Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

CLINICAL TRIALS (3)

Dr. Judit PongráczThree dimensional tissue cultures and tissue engineering – Lecture 25

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

TÁMOP-4.1.2-08/1/A-2009-0011

Tissue engineered blood vessel• TE blood vessels are used only in low pressure pulmonary

circulation• These grafts are not durable enough to withstand high arterial

pressure

Small-veinharvest

Cell seedingon polymer

Cell isolation

Cell expansion

Tissue-engineered graft

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TEBV production• A completely biological tissue-engineered

human blood vessel (Nicolas L'heureux, Stéphanie Pâquet, Raymond Labbé, Lucie Germain, and François A. Auger ) FASEB Journal 1998

• HUVEC and SMC were used

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Myocardial infaction• Stem cells are used in cases following

extensive damage• In most cases improvement is shown but

further studies are needed

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Urethra and bladder• Acellular collagen-based matrices• Intestinal or bladder epithelial cells• 4-7 years later 34 out of 40 patients had a

successful outcome

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Cartilage• Two multicentre clinical trials• In most cases improvement was noted• Long term effects are still being considered

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Lung

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Trachea - bronchi - lungs

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Lung diseases benefiting from cell based therapies• COPD (chronic obstuctive pulmonary disease)• ARDS (acute respiratory distress syndrome)• Asthma• Mechanical tissue damages

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Strategies for cell-based therapies for the lung

Pulmonary epithelial-like cells

Embryonic stem cells

Culture

Selection(genetic, air liquid interface, media co-culture)

Epithelium Vasculature

Stroma (fibroblast)

ESCs, MSCs, Fibrocytes

Acute cytoprotection/repair(survival, growth factors)

Cartilage

Intratracheal/Vascular infusionStructural grafts

Engraftment Gene transferDelivery of therapeutic

molecules

Engraftment

Organoid

Functional unit

Endothelium

Pulmonary epithelium

Mesenchyme

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Complexity of lung structures during development

Columnar cells

Fibroblasts

Goblet cell

Basal cell

Ciliated cellClara cell Type I cell

Type IIcell

I.Embryonic

E 9-12

II.Pseudoglandular

E 12-15

III.CanalicularE 15-E17

IV.Saccular

E 17-Birth

V.Alveolar

Birth-PN20

Lung budEs Es

T T

RESEARCH APPLICATION AND DRUG TESTING

Dr. Judit PongráczThree dimensional tissue cultures and tissue engineering – Lecture 26

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

TÁMOP-4.1.2-08/1/A-2009-0011

Research applications• Intercellular interaction• Study of Signaling pathway (inter and intra-

cellular)• Study of regeneration processes• Modeling diseases

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Thymus reaggregation

E15 mouse embryo

T-lymphocytes orlymphoid progenitors

Deoxiguanosine cultures

Thymic epithelial cells

E15 thymic lobes

Reaggregate

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Thymocyte development in the reaggregated thymus

Intracellular Notch(ICN)

• No T-cell commitment• Allows B-cell commitment

• Induces T-cell commitment• Blocks B-cell commitment

Nucleus

Stromal cell

Lymphocyte progenitor

Jagged/Delta-like

CSLCSLCoR CoA

Preseniling-Secretase

CoR

(ICN)

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Salivary gland aggregate

GFP-Ad FoxN1-Ad

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Tissue specific changes• Expression of transcription factors and other

genes are easily modified• Gene expression modification is tissue type

restricted• Effects on the whole tissue can be studied at

the level of morphology, cellular interactions and signaling

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Drug testing• Toxicity testing• Efficacy testing

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Hepatotoxicity testing• Purified primary human hepatocytes in 2D• Complex 3D liver micro-tissues for toxicity• Toxicity testing (acute and chronic)• Viability assays• Bile production• Molecular marker tests (albumin etc)

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Lung model for drug testing• Complex cellular composition• Close to physiological drug transporter expression• Easy handling• Suitability for HTS