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.