Deconstructing the Stalled Wound
Deconstructing the Stalled Wound
In many cases, the definition of a stalled wound overlaps with that of a chronic wound. A wound that does not decrease in size by 30% in 3 weeks or by 50% in 4–5 weeks is considered chronic. These figures are based on studies, such as Sheehan et al's, which demonstrated that if the size of the wound does not decrease by 50% in 4 weeks, the wound has a 91% chance of not healing in 12 weeks. However, the stalled wound may not necessarily always be a chronic wound, but may occur in the process of the normal healing of an acute wound that suddenly appears to halt in its tracks, often with no apparent reason.
In searching for a reason, obvious causes need to be excluded—those related to wound management and host factors. Thus, physical factors, as opposed to physiologic factors, should be examined first. These include ruling out infection and vascular complications, ensuring proper offloading, performing adequate debridement, and facilitating a moist healing environment.
Once these basic tenets of wound care are satisfied, molecular biological considerations should follow. The pathologic process of a chronic wound is similar to that of a stalled wound. The chemistry of the wound base encourages efficient healing in an acute wound or retards healing in a chronic wound. The physiology that results in pathology in a chronic wound can be applied to a stalled wound (Figure 1) in many cases, namely:
(Enlarge Image)
Figure 1.
Schematic representation of the physiologic factors contributing to a stalled wound.
Balanced inflammation is the "holy grail" of successful wound healing. It is an essential phase to completing wound closure, but its over exuberance and persistence causes delayed healing and chronicity. At a cellular level, this exaggerated inflammation is represented by the protracted presence of activated neutrophils. In an acute wound, activated neutrophils are virtually nonexistent after the first 72 hours, whereas in a chronic wound, neutrophils are present throughout the healing process. Although there is a paucity of articles in the literature relating to stalled wounds and their biologic background, it is likely that activated neutrophils are present in these wound beds. The continued presence and recruitment of activated neutrophils may result from tissue trauma (pressure in pressure ulcers, irritants from wound agents); increased bioburden; leukocyte trapping (peripheral pooling and white cell margination in venous disease); or the release of reactive oxygen metabolites with ischemia reperfusion injury (pressure ulcers, diabetic wounds, venous ulcers). The significance of these large amounts of activated neutrophils is the resultant stimulation of MMPs, especially MMP-8 and -9, and neutrophil-derived elastase. These agents systematically degrade the extracellular matrix (ECM) delaying the process of cellular proliferation and wound closure. More specifically, it will become important to be able to define the inflammatory profile of the wound bed to determine the healing potential of the wound. Thus, MMP-1, -8, -9; IL-1,-6, -8; TGF-β; TNF-α are pro-inflammatory, while IL-4, IL-10, and TIMPs are anti-inflammatory. It is likely that measurements of a CAP (cytokine and protease) profile at the wound bed interface will become important in predicting healing capacity of a wound.
MMP-9 levels may predict poor healing in both pressure ulcers and diabetic foot ulcers. Fibronectin appears to act as a substrate for MMP-9 action, leading to its degradation, thus promoting leukocyte infiltration and ongoing inflammation. While MMP-8 destroys the collagen matrix to prevent the wound from healing, elastase destroys cytokine receptor sites, further impeding the healing process. Additionally, elastase destroys the growth factors (GFs) in the wound that are either extrinsic (such as therapy with platelet-derived growth factor) or intrinsic. This is an important fact that has been overlooked in many therapeutic interventions—feeding a stalled, nonhealing, or chronic wound with GFs of varying types is often an expensive waste of time. If the MMP levels are high (as in most cases of nonhealing wounds), these need to be controlled before applying GFs to the wound, otherwise these GFs are digested as quickly as they are introduced to the wound milieu. Thus, a sequential modality of therapy is likely to be adopted in the future—controlling, MMPs, controlling bacteria, including biofilm, and then feasibly adding GFs to the mix.
Acting in concert, these proteases are capable of degrading every known constituent of soft connective tissue. The nonhealing wound fluid can therefore be regarded as a breakdown-provoking agent in its own right by virtue of these proteases and their "corrosive" tissue destroying capability. Targeting of the wound fluid exudate is, thus, a new suggested strategy in dealing with the nonhealing wound. Chronic wound fluid exudate has been proven to be anti-angiogenic as opposed to the angiogenic stimulatory nature of acute wound fluid. Angiogenesis, the formation of new capillaries, is the prelude to granulation tissue formation. The absence of this tissue is a typical feature of chronic wounds, such as decubitus, diabetic, and venous ulcers. Matrix metalloproteinase activity is now thought to be the principal protease activity responsible for generating the angiogenesis inhibitor angiostatin. Certain matrix metalloproteinases, including MMP-9, can degrade plasminogen to generate angiostatin that inhibits endothelial cell proliferation. In this way, matrix metalloproteinases may be antiangiogenic and CWF thus inhibits granulation tissue and is also considered anti-angiogenic.
The MMPs are usually kept in check by tissue inhibitors (TIMPs) and α-2 macroglobulin, but in nonhealing and chronic wounds, levels of these endogenous inhibitors are not in balance with those of increased proteases, which creates this degradative background. This results in fragmented and denatured extracellular matrix (ECM) that impedes the healing sequence, especially when the process of absorption and replacement of ECM is delayed. One of the critical fragments within the ECM that influences epithelialization is fibronectin. Studies have demonstrated that fragmented fibronectin is present in chronic wound fluid and following successful intervention in venous ulcer patients intact fibronectin collects and epithelialization proceeds. Thus, intact ECM components are extremely important to progressive healing pathways.
The processes of matrix synthesis and remodeling are also finely orchestrated. Fibroblasts travel within the ground substance by migrating along the path of the collagen fibrils and following their alignment. They bind first to matrix components, such as collagen, fibronectin, vitronectin, and fibrin via integrin receptors situated on the fibroblast cell surface. While one end of the fibroblast remains bound to the matrix component, the cell extends a cytoplasmic projection to find another binding site. When the next site is found, the attachment to the original site is broken by proteases secreted by the fibroblast, and the cell uses its cytoskeletal network of actin fibers to pull itself forward. Thus, MMPs are essential for fibroblast migration within the ECM. However, an abundance of MMPs results in excessive cleavage of fibroblast integrins bonds, lack of migration, and senescence of these fibroblasts.
The bioburden is the number of bacteria on the wound base. The higher the bioburden the slower the healing rate. This appears obvious and simplistic, and is made infinitely more complex by the discovery that in colonized, critically colonized (particularly), and infected wounds, the presence of biofilm may substantially halt the healing process. It accomplishes this by means of its own unique characteristics—the glycocalyx of surrounding armor and the method of self propagation of this bacterial variation make diagnosis, identification, and control difficult. Bioburden should be foremost in the mind of the clinician when analyzing the cause of intransigence in the healing sequence. Removal of tissue that is colonized with substantial bioburden that may include biofilms is an essential component of continuous wound management. Debridement, in order to remove biofilm, is an avenue used to "jump start" the wound healing process in a stalled wound.
Moisture control is a well-recognized prerequisite to efficient wound healing. Ideally, the clinician chooses a dressing that moistens a dry wound or absorbs copious drainage in an excessively wet wound. Moist wound healing is the gold standard for wound care. Evidence has shown that dry wounds increase the chance of infection, increase pain, and facilitates poor scar formation. The treatment plan also includes an evaluation of the patient's pain level. Does the patient only have pain with dressing changes or is it chronically present in the wound site area? Pain control is essential to wound healing.
Nitric oxide (NO) is formed by the enzymatic combination of molecular oxygen and the amino acid L-arginine. Nitric oxide activates guanylate cyclase, which elevates intracellular concentrations of cyclic guanosine monophosphate (cGMP), which is frequently used as an indirect measure of nitric oxide production. Because of its high diffusion coefficient, short half-life of about 5 seconds, and prompt decomposition, NO is ideal as a dynamic intercellular signal for wound repair. Once induced, production of NO within tissue can increase as much as 1000-fold, producing an environment that is toxic to invading microorganisms. NO from keratinocytes and endothelial cells is intimately involved in epithelial migration wound angiogenesis and granulation tissue formation. Ongoing research suggests that wound fluid NO measurements may predict wound outcomes, particularly for diabetic foot ulcers.
Pain resulting from tissue trauma, infection, dressing changes, and poor moisture balance (too much or too little) complicates the wound healing process. Logically, as a result of pain, patients restrict their physical activities, which impacts their lifestyle and has psychological implications and increased general health risks. Compounding this, physiologic release of inflammatory and pain mediators may have direct consequences on wound healing itself. These mediators sensitize inflamed tissue to pain, lowering the threshold of nociceptors to pain, resulting in the hyperlagesia and an exaggerated response to pain that is often seen in these patients. Additionally, these mediators often cause the release of each other increasing the pain, compounding the exaggerated inflammation, and negatively affecting wound healing itself. The pain mediators include bradykinin, prostaglandins, leukotrienes, nerve growth factor, histamine, serotonin, substance P, TNF-β, and nitric oxide. Thus, pain control takes on an added dimension related to general wound healing.
The "Stalled Wound" Concept
In many cases, the definition of a stalled wound overlaps with that of a chronic wound. A wound that does not decrease in size by 30% in 3 weeks or by 50% in 4–5 weeks is considered chronic. These figures are based on studies, such as Sheehan et al's, which demonstrated that if the size of the wound does not decrease by 50% in 4 weeks, the wound has a 91% chance of not healing in 12 weeks. However, the stalled wound may not necessarily always be a chronic wound, but may occur in the process of the normal healing of an acute wound that suddenly appears to halt in its tracks, often with no apparent reason.
In searching for a reason, obvious causes need to be excluded—those related to wound management and host factors. Thus, physical factors, as opposed to physiologic factors, should be examined first. These include ruling out infection and vascular complications, ensuring proper offloading, performing adequate debridement, and facilitating a moist healing environment.
Once these basic tenets of wound care are satisfied, molecular biological considerations should follow. The pathologic process of a chronic wound is similar to that of a stalled wound. The chemistry of the wound base encourages efficient healing in an acute wound or retards healing in a chronic wound. The physiology that results in pathology in a chronic wound can be applied to a stalled wound (Figure 1) in many cases, namely:
(Enlarge Image)
Figure 1.
Schematic representation of the physiologic factors contributing to a stalled wound.
As opposed to an acute wound with an immediate injury response, there is no trigger (bleeding, tissue damage) to jumpstart the healing process in a chronic wound (similarly in a stalled wound)
An extended or exaggerated inflammatory phase is usually present in both
Accompanying the lengthened inflammatory phase, a higher level of matrix metalloproteases (MMPs) and lower level of tissue inhibitors of proteases (TIMPs) are present with concomitant matrix destruction
Relative and often as a result of the increase in MMPs, a deficiency of growth factor receptor sites and/or growth factor destruction by MMPs is observed
Fibroblasts and other cell types involved in proliferation of the cellular ground substance appear to become inefficient or senescent
Higher levels of planktonic bacteria or the presence of biofilm
Dry, dehydrated wound or one with heavy exudate and excess moisture
Altered levels of nitric oxide.
Balanced inflammation is the "holy grail" of successful wound healing. It is an essential phase to completing wound closure, but its over exuberance and persistence causes delayed healing and chronicity. At a cellular level, this exaggerated inflammation is represented by the protracted presence of activated neutrophils. In an acute wound, activated neutrophils are virtually nonexistent after the first 72 hours, whereas in a chronic wound, neutrophils are present throughout the healing process. Although there is a paucity of articles in the literature relating to stalled wounds and their biologic background, it is likely that activated neutrophils are present in these wound beds. The continued presence and recruitment of activated neutrophils may result from tissue trauma (pressure in pressure ulcers, irritants from wound agents); increased bioburden; leukocyte trapping (peripheral pooling and white cell margination in venous disease); or the release of reactive oxygen metabolites with ischemia reperfusion injury (pressure ulcers, diabetic wounds, venous ulcers). The significance of these large amounts of activated neutrophils is the resultant stimulation of MMPs, especially MMP-8 and -9, and neutrophil-derived elastase. These agents systematically degrade the extracellular matrix (ECM) delaying the process of cellular proliferation and wound closure. More specifically, it will become important to be able to define the inflammatory profile of the wound bed to determine the healing potential of the wound. Thus, MMP-1, -8, -9; IL-1,-6, -8; TGF-β; TNF-α are pro-inflammatory, while IL-4, IL-10, and TIMPs are anti-inflammatory. It is likely that measurements of a CAP (cytokine and protease) profile at the wound bed interface will become important in predicting healing capacity of a wound.
MMP-9 levels may predict poor healing in both pressure ulcers and diabetic foot ulcers. Fibronectin appears to act as a substrate for MMP-9 action, leading to its degradation, thus promoting leukocyte infiltration and ongoing inflammation. While MMP-8 destroys the collagen matrix to prevent the wound from healing, elastase destroys cytokine receptor sites, further impeding the healing process. Additionally, elastase destroys the growth factors (GFs) in the wound that are either extrinsic (such as therapy with platelet-derived growth factor) or intrinsic. This is an important fact that has been overlooked in many therapeutic interventions—feeding a stalled, nonhealing, or chronic wound with GFs of varying types is often an expensive waste of time. If the MMP levels are high (as in most cases of nonhealing wounds), these need to be controlled before applying GFs to the wound, otherwise these GFs are digested as quickly as they are introduced to the wound milieu. Thus, a sequential modality of therapy is likely to be adopted in the future—controlling, MMPs, controlling bacteria, including biofilm, and then feasibly adding GFs to the mix.
Acting in concert, these proteases are capable of degrading every known constituent of soft connective tissue. The nonhealing wound fluid can therefore be regarded as a breakdown-provoking agent in its own right by virtue of these proteases and their "corrosive" tissue destroying capability. Targeting of the wound fluid exudate is, thus, a new suggested strategy in dealing with the nonhealing wound. Chronic wound fluid exudate has been proven to be anti-angiogenic as opposed to the angiogenic stimulatory nature of acute wound fluid. Angiogenesis, the formation of new capillaries, is the prelude to granulation tissue formation. The absence of this tissue is a typical feature of chronic wounds, such as decubitus, diabetic, and venous ulcers. Matrix metalloproteinase activity is now thought to be the principal protease activity responsible for generating the angiogenesis inhibitor angiostatin. Certain matrix metalloproteinases, including MMP-9, can degrade plasminogen to generate angiostatin that inhibits endothelial cell proliferation. In this way, matrix metalloproteinases may be antiangiogenic and CWF thus inhibits granulation tissue and is also considered anti-angiogenic.
The MMPs are usually kept in check by tissue inhibitors (TIMPs) and α-2 macroglobulin, but in nonhealing and chronic wounds, levels of these endogenous inhibitors are not in balance with those of increased proteases, which creates this degradative background. This results in fragmented and denatured extracellular matrix (ECM) that impedes the healing sequence, especially when the process of absorption and replacement of ECM is delayed. One of the critical fragments within the ECM that influences epithelialization is fibronectin. Studies have demonstrated that fragmented fibronectin is present in chronic wound fluid and following successful intervention in venous ulcer patients intact fibronectin collects and epithelialization proceeds. Thus, intact ECM components are extremely important to progressive healing pathways.
The processes of matrix synthesis and remodeling are also finely orchestrated. Fibroblasts travel within the ground substance by migrating along the path of the collagen fibrils and following their alignment. They bind first to matrix components, such as collagen, fibronectin, vitronectin, and fibrin via integrin receptors situated on the fibroblast cell surface. While one end of the fibroblast remains bound to the matrix component, the cell extends a cytoplasmic projection to find another binding site. When the next site is found, the attachment to the original site is broken by proteases secreted by the fibroblast, and the cell uses its cytoskeletal network of actin fibers to pull itself forward. Thus, MMPs are essential for fibroblast migration within the ECM. However, an abundance of MMPs results in excessive cleavage of fibroblast integrins bonds, lack of migration, and senescence of these fibroblasts.
The bioburden is the number of bacteria on the wound base. The higher the bioburden the slower the healing rate. This appears obvious and simplistic, and is made infinitely more complex by the discovery that in colonized, critically colonized (particularly), and infected wounds, the presence of biofilm may substantially halt the healing process. It accomplishes this by means of its own unique characteristics—the glycocalyx of surrounding armor and the method of self propagation of this bacterial variation make diagnosis, identification, and control difficult. Bioburden should be foremost in the mind of the clinician when analyzing the cause of intransigence in the healing sequence. Removal of tissue that is colonized with substantial bioburden that may include biofilms is an essential component of continuous wound management. Debridement, in order to remove biofilm, is an avenue used to "jump start" the wound healing process in a stalled wound.
Moisture control is a well-recognized prerequisite to efficient wound healing. Ideally, the clinician chooses a dressing that moistens a dry wound or absorbs copious drainage in an excessively wet wound. Moist wound healing is the gold standard for wound care. Evidence has shown that dry wounds increase the chance of infection, increase pain, and facilitates poor scar formation. The treatment plan also includes an evaluation of the patient's pain level. Does the patient only have pain with dressing changes or is it chronically present in the wound site area? Pain control is essential to wound healing.
Nitric oxide (NO) is formed by the enzymatic combination of molecular oxygen and the amino acid L-arginine. Nitric oxide activates guanylate cyclase, which elevates intracellular concentrations of cyclic guanosine monophosphate (cGMP), which is frequently used as an indirect measure of nitric oxide production. Because of its high diffusion coefficient, short half-life of about 5 seconds, and prompt decomposition, NO is ideal as a dynamic intercellular signal for wound repair. Once induced, production of NO within tissue can increase as much as 1000-fold, producing an environment that is toxic to invading microorganisms. NO from keratinocytes and endothelial cells is intimately involved in epithelial migration wound angiogenesis and granulation tissue formation. Ongoing research suggests that wound fluid NO measurements may predict wound outcomes, particularly for diabetic foot ulcers.
Pain resulting from tissue trauma, infection, dressing changes, and poor moisture balance (too much or too little) complicates the wound healing process. Logically, as a result of pain, patients restrict their physical activities, which impacts their lifestyle and has psychological implications and increased general health risks. Compounding this, physiologic release of inflammatory and pain mediators may have direct consequences on wound healing itself. These mediators sensitize inflamed tissue to pain, lowering the threshold of nociceptors to pain, resulting in the hyperlagesia and an exaggerated response to pain that is often seen in these patients. Additionally, these mediators often cause the release of each other increasing the pain, compounding the exaggerated inflammation, and negatively affecting wound healing itself. The pain mediators include bradykinin, prostaglandins, leukotrienes, nerve growth factor, histamine, serotonin, substance P, TNF-β, and nitric oxide. Thus, pain control takes on an added dimension related to general wound healing.
