Ira M. Herman, PhD, FAPWCA Jeffrey D. Lehrman, DPM, FASPS, MAPWCA Lee C. Ruotsi, MD, CWS, UHM Dr. Herman: Dr. Lehrman: Dr. Ruotsi:

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1 Faculty Ira M. Herman, PhD, FAPWCA Professor and Director Program in Cell, Molecular and Developmental Biology Center for Innovations in Wound Healing Research Tufts University School of Medicine Boston, Massachusetts Jeffrey D. Lehrman, DPM, FASPS, MAPWCA Adjunct Clinical Professor Temple University School of Podiatric Medicine Podiatrist, Foot & Ankle Specialists of Delaware County Springfield, Pennsylvania Lee C. Ruotsi, MD, CWS, UHM Catholic Health System Medical Director, Advanced Wound Healing Centers Cheektowaga, 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

2 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 The Chronic Wound Conundrum: Precipitating Factors and Pathophysiology Ira M. Herman, PhD, FAPWCA Professor and Director Program in Cell, Molecular and Developmental Biology Center for Innovations in Wound Healing Research Tufts University School of Medicine Boston, Massachusetts ira.herman@tufts.edu Chronic Wounds: A Global Problem Wound Type Venous Diabetic Pressure Prevalence 2.5 million 882,000 10% to 18% (acute care) Up to 28% (extended care) Estimated Annual Direct Cost (USD) $Many billions* > $6 billion $Many billions Doctor visits: $520/pt Hospital: ~$16,000/pt *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 pt = patient; USD = US dollars. Phillips T, et al. J Am Acad Dermatol. 1994;31(1): Brem H, et al. Am J Surg. 2004;188(Suppl 1A):1-8. Olin JW, et al. Vasc Med. 1999;4(1):1-7. Ramsey SD, et al. Diabetes Care. 1999;22(3): Gordois A, et al. Diabetes Care. 2003;26(6): Cuddigan J, et al. Adv Skin Wound Care. 2001;14(4): Kumar RN, et al. Adv Skin Wound Care.2004;17(3):

3 Regulation of Wound Healing: Dynamic and Reciprocal Signaling Growth control: Migratory and proliferative responses u-pa = urokinase plasminogen activator; MMP = matrix metalloproteinase; t-pa = tissue plasminogen activator. Schultz GS, et al. Wound Repair Regen. 2011;19(2): Phases of Wound Repair Coagulation: provisional matrix Inflammation: cytokine release Migration/proliferation Platelets Neutrophils Matrix/tissue remodeling Microbes Macrophages Lymphocytes Fibroblasts Endothelial cells Pericytes Smooth muscle cells Myofibroblasts Keratinocytes Time Post Wounding Normal Repair: Achieving an Equilibrium between Synthesis and Degradation PROTEASES INHIBITORS DEGRADATION SYNTHESIS

4 Overview of Chronic Wounds Non-Sequential Progression through Wound Healing Phases Phase 1: Hemostasis Phase 2: Inflammation Phase 3: Proliferation/ Epithelialization 0 to ~3 hours Prolonged Slow or Failed Phase 4: Maturation/ Remodeling Chronic Wounds: A Disrupted Equilibrium INHIBITORS PROTEASES SYNTHESIS DEGRADATION CHRONIC WOUND CONUNDRUM METABOLISM & NUTRITION

5 CHRONIC WOUND CONUNDRUM ELEVATED IMFLAMMATORY MEDIATORS Acute vs Chronic Wound Healing Excessive inflammation MMP production Matrix degradation Cell senescence Impaired angiogenesis Cell proliferation Apoptosis TIMP production Matrix remodeling TIMP = tissue inhibitor of metalloproteinase. TIME. February 23, 2004.

6 How Chronic Wounds Differ 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. Signaling through the Inflammatory Network: Role of Immune Modulators and Host Enzymes Bacterial Signals: Amplify Inflammation Immune Surveillance Cells: Elevated Extravasation? MMP-1 MMP-2 MMP-3 MMP-9 MMP-13 Elevated Proteases Decreased TIMPs 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):

7 Reversal of ECM Degradation: Active Healing in Venous Ulcers Fibronectin absence Fibronectin presence Herrick SE, et al. Am J Pathol. 1992;141(5): Pressure Ulcers: Can Wound Fluid Protease Activity Predict Healing Efficacy? Ratio of MMP-9 (pro+active): TIMP-1 (ng/ml) Good Healing > 95% area healed; n = 12 Intermediate Healing < 95% but > 65 area healed; n = 36 Poor Healing < 65% area healed; n = 8 0 Day 0 Day 10 Day 36 Ladwig GP, et al. Wound Repair Regen. 2002;10(1): Acute vs Chronic Wound Healing Normal Wound Chronic Wound MMP HB-EGF fibrin clot Delayed epithelial migration epithelialization TGF- Bioactive matrix fragments Matrix-bound growth factors PDGF TGF- MMP TGF- upa MMP FGF-2 VEGF EGF EPC recruitment excessive proteolysis ROS MMPs Insufficient cell proliferation Impaired Cytokine angiogenesis deficiency Impaired EPC recruitment Disorganized glycated ECM 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.

8 Importance of Aggressive Wound Management for Chronic Wounds Lee C. Ruotsi, MD, CWS, UHM Catholic Health System Medical Director, Advanced Wound Healing Centers Cheektowaga, New York The Importance of Aggressive Wound Bed Preparation Triple Aim

9 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): Enoch S, et al. Wounds. 2003;15(8): The Microenvironment of the Chronic Wound is Imbalanced 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) Lobmann R, et al. Diabetes Care. 2005;28(2): 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

10 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 that supports the growth of pathological organisms Bacteria thrive in presence of necrotic tissue Perpetuates inflammatory response Acts as a barrier to new tissue growth

11 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: Types of Debridement Strateg y Strategy Description Examples Surgical (Excisional/Sharp) Removal by surgical instrument Scalpel, scissors, hydrosurgery, lasers, curettes, Mechanical Removal of necrotic tissue by mechanical means Wet to dry dressings, hydrotherapy, ultrasound, abrasion Biosurgical Sterile larvae selectively digest necrotic tissue and bacteria Sterile blowfly or housefly larvae Autolytic Enzymatic Uses the body s own enzymes to dissolve necrotic tissue; assisted with moisture-retentive dressings Topical application of enzymes to liquefy necrotic tissue Moisture retentive dressings Collagenase 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: Debridement is a Key Component of Adequate Wound Bed Preparation

12 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

13 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): Falanga V. Wound Repair Regen. 2000;8(5): 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

14 Motley TA, et al. Wounds. 2014;26(3): 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 tool CCO = Clostridium collagenase ointment. Motley TA, et al. Wounds. 2014;26(3): 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.

15 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): 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 Accessed February 28, 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):

16 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 limerelated chemical burns with associated eschar. Day 1 5d post exposure Day 10

17 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 crosshatched 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

18 Hospital Day 1 Day 14 Day 28

19 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

20 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

21 Day 1 Day 30 Day 60 Impact of Chronic Wounds on Healthcare Costs and Quality of Life Jeffrey D. Lehrman, DPM, FASPS, MAPWCA Adjunct Clinical Professor Temple University School of Podiatric Medicine Podiatrist, Foot & Ankle Specialists of Delaware County Springfield, Pennsylvania

22 Neuropathic Ulcer 5-Year Mortality Rate Year Mortality Rate (%) Moulik PK, et al. Diabetes Care. 2003;26(2): Armstrong DG, et al. Int Wount J. 2007;4(4): American Cancer Society. Cancer Facts & Figures Accessed February 28, Quality of Life

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25 Chronic Wounds 6.5 Million Individuals affected and growing Estimated at $33 Billion annually in the United States Sen CK, et al. Wound Rep Regen. 2009;17(6): Rice JB, et al. J Med Econ. 2014;17(5): Age Population > 65 years 82% projected increase ( ) 12.1% 19% Diabetes Increase of x 3 x 3 Obesity Two-thirds with BMI > 25 BMI = body mass index. Sen CK, et al. Wound Rep Regen. 2009;17(6): Centers for Disease Control and Prevention. Diabetes Report Card Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; MACRA

26 2017 MIPS Score Sales Quality 60% ACI 25% Clinical Practice Improvement Activities 15% Cost 0% ACI = Advancing Care Information; MIPS = Merit-based Incentive Payment System MIPS Score Sales Quality 50% ACI 25% Clinical Practice Improvement Activities 15% Cost 10% 2019 MIPS Score Sales Quality 30% ACI 25% Clinical Practice Improvement Activities 15% Cost 30%

27 Triple Aim Comparative Effectiveness of Clostridial Collagenase Ointment to 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].

28 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