Advanced Wound Care

Modalities for the Treatment

of Pressure Ulcers
Improving the Standard of Care

Walter C. Chua, MD, FAPWCA

PVA Summit 2011
September 17, 2011
 Disclosures

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.
 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 Plastic Surgery Primary Care
WOCN Nursing
Wound Care Team Physiatry Nutritionists
VA Long Beach SCI/D HCG 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
Dermal Healing (fibroblasts):

d i(t) ui(t)
i(t) = s
dt ui(t)

i(t-t)
ui(t)=(1-r)c( i(t),t)+r
i(t-
t)

where s = cell speed

t = time lag
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

ln 2
Half-life, t =
l
Cardinal M et al. BMC Dermatology 2009;9:2-9.
Healing Rate of DFUs
Standard 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 -
ln 2
t = > 4 weeks
l

will likely fail to heal and result in a chronic wound.

 The Chronic Wound
Non-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
Healing Wounds Chronic Ulcers
Pro-inflammatory cytokines Pro-inflammatory cytokines
MMPs MMPs
Normal matrixfibronectin, Degraded matrixfibronectin,
collagen collagen
Cells capable of rapid
response Senescent fibroblasts

Cell mitosis Mitogenic activity

Growth factors Disordered patterns of growth
factors

Schultz G, Mast B. Wounds.1998;10:1F-9F.

 Chronic Wound
Prevention/Treatment

All risk factors addressed and corrected

But wound still not healing at reasonable rate

ln 2
t = > 4 weeks
l

Consider applying advanced wound care

 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 Therapy
Transcutaneous 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 -70C with 6-month shelf-life

Each unit measures approximately 2x3

Bioengineered Skin Substitutes

Dermagraft Apligraf
Dermagraft for Stalled Wounds
Long 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 #1
Coccygeal 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

 1st Dermagraft

Cadexomer
cm/cm2

Aquacel Ag

Granulex 17th Dermagraft

Case #2
Planter 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

 1st Dermagraft

Collagenase

Hydrogel

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
 Dakins

NPWT 1st Dermagraft

3rd DG
Hydrogel

9th DG
2nd DG

Cadexomer I2
Granulex
Hydrogel
6th DG
Collagenase 4th DG

5th DG
7th DG
8th DG
 Dermagraft for Pressure Ulcers
VA 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)

YES
Surgical
Flap Closure Candidate?

NO Advanced Wound Care

Biophysical Modalities
Growth Factors
ECM Products
Wound Bed Bioengineered Skin Substitutes
Preparation
(DIME)

YES NO

Has Wound Healed

50% in 4 weeks?

Weekly Wound Assessment

Measurements
Photography
Validated Tool (e.g. BWAT, PUSH, SCI-PUMT)
 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 its 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-1. 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.