Key to navigating the complex and dynamic cellular activity that occurs during wound healing is an understanding of a few basic principles.

W

ound bed preparation can be described as the management of the wound to accelerate endogenous healing or facilitate the effectiveness of other therapeutic measures. The aim of wound bed preparation is to convert the molecular and cellular environment of a chronic wound to that of an acute healing wound.¹ The wound microenvironment itself is a dynamic and complex cascade of cellular activity that occurs during the healing phase of a wound. It truly is a jungle in there.
       One must consider the activities within the wound bed by first understanding a few basic concepts. Much has been written to describe and identify actual cellular activity and communication during the healing phases of both the acute and chronic wound. Any type of tissue injury or damage will start the wound healing process. Common knowledge dictates that there are three concurrent, overlapping phases of acute wound healing. Cells proliferate to cause an inflammatory process, resulting in a final repair of the wound. In the chronic wound, however, a prolonged inflammatory phase of healing occurs. With a sound understanding and practical clinical application of this knowledge, successful outcomes are imminent.

Figure 1

       When patients sustain wounds, the disruption of the skin layers and vasculature leads to entry of platelets into the extracellular matrix of the wound bed. This initiates hemostasis and recruitment of various cell types. Specifically, neutrophils enter the wound to initiate an inflammatory response. As this subsides, fibroblasts have already entered the wound to initiate collagen synthesis and granulation. Tissue macrophages are present and function to eliminate foreign materials or bacteria in the wound. Endothelial cells begin to bud from the damaged blood vessels, generating new capillaries to supply necessary oxygen and nutrients to the new granulation tissue. Epithelial cells start to migrate over the newly formed granulation tissue after freeing themselves from the basement membrane and proliferate to reestablish the skin integrity. In order for these cellular activities to occur, appropriate nutritional intake must be maintained to provide the necessary energy requirements. Also, the temperature, moisture, and pH of the wound bed influence the efficiency of the cellular function within the microenvironment.
       A question may remain: How do these specific cells know when and how to intervene? Communication among these specific cells occurs via chemicals that are soluble mediator proteins. These include growth factors and cytokines. Growth factors deliver messages to those cells that result in cell proliferation or synthesis of granulation tissue. The cytokines deliver

Table 1

messages to those immune system cells that result in the release of enzymes to initiate a destructive inflammatory response. These mediators are produced within various sites of injured tissues and white blood cells.² Specific enzymes that initiate certain tasks of cellular communication are also concomitantly available to warrant wound healing. Additionally, a process of intercellular diffusion of these soluble mediator proteins into the extracellullar environment occurs in which they can diffuse to a specific cell surface receptor.³ Thus, a physiologically moist wound environment is vital.

Extracellular Environment

       One must examine the change that also occurs within the extracellular environment during the healing of wounds. The extracellular matrix consists of a complex assortment of proteins and polysaccharides, including collagens, elastin, fibrin, fibronectin, vitronectin, glycosaminoglycans, glycoproteins, and proteoglycins. Many of these cells are normally stationary in healthy unwounded tissue. But the cellular components of the extracellular matrix (ECM) must convert to a migrating type cell when a wound occurs. These migrating cells express specialized receptors called integrins. These receptors recognize and respond to the stimulus of the various matrix components, allowing the cell to adapt to its new function.³ Furthermore, these integrins have been found to be responsible not only for the signaling and gene expression processes that lead to cell migration but proliferation, differentiation, survival, and angiogenesis.⁴
       Angiogenesis is an essential component of wound healing that includes cellular adhesion, invasion, migration, proliferation, and capillary tube formation of endothelial cells. This is a highly regulated event that involves the dynamic interactions between microvascular endothelial cells and the ECM proteins.⁴
       In addition to stimulating cellular activity, simultaneous degradation of tissue must occur to allow for the deposition of new tissue. This function is the responsibility of a group of proteolytic enzymes

Figure 2

known as matrix metalloproteinases (MMPs). They are structurally related, protein-degrading enzymes that require calcium ions for structural conformation and zinc ions in their active site for function. The MMPs are capable of digesting most of the components of the ECM, including the required growth factors and cell surface receptors. These enzymes function optimally at neutral pH and are usually synthesized in response to multiple types of tissue injury. MMPs are not normally present in detectable levels in healing, uninjured tissue.⁵ It is therefore critical for a balance to occur during this degradation and rebuilding. The level of MMPs is controlled by several mechanisms, including the local secretion of endogenous enzyme inhibitors referred to as tissue inhibitors of metalloproteinases (TIMPs). The same cells that produce MMPs can synthesize TIMPs. These TIMPs serve to block the tissue destruction of the MMPs as the inflammatory phase subsides and proceeds into a proliferative phase.⁵
       Elastase is another important enzyme involved in the healing process. The primary substrate of this enzyme is the ECM protein elastin, which contributes to the elasticity of dermal tissue. Elastase activity is known to be high in the chronic wound. This somewhat nonspecific enzyme can also convert pro-MMPs (the natural precursor of MMPs) to active MMPs5 and, in doing so, elastase contributes heavily to the MMP load in the chronic wound.⁶
       Elastase, being a relatively nonspecific protease, can also bind to native collagen and degrade it.⁷ Results from laboratory experiments demonstrate that the affinity of the elastase enzyme for the triple helix domain of native collagen is substantial, so dressings containing native collagen will act as a substrate sink for elastase as well as MMPs.⁷ In summary, the chronic wound is characterized by both decreased collagen deposition and increased collagen breakdown (see Figure 1). Elastase is shown to play a key role in perpetuating the vicious cycle. It is clear from this picture that removal of elastase from this cycle essentially removes its hub, potentially terminating the wound’s chronic state.⁸

Microenvironment

       The wound microenvironments of the acute and chronic wound certainly differ. Healing or acute wounds appear to have low levels of the inflammatory cytokines and protein-degrading enzymes but higher levels of growth factors. Nonhealing or chronic wounds also contain similar components but in an inverse amount. The elevated level of cytokines appears to be the leading factor in why chronic wounds remain in a prolonged inflammatory phase of healing. There are multiple potential triggers for the excess cytokine cellular production, including interleukins, the presence of bacteria and their endotoxins, platelet degranulation products, and degradation products of ECM. There is also a growth factor reduction that results in less cellular communication and, thus, the halting of the wound healing process.³

Holistic Assessment

       From a clinical point of view, practical concepts and guidelines must be kept in mind when attempting to manipulate the wound bed at a cellular level. Wound care involves more than maintaining a moist wound environment. Examination of the patient as a whole is important to evaluate and correct potential causes of wound bed microenvironment damage. These include factors such as systemic diseases, medications, nutrition, and tissue perfusion and oxygenation.
       A general medical history, including a medication record, will help in identifying and correcting systemic causes of impaired healing. The presence of a major illness or systemic disease and drug therapies (eg, immunosuppressive drugs and systemic steroids) will interfere with wound healing through alterations in immune functioning, metabolism, inflammation, nutrition, and tissue perfusion. Autoimmune diseases (eg, rheumatoid arthritis, uncontrolled vasculitis, and pyoderma gangrenosum) can delay healing and may actually require systemic steroids or immunosuppressive agents before local wound healing can occur.
       Patients undergoing major surgery may also have a diminished wound healing capacity, as do chronic smokers. Smoking is associated with impaired wound healing and increased risk of infection. S

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imply stated, wounds will heal in an environment that is adequately oxygenated. Oxygen delivery to the wound will be impaired if tissue perfusion is inadequate. Cigarette smoking (or nicotine use) decreases tissue oxygen by stimulating peripheral vasoconstriction. Dehydration and factors that increase sympathetic tone (eg, cold, stress, and pain) will also contribute to decreased tissue perfusion. Accordingly, to sustain optimal tissue perfusion, these factors must be eliminated or minimized.
       Similarly, nutrition must provide sufficient protein to support the growth of granulation tissue. The patient’s weight, prealbumin level (reflecting recent protein consumption), and serum albumin (reflecting long-term protein consumption) are useful in identifying patients who are outside the norms. Protein-energy malnutrition has been reported to predispose patients to chronic wounds due to reduced tissue regeneration and integrity, increased catabolism, and altered inflammatory reaction and immune function.⁶ In view of that, a balanced diet that includes adequate intake of protein (usually 1.2–1.5mg/kg/day), sufficient calories (from 25–30 kcal/kg/day up to 40 kcal/kg/day7), and fluids is essential to optimize wound bed healing. Further, low serum albumin levels (< 3.5mg/dl) are associated with the presence or development of pressure ulcers. Patients with pressure ulcers are in critical need of greater amounts of protein, calories, vitamins, and trace element supplementation—particularly, vitamin C, zinc, and semi-essential amino acids like arginine—to improve wound healing and immune response.⁶ The diligent wound clinician will frequently observe and monitor a patient’s weight and record the percent of food and fluids consumed, noting significant weight loss or gain and ensuring adequate food and fluid intake. A simple addition of a 100% multivitamin/mineral supplement can offer the nutritional boost that many at-risk persons or those suffering with chronic wounds need.

Wound Bed Preparation

       Initial debridement is required to remove the obvious necrotic tissue, excessive bacterial burden, and cellular burden of dead and senescent cells. Maintenance debridement is needed to maintain the appearance and readiness of the wound bed for healing. The healthcare provider can choose from a number of debridement methods, including surgical, enzymatic, mechanical, biological, or autolytic. More than one debridement method may be appropriate. Sharp surgical debridement is often preferred. Necrotic tissue, excessive bacterial burden, senescent cells, and cellular debris can all inhibit wound healing. The method of debridement chosen may depend on the status of the wound, the capability of the healthcare provider, the overall condition of the patient, and any professional licensing restrictions.
       An innovative, nearly pain-free method for contemporary wound bed preparation is ultrasonic debridement, which introduces new options for the necrotic wound. This type of debridement permits the practitioner to manage the amplitude and, therefore, the level of pain experienced by the patient or resident. This helps increase the degree of accuracy while including an antimicrobial effect subdermally. This new type of debridement is changing the way bedside debridement is performed. The novel devices provide quick results, safely and effectively, while offering excellent granulation with minimal or no bleeding (see Figure 2). This technology is being used within inpatient and outpatient clinics, hospitals, and long-term care facilities throughout the country. This gentle wound bed preparation tool offers hope to patients whose wounds have stalled.
       An additional effortless solution is polyacrylate moist wound debriding dressings. They provide quick, simple, safe, and pain-free debridment in a trouble-free, user-friendly dressing that provides 24-hour simultaneous rinsing and debriding. The dressing is activated by Ringer’s solution, an ideal physiologic fluid, and is only changed once per day, making it one of the best choices in long-term care. Dressing changes can be taught to the family for home care at discharge. Another plus is that this system does not require wound cleansing, reducing costs. It provides constant cleansing of the wound bed, removing biofilm9 and devitalized material and debriding wounds just as well as collagenase.¹⁰
       Moreover, wounds should be cleansed initially and at each dressing change using a neutral, nonirritating, noncytotoxic solution. This is important to minimize complications associated with infection and to promote wound healing. Routine wound cleansing should be accomplished with a minimum of chemical and/or mechanical trauma. Irrigating and cleansing the wound mechanically removes loose impediments (eg, microorganisms) to wound healing. Isotonic sterile saline (0.9% NaCl) or sterile water is usually recommended for healing acute wounds because of their physiological, nontoxic, cost-effective properties. Experimental data suggest a nontoxic surfactant may be useful, as may fluid delivered by increased intermittent pressure. The force employed depends on the healing phase of the wound. High pressure is used to remove debris, fibrotic tissue, and wound care products during the inflammatory phase. Low pressure is used during the proliferative phase to prevent impaired epithelial growth and trauma. Cleansing agents with a small amount of surfactant and a low pH allow inhibition of acidophobic bacteria in addition to providing mobilization biofilm and other debris in chronic wounds.¹¹ Commercial wound cleansers with quaternary ammonium compounds, such as benzalkonium chloride (BZK) and benzethonium chloride (BZC), can also safely address the of overgrowth of pathogens and be used for short periods of time in critically colonized or locally infected ulcers.¹²

Dressing Choice

       The final step in the process of wound bed preparation is choosing a suitable dressing that incorporates the principals of the most advantageous manipulation of the wound bed microenvironment. Available dressings that optimize wound bed preparation number in the thousands. Many products are multi-action and will control many of the cellular functions and communication that occur within the wound bed. The clinician must keep in mind several factors when considering the selection of an appropriate wound dressing.
       A dressing must maintain a physiologically moist wound healing environment. Also, selection of a dressing that will manage the wound drainage/exudate and protect the periwound skin must be considered. There are multiple choices for topical treatment of wounds. Many dressings now combine wound bed preparation (ie, debridement and/or antimicrobial activity) with moisture control. The clinical judgement for choice of dressings must combine offloading and protection principles as well. Finally, guidelines are often necessary to assist the clinician in making decisions regarding the value and best use of these advanced wound care products.
       Silver dressings continue to be the top advanced wound care product choice available. These innovative dressings continue to gain widespread usage, not just for the worst wounds and sites but for safe, broad-spectrum prophylaxis of infection and increased healing outcomes across the spectrum of wound care. Perhaps one of the safest and easiest ways for clinicians to combat bioburden (ie, the total population of bacteria, fungi, and viruses) within a wound is to utilize ionic silver. Ionic silver can often provide the “kick start” that a stalled, chronic ulcer needs to begin healing again.
       Seek out dressings that deliver sustained release ionic silver over a period of time (three to seven days or longer) and can remain in situ for several days. Since silver has little chance of developing clinically significant resistance13 and very limited sensitivity and is available over the counter, it makes a good dressing choice. Preventing a wound from entering into critical colonization¹⁴ with silver dressings allows for avoidance of the complications, costs, and discomfort associated with infection. It also allows for potentially less frequent dressing changes and a reduction in nursing intervention and time, which is often one of the most expensive line items on a long-term care’s income statement. The most versatile silver dressings are recommended since they are able to handle a variety of wounds and their changing needs. Dressings that perform double or triple duty are particularly popular, offering multiples uses.
       Chronic wounds are also characterized by decreased collagen deposition and increased collagen breakdown. Collagen dressings can reduce elastase levels in a wound environment, disrupting the cycle of chronicity and MMP binding activity that helps the wound transition from a chronic to an acute and healing state.⁸

Conclusion

       There should be frequent and consistent documentation of wound history, recurrence, and characteristics. Wound location, size, base, exudate, staging, condition of the surrounding skin, and degree of pain are vital parameters involved in the assessment of wound bed preparation. It is also vital to evaluate the rate of wound healing to determine if treatment is optimal. Flanagan15 noted that 20–40% reduction in 2–4 weeks is likely a reliable predictor of healing, and Margolis et al16 found that if the wound is not 30% smaller by Week 4, it will not heal by Week 12. With a greater emphasis on regular evaluations and reassessment by the clinician, wounds that are not healing at the expected rate will more often require interventions for wound bed preparation. The longer the duration of the wound, the more difficult it is to heal. If a wound is recurrent, the etiology, patient education, and issues of prevention and long-term maintenance need to be reassessed. As a final point, during the quest to accelerate endogenous healing and facilitate the effectiveness of therapeutic measures, our aim to convert the molecular and cellular environment of a chronic wound to that of an acute healing wound can successfully be obtained. This is accomplished by merging the principles of wound bed preparation and microwound environment manipulation. Through this application, the clinician can gain confidence in one’s responsiveness to the dynamic and complex cascade of cellular activity that occurs during the healing phase of a wound, successfully prevailing through the jungle known as the wound bed.