Impaired Wound Healing

Function

Normal Wound Healing

At times difficult to appreciate, the wound healing process (WHP) is a highly structured and well-organized biological process [6][7][6]. Wound healing can be divided into 4 phases [8]:

• Hemostasis
• Inflammation
• Proliferation
• Tissue remodeling

When a wound forms, whether due to trauma or surgery, immediate vasoconstriction occurs via the action of thromboxane A2 and prostaglandin [8]. Parallel to this process, the initiation of the clotting cascade takes place. Platelets arrive first to provide hemostasis and release cytokines and growth factors [8]. These chemoattractants, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), as well as cytokines, promote the migration of inflammatory cells to the wound. After approximately 24 to 48 hours, vasodilation occurs, allowing for inflammatory cells such as neutrophils, monocytes, macrophages, and lymphocytes to arrive at the injured tissue and perform a host of different functions. Neutrophils are the first of the inflammatory cells to arrive, peaking at 24 hours. They phagocytize bacteria, clear microbial and other cellular debris. Also, polymorphonuclear leukocytes (PMNs) release reactive oxygen species that potentiate this killing process [8].

The next major step in wound healing involves the accumulation of macrophages, usually around 48 to 72 hours [8]. Macrophages help initiate the proliferation phase of the WHP. These cells also perform a variety of diverse functions, including promoting the inflammatory healing process through the release of cytokines, clearance of cellular debris, and attracting blast cells to the area of the wounding [8]. T-lymphocytes also play a critical but still poorly understood role, as their absence in the wound or delayed arrival has been associated with WHP impairment. As the proliferation phase gives way to remodeling, fibroblasts lay down the extracellular matrix (ECM) and allow for re-epithelialization of the wound. Fibroblasts produce components of the ECM, including collagen-glycosaminoglycan scaffolds and proteoglycans [8]. Furthermore, endothelial cells promote angiogenesis and formation of a new capillary bed to allow for continued remodeling [8]. Myofibroblasts promote wound contracture via actin filaments. Over time, the wound will regain up to 70% to 80% of its original tensile strength [8].

Issues of Concern

Factors Affecting Wound Healing

The WHP is very complex and involves high levels of coordination between multiple tissues and cell types [6]. Consequently, impairment in the process can occur at any step along the sequence that leads to process completion. Many known factors can affect or modulate wound healing [7]. In the subsequent sections, we will discuss major modulators (both positive and negative) of the WHP, including a summary of some of the methods and techniques devised to promote wound healing [9].

Diabetes

There is no doubt that diabetes plays a detrimental role in wound healing. It does so by affecting the WHP at multiple steps. Wound hypoxia, through a combination of impaired angiogenesis, inadequate tissue perfusion, and pressure-related ischemia, is a major driver of chronic diabetic wounds [10]. Ischemia can lead to prolonged inflammation, which increases the levels of oxygen radicals, leading to further tissue injury. Elevated levels of matrix metalloproteases in chronic diabetic wounds, sometimes up to 50-100 times higher than acute wounds, cause tissue destruction and prevent normal repair processes from taking place [10]. Furthermore, diabetes is associated with impaired immunity, with critical defects occurring at multiple points within the immune system cascade of the WHP. For example, neutrophils show impaired chemotaxis and phagocytosis. As a result, diabetic wounds are prone to chronic infection due to inadequate bacterial clearance [10]. To further complicate matters, these wounds have defects in angiogenesis and neovascularization. Normally, wound hypoxia stimulates mobilization of endothelial progenitor cells via vascular endothelial growth factor (VEGF)[8]. In diabetic wounds, there are aberrant levels of VEGF and other angiogenic factors such as angiopoietin-1 and angiopoietin-2 that lead to dysangiogenesis [11]. Diabetic neuropathy may also play a role in poor wound healing. Lower levels of neuropeptides, as well as reduced leukocyte infiltration as a result of sensory denervation, have been shown to impair wound healing [10]. When combined, all these diverse factors play a role in the formation and propagation of chronic, debilitating wounds in patients with diabetes.

Tobacco Abuse

Cigarette smoking leads to numerous adverse health consequences, including various types of cancer, primary lung disease, and cardiovascular disease, among others [12][13]. However, in addition to those, smoking has severe ill-effects on the WHP [14]. This occurs through multiple pathways, but most have the common theme of inducing wound ischemia. For example, nicotine in smoke acts as a vasoconstrictor. Also, tobacco use stimulates the release of catecholamines such as epinephrine, leading to further reductions in tissue blood flow and hypoxia [15]. Relative wound ischemia can also result from the development of chronic obstructive pulmonary disease, which can lead to the permanent lowering of oxygen tension in the blood. Furthermore, nicotine reduces fibrinolysis, causing blood to become more viscous, leading to decreased tissue/regional blood flow. Carbon monoxide (CO) in cigarette smoke binds to hemoglobin with 200 times greater affinity than oxygen, so even small amounts of carbon monoxide can profoundly reduce the oxygen carrying capacity of hemoglobin. CO binding to hemoglobin will cause a leftward shift of the oxyhemoglobin dissociation curve, leading to less oxygen unloading at the tissue level [16][14][16]. In addition to the induction of ischemia, smoking leads to immunopathy of the wound via impaired PMN migration into the wound. Fibroblast migration and proliferation are also hindered, leading to decreased production of ECM and ultimately weaker scar formation. Not surprisingly, patients who stop smoking show improvement in wound healing [17].

Malnutrition

The nutritional needs of the healing wound are very complex. Wounds require a myriad of different micro and macronutrients to heal properly [18]. Regarding macronutrients, proteins are the key building blocks of our tissues, highlighting the importance of ample supply of protein/amino acid-rich nutrition to ensure adequate wound healing. Among amino acids of importance to the WHP, arginine, and glutamine play a critical in the overall process. Arginine improves immune function, supports collagen deposition (as a precursor to proline), and plays a role in neovascularization. Arginine supplementation also has a positive effect on wound healing. Glutamine is a critical energy source in proliferating cells (e.g., connective tissue including immune and progenitor blast cells). This amino acid is thought to improve the overall wound strength by increasing levels of mature collagen. The 2 other major macronutrients, fatty acids and carbohydrates, are also critical to wound healing. Carbohydrates, primarily glucose, act as the primary fuel for cells as it becomes broken down to form adenosine triphosphate (ATP). Polyunsaturated fatty acids, such as omega-3 and omega-6 fatty acids, both of which are essential fatty acids, may enhance the WHP by having an overall positive effect on host immune function [19][20].

Several micronutrients are worth mentioning because they play a particularly important role in wound healing [21]. These include ascorbic acid, or vitamin C, vitamin A, vitamin E, as well as magnesium, zinc, and iron. Vitamin C supports the hydroxylation of proline to hydroxyproline, which is essential for proper collagen formation. Vitamin A similarly supports collagen formation, as well as immune modulation, and decreased metalloprotease ECM degradation. As an antioxidant, vitamin E helps protect against oxidative tissue destruction, as well as may decrease excess scar formation. Magnesium is a cofactor in enzymes involved in collagen synthesis. Zinc, on the other hand, is a cofactor for DNA and RNA polymerase, playing a vital role in cell division. Finally, iron deficiency has been shown to result in impaired collagen synthesis. Further discussion of the most critical among the above micronutrients is provided at the end of this manuscript [22].

Obesity

Obesity is a significant factor in surgical wound healing. Abdominal obesity is correlated with oxidative stress, a phenomenon associated with deficiency of adiponectin (e.g., adipose-derived cytokine with antioxidant and anti-inflammatory properties). Adiponectin-deficient state leads to impaired perfusion and reepithelialization of the wound. Moreover, hypovolemia combined with relative hypoperfusion and reduction in oxygen delivery lead to further tissue injury. Consequently, wound complications, including surgical site infections and fat necrosis are more prevalent in obese patients. Various combinations of the same factors may be associated with impaired secondary healing following primary wound-related morbidity [23].

Pressure ulcers are more likely to develop in obese patients through pressure-related ischemia and hypovascularity, as well as decreased mobility. Contact between the skin and various hospital surfaces (e.g., stretchers, operating room tables) may result in friction, leading to ulceration and wound formation. Systemic effects of obesity, such as hypertension, hyperglycemia, and upregulation of the stress hormones in response to the physiologic burden of surgery and acute illness, all work to impair further wound healing. Additional factors involved in this complex process include blunting of the immune and inflammatory responses. Interestingly, these ill-effects of obesity are largely reversible through weight loss [24].

Stress

Stress has been demonstrated to be a major contributor to a broad range of health conditions and illnesses, including cardiovascular disease, cancer, and obesity. Stress states lead to upregulation of stress hormones via the hypothalamic-pituitary axis and the release of adrenocortical hormones. Resultant changes include elevated levels of cortisol, glucocorticoids, and catecholamines. Cortisol works to blunt the immune response by blocking the production of important cytokines such as IL-1beta, IL-6, and TNF-alpha. The impairment of immune response ultimately leads to deficient wound healing [25][26].

Clinical Significance

Wound healing is a vast topic area, with many aspects remaining poorly understood despite the tremendous amount of progress over the past few decades. Successful wound healing requires attention to multiple factors, incorporating nutritional, microbiologic, mechanical/coverage/dressing, and circulatory considerations. Various co-morbid conditions (e.g., diabetes, cardiovascular diseases, chronic steroid administration) and environmental factors (e.g., tobacco abuse) play important roles as modulators of the WHP. More recently, a better understanding of the role micronutrients play in wound healing, along with the introduction of novel wound care therapeutics (e.g., NPWT, MDT, hyperbaric oxygen therapy, growth factors), created a foundation for further progress in this critically important area of patient care.

Other Issues

Methods and Techniques Known to Improve Wound Healing

Negative Pressure Therapy

Numerous wound management devices have been introduced over the years to improve wound healing. However, none have been as influential and successful as negative pressure wound therapy (NPWT) therapy. NPWT involves the application of subatmospheric pressure on wound via a sponge-based system with an airtight seal directly over the wound, connected under sealed conditions to a suction device. Benefits of NPWT are realized via several different mechanisms. First, the subatmospheric pressure applied to the wound helps to remove wound exudate and other materials that are known to impair the WHP. Secondly, the presence of subatmospheric pressure promotes angiogenesis and tissue perfusion by increasing cellular proliferation and migration into the wound. The suction also assists in bringing wound edges together. When combined, all of the above elements and mechanisms work synergistically to help speed up wound healing. NPWT devices can be used on a wide variety of wounds, such as pressure ulcers, large abdominal wounds, traumatic wounds, as well as complex, difficult-to-cover tissue defects following debridement operations (e.g., in the setting of necrotizing soft tissue infections) [27][28][29][30][31][30][27]. Of note, NPWT is contraindicated in certain situations, such as wound surfaces involving malignancy, untreated osteomyelitis, non-enteric and unexplored fistulae, and necrotic tissue with eschar (e.g., non-debrided wounds) [27][32][33][31][27].

Vitamins, Trace Elements, and Growth Factors

Although a detailed discussion of the role of vitamins and trace elements in the WHP is well beyond the scope of the current review/synopsis of this topic, the authors feel strongly that a brief overview of this topic is fully warranted. It has long been known that Vitamin A may have beneficial effects on wound healing in the setting of previous systemic exposure to corticosteroids. More specifically, Vitamin A has been shown to overcome the inhibitory effects of cortisone (and related corticosteroids) on the rate of gain in tensile strength of the wound [34][35][34]. This may be especially pronounced in early stages of the WHP. At the same time, Vitamin A by itself does not seem to be a significant modulator of the WHP, suggesting that its beneficial action in the setting of prior corticosteroid use is related to the interaction(s) specific to corticosteroid-specific pathway(s) [36][37][36].

Vitamin C and zinc have both been found to improve wound healing characteristics, although clinical adoption and implementation of this therapeutic combination is less than universal. Mechanistically, vitamin C has several favorable effects on the WHP. First, it is a powerful antioxidant and free radical scavenger. Second, it is important to systemic immunity, and along with Zinc helps boost the immune system when taken in the postoperative period. Together with Arginine and Zinc, Vitamin C is important for collagen synthesis. The evidence is strongest for supplementing vitamin C and zinc during the immediate postoperative period [38][39][40][38].

Among other interesting (and important) developments in wound care, there is evidence that vitamin-D supplementation may help positively modulate impaired wound healing, although further research toward mechanistic understanding is required in this area. More specifically, the role of vitamin D in the WHP may be indirect, through beneficial effects on closely related physiological processes, such as glucose homeostasis [41][42].

Finally, another vast topic area that is worth mentioning (but too extensive to fully discuss in this review) is the use of growth factors in the modulation of the WHP.  It has been demonstrated that delivery of various specific growth factors (e.g., basic fibroblast growth factor, epidermal growth factor, keratinocyte growth factor) may produce beneficial effects on chronic wounds, with many experimental and clinical applications highlighting promise in the area of diabetic wound care [43][44][45]. Further research is required to better define mechanisms of action, potential side effects, and the overall risk-benefit of human application of such therapies.

Maggot Debridement

While considered by many as archaic, maggot debridement therapy (MDT) has been shown unequivocally to be of benefit in wound healing [46][47]. MDT is based on the observation that fly larvae only debride dead, devitalized, and necrotic tissue. Healthy, viable tissue is not threatened during the MDT, making this therapy uniquely suited for debridement of devitalized tissues with truly surgical precision [48]. In fact, MDT is considered a form of "biosurgery." While feeding on non-viable tissue, maggots secrete proteolytic enzymes that liquefy necrotic tissue within the wound. This liquefied material is then ingested, resulting in effective debridement of the tissue of interest. It has been shown that MDT can help debride large wounds in as little as 72 hours, resulting in a viable granulation bed that is suitable for conventional wound management. In addition to chemical debridement, larval secretions are also characterized by significant antimicrobial activity, active against a wide range of pathogenic (and often antibiotic-resistant) bacteria, mostly gram-positive species. Maggots work best on moist environments with sufficient oxygen supply [49]. They are approved for use in non-healing necrotic skin and soft tissue wounds, pressure and venous stasis ulcers, neuropathic foot ulcers, and non-healing traumatic or surgical wounds [50]. Most recent developments in this area include the introduction of transgenic maggots that secrete human growth factors in their saliva [51]. Clinical applications of this therapy are continually expanding. Of interest, application of MDT can be accomplished through direct exposure of the maggots to the wound bed (using a specialized "housing") or through indirect exposure (using larvae contained within a sealed, semi-permeable bag) [52][53].

Hyperbaric Oxygen

Hyperbaric oxygen therapy (HBOT) is another treatment modality that has been around for quite some time, but only recently saw a resurgence in interest due to promising effects on the WHP, especially in the setting of chronic and complicated wounds [54][55]. Chronic wounds, often seen as a consequence of diabetes, arterial or venous disease, are increasingly common and result in significant impact on the affected patients, their caretakers, and the healthcare system in general. The beneficial action of HBOT on wound healing is predicated on the increased supply of oxygen to wounds that are refractory to other, more conventional treatment approaches [56]. In practice, HBOT involves the patient being temporarily enclosed in a special chamber that in many ways approximates conditions used for deep sea divers and involves gradual "dive" followed by a pre-defined time interval at a certain "oxygen pressure level," and subsequent gradual "resurfacing" process. While in the chamber, the patient is exposed to markedly elevated concentrations of pure oxygen, leading to elevation of systemic and tissue oxygen levels. Effectively, the patient is receiving 100% oxygen at 2 to 3 times the atmospheric pressure at the sea level (see below regarding potential dangers of this therapy) [5][57].

It has been demonstrated that HBOT is effective in improving the course of chronic diabetes-related extremity wounds, potentially reducing the need for major (but not necessarily minor) amputations. Available evidence suggests beneficial effects of HBOT on wounds are usually apparent within approximately 6 weeks of therapy, but long-term beneficial effects continue to be questionable. Another area where HBOT can be beneficial is the management of necrotizing soft tissue infections (e.g., necrotizing fasciitis), with evidence showing potential mortality benefit, lower amputation rates, and an overall reduction in surgical debridements [58][59]. Additional difficult-to-treat types of wounds that have been speculated to benefit from HBOT are the chronic pressure ulcers (due to its inherently "ischemic" nature) and venous ulcers; however, there is no solid evidence to support HBOT for either of these indications at this time [57][60]. 

Despite its potential benefits, there are significant potential dangers of HBOT, including the risk of oxygen fire/explosion, the risk of pneumothorax, as well as the possibility of damage to eardrums during repeated "dives." Consequently, appropriate provider is credentialing and patient/staff safety procedures must be strictly followed to reduce any undue risks of harm [61][62].

Enhancing Healthcare Team Outcomes

The best management of wounds is taken care of by an interprofessional team of a nurse specializing in wound care and a clinician with significant wound experience. Caring for wounds not only involves regular follow-ups but patient education. A coordinated team approach has been shown to be most effective in wound management.