachea model was developed at
the Fraunhofer IGB for the investigation of the effect of pen-
etrated particles on the cells of the upper respiratory system.
Here, human trachea epithelial cells or appropriate cell lines
(Calu-3) were seeded upon decellularized small intestine seg-
ments. Calu-3 cells grew on the biological matrix and form
the highly prismatic morphology of trachea epithelial cells.
The trachea models are cultured in a bioreactor system that
simulates human respiration.
Synthetic electrospun scaffolds
Decorin is a structural and functional proteoglycan (PG)
residing in the complex network of extracellular matrix (ECM)
of the trachea. To biofunctionalize an electrospun synthetic
scaffold for tissue engineering applications, we introduced
decorin into the polymer solution before electrospinning
the scaffold. Scanning electron microscopy, atomic force
microscopy, contact angle measurements and dynamic
mechanical analysis were used to analyze the spun scaffolds.
PG functionality was confirmed with immunostaining and
1,9-dimethylmethylene blue. To determine cell-matrix-inter-
actions, tracheal cells (hPAECs) were seeded and analyzed
using an FOXJ1-antibody. Our analysis showed a significant
increase in cell proliferation, which is extremely difficult to
TRACHEA MODEL
20 μm
Contact
Svenja Hinderer
Phone +49 711 970-4082
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Prof. Dr. Katja Schenke-Layland
Head of Department
Cell and Tissue Engineering
Phone +49 711 970-4082
katja.schenke-layland@
igb.fraunhofer.de
Prof. Dr. Petra Kluger
Head of Department
Cell and Tissue Engineering
Phone +49 711 970-4072
� Cell isolation from primary material (biopsies)
� Derivation of tissue-specific cell types from pluripotent
stem cells
� In-depth cell characterization
� Construction, establishment and validation of 3D static
and dynamic testing systems
� Studies and testing services
� Histology, molecular, cellular and biochemical analyses
of tissues and medium supernatants
RANGE OF SERVICES Contact
References
[1] Brauchle, E.; Johannsen, H.; et Int, and Schenke-Layland K.
(2013) Design and analysis of a squamous cell carcinoma in vitro
model system. Biomaterials
[2] Novosel, E. C.; Kleinhans, C. and Kluger, P. J. (2011)
Vascularization is the key challenge in tissue engineering. Advanced
Drug Delivery Reviews
[3] Novosel, E. C.; Meyer, W. M.; et Int, and Kluger, P. J. (2011)
Evaluation of Cell-Material Interactions on Newly Designed,
Printable Polymers for Tissue Engineering Applications. Advanced
Engineering Materials
[4] Pusch, J.; Votteler, M.; et Int, and Schenke-Layland K. (2011)
The physiological performance of a three-dimensional model that
mimics the microenvironment of the small intestine. Biomaterials
[5] Hinderer, S.; Schesny, M.; et Int, and Schenke-Layland K. (2012)
Engineering of fibrillar decorin matrices for a tissue-engineered
trachea. Biomaterials
[6] Hinderer, S.; Schenke-Layland, K. (2013) Tracheal tissue
engineering: building on a strong foundation. Expert Review of
Medical Devices1 Native trachea tissue.
2 Electrospun decorin containing
scaffold seeded with hPAECs.
3D TEST SYSTEM APPLICATION AREAS ADMET
skin equivalent penetration, irritation and toxicity studies absorption, distribution, toxicity
intestine test system resorption and toxicity studies, testing of toxicity drug formulations
trachea model resorption, biocompatibility and toxicity studies absorption, toxicity
bone model material resorption and osteoinduction
cardiac muscle cell function, cytotoxicity, pace testing
cardiac blood vessel biocompatibility, functionality
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Stay in contact:
Fraunhofer Institute
for Interfacial Engineering
and Biotechnology IGB
Nobelstrasse 12
70569 Stuttgart | Germany
Phone +49 711 970-4401
Fax +49 711 970-4200
www.igb.fraunhofer.de
Fraunhofer IGB
The Fraunhofer IGB develops and optimizes processes and products in the fields of medicine,
pharmacy, chemistry, the environment and energy. We combine the highest scientific stan-
dards with professional know-how in our competence areas of Interfacial Engineering and
Materials Science, Molecular Biotechnology, Physical Process Technology, Environmental Bio-
technology and Bioprocess Engineering, as well as Cell and Tissue Engineering – always with
a view to economic efficiency and sustainability. Our strengths are to offer complete solutions
from laboratory scale to pilot plant. Customers also benefit from the constructive interplay
of the various disciplines at our institute, which opens up new approaches in areas such as
medical engineering, nanotechnology, industrial biotechnology, and environmental technology.
The Fraunhofer IGB is one of 67 institutes and independent research units of the Fraunhofer-
Gesellschaft, Europe’s largest organization for application-oriented research.
www.igb.fraunhofer.de
Director
Prof. Dr. Thomas Hirth
Phone +49 711 970-4400