1. T HE USE OF “A CELLULAR D ERMIS ” IN LEG ULCER MANAGEMENT Nicholas Greaves 14.05.12

3. T HE S IZE OF THE P ROBLEM Prevalence – 1:100 in the elderly. Increasing incidence secondary to aging population and increasingly prevalent risk factors such as diabetes, obesity and atherosclerosis. Cost: Venous ulcers - £400 million/annum Diabetic ulcers - £252 million/annum Pressure ulcers - £300 million/annum Cost secondary to dressings, staffing and hospital admissions.

4. C URRENT MANAGEMENT Dependent on aetiology: Arterial - medical therapy, angioplasty, stenting or bypass surgery. Neuropathic/Pressure Good diabetic control Regular podiatry and foot care Pressure relieving methods Venous - compression bandaging Success ~60% healed in 26 weeks. Labour intensive, expensive and prone to recurrence. 30-50% of district nurse workload.

5. N EW T HERAPIES Factors influencing the formation & persistence of chronic wounds Topical growth factors – e.g PDGF (Regranex) Skin substitutes Epidermal Dermal Bilayer

6. Dermal Skin Substitutes Cell Source Cells Included? Acellular Hyalograft Dermagraft Transcyte Dermagraft Transcyte Oasis Strattice BioBrane Oasis Strattice BioBrane Silicon Petrolatum gauze Nylon Silicon Petrolatum gauze Nylon Collagen Chondroitin -6 sulphate Collagen Chondroitin -6 sulphate Transcyte Hyalograft Dermagraft ICX-SKN Transcyte Hyalograft Dermagraft ICX-SKN Integra Alloderm Strattice NHSBT DCD Integra Alloderm Strattice NHSBT DCD Cellular Xenogenic Allogenic Autogenic Biomaterial Biological Synthetic

7. M ODE OF A CTION Provision of 3D biomaterial matrix acting as an ECM equivalent. Actively stimulates cell migration, angiogenesis and epithelialisation through provision of a scaffold that guides host infiltration and cellular differentiation. Integrates and is eventually replaced by surrounding native tissues.

8. NHSBT D ECELLULARISED D ERMIS Obtained from donated cadaveric skin. Epidermis removed and the dermis is decellularised through unique patented multistep method. Terminally sterilised and tested for HIV, Hep B&C etc. Long shelf life ~ 18months. Stored at -20 o C. 1-2mm thickness. Upper shiny epidermal side Lower matt dermal side Good handling characteristics.

9. T HE USE OF A CELLULAR D ERMIS IN THE T REATMENT OF C HRONIC W OUNDS Pilot study of 20 patients REC approved Recruitment sites – South Manchester, Stockport, Trafford, Salford, Central Manchester Inclusion criteriaExclusion criteria Age > 16BMI > 45 Competent to consentWarfarin Ulcer of lower limbSteroids Venous ulcerRheumatoid arthritis Arterial ulcer with ABPI > 0.7 Severe heart failure Neuropathic ulcer in non- weightbearing area Chronic kidney or liver disease >2cm diameterCancer in the last 5 years Pregnancy Current or ex-IVDU

10. S TUDY D ESIGN Patient deemed suitable by clinical care team to take part in the study Patient provided with information pack Patient has pre-study screening appointment Patient fits inclusion/exclusion criteria and continues to express an interest to participate, history and examination performed Patient fits inclusion/exclusion criteria and continues to express an interest to participate, history and examination performed Duplex scan completed on lower limbs & wound swabbed Written informed consent obtained Duplex scan completed on lower limbs & wound swabbed Written informed consent obtained

11. S TUDY DESIGN Day 42 Wound check Photograph,other objective measures & wound swab 5mm punch biopsy Day 42 Wound check Photograph,other objective measures & wound swab 5mm punch biopsy Day 32 Wound check Photograph & other objective measures Day 32 Wound check Photograph & other objective measures Day 21 Wound check Photograph, other objective measures & wound swab 5mm punch biopsy Day 21 Wound check Photograph, other objective measures & wound swab 5mm punch biopsy Day 14 Wound check Photograph & other objective measures Day 14 Wound check Photograph & other objective measures Day 7 Wound check Photograph & other objective measures Day 7 Wound check Photograph & other objective measures Day 0 Photograph, other objective measures & wound swab NHSBT DCD applied 5mm punch biopsy Day 0 Photograph, other objective measures & wound swab NHSBT DCD applied 5mm punch biopsy Month 6 Wound check Photograph & other objective measures End of Trial Month 6 Wound check Photograph & other objective measures End of Trial Month 4 Wound check Photograph & other objective measures Month 4 Wound check Photograph & other objective measures

12. O THER OBJECTIVE MEASURES 1. Plain and 3D digital photography 2. FLPI – Full Field Laser Perfusion Imaging 3. SIAscopy – Spectrophotometric Intracutaneous analysis

13. W OUND B IOPSIES Obtained at day 0, 21 and 42. Taken from wound periphery to include surrounding normal skin and ulcerated tissue. Specimen processed for H&E and immunohistochemistry Collagen I Collagen III Fibronectin CD31 SMA

14. ACD APPLICATION

15. A DVANTAGES No hospital admission No anaesthetic Minimal analgesia required One stage application takes 15-20 minutes. Can be used “off the shelf” and tailor fit to any wound. No split thickness skin graft with inherent second wound site.

16. P ATIENT C OHORT Study number Patient Age SexDuration of Ulcer Location of Ulcer Surface Area of Ulcer/cm 2 Ulcer Aetiology CAD0094F16 monthsR lat gaiter25.42Venous CAD0171F13 yearsL med malleolus 22.72Venous CAD0286F3 yearsL med malleolus 8.1Venous CAD0364M2 yearsR lat gaiter33.26Venous CAD0492F18 monthsR tib crest8.09Venous CAD0560F3 yearsR lat malleolus 6.09Venous CAD0674M40 yearsL med malleolus 34.83Arteriovenous CAD0788M4 yearsR med malleollus 9.24Venous CAD0865M2 yearsL lat gaiter15.21Venous Glucose intolerant CAD0955M4.5 yearsR med malleolus 38.86Venous Traumatic CAD1072F15 monthsL tib crest4.88Venous CAD1281F2 yearsR med gaiter34.38Venous

17. W OUND SIZE REDUCTION Study numberDuration of Ulcer Length of time in Study % change in size CAD0016 months26 weeks ↓100 CAD0113 years18 weeks ↓13.4 CAD023 years16 weeks ↓65.8 CAD032 years16 weeks ↓5.8 CAD0418 months16 weeks ↓100 CAD053 years8weeks ↓57.3 CAD0640 years7weeks ↑4↑4 CAD074 years7weeks ↓18.8 CAD082 years7weeks ↓27.4 CAD094.5 years1 week - CAD1015 months6 weeks ↓45.3 CAD122 years6 weeks ↓39.6

18. SIA SCOPY

19. S UCCESSES Day 0 Day 14 Day 21Day 42 6 months

20. S UCCESSES Day 0 10 weeks Day 42 Day 32 Day 21 Day 14

21. C ONCLUSIONS Skin substitutes have a growing evidence base in the management of chronic wounds and leg ulcers. NHSBT acellular dermis has shown promising early results in this pilot trial. Application is simple and can be performed in a clinic environment. Use of ACD can be combined with compression therapy.

22. M ANY T HANKS Any Questions?