1. And Now For Something Completely Different Lee Landeen, Ph.D. Associate Director, Research Advanced BioHealing

2. Regenerative medicine company – Not wound care company Celaderm – Keratinocyte-based, tissue-engineered product Purchased rights to Advanced Tissue Sciences / Smith & Nephew dermal products – May 2006 – Dermagraft and TransCyte Acquired by Shire – June 2011 ($750M)

3. The History 1986: Marrow-Tech incorporates; tissue-engineering platform technology 1990: Markets skin 2 for cytotoxicity testing (pre-cursor to Dermagraft) 1991: Marrow-Tech renamed Advanced Tissue Sciences; began development of Dermagraft (burns) 1993: Began development of TransCyte (burns) 1996: ATS / Smith & Nephew form joint venture 1996: Dermagraft clinical trials for ulcers initiated 1997: TransCyte approved for partial and full-thickness burns 1998: ATS / S&N joint venture expanded to include TransCyte 2001:Dermagraft approved for diabetic foot ulcers 2002: ATS files Chapter 11; S&N acquires the JV Dec 2005: S&N decided to exit the business, put assets related to Dermagraft and TransCyte up for sale May 2006: ABH purchased assets Feb 2007: ABH revalidated Manufacturing facility and shipped first Dermagraft to customers

4. Why Has ABH Succeeded (When Others Have Failed)? To date, ABH has generated > $400MM in sales revenue on Dermagraft Principles of Jim Collins’ “Good to Great” – Narrow focus, culture of discipline, hire the right people, flywheel concept Selling price doubled – Dermagraft was off market for >6 mo Positioned as the “Standard of Care” – Close the wound vs. manage the wound – Non-healing wounds after 4 weeks need an advanced therapy Commercially focused Sales team – Multiple disciplines including pharma, biologics and device – Single product portfolio Dedicated reimbursement staff and expertise – Heal2Gether program to work with patient compliance issues – Health economics of using vs. not using Dermagraft – Physicians get reimbursed

5. Case Studies BeforeAfter Case 1 (plantar surface) (ulcer > 2 yr) (healed at 8 wk) Case 2 (heel) (healed at 11 wk) Case 3 (toe) (ulcer 3 mo) (healed at 7 wk)

6. Tissue Engineering PolymerScience Biochemistry Cell Biology Bioengineering Transplantation SEM of Fibroblasts on Nylon SEM of Vicryl SEM of Dermagraft

7. Dermagraft Human neonatal dermal fibroblasts (MCB, WCB) Resorbable knitted mesh scaffold (poly[glycolide-co-L-lactide]) Class III medical device (CDRH, 2001) (biologic, cell therapy) Treatment of diabetic foot ulcers (1 x 8 wks) Cryopreserved dermal replacement (-75 o C ± 10 o C) Past/present evaluation in venous leg ulcers, epidermolysis bullosa, gingival resectioning, epicardial revascularization, rotator cuff repair

8. Dermagraft Manufacturing

9. Cell Expansion

10. Dermagraft Bioreactor Manifold Product Manifold (up to 12 per lot) (up to 1,152 units) 8-cavity bag

11. HEMOSTASIS PLATELET AGGREGATION REMODELING SECOND MINUTE DAY WEEK MONTH YEAR SCAR FORMATION WOUND CLOSURE RE-EPITHELIALIZATION GRANULATION TISSUE MONOCYTE IMMIGRATION NEUTROPHIL IMMIGRATION Normal Wound Healing

12. HEMOSTASIS PLATELET AGGREGATION REMODELING SECOND MINUTE DAY WEEK MONTH YEAR SCAR FORMATION WOUND CLOSURE RE-EPITHELIALIZATION GRANULATION TISSUE MONOCYTE IMMIGRATION NEUTROPHIL IMMIGRATION Ulcers

13. Proposed Mechanisms of Action of Dermagraft ® Delivery of normal, non-senescent fibroblasts Delivery of growth factors – Extracellular matrix-bound – Secreted Substrate for re-epithelialization – Extracellular matrix molecules Influence on inflammatory processes – Neutrophils

14. Proposed Mechanisms of Action of Dermagraft ® Delivery of normal, non-senescent fibroblasts Delivery of growth factors – Extracellular matrix-bound – Secreted Substrate for re-epithelialization – Extracellular matrix molecules Influence on inflammatory processes – Neutrophils

15. Normal Fibroblast Replicative Senescence Hayflick’s proposed 50 cell doublings

16. Reactive Oxygen Species ROS Pressure Ulcers Diabetic Ulcers Venous Stasis Ulcers Chronic ischemia/reperfusion injury High mitochondrial potential Chronic neutrophil activation Chronic inflammation Iron from extravasated red cells Chronic neutrophil activation Chronic Inflammation Protein DNA Lipid Senescence-like Phenotype

17. Role of Senescence Fibroblasts with a stress-induced premature senescent phenotype fail to respond appropriately to injury Neutrophil activation fails Bacterial colonization occurs Keratinocyte closure of the wound is delayed

18. Proposed Mechanisms of Action of Dermagraft ® Delivery of normal, non-senescent fibroblasts Delivery of growth factors – Extracellular matrix-bound – Secreted Substrate for re-epithelialization – Extracellular matrix molecules Influence on inflammatory processes – Neutrophils

19. Growth Factor Expression in Dermagraft IGF-II IGFBP-4 IGF-BP-5 IGFBP-6 IL-l  IL-1 RA Pro-IL-1  IL-6 IL-8 IL-11 TNF-  MCP-1 MCP-3 SDF-1 Interferon-  Gro-  Gro-  Gro-  CSF-1 G-CSF GM-CSF MAC25 PDGF A chain KGF TGF-  1 TGF-  1 BP TGF-  -related TGF-  latency protein CTGF Wnt 4 Wnt 6 Wnt 11 WISP-2 VEGF VEGF-B HGF PLGF bFGF Cyr61 FGF-1BP FGF-5 HSFGF AAMP Angiopoietin-1

20. ECM-bound Growth Factors Immunohisto for bFGFELISA for bFGF

21. Secretion of VEGF by Dermagraft ® After Thawing

22. Chick Chorioallantoic Membrane Assay for Angiogenesis Control, ScaffoldDermagraft ®

23. Chick Chorioallantoic Membrane Assay for Angiogenesis

24. Laser-Doppler Showing Blood Supply in a Treated Diabetic Ulcer Pre-treatment 2 weeks 5 weeks

25. Proposed Mechanisms of Action of Dermagraft ® Delivery of normal, non-senescent fibroblasts Delivery of growth factors – Extracellular matrix-bound – Secreted Substrate for re-epithelialization – Extracellular matrix molecules Influence on inflammatory processes – Neutrophils

26. Extracellular Matrix Composition Biglycan Collagen I Collagen III Collagen V Collagen VI Collagen VII Decorin Elastin Fibronectin Glycosaminoglycans (HSPG) Lumican SPARC Tenascin Thrombospondin II

27. Keratinocyte Migration On Wound bed On Dermagraft Krejci-Pappa, et al. 1999

28. Proposed Mechanisms of Action of Dermagraft ® Delivery of normal, non-senescent fibroblasts Delivery of growth factors – Extracellular matrix-bound – Secreted Substrate for re-epithelialization – Extracellular matrix molecules Influence on inflammatory processes – Neutrophils

29. Factors Induced in DERMAGRAFT® Dermagraft ® Monolayer IL-8

30. IL-8 secretion by Dermagraft

31. Monolayer fibroblasts 3D fibroblasts Keratinocytes Macrophage attractants Neutrophil attractants Stem cell attractants Dendritic cell attractants Chemokine Message in Dermagraft

32. CXCL-1, 5, 6, 8 (Gro- , ENA-78, GCP-2, IL-8) Secreted by fibroblasts, neutrophils, keratinocytes, and other cells Chemoattractants and activators for neutrophils Primes neutrophil respiratory burst Antibacterial/antimicrobial activity Heparan sulphate-binding Activated by MMP-9

33. Overall Hypothesis Ulcer Fibroblasts (Senescence-like Phenotype) Bacterial Colonization No Closure Inappropriate Response to Injury Chronic Wound

34. HEMOSTASIS PLATELET AGGREGATION Dermagraft ® Cells G-CSF IL-8 Gro-  ENA-78 GCP-2 TGF  1 IL-6 IL-11 VEGF ECM Substrate HGF KGF Dermagraft ® SECOND MINUTE DAY WEEK MONTH YEAR Proposed Dermagraft MOA REMODELING SCAR FORMATION WOUND CLOSURE RE-EPITHELIALIZATION GRANULATION TISSUE MONOCYTE IMMIGRATION NEUTROPHIL IMMIGRATION HSPs, necrotic cells, scaffold MCP-1 MCP-3 MCP-4 bFGF

35. “Doctor, my brain hurts”