1. Skin substitutes: Which ones really help heal ulcers and if so, when should we use them?
Bill Marston, MD
Professor and Chief, Division of Vascular Surgery
Director, Wound Healing/Limb Salvage Center
University of North Carolina Medical School

2. Disclosures Spiracur Organogenesis Healthpoint/Smith and Nephew
Scientific consultant
Organogenesis
Healthpoint/Smith and Nephew
Clinical trial investigator

3. Ancillary Therapies for Chronic leg ulcers
Growth Factor
Becaplermin
Living cellular therapies
Apligraf
Dermagraft
Non-living matrix dressings
Oasis
Other skin subs
Negative pressure therapy
Hyperbaric oxygen
Revascularization
Total contact casting
Noninvasive Strategies
Altered Mechanical Environment
Charcot Foot

4. “Active” healing modalities
Stimulate more rapid wound healing by
Accelerated angiogenesis
Stimulation of growth factor release
Providing wound matrix for cellular ingrowth
Production of required proteins/GFs
FDA approved for healing DFUs
Platelet-derived growth factor (Becaplermin)
Living human dermal substitutes
Apligraf
Dermagraft

5. Factors for Not Healing: Cohort Study
Margolis DJ, et al. Diabetes Care. 2002;25(10):

6. 4-Week 50% Reduction
Coerper S, et al. J Diabetes Complications. 2009;23(1):49-53.

7. If a wound has not healed 30-50% in a month with a specific treatment plan it is very unlikely to heal completely with another 8-12 weeks of the same plan

8. When to consider ancillary Rx
High risk of poor healing on initial evaluation
Poor response to initial trial of standard treatment modalities
Debridement
Bacterial control
Offloading
Adequate blood/O2 supply established if possible

9. Preparation for adjuvant skin subs

10. Engineered Human Skin Equivalents for chronic wounds
Living Cellular
Apligraf
Dermagraft
Non-living animal
Oasis
Primatrix
Human sourced non-living
Grafix
Theraskin

11. APLIGRAF

12. Human Dermal Fibroblasts
CYTOKINE EXPRESSION IN APLIGRAF AND HUMAN SKIN
Human Keratinocytes
Human Dermal Fibroblasts
Apligraf
Human Skin
FGF-1
FGF-2
FGF-7
ECGF
IGF-1
IGF-2
PDGF-AB
TGF-
IL-1
IL-6
IL-8
IL-11
TGF-1
TGF-3
VEGF + – + – + +
FGF = fibroblast growth factor; ECGF = endothelial cell growth factor; IGF = insulin-like growth factor; PDGF = platelet-derived growth factor; TGF = transforming growth factor; IL = interleukin; VEGF = vascular endothelial growth factor.

13. Apligraf: venous leg ulcer pivotal trial
240 patients
Ulcers present > 1 month
Average 3.3 applications
Applied with compression
Percent closed at 24 weeks compared to compression alone
57%
40%
P=0.02

14. Apligraf in diabetic foot ulcers
208 patients randomized prospectively
24 wound care centers
All received standard wound care, etc
followed 12 weeks
56%
38%
P=0.003
47% increased probability
of healing

15. Apligraf: venous leg ulcer pivotal trial
47% %
19%
N=120
N=120
P = NS
P = 0.002
Ulcer duration > 1 year
Ulcer duration < 1 year

16. Number needed to treat to heal additional wound
6 patients with AG
Cost for each additional healed wound
$15, ,000
PLAVIX: To prevent an ischemic event
Need to treat 59 patients with plavix instead of ASA
Cost for each prevented event $85,000

17. OASIS Porcine small intestine submucosa
Processed to lyse submocosal cells and remove debris
Sterilized w ethylene chloride process
Contents
Acellular collagen-based ECM
Functions as support structure for rapidly growing/active mucosal layer

18. Bioactive FGF-2 found at significant concentrations in matrix
Wounds 2001;13:

19. Apply and Wet

20. Prospective randomized trial of Oasis for Leg Ulcers
120 patients randomized to SOC or SOC plus Oasis application weekly
Standard of care
Debridement as needed
Cover with non-adherent foam dressing
Application of multi-layer compression bandage
Weekly dressing changes

21. Venous Ulcer Study Results
120 total patients
62 SIS + SOC
58 SOC
Gender Male Female
SIS
SOC
Age Mean Range
SIS (21-90)
SOC (36-93)
96 patients completed the study (follow-up available until healing or through 12 weeks)
50 in SIS group
46 in SOC group
120 patients were enrolled in the trial and 96 completed the trial either to an endpoint of healing or the 12 week time period. Patient dropouts were due to withdrawal of consent, protocol violations, hospitalization/complications. The SOC and SIS arms of the study were roughly equivalent in terms of numbers included, gender and age
20% dropout rate

22. Oasis VLU Study: Time to healing
20/58 =34% Standard
P=.02

23. Comparative studies using “real world” data

24. Wound Expert-derived data
1801 venous leg ulcers
1451 treated with BLCC (Apligraf)
350 treated with SIS
Baseline wound patient demographics and wound characteristics similar

25. Wound closure up to 36 weeks

26. Other skin substitutes
Integra
Graftjacket
Primatrix
Gammagraft
Alloderm
Talymed
Theraskin
Grafix
Ezderm
Epifix

27. Grafix 3-dimensional cellular matrix produced from placental membrane
contains
510K approved by FDA for treatment of chronic wounds
At SAWC last year presented interim results on randomized trial in DFUs

28. Grafix study design
131 patients enrolled with DFUs 1-15 cm sq and ABI > 0.7 and < 1.3
1:1 randomization to control dressings or Grafix
Single blind design
CPC clinical research CRO performed independent oversight and confirmation of wound size and closure data

29. Top-Line Data from the Interim Analysis of Protocol 302
           
Grafix Control P-value
(n=50) (n=47)
Primary
Complete Wound Closure at 12 Weeks % 21.3% p < .01
Secondary
Complete Closure for Pts Receiving All Treatments* 71.4% 27.0% p=0.0001
Time to Complete Closure days 70 days p=0.017
Number of Treatments to Closure p=0.0001
Safety
Patients with at least One Adverse Event % 66.0% p=0.008
Awaiting final results along with peer-reviewed publication to
evaluate methods. Do the results relate to real wound patients?

30. Other skin equivalents with well designed validated randomized studies

31. Methods to optimize results with skin equivalents in DFU
Optimize offloading
Eliminate biofilm/bacteria
Consider biopsy for culture in wounds of long duration
Proper debridement to eliminate all non-viable tissue

32. Questions?