Proactive and Early Aggressive Wound Management:

Transcription

1 Supplement to WOUNDS November 2017 C AT E Proactive and Early Aggressive Wound Management: D O N O T D U PL I A Shift in Strategy Developed by a Consensus Panel Examining the Current Science, Prevention, and Management of Acute and Chronic Wounds Supported by Hollister Incorporated. This supplement was accepted according to the WOUNDS peer-review process.

2 Gregory A. Bohn, MD 1 ; Gregory S. Schultz, PhD 2 ; Brock A. Liden, DPM 3 ; Michael N. Desvigne, MD 4 ; Eric J. Lullove, DPM 5 ; Igor Zilberman, DPM 6 ; Mary B. Regan, PhD, RN 7 ; Marta Ostler, PT 8 ; Karen Edwards, MSS, RN, BSN, WOCN 9 ; Georgia M. Arvanitis, PhD 10 ; and Jodi F. Hartman, MS 11 From the 1 Central Michigan University, Department of Surgery, St. Joseph s Health System, Tawas, MI; 2 Institute for Wound Research, University of Florida, Gainesville, FL; 3 Circleville Foot & Ankle Center, Circleville, OH; 4 MD Health Services LLC, Peoria, AZ; 5 West Boca Raton Center for Wound Healing, Boca Raton, FL; 6 South Florida Lower Extremity Center, Hollywood, FL; 7 Hollister Incorporated, Libertyville, IL; 8 Sheridan Memorial Hospital, Sheridan, WY; 9 University of Alabama at Birmingham Hospital, Birmingham, AL; 10 MbGa Scientific LLC, Pennington, NJ; and 11 Orthopaedic Research & Reporting, Ltd, Westerville, OH Address correspondence to: Brock A. Liden, DPM Circleville Foot & Ankle 210 Sharon Rd, Suite A Circleville, OH dpmresearch@gmail.com

3 Proactive and Early Aggressive Wound Management: A Shift in Strategy Developed by a Consensus Panel Examining the Current Science, Prevention, and Management of Acute and Chronic Wounds Gregory A. Bohn, MD; Gregory S. Schultz, PhD; Brock A. Liden, DPM; Michael N. Desvigne, MD; Eric J. Lullove, DPM; Igor Zilberman, DPM; Mary B. Regan, PhD, RN; Marta Ostler, PT; Karen Edwards, MSS, RN, BSN, WOCN; Georgia M. Arvanitis, PhD; and Jodi F. Hartman, MS Abstract: Normal wound healing is accomplished through a series of well-coordinated, progressive events with overlapping phases. Chronic wounds are described as not progressing to healing or not being responsive to management in a timely manner. A consensus panel of multidisciplinary wound care professionals was assembled to (1) educate wound care practitioners by identifying key principles of the basic science of chronic wound pathophysiology, highlighting the impact of metalloproteinases and biofilms, as well as the role of the extracellular matrix; and (2) equip practitioners with a systematic strategy for the prevention and healing of acute injuries and chronic wounds based upon scientific evidence and the panel members expertise. An algorithm is presented that represents a shift in strategy to proactive and early aggressive wound management. With proactive management, adjunct therapies are applied preemptively to acute injuries to reduce wound duration and risk of chronicity. For existing chronic wounds, early aggressive wound management is employed to break the pathophysiology cycle and drive wounds toward healing. Reducing bioburden through debridement and bioburden management and using collagen dressings to balance protease activity prior to the use of advanced modalities may enhance their effectiveness. This early aggressive wound management strategy is recommended for patients at high risk for chronic wound development at a minimum. In their own practices, the panel members apply this systematic strategy for all patients presenting with acute injuries or chronic wounds. Key words: chronic wounds, wound healing, acute wounds, prevention, wound management, bioburden Wounds 2017;29(11 Suppl):S37 S42. BACKGROUND Prior to a discussion of chronic wounds, a thorough understanding of the normal physiology involved with wound healing is crucial. Normal wound healing is achieved through a series of well-coordinated, progressive events designed to restore the barrier function and mechanical integrity of the skin. 1,2 Wound healing involves biochemical and biomechanical interactions between cells and their microenvironment, of which the extracellular matrix (ECM) with its diverse collection of structural, adhesive, and resilient biomolecules is the primary component. Because the interactions between the cells and ECM are reciprocal and dynamic (ie, continually changing in response to cues from their microenvironment), the term dynamic reciprocity was developed to indicate the ongoing, bidirectional interactions between cells and the ECM. 2-4 This concept of dynamic reciprocity provides a context from which to understand developmental processes, tumor growth, and wound healing. 2,3,5-7 The molecular events associated with wound healing commonly are categorized into 4 phases and are summarized in Figure 1. The first phase (vascular response/hemostasis phase) begins upon disruption of blood vessels, which leads to a series of molecular events designed to stop blood loss. These events include vasoconstriction, formation of a platelet plug, and coagulation, during which cells respond to changes in the ECM and vice versa. 1,2,4,8 The second phase (inflammatory) is characterized by the sequential influx of immune cells that have a range of functions, including removal of bacteria, debris, and devitalized tissue. 1,2,4,8 The repair, or proliferative, phase involves the formation of granulation tissue, new blood vessels, macrophages, fibroblasts, and loose connective tissues. 1,2,4,8 Early contraction and reepithelialization also occur during this third phase of wound healing. During the fourth phase (remodeling/maturation), myofibroblasts interact with collagen bundles and growth factors to contract the wound. 1,2,4,8-10 Metalloproteinases (MMPs) are released by macrophages, endothelial cells, and epidermal cells and, besides removing damaged ECM and bacteria, play a necessary role in remodeling the early matrix. 1,2,4,8 Myofibroblasts and fibroblasts replace the early matrix with stronger type I collagen. 2,4 This slow remodeling of collagen, including formation of bundles and crosslinks, progresses to scar formation over several months. 2 Disclosure: Dr. Bohn is a consultant for Acelity (San Antonio, TX) and Medline (Northfield, IL) and a consultant and speaker for Hollister Incorporated (Libertyville, IL). Dr. Schultz provides research support for Bovie Medical (Purchase, NY) and CorMedix (Bedminster, NJ); is a consultant for Exoxemis, Inc (Little Rock, AR), Organogenesis (Canton, MA), and Hollister Incorporated; provides research support and is a consultant for Medline and Smith & Nephew (London, UK). Dr. Liden is a consultant for Calgon Carbon (Downingtown, PA), Osteosolutions (South Croydon, UK), Tissue Regenix (London, UK), and Vivex (Miami, FL); and a consultant and speaker for Hollister Incorporated. Dr. Desvigne is a consultant for Regenesis Biomedical Inc (Scottsdale, AZ), Board Member of Wound Research Foundation, and a consultant and speaker for Acelity, Smith & Nephew, Hollister Incorporated, and Tissue Regenix. Dr. Lullove is a consultant for Cumberland Pharmaceuticals (Nashville, TN), Hollister Incorporated, Osiris Therapeutics (Columbia, MD), and Skye Biologics (El Segundo, CA). Dr. Zilberman, Ms. Ostler, and Ms. Edwards are speakers for Hollister Incorporated. Dr. Regan is an employee of Hollister Incorporated. Dr. Arvanitis is a consultant for Hollister Incorporated. Editorial support and honorariums for panel members were provided by Hollister Incorporated. Evelyn Quintin, RN, BSN, CWCN, CWS, provided assistance in figure preparation. Supported by Hollister Incorporated NOVEMBER 2017 WOUNDS S37

4 Proactive and Early Aggressive Wound Management Figure 1. Four phases of wound healing. As illustrated in Figure 1, the phases of wound healing overlap. 1,2,4,8,11-13 The duration of each phase is dependent on multiple factors. Wounds that do not progress to healing or that are not responsive to management in a timely manner have defective remodeling of the ECM, fail to reepithelialize, and have prolonged elevated inflammation. 2,11,12,14-20 Wounds in this nonhealing phase are typically referred to as chronic wounds. Chronicity has various causative factors (eg, diabetes mellitus, venous or arterial insufficiency, immunosuppression, a period of immobility leading to prolonged pressure, and infection). 2,12,16 A consensus panel comprised of multidisciplinary wound care professionals was assembled to (1) educate wound care practitioners by identifying key principles of the basic science of chronic wound pathophysiology, highlighting the impact of MMPs and biofilms, as well as the role of the ECM; and (2) equip practitioners with prevention and management guidelines for acute injuries and chronic wounds. The project culminated with the development of a systematic strategy and algorithm for the prevention and healing of acute injuries and chronic wounds based upon the expertise of panel members and scientific evidence. METHODS The consensus panel consisted of 9 members (5 surgeons, 2 nurses, 1 physical therapist, and 1 researcher with expertise in wound care) who convened with a moderator on 2 occasions to discuss the basic science of chronic wound pathology and formulate a prevention and management strategy for healing acute injuries and chronic wounds. The first meeting was conducted on May 2, 2015, in San Antonio, Texas. The goals of this initial meeting were to develop a framework for discussing chronic wound pathophysiology, identifying key principles regarding chronic wound basic science, and discussing prevention and management practices to identify areas of similarity. The second meeting took place on August 15, 2015, in Chicago, Illinois. During this meeting, the basic science key principles were revised and finalized. In addition, prevention and management guidelines, including an algorithm, were developed. The management strategy and algorithm were revised and finalized during subsequent electronic correspondence and teleconference between panel members. The resulting prevention and management guidelines and algorithm were unanimously approved. Chronic Wound Basic Science: Key Principles Wounds fail to heal when they enter a pathophysiology cascade stimulated by repeated tissue injury, ischemia, and elevated bioburden (Figure 2). Prolonged inflammation ensues, which leads to elevated proteases that destroy essential proteins, such as growth factors, and the ECM that is requisite for healing. This cycle must be broken to achieve healing. The panel identified key principles regarding the basic science of chronic wound pathophysiology using the phases of this cascade as a framework for discussion. Repeated tissue injury. 1. Injuries are the result of trauma, microtrauma, pressure, or iatrogenic causes Repeated microtrauma may lead to the development of chronic wounds due to the prolonged elevated inflammation caused by recurrent tissue injury. 1,22 3. Ischemia may lead to chronic wounds, as adequate blood flow provides the nutrition and oxygen necessary for sustaining healthy tissue. 22,23 Decreased oxygen levels impair an active immunological response to microorganisms, collagen production, and epithelialization Pressure, shear, and friction may lead to tissue injury that could result in ulcer formation. 8,22 5. Vascular impairment may cause tissue breakdown, which then may lead to chronic ulcer formation. 20,22 6. Prolonged microischemia is a major factor in the development of neuropathy and loss of protective sensation, leading to tissue breakdown and possible formation of a neuropathic ulcer. 22 Role of bioburden and biofilm. 1. Chronic wounds have a high bioburden by a host of microorganisms, some of which are free-living (planktonic bacteria) and others that may colonize within an insoluble ECM barrier to form biofilm. 8,12,17,19, Biofilm can develop within 2 to 4 days of initial colonization and is very difficult to remove by surface irrigation or cleansing. 12,15 In addition, biofilm is not highly susceptible to intravenous or oral antibiotics or topical antimicrobials. 15,25,29-31,34,35 Therefore, prevention and excisional debridement are critical for biofilm management. 15,17,26,30,31,34,35 3. The presence of microorganisms stimulates production of proteases by the body s inflammatory cells. 8,15,16,20,28 4. Bacterial proteases contribute to overall protease levels in the colonized wound and also disrupt the host s protease/protease inhibitor systems. 1,8,15,16,20,24,28 5. Effective management of bioburden may reduce excessive protease production in the chronic wound. 16,19,36 S38 WOUNDS NOVEMBER 2017 Supported by Hollister Incorporated

5 Management of Acute and Chronic Wounds Figure 2. Chronic wound pathophysiology. ECM: extracellular matrix; TIMP: tissue inhibitor of metalloproteinase; α1-p1: alpha 1-proteinase inhibitor; MMP: matrix metalloproteinase Prolonged elevated inflammation. 1. Proteases are produced by inflammatory cells stimulated by bioburden. 1,15,16,28 2. Excessive protease activity in the wound leads to degradation of key proteins (ie, ECM proteins, growth factors, receptors), thereby impairing healing. 1,10,13,15,16,18,24,28,37-40 This prolongation of the inflammatory stage of healing prevents the wound from progressing to the proliferative phase. 2,10,20, Fibronectin is sensitive to many proteases, including neutrophil elastase, and is degraded in chronic wounds. 16,47,48 Because fibronectin promotes adhesion, migration, chemotaxis, and phagocytosis by diverse cell types, it plays a role in multiple phases of wound repair, including thrombosis, inflammation, angiogenesis, and epithelialization. 48 Therefore, degradation of fibronectin by proteases has an inhibitory effect on healing. 48 Imbalanced proteases and protease inhibitors. 1. The major proteases involved in wound healing are the MMPs and the serine proteases, such as neutrophil elastase. 15,16,19,37,43,45, Proteases are secreted by cells involved in wound repair, such as fibroblasts and endothelial cells, and also by immune cells, as previously described. 1,15,16,37-39,42,49,52,53 3. In chronic wounds, excessive levels of protease activity disrupt the balance between tissue breakdown and repair. 16,18,19,39,42,43, In nonhealing or chronic wounds, there is an imbalance between increased levels of various MMPs and decreased levels of tissue inhibitors of MMPs (TIM Ps). 1,2,11,15,16,22,28,38,40-42,45,50,52,54, In chronic wounds, elevated levels of proteases (ie, MMPs and neutrophil elastase) degrade ECM, growth factors (ie, platelet-derived growth factor [PDGF]), and cellular receptors (ie, transforming growth factor beta [TGF-β] receptor). 1,2,10,15,18,22,28,39,43,45,51,63,64 6. Excessive degradation of ECM, growth factors, and receptors reduces cell attachment, migration, proliferation, and differentiation, which disrupts the microenvironment in the wound bed and interrupts the dynamic reciprocity communication, resulting in impaired healing. 2 Destruction of essential proteins. 1. In addition to proteases, alterations in many other proteins have been observed in chronic wounds, including decreased levels of intact fibronectin, an increase in fibronectin degradation products, a loss of type II TGF-β receptors on fibroblasts, reduced levels of PDGF, a down-regulation of keratins in epithelial cells, and an up-regulation of β6 integrins. 1,2,22,28,37-39,44,48,64-66 Early Aggressive Wound Management: A Shift in Strategy An increased understanding of the normal wound healing process, the pathophysiology of chronic wounds, and the advances in molecular biology and technology have resulted in the development of a wide range of advanced modalities that have the potential to positively influence the molecular events associated with wound healing (Figure 1). Advanced wound management therapies are often defined as interventions used when standard wound care has failed. 67 Although not an exhaustive list, modalities employed in such situations include topical biological products (ie, PDGF, platelet-rich plasma), advanced dressings (ie, antimicrobial, collagen, calcium alginate, cavity, honey), tissue-engineered skin substitutes, allograft or xenograft matrix, negative pressure wound therapy, hyperbaric oxygen therapy, stem cell therapy, and intermittent pneumatic compression therapy. Promising clinical outcomes of chronic wounds managed with such advanced modalities have been reported in studies with varying levels of clinical evidence. 34,53,68-89 However, when normal wound healing is regarded as adequate rather than optimal, wound care professionals can employ many of the aforementioned interventions typically reserved for chronic wound management early in the acute wound phase as adjunct therapy to enhance healing. Viewing normal wound healing as a continuum, just as healing may be stalled and possibly lead to the development of a chronic wound, it also may be expedited. The consensus panel developed an algorithm (Figure 3) to illustrate this shift in strategy to proactive and early aggressive wound management; the Supported by Hollister Incorporated NOVEMBER 2017 WOUNDS S39

6 Proactive and Early Aggressive Wound Management Figure 3. Proactive and early aggressive wound management algorithm. pathway depicted in blue represents the phases of normal wound healing. With proactive wound management (Figure 3; illustrated in green), adjunct therapies are applied to the acute injury early in the wound healing process preemptively intervening prior to the development of chronicity instead of responding afterward. By enhancing healing, wound duration and risk of chronicity may be reduced. This proactive approach has emerging support, as Utz et al 90 demonstrated in their investigation of MMP expression in traumatic acute wounds, where they reported significantly higher serum levels of MMPs in patients with impaired healing versus those with normally healing wounds. Furthermore, serum levels of these MMP biomarkers were shown to be significant predictors of wound healing, as the elevated levels among patients with impaired healing likely are contributing to an exaggerated inflammatory response and the subsequent impairment. 90 With this preliminary evidence of elevated MMP levels in acute wounds correlating with wound failure and chronicity, 37 wound care practitioners have the knowledge that excessive proteases and their resulting activities contribute to failed healing in both acute injuries and chronic wounds, underscoring the importance of a proactive strategy, particularly in terms of protease management. In the other scenario, as previously discussed, if healing does not progress and prolonged inflammation ensues, the wound may enter the pathophysiology cascade (Figure 3; illustrated in red). Early aggressive wound management (Figure 3; illustrated in green), involving the use of adjunct therapies, may be employed to break the pathophysiology cycle in a chronic wound and drive it toward healing. A chronic wound may exit the pathophysiology cycle at any point and have delayed healing (Figure 3; illustrated in light blue), but this is unlikely without some type of intervention. Each wound care practitioner must decide when to apply his/her preferred advanced modality(ies) to an acute injury. Some justifiably may reason that adjunct therapy should be applied to all acute injuries to enhance healing, while others may choose to reserve use for chronic wounds. At a minimum, the consensus panel recommends this early aggressive wound management strategy for patients already considered at high risk for the development of chronic wounds. In this regard, advanced modalities may be prophylactically applied to acute injuries as a means of active wound management to enhance healing and reduce the likelihood of chronic wound development in patients with established risk factors for chronicity. In their own practices, the panel members utilize this management strategy for all patients presenting with acute injuries or chronic wounds and have summarized a series of guidelines related to their wound management philosophies. Prevention and Management Guidelines Early aggressive wound management involves the use of advanced intervention (as appropriate to the time between injury and treatment) at the beginning of wound care treatment to optimize wound bed preparation. Initial use of appropriate adjunct therapies, such as calcium alginate, collagen, antimicrobial, and compressive dressings, increases the probability of achieving sufficient wound area reduction by the second to fourth week, which, in turn, improves the likelihood that the wound will advance to full closure. For example, a 20% to 40% reduction in wound area of venous leg ulcers within 2 to 4 weeks is a good predictor of healing. 91 Diabetic foot ulcers that exhibit a reduction of at least 50% by week 4 is predictive of healing Debridement and bioburden management 1. Debridement of dead, devitalized tissue, as appropriate to the injury/wound, may help reduce excessive protease activity by removing necrotic tissue and reducing the bacterial load that may be contributing to inflammation. 8,15-17,20,24,32,34,35,46,95-97 Debridement also has been shown to stimulate healing, promoting the release of tissue cytokines and growth factors. 17,20,97 2. The least cytotoxic bioburden management strategy that addresses wound bioburden during the healing process should be used. Appropriate bioburden management options include topical broad-spectrum-based antimicrobials (iodine, silver therapy, methylene blue with gentian violet, polyhexamethylene biguanide [PHMB], hypochlorous acid [HOCl], and honey). 15,17,24,31,46, The resultant reduction in bacterial levels may reduce overall protease activity in the wound by reducing host and bacterial protease production. 16,28 3. Collagen dressings and topical doxycycline are recommended for protease management. 1,15,28,43,49,51,63,113, S40 WOUNDS NOVEMBER 2017 Supported by Hollister Incorporated

7 Management of Acute and Chronic Wounds 4. Certain advanced modalities, such as topical growth factors and bioengineered skin substitutes, may not be effective if high protease levels are not addressed first. 37,64,119 Adjunct therapies that modulate MMP activity (eg, collagen dressings) may be used prior to these options to reduce excess proteases in the wound bed and also to potentially protect endogenous and exogenous growth factors. 43,49,64,116,117,120 Management of fluids through dressing selection. The wound environment may be influenced through dressing selection to achieve the desired level of moisture in the wound bed. 17,46,96 Appropriate fluid management promotes a healthy microenvironment and optimizes the wound bed for acceptance of later advanced modalities. A nonoptimal wound bed environment in either direction either hyperhydrated or desiccated has been linked to a host of negative consequences, including maceration of surrounding skin, biofilm development, eschar formation, and inhibition of cellular activity, all of which may impede wound healing. 17,20,26,46,96 The accumulation of wound fluid must be managed, as prolonged contact leads to the breakdown of ECM proteins and growth factors, as well as the inhibition of cell proliferation. 20,95 The appropriate wound dressing is capable of removing wound exudate while retaining a moist environment to accelerate healing. 20,96,121 Wound dressings also assist in reducing protease levels in the wound bed because proteases are held within the dressing as exudate is absorbed. 15 Chronic wound management should focus on conditioning the wound bed and its microenvironment (ie, rebalancing growth factors, cytokines, proteases, and their natural inhibitors to levels observed in acute wounds). 13,20 1. Dressings with antimicrobial properties should be used only when needed. If used, antimicrobial dressings should be selected based upon the environment in which the injury/wound was created and the resultant level of potential infection. 2. Dressings impregnated with methylene blue and gentian violet are antibacterial options that may be safely used with tissue-engineered skin substitutes or collagen dressings. 113 Methylene blue with gentian violet also may be used with enzymatic debridement agents. 99, As drainage is reduced, conversion to a polyurethane sponge or other reduced-fluid capacity dressing may be used to maintain a moist wound environment, which has been shown to accelerate wound healing while reducing pain, tenderness, fibrosis, and infection incidence. 20,121 Special consideration of collagen dressings. Collagen dressings used in wound care are comprised of a variety of carriers and combining agents, including gels, pastes, polymers, oxidized regenerated cellulose (ORC), and ethylenediaminetetraacetic acid. 42,123 Dressing additives, such as alginates and cellulose derivatives, enhance absorbency, flexibility, comfort, and retain moisture. 42,50 Antimicrobial agents, including silver ions (Ag + ) and PHMB, may be included to control pathogen levels within the wound. 42,46,50 Collagen is derived from various sources (bovine, equine, fish, ovine, and porcine) and varies in type, composition, and structure, with some dressings containing native collagen with a triple-helix formation and others utilizing denatured or reconstituted collagen (gelatin). 11,34,42,50,123,124 The use of collagen dressings is advantageous because collagen has multiple roles in wound healing due to its chemotactic properties, including attracting fibroblasts and keratinocytes to the wound, which encourages debridement, angiogenesis, and reepithelialization. 4,50,123,125 Research has shown that collagen-based dressings attract and stimulate a variety of cells (fibroblasts, macrophages, epithelial cells) and promote the deposition and organization of newly formed collagen. 42,50,123, Biomaterials derived from an intact ECM provide options that take advantage of the evolving understanding of the complex nature of a native ECM and the retention of its structure and function. 10,11 Collagen ECM dressings are a specific subset of collagen dressings, and to date there is only 1 such dressing available commercially. In vitro biophysical analysis has demonstrated that this biomaterial, derived from decellularized ovine forestomach matrix, retains a native collagen architecture (types I and III), along with intact and functional secondary ECM components necessary for structural, adhesive, and resilience properties. It is relatively strong and elastic, making it ideal for wound healing and tissue regeneration applications. 129,130 Along with the preserved collagen microarchitecture of native ECM, the biomaterial contains many components of the ECM, including fibronectin, glycosaminoglycans, and elastin. 130 Basement membrane components, such as laminin and collagen IV, also are retained. 129,130 These secondary ECM components may have a protective effect on the de novo matrix produced by the wound fibroblast during healing. 63 The collagen architecture and secondary ECM molecules function together to support cell adhesion and proliferation and to promote cell differentiation Complete remodeling of the collagen structure has been demonstrated in vivo, resulting in organized tissues with increased blood vessel density within granulation tissue during the course of tissue regeneration. 129,131 Finally, soluble components of this biomaterial have been shown to inhibit a broad spectrum of MMPs (collagenases, stromelysins, and gelatinases) and neutrophil elastase Collagen dressings buffer excess MMP activity in the wound. 10,28,42,43,49,53,63,116,117, Given the overexpression and high concentration of proteases (such as MMPs and neutrophil elastase that disrupt the balance between tissue breakdown and repair in chronic wounds), the ability to modulate MMP activity in the wound is beneficial. Collagen dressings may help reduce the destructive effects of elevated levels of proteases and reactive oxygen species, reducing excessive protease activity to a level at which healing may proceed. 28,43,45,49,63,116, Application of collagen dressings should be sufficient to buffer MMP activity for the duration of the treatment interval. 49,63 3. Use of collagen dressings early in chronic wound management may have a protective effect on the physiological processes of healing by facilitating epithelialization Due to varying levels of protease activity in the wound bed, different quantities of collagen dressing are required to balance elevated protease levels. 45,70 5. Different collagen dressings exhibit substrate specificity and inhibit different proteases with varying efficiencies. 45, Collagen ECM dressings exhibit broad-spectrum MMP reduction. 45,63 A recent assay analysis comparing a collagen ECM dressing with an ORC/collagen dressing demonstrated that the former had inhibitory potency for collagenases (MMP-1 and MMP-8), stromelysins (MMP-3, MMP-10, and MMP-11), gelatinases (MMP-2 and MMP-9), and neutrophil elastase. 45 The ORC/collagen dressing exhibited similar inhibitory potency of the gelatinases, but had no significant inhibitory impact on the other MMPs tested. 45 Through Supported by Hollister Incorporated NOVEMBER 2017 WOUNDS S41

8 Proactive and Early Aggressive Wound Management the inhibition of a wide range of MMP classes, collagen ECM dressings may offer a significant clinical advantage by more effectively addressing protease imbalance compared with ORC/collagen dressings Collagen ECM dressings can provide a provisional matrix that will not degrade when protease levels are buffered satisfactorily. The intact ECM provides a natural scaffold or substrate for wound cell ingrowth, 63,130,131 an advantage not offered by dressings comprised of denatured or reconstituted collagen. 8. Collagen ECM dressings also have been shown to contain secondary molecules associated with the ECM, including laminin, fibronectin, and glycosaminoglycans, all of which may have a protective effect on degradation of the matrix being produced by wound fibroblasts. 63,129,130 Differentiating between the collagen compositions offered by the various collagen dressings currently marketed is important. Due to substrate specificity, each type of collagen dressing has different mechanisms of action on the wound bed and attracts different proteases. 20,42,50,135 Dressings utilizing native collagen that has not been denatured or reconstituted, especially those with an intact ECM, have the ability to affect multiple steps in the pathophysiology of chronic wounds and may be more effective in rebalancing the wound microenvironment and promoting healing. 2,50,63,82 Utilization of a dressing in which the native structure of collagen is retained has been shown to offer several advantages versus their denatured counterparts, including promoting more efficient angiogenesis and greater fibroblast chemotaxis, as well as maximizing the functional behavior of fibroblasts and macrophages, as they are anchored to a three-dimensional architectural structure. 11,50,123, Collagen ECM dressings have the ability to function as a dual-phase dressing throughout the wound management process, which is essential to the success of the early aggressive wound management advocated by the consensus panel. By applying collagen ECM dressings in 2 phases early in the wound management process for proactive protease management and, again, later in the healing cycle, as is more common the characteristics of collagen as both a protease reduction agent and a cellular tissue scaffold can be optimized because the collagen ECM retains the properties and functions of native tissue. The first phase of collagen use early in chronic wound management addresses elevated protease levels. In this scenario, a collagen ECM dressing provides consumable intact collagen, with proteases breaking down the collagen in the dressing, thereby reducing the protease activity in the wound bed and preserving the resident collagen in the wound tissues. 42,63 Choosing a dressing with broad-spectrum MMP management abilities, such as those with native collagen and an intact ECM, may optimize protease balance in the wound bed. Furthermore, because elastase has a substantial affinity for the triple-helix structure of native collagen, dressings containing native collagen alter the proteolytic environment for elastase, as well as MMPs. 50,123 Due to elastase converting precursor pro-mmps to active MMPs, the MMP levels may be substantially reduced by lowering elastase levels in the wound. 50,123 Once optimal protease balance has been achieved, the role of collagen ECM dressings shifts to the second phase, serving as a cellular scaffold that may be incorporated into the wound bed and utilized to achieve cellular migration, proliferation, and organization. 63,130,131 The quantity of collagen delivered to the wound must be sufficient to buffer protease activity during the treatment interval; however, protease levels are difficult to assess in the wound bed. 16 Therefore, as a general guideline, if all of the collagen has been resorbed at the next dressing change, then an insufficient amount was used and more dressing should be applied for the next treatment interval or the frequency of dressing changes should increase. 87 Each application provides the wound a fresh start for achieving protease balance as well as support for production of granulation tissue. Conversely, if too much collagen remains or is dried out, then more moisture should be applied for the next treatment interval. Consistent formation of granulation tissue indicates the quantity and interval of dressing changes are adequate. Using collagen ECM as a dual-phase dressing for wound bed preparation also is advantageous if later advanced modalities (such as skin grafts or tissue-engineered skin substitutes) are planned or required for full wound closure. 139 Biological therapies that aid in wound closure, including recombinant growth factors and grafts, may not be as effective in the presence of excessive proteases or may be destroyed. 37,64,119 A collagen ECM dressing assists in balancing protease levels in the wound, while its cellular scaffold feature further enhances the wound bed for the acceptance and optimization of skin grafts or tissue-engineered skin substitutes. Collagen matrices with intact collagen molecules may serve as a dermal template, supporting the migration of dermal fibroblasts and vascular endothelial cells into the matrices, which may enhance the formation of granulation tissue. 125,130 Continuing collagen ECM use following the application of advanced modalities in chronic wound management may be beneficial in protecting the integrity of later advanced modalities and supporting progression to full closure. The collagen ECM continues to provide structural elements and secondary biomolecules during this process. In addition, proactive use of collagen is beneficial in acute injuries, as the protease management aspect of collagen may prevent the progression to a chronic wound. Otherwise, the collagen will be used as a cellular scaffold to assist in timely wound closure. 63 CONCLUSIONS Normal wound healing is accomplished through a series of well-coordinated, progressive events with overlapping phases. Chronic wounds do not progress to healing or are not responsive to management in a timely manner and have defective remodeling of the ECM, fail to reepithelialize, and have prolonged inflammation. Reducing bioburden through debridement and bioburden management and using collagen dressings to balance protease activity in chronic wounds prior to the use of skin substitutes or other modalities may enhance the effectiveness of the latter. This presented algorithm developed by the consensus panel represents a shift in strategy to proactive and early aggressive wound management. With proactive management, adjunct therapies are applied preemptively to the acute injury early in the wound-healing process to reduce the likelihood of an acute injury failing to progress. Early aggressive wound management may be employed to break the pathophysiology cycle in an existing chronic wound to drive it toward healing. The consensus panel recommends this active wound management strategy for patients at high risk for chronic wound development at a minimum. In their own practices, the panel members utilize this strategy for all patients presenting with acute injuries or chronic wounds. n REFERENCES References are available at S42 WOUNDS NOVEMBER 2017 Supported by Hollister Incorporated

9 Management of Acute and Chronic Wounds REFERENCES 1. Lobmann R, Schultz G, Lehnert H. Proteases and the diabetic foot syndrome: mechanisms and therapeutic implications. Diabetes Care. 2005;28(2): Schultz GS, Davidson JM, Kirsner RS, Bornstein P, Herman IM. Dynamic reciprocity in the wound microenvironment. Wound Repair Regen. 2011;19(2): Bissell MJ, Hall HG, Parry G. How does the extracellular matrix direct gene expression? J Theor Biol. 1982;99(1): Clark RA. Biology of dermal wound repair. Dermatol Clin. 1993;11(4): Bornstein P, Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Coll Biol. 2002;14(5): Hynes RO. Extracellular matrix: not just pretty fibrils. Science. 2009;326(5957): Nelson CM, Bissell MJ. Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2006;22: Demidova-Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care. Adv Skin Wound Care. 2012;25(7): Singer AJ, Clark RAF. Cutaneous wound healing. N Engl J Med. 1999;341: Turner NJ and Badylak SF. The use of biologic 13. Tarnuzzer RW, Schultz GS. Biochemical analysis of acute and chronic wound environments. Wound Repair Regen. 1996;4(3): Cook H, Davies KJ, Haring KG, Thomas DW. Defective extracellular matrix reorganization by chronic wound fibroblasts is associated with alterations in TIMP-1, TIMP-2, and MMP-2 activity. J Invest Dermatol. 2000;115(2): Gibson D, Cullen B, Legerstee R, Harding KG, Schultz G. MMPs made easy. Wounds Int. 2009; 1(1): Harding K, Armstrong DG, Barrett S, et al. International consensus. The role of proteases in wound diagnostics. Wounds Int woundsinternational.com/media/issues/419/ files/content_9869.pdf. 17. Leaper DJ, Schultz G, Carville K, Fletcher J, Swanson T, Drake R. Extending the TIME concept: what have we learned in the past 10 years? Int Wound J. 2012;9(Suppl 2): Muller M, Trocme C, Lardy B, Morel F, Halimi S, Benhamou PY. Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing. Diabet Med. 2008;25(4): Naidoo C, Gould A, Peters J, Candy GP. Matrix metalloproteinase inhibition and antibiotics in the treatment of chronic wounds. Wound Healing Southern Africa. 2009;2(2): Schultz GS, Sibbald RG, Falanga V, et al. Wound bed preparation: a systematic approach to wound management. Wound Repair Regen. 2003;11(Suppl 1):S1 S Stojadinovic A, Carlson JW, Schultz GS, Davis 21. Orsted HL, Keast D, Forest-Lalande L, Megie MF. Basic principles of wound healing. Wound Care Canada. 2011;9(2):4 12. TA, Elster EA. Topical advances in wound care [published online ahead of print September 14, 2008]. Gynecol Oncol. 2008;111(2 Suppl):S70 S Mast BA, Schultz GS. Interactions of cytokines, 37. Gibson DJ, Schultz GS. Molecular wound assessments: growth factors, and proteases in acute and chronic matrix metalloproteinases. Adv Wound wounds. Wound Repair Regen. 1996;4(4): Care (New Rochelle). 2013;2(1): Mustoe TA, O Shaughnessy K, Kloeters O. Chronic 38. Mwaura B, Mahendran B, Hynes N, et al. The wound pathogenesis and current treatment impact of differential expression of extracel- strategies. Plast Reconstr Surg. 2006;117(7 Suplular matrix metalloproteinase inducer, matrix pl):35s 41S. metalloproteinase-2, tissue inhibitor of matrix 24. Bowler PG, Duerden BI, Armstrong DG. Wound metalloproteinase-2 and PDGF-AA on the chronicity microbiology and associated approaches to wound of venous leg ulcers. Eur J Vasc Endovasc management. Clin Microbiol Rev. 2001;14(2): Saito S, Trovato MJ, You R, et al. Role of matrix 25. Davis SC, Ricotti C, Cazzaniga A, Welsh E, Eaglstein WH, Mertz PM. Microscopic and physiologic evidence for biofilm-associated metalloproteinases 1, 2, and 9 and tissue inhibitor of matrix metalloproteinase-1 in chronic venous insufficiency. J Vasc Surg. 2001;34(5): ;16(1): Hurlow J, Bowler PG. Potential implications of in wounds: management strategies. J Wound Care. 2008;17(11): Wolcott RD, Rhoads DD. A study of biofilm-based wound management in subjects with critical limb ischaemia. J Wound Care. 2008;17(4): , , Wolcott RD, Rhoads DD, Dowd SE. Biofilms and chronic wound inflammation. J Wound Care. 2008;17(8): Holmes C, Wrobel JS, Maceachern M, Boles BR. Collagen-based wound dressings for the treatment of diabetes-related foot ulcers: a systematic review [published online ahead of print January 17, 2013]. Diabetes Metab Syndr Obes. 2013;6: Wolcott RD, Kennedy JP, Dowd SE. Regular debridement is the main tool for maintaining a healthy wound bed in most chronic wounds. J Wound Care. 2009;18(2): Surg. 2006;31(3): wound colonization in vivo. Wound Repair Regen. 40. Trengove NJ, Stacey MC, MacAuley S, et al. Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. Wound scaffolds in the treatment of chronic nonhealing wounds. Adv Wound Care (New Rochelle). 2015; 4(8): Gould LJ. Topical collagen-based biomaterials for chronic wounds: rationale and clinical application. Adv Wound Care (New Rochelle). 2016;5(1): Swanson T, Schultz G, Grothier L. Wound infection made easy. Wounds Int woundsinternational.com/made-easys/view/ biofilm in chronic wounds: a case series. J Wound Care. 2012;21(3): Repair Regen. 1999;7(6): Beidler SK, Douillet CD, Berndt DF, et al. Multiplexed wound-infection-made-easy. 27. James GA, Swogger E, Wolcott R, et al. Biofilms analysis of matrix metalloproteinases in in chronic wounds [published online ahead of print December 13, 2007]. Wound Repair Regen. 2008;16(1): leg ulcer tissue of patients with chronic venous insufficiency before and after compression therapy. Wound Repair Regen. 2008;16(5): McCarty SM, Percival SL. Proteases and delayed wound healing. Adv Wound Care (New Rochelle). 2013;2(8): Brett D. A review of collagen and collagen-based wounds dressings. Wounds. 2008;20(12): Cullen B. The role of oxidized regenerated cellulose/collagen 29. Percival SL, Bowler PG. Biofilms and their potential role in wound healing. Wounds. 2004;16(7): in chronic wound repair. Part 2. Ostomy Wound Manage. 2002;48(6 Suppl):8 13. Hakkinen L, Koivisto L, Gardner H, et al. Increased 30. Phillips P, Sampson E, Yang Q, Antonelli P, Progulske-Fox A, Schultz G. Bacterial biofilms in wounds. Wound Healing Southern Africa. 2008;1(2): expression of beta6-integrin in skin leads to spontaneous development in chronic wounds. Am J Pathol. 2004;164: Negron L, Lun S, May BCH. Ovine forestomach 31. Rhoads DD, Wolcott RD, Percival SL. Biofilms matrix biomaterial is a broad spectrum inhibitor of Supported by Hollister Incorporated NOVEMBER 2017 WOUNDS S43

10 Proactive and Early Aggressive Wound Management matrix metalloproteinases and neutrophil elastase [published online ahead of print November 1, 2012]. Int Wound J. 2014;11(4): Sibbald RG, Goodman L, Woo KY, et al. Special considerations in wound bed preparation 2011: an update. Adv Skin Wound Care. 2011;24(9): Grinnell F, Zhu M. Fibronectin degradation in chronic wounds depends on the relative levels of elastase, alpha1-proteinase inhibitor, and alpha2-macroglobulin. J Invest Dermatol. 1996;106(2): Wysocki AB, Grinnell F. Fibronectin profiles in normal and chronic wound fluid. Lab Invest. 1990;63(6): Cullen B, Smith R, McCulloch E, Silcock D, Morrison L. Mechanism of action of PRO- MOGRAN, a protease modulating matrix, for the treatment of diabetic foot ulcers. Wound Repair Regen. 2002;10(1): Fleck CA, Simman R. Modern collagen wound dressings: function and purpose. J Am Col Certif Wound Spec. 2011;2(3): Serena TE. Development of a novel technique to collect proteases from chronic wounds. Adv Wound Care (New Rochelle). 2014;3(12): Lobmann R, Ambrosch A, Schultz G, Waldmann K, Schiweck S, Lehnert H. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients [published online ahead of print May 25, 2002]. Diabetologia. 2002;45(7): and diminished levels of proteinase inhibitors. J Diabetes Complications. 2006;20(5): Motzkau M, Tautenhahn J, Lehnert H, Lobmann R. Expression of matrix-metalloproteases in the fluid of chronic diabetic foot wounds treated with a protease absorbent dressing [published online ahead of print October 28, 2010]. Exp Clin Endocrinol Diabetes. 2011;119(5): Liu Y, Min D, Bolton T, et al. Increased matrix 66. Cowin AJ, Hatzirodos N, Holding CA, et al. of an extracellular matrix graft (OASIS wound metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers [published online ahead of print October 3, 2008]. Diabetes Care. 2009; 32(1): Norgauer J, Hildenbrand T, Idzko M, et al. Elevated expression of extracellular matrix metalloproteinase inducer (CD147) and membrane-type matrix metalloproteinases in venous leg ulcers. Br J Dermatol. 2002;147(6): Wysocki AB, Staiano-Coico L, Grinnell F. Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol. 1993;101(1): Yager DR, Zhang LY, Liang HX, Diegelmann RF, Cohen IK. Wound fluids from human pressure ulcers contain elevated matrix metalloproteinase levels and activity compared to surgical wound fluids. J Invest Dermatol. 1996;107(5): Bullen EC, Longaker MT, Updike DL, et al. Tissue inhibitor of metalloproteinases-1 is decreased and activated gelatinases are increased in chronic wounds. J Invest Dermatol. 1995;104(2): Ladwig GP, Robson MC, Liu R, Kuhn MA, Muir D, Schultz GS. Ratios of activated matrix metalloproteinase-9 to tissue inhibitor of matrix metalloproteinase-1 in wound fluids are inversely correlated with healing of pressure ulcers. Wound Repair Regen. 2002;10(1): Nwomeh BC, Liang HX, Cohen IK, Yager DR. MMP-8 is the predominant collagenase in healing wounds and nonhealing ulcers. J Surg Res. 1999;81(2): Subramaniam K, Pech CM, Stacey MC, Wallace HJ. Induction of MMP-1, MMP-3 and TIMP-1 in online ahead of print June 21, 2015]. Int Wound normal dermal fibroblasts by chronic venous leg ulcer wound fluid*. Int Wound J. 2008;5(1): Iorio ML, Goldstein J, Adams M, Steinberg J, 62. Vaalamo M, Leivo T, Saarialho-Kere U. Differential expression of tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and -4) in normal and aberrant Attinger C. Functional limb salvage in the diabetic patient: the use of a collagen bilayer matrix and risk factors for amputation. Plast Reconstr Surg. wound healing. Hum Pathol. 1999;30(7): Bohn G, Liden B, Schultz G, Yang Q, Gibson DJ. 74. Liden BA, May BC. Clinical outcomes following Ovine-based collagen matrix dressing: next-generation the use of ovine forestomach matrix (endoform collagen dressing for wound care. Adv dermal template) to treat chronic wounds. Adv wound fluids to degrade peptide growth factors is associated with increased levels of elastase activity wounds treated with a protease absorbent dressing. Wound Repair Regen. 1997;5(1): McCulloch JM, Marler KC, Neal MB, Phifer TJ. 65. Charles CA, Tomic-Canic M, Vincek V, et al. A gene signature of nonhealing venous ulcers: Intermittent pneumatic compression improves venous ulcer healing. Adv Wound Care (New potential diagnostic markers [published online ahead of print August 20, 2008]. J Am Acad Dermatol. 2008;59(5): King D; OASIS Ulcer Study Group. Effectiveness Effect of healing on the expression of transforming matrix) in the treatment of chronic leg ulcers: growth factor beta(s) and their receptors a randomized clinical trial. J Vasc Surg. 2005; in chronic venous leg ulcers. J Invest Dermatol. wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial [published online ahead of print December 27, 2007]. Diabetes Care. 2008;31(4): Bohn GA, Gass K. Leg ulcer treatment outcomes with new ovine collagen extracellular matrix dressing: a retrospective case series. Adv Skin Wound Care. 2014;27(10): Gentzkow GD, Iwasaki SD, Hershon KS, et al. Use of dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care. 1996;19(4): Harding KG, Szczepkowski M, Mikosinski J, et al. Safety and performance evaluation of a next-generation antimicrobial dressing in patients with chronic venous leg ulcers [published J. 2016;13(4): ;127(1): Wound Care (New Rochelle). 2016;5(1):1 10. Skin Wound Care. 2013;26(4): Yager DR, Chen SM, Ward SI, Olutoye OO, 75. Lobmann R, Zemlin C, Motzkau M, Reschke Diegelmann RF, Cohen IK. Ability of chronic K, Lehnert H. Expression of matrix metalloproteinases and growth factors in diabetic foot Rochelle). 1994;7(4): Mostow EN, Haraway GD, Dalsing M, Hodde JP, 41(5): ;117(5): Picard F, Hersant B, Bosc R, Meningaud JP. The 67. Greer N, Foman N, Dorrian J, et al. Advanced wound care therapies for non-healing diabetic, venous, and arterial ulcers: a systematic review. VA-ESP Project #09-009; 2012 Nov. Washington (DC): Department of Veterans Affairs (US). growing evidence for the use of platelet-rich plasma on diabetic chronic wounds: a review and a proposal for a new standard of care [published online ahead of print August 25, 2015]. Wound Repair Regen. 2015;23(5): esp/wound-care.pdf. 79. Reyzelman AM, Bazarov I. Human acellular dermal wound matrix for the treatment of DFU: 68. Badiavas EV, Falanga V. Treatment of chronic wounds with bone marrow-derived cells. Arch literature review and analysis. J Wound Care. 2015;24(3): Dermatol. 2003;139(4): Romanelli M, Mulder G, Paggi B, Macchia M, 69. Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist Panduri S, Dini V. The use of a collagen matrix in hard-to-heal venous leg ulcers. J Wound Care. 2015;24(11): S44 WOUNDS NOVEMBER 2017 Supported by Hollister Incorporated