Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP /1/A

CLINICAL TRIALS (3) Dr. Judit Pongrácz Three dimensional tissue cultures and tissue engineering – Lecture 25 Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP /1/A

TÁMOP /1/A 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 seeding on polymer Cell isolation Cell expansion Tissue-engineered graft

TÁMOP /1/A 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

TÁMOP /1/A Myocardial infaction Stem cells are used in cases following extensive damage In most cases improvement is shown but further studies are needed

TÁMOP /1/A 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

TÁMOP /1/A Cartilage Two multicentre clinical trials In most cases improvement was noted Long term effects are still being considered

TÁMOP /1/A Lung

TÁMOP /1/A Trachea - bronchi - lungs

TÁMOP /1/A Lung diseases benefiting from cell based therapies COPD (chronic obstuctive pulmonary disease) ARDS (acute respiratory distress syndrome) Asthma Mechanical tissue damages

TÁMOP /1/A 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 infusion Structural grafts Engraftment Gene transfer Delivery of therapeutic molecules Engraftment Organoid Functional unit Endothelium Pulmonary epithelium Mesenchyme

TÁMOP /1/A Complexity of lung structures during development Columnar cells Fibroblasts Goblet cell Basal cell Ciliated cellClara cell Type I cell Type II cell I.Embryonic E 9-12 II.Pseudoglandular E III.Canalicular E 15-E17 IV.Saccular E 17-Birth V.AlveolarBirth-PN20 Lung bud Es TT

RESEARCH APPLICATION AND DRUG TESTING Dr. Judit Pongrácz Three dimensional tissue cultures and tissue engineering – Lecture 26 Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP /1/A

TÁMOP /1/A Research applications Intercellular interaction Study of Signaling pathway (inter and intra-cellular) Study of regeneration processes Modeling diseases

TÁMOP /1/A Thymus reaggregation E15 mouse embryo T-lymphocytes or lymphoid progenitors Deoxiguanosine cultures Thymic epithelial cells E15 thymic lobes Reaggregate

TÁMOP /1/A 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 CSL CoR CoA Presenilin  -Secretase Presenilin  -Secretase CoR (ICN)

TÁMOP /1/A Salivary gland aggregate GFP-AdFoxN1-Ad

TÁMOP /1/A 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

TÁMOP /1/A Drug testing Toxicity testing Efficacy testing

TÁMOP /1/A 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)

TÁMOP /1/A Lung model for drug testing Complex cellular composition Close to physiological drug transporter expression Easy handling Suitability for HTS