1. © CellTran Limited TM Stem Cell Research and Tissue Engineering Sheila Mac Neil Professor Of Tissue Engineering and founder Director of Celltran Ltd Ethical & legal challenges to Stem Cell research Sheila MacNeil University of Sheffield Skin Forum Sheffield June 2006

2. © CellTran Limited TM Contents Tissue engineering research using adult cells Skin-burns patients Skin-chronic ulcers Oral mucosa-scarring of the urethra Melanocytes-vitiligo Corneal epithelial cells-corneal diseases Ethical Regulatory and Economic issues

3. © CellTran Limited TM Surface engineering for delivery of epithelial cells

4. © CellTran Limited TM Do we have stem cells in our cultures? Adult epithelial cells (skin, oral mucosa and cornea) cultured in the laboratory contains cells with colony forming ability which give rapid expansion Patients who received cultured skin in the 1980’s still doing well-no loss of skin Concensus view is that culture protocols maintain a population of cells with “stem like” properties but that without gene manipulation these are destined to give rise to only one tissue

5. © CellTran Limited TM A wonderful stuff is skin. It’s the stuff that keeps you in” Spike Milligan

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14. © CellTran Limited TM 10 year audit of use of CEA (Hernon et al 2006)

15. © CellTran Limited TM There had to be a simpler way to get cells to patients… Professor Rob Short-Surface Engineer Professor Sheila MacNeil-Tissue Engineer “Lets make a post-it note for delivering skin cells to patients” 1997

16. © CellTran Limited TM University of Sheffield spin-out company Formed 2000 16 staff MHRA approved cleanrooms in 2003 Launched Myskin in 2004 Merged with Xcellentis in 2006 Raised 5 Million in funding Full details of development and proof of concept clinical studies with myskin available on www.celltran.co.ukFull details of development and proof of concept clinical studies with myskin available on www.celltran.co.uk Celltran Ltd

17. © CellTran Limited TM Autologous keratinocytes Proprietary materials technology Chronic wounds, burns DFU/VLU trials Case studies Revenues since April 2004 Myskin™

18. © CellTran Limited TM Patient Information Thin shave biopsy taken and delivered to CellTran Cryogenic cell storage myskin surface Cell expansion at CellTran laboratory Repeat myskin delivery as required Wound healing Wound bed preparation – debride and optimise* Myskin couriered to patient Week 0Week 1Weeks 2-6-2 days myskin process

19. © CellTran Limited TM Myskin-a cell delivery surface for keratinocytes

20. © CellTran Limited TM USE OF MYSKIN IN ACUTE BURNS

21. © CellTran Limited TM Use of Myskin for failed skin grafts Patient 5 Male, 80 years old 4 weeks non-healing Right leg before applications After 12 applications – 78% healed, suitable for grafting 2 months post treatment

22. © CellTran Limited TM USE OF MYSKIN IN CHRONIC WOUNDS

23. © CellTran Limited TM Single blind study with Myskin

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25. © CellTran Limited TM What types of patients can benefit ? Acute burns-where it provides valuable adjunct to SSG and donor skin Chronic wounds-BUT-the earlier it is used the better the outcome and the fewer applications will be needed Chronic wounds of long standing may need pretreatment to improve the wound bed prior to application

26. © CellTran Limited TM Vascular surgery and amputation of toes

27. © CellTran Limited TM Larval therapy and VAC therapy

28. © CellTran Limited TM Honey used as an antimicrobial followed by cell therapy

29. © CellTran Limited TM Wound bed pre and post 2 applications of myskin

30. © CellTran Limited TM D evelopment a carrier surface for surgical treatment of vitiligo Cells on carrier surface Biopsy

31. © CellTran Limited TM Transfer of melanocytes and keratinocytes from carrier to in vitro human wound bed model MTT of carrier dressing MTT of fresh skin S100 Melanocytes Mel-5 Melanocytes

32. © CellTran Limited TM Developing a coated contact lens as a carrier for cultured corneal cells for corneal diseases Contact lens Agar Stroma Sclera Contact lens seeded with limbal epithelial cells Organ culture

33. © CellTran Limited TM Tissue engineered skin and oral mucosa for reconstructive surgery Tissue engineered skin for release of contractures due to earlier burns injuries Tissue engineered oral mucosa for replacing chronically scarred urethral tissue

34. © CellTran Limited TM Making reconstructed skin based on human dermis

35. © CellTran Limited TM USE OF RECONSTRUCTED SKIN IN RELEASE OF CONTRACTURES

36. © CellTran Limited TM Tissue engineered oral mucosa for scarring of the urethra

37. © CellTran Limited TM Ethical, Regulatory and Economic issues Ethical issues Why do this? -Because existing clinical treatments not adequate for job What is the risk versus the benefit for patients? What can go wrong? How likely is it? Obtaining Ethical Committee consent Making sure patients are fully informed and properly consented

38. © CellTran Limited TM Ethical, Regulatory and Economic issues Ethical issues-in practice Patients very willing to use own tissues (small biopsy) for burns, chronic wounds and reconstructive surgery problems Ethical Committees open to research which seeks to tackle such problems

39. © CellTran Limited TM Regulatory issues Regulatory bodies react to established procedures Strong drive to classify work according to previous medical technologies-is it a device? –is it a medicine? Tissue Engineering doesn’t fit either of above well and is being driven towards Medicinal Products Running trials on autologous cell treatments not like drug development……not a great fit…

40. © CellTran Limited TM Regulatory issues UK Regulatory bodies can be approached-you can get meetings –decisions are harder Real need to work closely with MHRA and HTA to inform them of how fields are progressing

41. © CellTran Limited TM Economic issues Products currently represent a small proportion of treatment cost New technology will increase cost of product but reduce total cost to provider Health economics are driving cure over treatment Cost of healing index TraditionalActiveAdvanced Nursing time Products Other costs Over 4 years Source: Husing et al, 2003. The Future of Wound Care, MX (Market Analysis II) LEK Consulting, Feb 2006 UK cost per ulcer per year Source: Swedish Institute for Health Economics, 2000 £ 11,500

42. © CellTran Limited TM Our philosophy of product development based on adult autologous cells is that these should be Clinically effective Low risk for the patient Developed by working with clinicians and patients Convenient to use –streamlined delivery We have developed a range of products and indications in the ‘active’ sector using autologous cells Summary

43. © CellTran Limited TM Acknowledgements Grateful thanks to all those patients and clinicians who have worked with us to develop tissue engineered skin products for the treatment of burns and chronic wounds.