1. 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-4.1.2-08/1/A-2009-0011

2. CLINICAL TRIALS (1) Dr. Judit Pongrácz Three dimensional tissue cultures and tissue engineering – Lecture 23 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-4.1.2-08/1/A-2009-0011

3. TÁMOP-4.1.2-08/1/A-2009-0011 Definition of a clinical trial Health related research studies performed in human beings

4. TÁMOP-4.1.2-08/1/A-2009-0011 Types of clinical trials Treatment trials Prevention trials Diagnostic trials Screening trials Quality of life trials

5. TÁMOP-4.1.2-08/1/A-2009-0011 Participants in a clinical trial To gain access to novel research treatment Provide information on drug efficacy and potential toxicity

6. TÁMOP-4.1.2-08/1/A-2009-0011 Benefits of taking part in a clinical trial Gain access to novel therapies Obtain expert medical care Contribution to medical research

7. TÁMOP-4.1.2-08/1/A-2009-0011 Risks of clinical trials Unpleasant or life-threatening side effects The experimental treatment may not be effective

8. TÁMOP-4.1.2-08/1/A-2009-0011 Process of clinical trials Based on research results Based on a specific protocols Participants are continuously monitored Results assessed and statistics are performed

9. TÁMOP-4.1.2-08/1/A-2009-0011 Phases of clinical trials Phase IPhase I – small group of people (20- 80) Phase IIPhase II – larger group of people (100-300) Phase IIIPhase III –large group of people (1000-3000) Phase IVPhase IV – marketing studies

10. TÁMOP-4.1.2-08/1/A-2009-0011 Stem cell therapy and clinical trials Hematopoietic stem cell transplantation is the first stem cell based therapy strategy that has gone into clinical trials

11. TÁMOP-4.1.2-08/1/A-2009-0011 Stages to reach a marketable cell-based therapeutic product Research Animal tests Market research Marketable product Clinical trials Production Phase I, II, III, IV

12. CLINICAL TRIALS (2) Dr. Judit Pongrácz Three dimensional tissue cultures and tissue engineering – Lecture 24 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-4.1.2-08/1/A-2009-0011

13. TÁMOP-4.1.2-08/1/A-2009-0011 Clinical trials for cellular therapy of liver failure Autologous BMSC – not ready for routine clinical therapy Differentiated BMSC using HGF

14. TÁMOP-4.1.2-08/1/A-2009-0011 Liver dialysis Ammonia causes encephalopathia Extracorporeal detoxification Dialysis-like solutions

15. TÁMOP-4.1.2-08/1/A-2009-0011 Bioartificial liver Patient’splasma Oxygen PKM-19 Liver cells PlasmafilterBioreactor

16. TÁMOP-4.1.2-08/1/A-2009-0011 ELAD ® bioartificial liver Blood circuit Ultrafiltrate circuit Glucose ELAD TM Plasma filter Oxygenator Pumping system Reservoir Blood pump Ultrafiltrate pump Recirculation pump Glucose infusion pump Priming infusion line Heparin infusion Incubator Cell filter

17. TÁMOP-4.1.2-08/1/A-2009-0011 Cell-free ELAD: MARS MarsFlux Dialyzer diaMarsFlux Adsorption columns diaFlux Dialyzer Blood circuit Mars-Albumin circuit Dialysate circuit Blood pump Albumin pump Activated charcoal Anion exchange resin

18. TÁMOP-4.1.2-08/1/A-2009-0011 Skin grafting and replacement Burn injuries Chronic wounds, e.g. diabetic or PAD ulcers Cosmetic surgery

19. TÁMOP-4.1.2-08/1/A-2009-0011 Structure of the skin Artery Nerve (Adipose tissue) Epidermis Dermis Fat Sweat gland Erector pili muscle Hair Sebaceous gland Stratum corneum Stratum lucidum Stratum mucosum Stratum granulosum Stratum germinativum

20. TÁMOP-4.1.2-08/1/A-2009-0011 Purpose of skin grafting Restore the barrier function- keratinocytes Recently no nerve, vascular, sweat glans or hair follicles can be included into tx skin

21. TÁMOP-4.1.2-08/1/A-2009-0011 Skin grafts Full thickness burns - dermis and epidermis are both lost Partial thickness burns - epidermis is largely intact If more, than 30-40% body surface is burnt Smaller surface burns may be cured with split thickness autografts

22. TÁMOP-4.1.2-08/1/A-2009-0011 Autologous skin grafts Skin is meshed to cover a large wound Graft taken from patient’s healthy skin Wound

23. TÁMOP-4.1.2-08/1/A-2009-0011 I Cultured Epithelial Allograft (CEA) I CEA alone Intagra combined with CEA

24. TÁMOP-4.1.2-08/1/A-2009-0011 II Cultured Epithelial Allograft (CEA) II Transplantation of autologous cultured epidermis Patient Injured area Skin biopsy Skin specimen Isolation of keratinocytes Feeder cells Cell seeding/ Inoculation Culture Sheet formation Grafting

25. TÁMOP-4.1.2-08/1/A-2009-0011 Tissue engineered skin methodology The epithelial sheets are removed for clinical use 9x Enzymatic removal of 3T3s Proliferation and differentiation of multilayer epithelial sheets 9x P2 Medium change P0 P1 Dermis Epidermis Isolation of keratinocytes Feeder 3T3 fibroblast s Enzymatic segregatio n 24hr

26. TÁMOP-4.1.2-08/1/A-2009-0011 Tissue engineered skin products available for clinical use TypeProducts Epidermal cover CEpicell (Genzyme) –cultured epitermal sheets Epidex (Modex Therapeutics)- epidermal sheets from hair biopsies Myskin (CellTran)- cells in a synthetic carrier C3- cells in a spray Cultured allogenic keratinocytes Cultured autologous keratinocytes Dermal replacement Integra (Integra) Alloderm (Lifecell) Permacol (Tissue Science Labs) Dermagraft (Advaced BioHealing) Transcyte (Advanced BioHealing) Epidermal/dermal replacement Permaderm (Cambrex) Apligraf (Novartis) Orcel (Ortec International)