Faculty

Ira M. Herman, PhD, FAPWCAProfessor and Director

Program in Cell, Molecular and Developmental BiologyCenter for Innovations in Wound Healing Research

Tufts University School of MedicineBoston, Massachusetts

Jeffrey D. Lehrman, DPM, FASPS, MAPWCAAdjunct Clinical Professor

Temple University School of Podiatric MedicinePodiatrist, Foot & Ankle Specialists of Delaware County

Springfield, Pennsylvania

Lee C. Ruotsi, MD, CWS, UHMCatholic Health System

Medical Director, Advanced Wound Healing CentersCheektowaga, New York

Disclosures

Dr. Herman: Grant/Research—Tufts University; Research—Smith & Nephew

Dr. Lehrman: Board of Directors—American Society of Podiatric Surgeons, American Professional Wound Care Association; Consultant—Endo, Smith & Nephew, Molnlycke, MTF; Speakers’ Bureau—BSN Medical, Smith & Nephew

Dr. Ruotsi: Speakers’ Bureau—Organogenesis, Smith & Nephew

Learning Objectives

• Describe the pathophysiology of chronic wounds

• Recognize the importance of aggressive wound management for chronic wounds

• Examine the role of enzymatic debridement as an adjunct to sharp debridement in progressing chronic wounds toward healing

• Recognize the impact of chronic wounds on healthcare costs and patient’s quality of life

Ira M. Herman, PhD, FAPWCAProfessor and DirectorProgram in Cell, Molecular and Developmental BiologyCenter for Innovations in Wound Healing ResearchTufts University School of MedicineBoston, Massachusettsira.herman@tufts.edu

The Chronic Wound Conundrum:Precipitating Factors and Pathophysiology

Chronic Wounds: A Global Problem

*Based on estimated prevalence of 2.5 million and actual mean direct cost of $9685/person; †Based on 14.7 million diabetics, 6% of whom expected to develop ulcers over 3 years; ‡Direct costs of treating noninfected diabetic foot ulcers; §Costs in 1996 and 1998. pt = patient; USD = US dollars.Phillips T, et al. J Am Acad Dermatol. 1994;31(1):49-53. Brem H, et al. Am J Surg. 2004;188(Suppl1A):1-8. Olin JW, et al. Vasc Med. 1999;4(1):1-7. Ramsey SD, et al. Diabetes Care. 1999;22(3):382-387. Gordois A, et al. Diabetes Care. 2003;26(6):1790-1795. Cuddigan J, et al. Adv Skin Wound Care. 2001;14(4):208-215. Kumar RN, et al. Adv Skin Wound Care.2004;17(3):143-149.

$Many billions§

• Doctor visits: $520/pt§

• Hospital: ~$16,000/pt§

10% to 18% (acute care)

Up to 28% (extended care)Pressure

> $6 billion‡882,000†Diabetic

$Many billions*2.5 millionVenous

Estimated

Annual Direct Cost (USD)PrevalenceWound Type

Regulation of Wound Healing:Dynamic and Reciprocal Signaling

u-PA = urokinase plasminogen activator; MMP = matrix metalloproteinase; t-PA = tissue plasminogen activator.Schultz GS, et al. Wound Repair Regen. 2011;19(2):134-148.

Growth control:Migratory

and proliferative responses

Coagulation: provisional matrix

Inflammation: cytokine releaseMigration/proliferation

Matrix/tissue remodelingPlatelets

Time Post Wounding

Fibroblasts Endothelial cells

PericytesSmooth muscle cells

MyofibroblastsKeratinocytes

MacrophagesLymphocytes

NeutrophilsMicrobes

Phases of Wound Repair

Normal Repair: Achieving an Equilibrium between Synthesis and Degradation

PROTEASES

DEGRADATION

INHIBITORS

SYNTHESIS

Overview of Chronic Wounds

Phase 1:Hemostasis

Phase 4:Maturation/ Remodeling

Phase 3:Proliferation/

Epithelialization

Phase 2:Inflammation

0 to ~3 hours Prolonged Slow or Failed

Non-Sequential Progression through Wound Healing Phases

PROTEASES

DEGRADATION

INHIBITORS

SYNTHESIS

Chronic Wounds:A Disrupted Equilibrium

CHRONICWOUND

CONUNDRUM

METABOLISM &NUTRITION

CHRONICWOUND

CONUNDRUM

ELEVATEDIMFLAMMATORY

MEDIATORS

Acute vs Chronic Wound Healing

TIMP = tissue inhibitor of metalloproteinase.

Excessive inflammationMMP production

Matrix degradationCell senescence

Impairedangiogenesis

Cell proliferationApoptosis

TIMP productionMatrix

remodeling

TIME. February 23, 2004.

How Chronic WoundsDiffer from Acute Wounds

• Within chronic wounds, several issues can affect healing, ie, quantity and activity of inflammatory cytokines, MMPs and their inhibitors, all of which can lead to decreased levels of certain growth factors (eg, PDGF, EGF and TGF-β), when compared to acute/ normal wounds

• Bacteria and biofilms contaminating chronic wounds may be deleterious compared to those beneficial bacteria found in acute wounds

• Excessive MMPs can degrade the cytokines, eliminating the mediators of cellular processes that are critical to wound healing

EGF = epidermal growth factor ; PDGF = platelet-derived growth factor; TGF-β = transforming growth factor beta.Robbins SL, et al. Pathologic Basis of Disease. Third Edition. Philadelphia, PA: WB Saunders; 1984:1-85.

Chronic Wounds: Inflammatory Cycle

• Elevated levels of TNF (neutrophils, macrophages)

• Elevated levels of ILs (IL-1β, IL-6)

• Imbalanced protease and inhibitor profiles

– Elevated MMPs

– Decreased TIMPs

• Destruction of key survival agents (growth modulators and receptors)

• Altered microenvironment (ECM)

– Perturbation of cellular responses to injury (migration and growth)

ECM = extracellular matrix; TNF = tumor necrosis factor; IL = interleukin.Robbins SL, et al. Pathologic Basis of Disease. Third Edition. Philadelphia, PA: WB Saunders; 1984:1-85.

Bacterial Signals: Amplify Inflammation

Elevated Proteases–Decreased TIMPs

Immune Surveillance Cells:Elevated Extravasation?

Signaling through the Inflammatory Network:Role of Immune Modulators and Host Enzymes

ICAM = intercellular adhesion molecule; LFA = lymphocyte function; VLA = very late antigen; VCAM = vascular cell adhesion molecule; PMN = ploymorphonuclear neutrophils.Eming SA, et al. J Invest Dermatol. 2007;127(3):514-525.

MMP-1MMP-2MMP-3MMP-9MMP-13

Fibronectin absence

Fibronectin presence

Reversal of ECM Degradation:Active Healing in Venous Ulcers

Herrick SE, et al. Am J Pathol. 1992;141(5):1085-1095.

Pressure Ulcers: Can Wound FluidProtease Activity Predict Healing Efficacy?

Ladwig GP, et al. Wound Repair Regen. 2002;10(1):26-37.

Ra

tio

of

MM

P-9

(p

ro+

ac

tiv

e):

TIM

P-1

(n

g/m

l)

350

450

300

250

200

150

100

0

50

Day 0 Day 10

400

Day 36

Intermediate Healing

Poor Healing

Good Healing

< 95% but > 65 area healed; n = 36

< 65% area healed; n = 8

> 95% area healed; n = 12

MMP

PDGFTGF-TGF-

MMP

TGF-

uPAMMP

EGF

HB-EGF fibrin clot

FGF-2VEGF

EPC recruitment

Bioactive matrix

fragments

Matrix-bound growth factors Impaired

EPC recruitment

excessiveproteolysis ROS

MMPsDisorganizedglycated ECM

Impaired angiogenesis

Delayed epithelial migration

epithelialization

Normal Wound Chronic Wound

Cytokine deficiency

Insufficientcell proliferation

Acute vs Chronic Wound Healing

EPC = endothelial progenitor cell; FGF = fibroblast growth factor; ROS = reactive oxygen species; VEGF = vascular endothelial growth factor.Demidova-Rice TN, et al. Wound Repair Regen. 2011;19(1):59-70.

Lee C. Ruotsi, MD, CWS, UHMCatholic Health SystemMedical Director, Advanced Wound Healing CentersCheektowaga, New York

Importance of Aggressive Wound Management for Chronic Wounds

The Importance of Aggressive Wound Bed Preparation

Triple Aim

Wound Bed Preparation: Restoring the Balance

• Integrates proven concepts to build a platform for the treatment of chronic wounds

• Organizes medical procedures into a holistic approach that can be used to evaluate and remove barriers to the wound healing process

• Ultimate aim of the formation of good quality granulation tissue leading to complete wound closure

• Optimal management of a wound in order to accelerate endogenous healing, or to facilitate the effectiveness of other therapeutic measures

Falanga V. Wounds. 2002;14(2):47-57. Enoch S, et al. Wounds. 2003;15(8):213-229.

The Microenvironment of theChronic Wound is Imbalanced

Lobmann R, et al. Diabetes Care. 2005;28(2):461-471.

HEALING WOUNDS

•Low Inflammatory cytokines•Low proteases, ROS•Functional ECM and growth factors•Mitotically competent cells•Apoptotic clearing (without necrosis)

CHRONIC WOUNDS

•High inflammatory cytokines, bacteria•High proteases, ROS•Degraded ECM and growth factors•Quiescent and senescent cells•Necrosis (without regulation of apoptosis)

Treat the Cause

• Determine the etiology

– Assess ability to support

• Offloading / pressure redistribution

• Compression

• Glucose control

• Re-establish blood flow

• Assess potential for healing

• Assess comorbid conditions

Treat the Cause

• Determine the etiology

– Assess ability to support

• Offloading / pressure redistribution

• Compression

• Glucose control

• Vascular interventions

• Nutritional support

• Assess potential for healing

• Assess comorbid conditions

TIME

• Tissue• Infection• Moist wound environment• Edge Don’t waste it…

Necrotic Tissue

• Devitalized tissue thatsupports the growth of pathological organisms

– Bacteria thrive in presence of necrotic tissue

• Perpetuates inflammatory response

• Acts as a barrier to new tissue growth

Why Debride Non-Viable Tissue?

• To remove dead, devitalized, contaminated tissue or foreign material, senescent cells

• To reduce microbes, toxins, and other substances that inhibit healing

• To provide a clinician the ability to assess the depth of wound and the condition of surrounding tissue

• To remove the physical barrier to healing and reduce bacterial growth

• To adequately prepare for advanced agents, CTPs

• Recommended in all guidelines

CTP = cellular tissue-based product.Weir D, et al. Wound debridement. In: Krasner DL, et al. (Eds.). Chronic Wound Care: A Clinical Source Book for Healthcare Professionals. Fourth Edition. Malvern, PA: HMP Communications; 2007:343-355.

Types of Debridement

Weir D, et al. Wound debridement. In: Krasner DL, et al. (Eds.). Chronic Wound Care: A Clinical Source Book for Healthcare Professionals. Fourth Edition. Malvern, PA: HMP Communications; 2007:343-355.

Strategy

Strategy Description Examples

Surgical (Excisional/Sharp)

Removal by surgical instrumentScalpel, scissors, hydrosurgery,

lasers, curettes,

Mechanical

Removal of necrotic tissue by mechanical means

Wet to dry dressings, hydrotherapy, ultrasound,

abrasion

BiosurgicalSterile larvae selectively digest

necrotic tissue and bacteria

Sterile blowfly or housefly larvae

AutolyticUses the body’s own enzymes to dissolve necrotic tissue; assisted with moisture-retentive dressings

Moisture retentive dressings

EnzymaticTopical application of enzymes

to liquefy necrotic tissueCollagenase

Debridement is a Key Component of Adequate Wound Bed Preparation

Advantages of Sharp Debridement

• The fastest way to remove necrotic tissue

• Able to completely remove surface debris, biofilm

• May re-ignite an inflammatory response

– Return wound to healing trajectory

Adjunctive Debridement with Collagenase

• Daily debridement adjunct to weekly or bi-weekly sharp debridement

• Exogenously applied agent works directly on devitalized tissue or indirectly by dissolving collagen anchoring devitalized tissue to wound bed

• Little to no effect on healthy collagen or tissue

• Easily applied by patient or caregivers

• Collagenase is the only enzymatic debriding agent approved by the FDA

Collagenase

• Collagenase belongs to a family of MMPs

– Naturally occurring enzymes produced by in response to bacteria, debris, and are produced by activated inflammatory cells and certain wound cells

• Exogenous collagenase is a derived from fermentation by clostridium histolyticum

– Complex biologic that requires a year-long manufacturing process in a sterile environment

– Digests collagen in the necrotic wound environment

– Targets only devitalized collagen

Sibbald GR, et al. Ostomy Wound Manage. 2000;46(11):14-35. Falanga V. Wound Repair Regen. 2000;8(5):347-352.

Collagenase

• Continuously removes necrotic tissue from the wound while allowing normal granulation to proceed

• Selectively attacks and cleaves collagen strands anchoring cellular debris

• Enables it to work from the “bottom up”

Motley TA, et al. Wounds. 2014;26(3):57-64.

Debridement with and without Adjunctive Clostridial Collagenase Ointment

• Objective– Provide descriptive outcomes data regarding

chronic diabetic foot ulcers treated with 6 weeks of serial sharp debridement with or without adjunctive CCO debridement

• Endpoints– Primary

• Percent change in ulcer area from baseline at end of the treatment period (Week 6) and after an additional 6 weeks of follow-up (Week 12)

– Secondary• Wound appearance at Week 6 and Week 12

using a standardized wound assessment toolCCO = Clostridium collagenase ointment.Motley TA, et al. Wounds. 2014;26(3):57-64.

Debridement with and without Adjunctive Clostridial Collagenase Ointment (cont’d)

• Aim was to generate rather than not test a hypothesis based on sample size (N = 55)

• Objective decision making relative to sharp debridement

– Bates-Jensen Wound Assessment Score

• Edges

• Undermining

• Necrotic tissue type and amount

• Exudate type and amount

• Periwound skin color

• Granulation tissue

Motley TA, et al. Wounds. 2014;26(3):57-64.

Debridement with and without Adjunctive Clostridial Collagenase Ointment: Results

• Wound appearance scores improved in both treatment groups

• On average, ulcers receiving serial sharp debridement decreased in size more rapidly with the addition of CCO

– The CCO group demonstrated a 68% decrease in ulcer area from baseline at Week 6 (P < .001) vs 36% in the control group (P = NS)

• This was designed as a descriptive study; further work underway

Motley TA, et al. Wounds. 2014;26(3):57-64.

Precautions

• The optimal pH range of collagenase is 6 to 8

• Adversely affected by certain detergents, and heavy metal ions such as mercury and silver which are used in some antiseptics

• Soaks containing metal ions or acidic solutions should be avoided because of the metal ion and low pH

• A slight transient erythema has been noted occasionally in the surrounding tissue, particularly when CCO was not confined to the wound. Therefore, the ointment should be applied carefully within the area of the wound

www.santyl.com/content/pdf/SANTYL_Package_Insert-2013.pdf. Accessed February 28, 2017.

With that said…

• Thoroughly flush with saline if agents are used

• Awareness of compatibility with cleansers and antimicrobial dressings/agents helpful

Jovanovic A, et al. Wounds. 2012;24(9):242-253.

Case Study 1

• 24-year-old male spent a morning pouring a cement sidewalk in sneakers with no protection from the wet cement and lime contained therein. These are lime-related chemical burns with associated eschar.

Day 1

5d post

exposure

Day 10

Case Study 2

• 44-year-old male with leukocytoclastic vasculitis and hospitalized after several weeks of ineffective treatment

• Biopsy done in hospital and seen in Wound Center 5 days later

• Thick, broad-based hard black eschars were cross-hatched on Day 1

• Concomitant systemic steroids and CCO

Day 1 Day 12

Case Study 3

• 82-year-old Egyptian male presented to hospital with huge bulla on foot

• Bulla decompressed at bedside

• Cultures unremarkable and vascular workup satisfactory

• Discharged with conservative wound care and initially reluctant to come for follow-up

Hospital

Day 1

Day 14 Day 28

Case Study 4

• 62-year-old male awoke on Saturday morning with intense redness and warmth around his ankle

• Took a shower and the skin peeled off in affected area

• Went to urgent care center and sent home with cephalexin 500 qid

• Saw me 48 hours later

Day 1

Day 1 - Crosshatched

Day 14

Day 28

Case Study 5

• 82-year-old female tripped going up stairs striking her leg on edge of stair

• Developed huge hematoma and went to orthopedist as she had total knee replacement

• He debrided the eschar leaving huge underlying wound and referred to me

• Remained on prophylactic antibiotics for about a month

Day 1

Day 30

Day 60

Jeffrey D. Lehrman, DPM, FASPS, MAPWCAAdjunct Clinical ProfessorTemple University School of Podiatric MedicinePodiatrist, Foot & Ankle Specialists of Delaware CountySpringfield, Pennsylvania

Impact of Chronic Wounds on Healthcare Costs and Quality of Life

1

56

45

911

22

2935

41

56

83

94

Neuropathic Ulcer5-Year Mortality Rate

Moulik PK, et al. Diabetes Care. 2003;26(2):491-494. Armstrong DG, et al. Int Wount J. 2007;4(4):286-287. American Cancer Society. Cancer Facts & Figures 2014. www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2014.html. Accessed February 28, 2017.

20

100

0

5 -

Ye

ar

Mo

rta

lity

Ra

te (

%)

40

60

80

Quality of Life

Chronic Wounds

Sen CK, et al. Wound Rep Regen. 2009;17(6):763-771. Rice JB, et al. J Med Econ. 2014;17(5):347-356.

6.5 MillionIndividuals affected and

growing annually in the United States

Estimated at

$33 Billion

BMI = body mass index.Sen CK, et al. Wound Rep Regen. 2009;17(6):763-771. Centers for Disease Control and Prevention. Diabetes Report Card 2012. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2012.

Age

Population > 65 years

82% projected increase

(2009 – 2030)

Diabetes

1990 – 2010Increase of x 3

Obesity

Two-thirds with

BMI > 25

12.1% 19%

x 3

MACRA

2017 MIPS Score

ACI = Advancing Care Information; MIPS = Merit-based Incentive Payment System.

Sales

Quality 60%

ACI 25%

Clinical PracticeImprovementActivities 15%

Cost 0%

2018 MIPS Score

Sales

Quality 50%

ACI 25%

Clinical PracticeImprovementActivities 15%

Cost 10%

2019 MIPS Score

Sales

Quality 30%

ACI 25%

Clinical PracticeImprovementActivities 15%

Cost 30%

Triple Aim

Comparative Effectiveness of Clostridial Collagenase Ointmentto Medicinal Honey for Treatment of Pressure Ulcers

Gilligan AM, et al. Advances in Wound Care. 2017;[Epub ahead of print].

Clostridial Collagenase Ointment vs Honey

• 517 CCO Treated Pressure Ulcers

• Matched to Honey Treated Pressure Ulcers

• CCO group: 38% more likely to achieve 100% granulation at 1 year

• CCO group: 47% more likely to epithelialize at 1 year

Gilligan AM, et al. Advances in Wound Care. 2017;[Epub ahead of print].

Clostridial Collagenase Ointment vs Honey

• CCO group:

– Fewer office visits

– Fewer debridements

– Less likely to require NPWT

NPWT = negative pressure wound therapy.Gilligan AM, et al. Advances in Wound Care. 2017;[Epub ahead of print].

Summary

• Pathophysiology

• Aggressive Management!

• Enzymatic Debridement + Sharp Debridement

• Quality of Life

• Healthcare Costs

Q & A