Advanced Wound Care Modalities for the Treatment of Pressure Ulcers
Walter C. Chua, MD, FAPWCA
PVA Summit 2011
September 17, 2011
Improving the Standard of Care
Walter C. Chua, MD, FAPWCA
Speakers Bureau: Advanced BioHealing, Inc.
CME Staff Disclosures
Professional Education Services Group staff have no
financial interest or relationships to disclose.
Disclosures
Learning Objectives
At the conclusion of this activity, the participant will
be able to:
A. Explain the physiology of wound healing and the
pathophysiology of stalled wounds
B. Describe current standard of care for wounds,
specifically pressure ulcers
C. Discuss advanced wound care modalities
including biophysical modalities, growth factors,
extracellular matrices, and bioengineered skin
substitutes
Introduction
Pressure Ulcers are a major complication of SCI/D
Will develop in ≥50% of veterans with SCI/D
Overall prevalence of 39%
Majority of pressure ulcers are Stage IV (NPUAP)
Ischia most common anatomic site
Recurrence rate is significant (~40%)
Bates et al. J Spinal Cord Med 2009;32:34-42.
Garber SL et al. J Rehabil Res Dev 2003;40:433-442.
Physiology of Wound Healing
Acute Wound Healing
Orderly and Timely Process
Proceeds through three general phases:
1. Inflammation
2. Proliferation
3. Remodeling
Results in restoration of skin/tissue integrity
Townsend et al. Elsevier 2004:184.
Townsend et al. Elsevier 2004:186.
Townsend et al. Elsevier 2004:185.
Major Growth Factors
Townsend et al. Elsevier 2004:188.
Standard Wound Management
1. Wound Bed Preparation
2. Infection Control
3. Correction of Ischemia
4. Nutritional repletion
5. Correction of Hyperglycemia
6. Pressure Relief (Offloading)
Defining Therapeutic Goal
Wound Closure vs. Wound Maintenance
Maintenance Wound Goals (palliative):
1. Prevent further tissue loss
2. Prevent infection
3. Control exudate/drainage
4. Control odor
Multidisciplinary
Wound Care TeamVA Long Beach SCI/D HCG
Plastic Surgery Primary Care
WOCN Nursing
Physiatry Nutritionists
Physical Therapy Research
Wound Bed Preparation
Debridement – Remove non-viable tissue
Infection/Inflammation – Reduce bacterial load,
inflammation
Moisture – Control for edema/maceration vs.
desiccation
Edge Advancement – Support cellular
proliferation/migration
Schultz et al. Wound Repair Reg 2005:13(4 Suppl):S1-S11.
Wound Assessment Tools
―Is this wound healing appropriately?‖
―I know it when I see it…‖
– SCOTUS Justice Potter Stewart
Wound Assessment Tools
Numeric scales to score pressure ulcer healing:
1. Bates-Jensen Wound Assessment Tool (BWAT)
13 characteristic sub-scores
2. Pressure Ulcer Scale for Healing (PUSH)
3 characteristic sub-scores
3. Spinal Cord Impairment Pressure Ulcer
Monitoring Tool (SCI-PUMT)
7 characteristic sub-scores
Wound Healing Kinetics
―How long will it take to heal?‖
Depends on:
1. Fibroblast proliferation & migration
2. ECM deposition rate
3. Keratinocyte proliferation & migration
4. Myofibroblast wound contraction
Mathematical Modeling
d i(t)≣ ḟi(t) = s
ui(t)
⎟⎢ui(t)⎟⎢dt
ui(t)=(1-r)c( i(t),t)+rḟi(t-t)
⎟⎢ḟi(t-
t)⎟⎢
where s = cell speed
t = time lag
Dermal Healing (fibroblasts):
McDougall S et al. Phil Trans R Soc A 2006;364:1385-1405.
Mathematical Modeling
Wound healing as exponential decay:
N(t) = N0e-lt
where N0 = initial wound size
l = healing rate
t = time
Cardinal M et al. BMC Dermatology 2009;9:2-9.
Half-life, t½ =ln 2
l
Healing Rate of DFUsStandard Wound Care Alone
Margolis et al. Diabetes Care 1999;22:692.
Sheehan et al. Diabetes Care 2003;26:1879-1882.
Clinical Modeling
Wounds that do not achieve 50% healing in 4 weeks
- or -
t½ =ln 2
l> 4 weeks
will likely fail to heal and result in a chronic wound.
The Chronic WoundNon-healing/Stalled/Problem Wound
Pathways to Non-healing:
1. Infection – Biofilm, Osteomyelitis
2. Hypoxia – Edema, Scarring, Vasculopathy, Nicotine
3. Cellular Failure – Diabetes, Malnutrition
4. Trauma – Pressure
Suspect chronic inflammation in absence of above
Chronic Inflammation
Fibroblast senescence hypothesized as major factor
May result from prolonged exposure to reactive
oxygen species
Impaired synthetic and replicative capacity
Decreased secretion of neutrophil attracting cytokines
Increased fibroblast senescence in pressure ulcers
Elevated plasmin production by pressure ulcer
fibroblasts
Mansbridge J. Adv Skin Wound Care 2009;22:158-160.
Vande Berg JS et al. Wound Repair Reg 2005;13:76-83.
Biochemical Differences
• ↓Pro-inflammatory cytokines
• ↓MMPs
• Normal matrix—fibronectin, collagen
• Cells capable of rapid response
• ↑Cell mitosis
• ↑Growth factors
• ↑Pro-inflammatory cytokines
• ↑MMPs
• Degraded matrix—fibronectin, collagen
• Senescent fibroblasts
• ↓Mitogenic activity
• Disordered patterns of growth factors
Healing Wounds Chronic Ulcers
Schultz G, Mast B. Wounds.1998;10:1F-9F.
Chronic WoundPrevention/Treatment
All risk factors addressed and corrected
But wound still not healing at reasonable rate
Consider applying advanced wound care
t½ =ln 2
l> 4 weeks
Advanced Wound Care
AKA Adjuvant wound care, Advanced therapeutics
1. Biophysical
Hyperbaric O2, Negative pressure wound therapy
(NPWT), Electrical stimulation, Ultrasound, Radio
Frequency, Ultraviolet Light, Low-level Laser Therapy
2. Growth Factors
Platelet-derived growth factor (Regranex), Platelet-rich
plasma
3. Extracellular Matrix
Oasis, Integra, MatriStem, Unite Biomatrix
4. Bioengineered skin substitutes
Apligraf, Dermagraft
Hyperbaric Oxygen Therapy
100% Oxygen delivered at >1.5 atmospheres absolute
Reverses tissue hypoxia
Reverses edema
Stimulates fibroblast proliferation, keratinocyte differentiation
Promotes neovascularization
Stimulates production of growth factors/cytokines
Accelerates microbial oxidative killing
Hyperbaric Oxygen Therapy
Wound Indications:
1. Problem Wound
2. Refractory Osteomyelitis
3. Endangered Flap/Graft
4. Delayed Radiation Injury
100% O2 at 2.0-2.4ATA
90 minutes, once a day
Hyperbaric Oxygen TherapyTranscutaneous Oximetry (tcpO2)
Noninvasive estimation of pO2 on skin surface
Diagnostic tool for wounds and skin flaps
Screening tool for HBO
tcpO2<40 mmHg suggests hypoxia-impaired healing
In diabetes/renal failure hypoxia at tcpO2<50 mmHg
Fife et al. Undersea Hyperb Med 2009;36:43-53.
Smart DR et al. Diving and Hyperbaric Medicine. 2006;36:72-86.
Negative Pressure Wound
Therapy (NPWT)
Electrical Stimulation
Transepithelial potential of 20-50mV in unwounded skin
Skin wounding results in DC voltage gradient
Wound electric field stimulates:
1. Cell migration
2. Cellular proliferation rate
3. Alignment of axis of cellular division
4. Growth factor secretion
Pullar CE. Journal of Wound Technology 2009;6:20-24.
Electrical Stimulation
Anode (+) attracts:
1. Macrophages
2. Neutrophils
3. Keratinocytes
Cathode (-) attracts:
1. Activated neutrophils
2. Fibroblasts
3. Myofibroblasts
4. Endothelial cells
Kloth LC, McCulloch JM. Adv Wound Care 1996;9:42-45.
Electrical Stimulation
Level A evidence strength
High-Voltage Pulsed
Current (HVPC)
Wound filled with saline-
gauze/hydrogel
50-100V at 100Hz
60 minutes once a day
Electrical Stimulation
Bioengineered Skin Substitutes
Products with living cells as functional skin equivalents
Mechanisms of action:
1. Colonization of wound bed with non-senescent cells
Recruitment of stem cells
2. Production of growth factors
Stimulation of angiogenesis
3. Re-epithelialization
Substrate for keratinocyte migration
4. Modification of inflammatory processes
Recruitment of neutrophils, prevention of biofilms
Mansbridge J. J Biomater Sci Polymer Edn 2008;19:955-968.
Apligraf®
Organogenesis, Inc.
Living bi-layered dermal-epidermal skin substitute
Dermal layer: fibroblasts in bovine type I collagen
Epidermal layer: keratinocytes
Cells from human neonatal foreskin tissue
FDA-approved for venous leg ulcers, diabetic ulcers
Shipped overnight, viable for 2-3 days
Each circular unit measures about 7.5cm in diameter
Dermagraft®
Advanced BioHealing, Inc.
Cryopreserved bioengineered dermal substitute
Fibroblasts seeded into polyglactin (Vicryl™) mesh
Cells derived from human neonatal foreskin tissue
FDA-approved for diabetic ulcers
Preserved at -70°C with 6-month shelf-life
Each unit measures approximately 2‖x3‖
Dermagraft® Apligraf®
Bioengineered Skin Substitutes
Dermagraft for Stalled WoundsLong Beach SCI Experience
Total 43 patients treated since December 23, 2009
Total 65 wounds treated
46 Pressure Ulcers
6 Surgical Dehiscences
3 Open Wound from Flap Loss
2 Open Wounds after Abscess Drainage
2 Open Digital Amputations
1 Diabetic Foot Ulcer
1 Open Wound after Skin Graft Loss
1 Chronic Sinus Tract
1 Non-healing Burn
2 Other
Case #1Coccygeal Pressure Ulcer, Stage IV
67 Year-old man with Multiple Sclerosis
Followed by Wound Care Team as Inpatient
Chronic Renal Failure, Ventilator-dependent
Ulcer first noted on 4/27/2009
Treated with: Granulex, Aquacel Ag, Cadexomer I2
First Dermagraft applied on 3/26/2010
Granulex
Aquacel Ag
Cadexomer
1st Dermagraft
17th Dermagraft
cm
/cm
2
Case #2Planter Heel Ulcer, Stage III
62 Year-old man with Paraplegia (T2 complete)
Followed by Wound Care Team as Outpatient
Non-Diabetic, Non-Smoker
Ulcer first noted on 12/30/2009
Treated with: collagenase, hydrogel
First Dermagraft applied on 4/14/2010
Collagenase
Hydrogel
1st Dermagraft
2nd Dermagraft
3rd Dermagraft
4th Dermagraft
5th Dermagraft
Healing with Dermagraft vs.
without Dermagraft
Patient A: 52 year-old man, C3 tetraplegic, ASIA D
stage IV coccygeal pressure ulcer
initial size 4.4x1.6cm, 1.4cm deep
initial volume of 9.86 cm3
Patient B: 25 year-old man, C4 tetraplegic, ASIA B
stage IV coccygeal pressure ulcer
initial size 5.2x5.4cm, 0.9cm deep
initial volume of 25.27cm3
NPWT
Dakin’s
Hydrogel
Cadexomer I2
Hydrogel
Collagenase
1st Dermagraft
2nd DG
3rd DG
4th DG
5th DG
6th DG
7th DG
8th DG
9th DG
Granulex
Dermagraft for Pressure UlcersVA Long Beach SCI Initial Numbers
12 Patients: 7 tetraplegic, 5 paraplegic
15 pressure ulcers: 5 stage III, 10 stage IV
80% of ulcers older than 90 days
10 (67%) ulcers healed, with average 4.7 grafts
Healers had smaller ulcers (4.1cm3 vs. 14.7cm3)
Healed ulcers less chronic (237.8 days vs. 1,300 days)
Summary
1. Diagnose and correct reversible risk factors
2. Manage wound bed (DIME)
3. Assess healing after 4 weeks of standard wound care
4. If healing<50% consider advanced wound therapies
Pressure
Ulcer
Infection Control
Correction of Ischemia
Nutritional repletion
Correction of Hyperglycemia
Pressure Relief (Offloading)
Wound Bed
Preparation
(DIME)
Surgical
Candidate?Flap Closure
Weekly Wound Assessment
Measurements
Photography
Validated Tool (e.g. BWAT, PUSH, SCI-PUMT)
Has Wound Healed
≥50% in 4 weeks?
Advanced Wound Care
Biophysical Modalities
Growth Factors
ECM Products
Bioengineered Skin Substitutes
YES
YES NO
NO
References
1. Baranoski S, Ayello EA, eds. Wound care essentials: practice principles. 2nd ed. Philadelphia: Lippincott
Williams & Wilkins, 2008.
2. Bates-Jensen BM, Guihan M, Garber SL, Chin AS, Burns SP. Characteristics of recurrent pressure ulcers in
veterans with spinal cord injury. J Spinal Cord Med 2009;32:34-42.
3. Cardinal M, Phillips T, Eisenbud DE, Harding K, Mansbridge J, Armstrong DG. Nonlinear modeling of
venous leg ulcer healing rates. BMC Dermatology 2009;9:2.
4. Consortium for Spinal Cord Medicine. Pressure ulcer prevention and treatment following spinal cord
injury: a clinical practice guideline for health-care professionals. Washington DC: Paralyzed Veterans of
America; 2000.
5. Dimitrijevich SD, Paranjape S, Wilson JR, Gracy RW, Mills JG. Effects of hyperbaric oxygen on human skin
cells in culture and in human dermal and skin equivalents. Wound Repair Reg 1999;7:53-64.
6. Fife CE, Smart DR, Sheffield PJ, Hopf HW, Hawkins G, Clarke D. Transcutaneous oximetry in clinical
practice: consensus statements from an expert panel based on evidence. Undersea Hyperb Med
2009;36:43-53.
7. Garber SL, Rintala DH. Pressure ulcers in veterans with spinal cord injury: a retrospective study. J Rehabil
Res Dev 2003;40:433-442.
8. Kloth LC. Wound healing with conductive electrical stimulation – it’s the dosage that counts. Journal of
Wound Technology 2009;6:30-37.
9. Kloth LC, McCulloch JM. Promotion of wound healing with electrical stimulation. Adv Wound Care
1996;9:42-45.
10. Lee BY, ed. The wound management manual. New York: McGraw-Hill, 2005.
11. McDougall S, Dallon J, Sherratt J, Maini P. Fibroblast migration and collagen deposition during dermal
wound healing: mathematical modelling and clinical implications. Phil Trans R Soc A 2006;364:1385-1405.
12. Mansbridge J. Hypothesis for the formation and maintenance of chronic wounds. Adv Skin Wound Care
2009;22:158-160.
References
13. Mansbridge J. Skin tissue engineering. J Biomater Sci Polymer Edn 2008;19:955-968.
14. Margolis D, Kantor J, Berlin J. Healing of neuropathic ulcers receiving standard treatment: a meta-
analysis. Diabetes Care 1999;22:692-695.
15. National Pressure Ulcer Advisory Panel and European Pressure Ulcer Advisory Panel. Prevention and
treatment of pressure ulcers: clinical practice guideline. Washington DC: National Pressure Ulcer
Advisory Panel; 2009.
16. Pullar CE. The biological basis for electrical stimulation as a therapy to heal chronic wounds. Journal of
Wound Technology 2009;6:20-24.
17. Schultz G, Mozingo D, Romanelli M, Claxton K. Wound healing an TIME; new concepts and scientific
applications. Wound Repair Reg 2005;13(4 Suppl):S1-S11.
18. Sheehan P, Jones P, Caselli A, et al. Percent change in wound area of diabetic foot ulcers over a 4-
week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care
2003;26:1879-1882.
19. Smart DR, Bennett MH, Mitchell SJ. Transcutaneous oximetry, problem wounds and hyperbaric oxygen
therapy. Diving and Hyperbaric Medicine 2006;36:72-86.
20. Townsend CM, et al, eds. Sabiston textbook of surgery: the biological basis of modern surgical practice.
17th ed. Philadelphia: Elsevier, 2004.
21. Vande Berg JS, Rose MA, Haywood-Reid PL, Rudolph R, Payne WG, Robson MC. Cultured pressure ulcer
fibroblasts show replicative senescence with elevated production of plasmin, plasminogen activator
inhibitor-1, and transforming growth factor-β1. Wound Repair Reg 2005;13:76-83.
Obtaining CME Credit
If you would like to receive CME credit for this activity, please visit:
http://www.pesgce.com/PVAsummit2011/
This information can also be found in the
Summit 2011 Program on page 8.