Healing Process in Acute and Chronic Wound and Factors Affecting Healing Process

Ummu Asma’ binti Mohd Rosli

Faculty of MedicineHasanuddin University Makassar

ummuasma1101@gmail.com

Introduction

Tremendous advancements have been made in understanding the processes of wound healing. 1 The cell types and the order in which they appear in the wound have been established; many growth factors and their functions have been elucidated. 2 The wound repair process can be divided into 4 temporarily and spatially overlapping phases: coagulation (hemostasis), inflammation, formation of granulation tissue (proliferative phase), and remodeling or scar formation phase. 3 These phases and their biophysiological functions must occur in the proper sequence, at a specific time, and continue for a specific duration at an optimal intensity. There are many factors that can affect wound healing which interfere with one or more phases in this process, thus causing improper or impaired tissue repair. Wounds that exhibit impaired healing, including delayed acute wounds and chronic wounds, generally have failed to progress through the normal stages of healing. Such wounds frequently enter a state of pathologic inflammation due to a postponed, incomplete, or uncoordinated healing process. Most chronic wounds are ulcers that are associated with ischemia, diabetes mellitus, venous stasis disease, or pressure.2

Definition of cell and tissue

The cell is the smallest functional unit of a living organism. A cell is able to perform essential vital functions such as metabolism, growth, reproduction, and hereditary transmission can be achieved by cell division.4

Tissue is a group of cells, which specialized with same functions. There are four types of tissue which are epithelium, connective tissue, muscle dan nerve tissue.5

Definition of wound

A wound is an injury, especially one in which the skin or another external surface is torn, pierced, cut, or otherwise broken.6 A wound can also be described as a defect or a break in the skin, resulting from physical or thermal damaage. 7 According to the Wound Healing Society, a wound is a result of disruption of normal anatomic structure and function.7

Types of wound

There are several classification of wound. We can divided wound by the time of healing and how it happen.

Based on time of healing, we can divided into acute and chronic wound.8

Table 1. Wound : based on time of healing8

Based on how in happen , we can divided into two, blunt force injury and sharp force injury.8 in other reference, we can also divided into open and closed wound.4

Blunt force trauma can be divided by tree types, abrasion, contusion and laceration. An abrasion or scrape occurs when the skin contacts an opposing surface and the movement of either the skin or the surface results in friction that pulls away the superficial layer(s) of skin.8

A contusion or bruise occurs when a blunt impact tears capillaries and larger blood vessels, resulting in the escape of blood into the extravascular space. Bruises can be differentiated from livor mortis (bruise on corpse) in that livor involves the settling of blood to dependent portions of the vascular system, and not the surrounding tissues. As such, incised areas with dependent lividity will not appear hemorrhagic. Various terms exist to describe the gross appearance of a contusion. These include petechiae (small punctate hemorrhages), ecchymoses (generally small contusions), and hematoma (focal space-occupying collection of blood that expands and/or distorts the tissue configuration).8

A laceration forms when an object impacts the body with a force that exceeds the elastic capacity of the skin and underlying tissues. Thus, a laceration is a forceful tearing of the skin. This is in contradistinction to the vague and varied usage of the word by clinicians and lay public in which it commonly refers nonspecifically to all cuts of tears of skin.8

Picture 1. Blunt force injury. A. Abrasion. B. Contusions. C. Laceration. 8

Sharp force injuries span the spectrum of incised and stab wounds. An incised wound made by a sharp instrument such as a knife, scalpel blade, or razor blade has defined, nonabraded edges with no tissue bridging. It is a slicing wound that is longer than it is deep. A stab wound is deeper than its surface length.8

Picture 2. Stab wound .8

Some types of open wounds include: first, incisions, which are caused by a clean, sharp-edged object such as a knife, a razor or a glass splinter. Second, lacerations which are rough, irregular wounds caused by crushing or ripping forces. Third, abrasions (grazes),a superficial wound in which the topmost layers of the skin are scraped off, often caused by a sliding fall onto a rough surface. Fourth, puncture wounds, which are caused by an object puncturing the skin, such as a nail or needle. Fifth, penetration wounds which caused by an object such as a knife entering the body. And the last one, avulsion wounds. This is a wound that occurs due to the integrity of any tissue is compromised.5

A B C

Closed wounds are like open wounds and have numerous amount of types. However closed wounds have less than open. But are just as dangerous. There are three types of closed wound, which are contusions (bruise), caused by blunt force trauma that damages tissues under the skin, hematoma ,caused by damage to a blood vessel that in turn causes blood to collect under the skin and crushing injuries, caused by a great or extreme amount of force applied over a long period of time.5

Wound Healing

Wound healing is a specific biological process related to the general phenomenon of growth and tissue regeneration.12 It is a complex and dynamic process with the wound environment changing with the changing health status of the individual.10 Wound healing involves the organization of cells, chemical signs and extra cellular matrix to repair the tissue. In turn, the treatment of wounds tries to quickly close the damage to obtain a functionally and aesthetically satisfactory scar. To that end, it is indispensable to have greater understanding of the biological process involved in the healing of wounds and tissue regeneration.10

Research work on acute wounds in an animal model shows that wounds heal in four phases. It is believed that chronic wounds must also go through the same basic phases. The phases of wound healing are: hemostasis, inflammation ,proliferation or granulation and remodeling or maturation.11

Phases of normal wound healing

The wound repair process can be divided into 4 temporarily and spatially overlapping phases: coagulation, inflammation, formation of granulation tissue (proliferative phase), and remodeling or scar formation phase.2

Table 2. Phases of healing.11

1. Hemostasis (seconds to hours12)

Hemostasis process occurs second to hours after injury or wound , when the blood vessels damaged., releasing blood plasma and peripheral blood cells into the wound site. The earliest signals of tissue injury are the release of molecules such as ATP and the exposure of collagen on the blood vessel wall. In all tissues, a clot is formed that acts as a temporary barrier that prevents excess bleeding and limits the spread of pathogens into the blood stream. 12

Primary hemostasis occurs as platelets adhere to collagen fibers exposed in the damaged endothelium using specific collagen receptor glycoproteins (GPIb/IX/V) to form the primary hemostatic plug. As platelets attach to the lesion site, they rapidly upregulate the highaffinity platelet integrin αIIbβ3, which mediates platelet aggregation . Once platelets bind, they activate and degranulate, releasing their contents into the plasma to stimulate local activation of plasma coagulation factors. These factors trigger the generation of a fibrin clot. Exposure of blood plasma to tissue factor, produced by subendothelial cells not normally exposed to blood, such as smooth muscle cells and fibroblasts, or to foreign surfaces, such as implants, initiates an accelerated cascade of activated proteins that leads to fibrin formation. The cleaving of fibrinogen to fibrin monomers and its polymerization and cross linking forms an intertwined gelatinlike platelet plug, producing a stable clot .12

Platelet activation also causes the release of a number of signaling molecules such as platelet derived growth factor (PDGF), transforming growth factorβ(TGFβ), and vascular endothelial growth factor (VEGF) from their cytoplasmic granules. Inflammatory and reparative cells are chemotactically attracted to the “reservoir” of molecules stored within the clot that gives rise to inflammation, the next step in the sequence of healing.12

2. Coagulation/Inflammatory Phase (hours to days12)

Clinically inflammation, the second stage of wound healing presents as erythema, swelling and warmth often associated with pain,the classic “rubor et tumor cum calore et dolore”.Inflammatory phase occurs hours to days,this stage usually lasts up to 4 days post injury.11

In the wound healing analogy the first job to be done once the utilities are capped is to clean up the debris. This is a job for non-skilled laborers. These non-skilled laborers in a wound are the neutrophils or PMN’s (polymorphonucleocytes). The inflammatory response causes the blood vessels to become leaky releasing plasma and PMN’s into the surrounding tissue4. The neutrophils phagocytize debris and microorganisms and provide the first line of defense against infection. They are aided by local mast cells. As fibrin is broken down as part of this clean-up the degradation products attract the next cell involved. The task of rebuilding a house is complex and requires someone to direct this activity or a contractor. The cell which acts as “contractor” in

wound healing is the macrophage. Macrophages are able to phagocytize bacteria and provide a second line of defense. They also secrete a variety of chemotactic and growth factors such as fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor beta (TGF- and interleukin-1 (IL-1) which appears to direct the next stage.11

3. Proliferative Phase: Granulation Tissue Formation (days to weeks12)

As the inflammatory phase subsides, the proliferative phase of repair begins. At this stage, growth factors produced by remaining inflammatory cells and migrating epidermal and dermal cells act in autocrine, paracrine, and juxtacrine fashion to induce and maintain cellular proliferation while initiating cellular migration; all these events are required for the formation of granulation tissue while supporting epithelialization. As dermal and epidermal cells migrate and proliferate within the wound bed, there is a frank requirement for an adequate blood supply for nutrient delivery, gas, and metabolite exchange. Therefore, for wound healing to progress normally, a robust angiogenic response must be initiated and sustained.3

Wound healing angiogenesis begins immediately after injury when local hypoxia, secondary to injury-induced blood vessel disruption, occurs. This event fosters the production of proangiogenic factors. Vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF-2), and PDGF initially released by platelets and then by resident cells within the wound bed, are all central mediators of injury-induced angiogenic induction. In response, endothelial cells degrade basement membrane, migrate toward the wound site, proliferate, and form cell-cell contacts and eventually new blood vessels. More recently, it has been revealed that endothelial progenitor cells (EPCs) are also required for wound revascularization. 3

Normally, EPCs reside in the bone marrow and are recruited into the circulation in response to injury. Subsequently, EPCs are engrafted into the remodeling microvasculature, taking residence adjacent to endothelial cells bordering the injury site. Endothelial progenitor cell mobilization is mediated by nitric oxide, VEGF, and matrix metalloproteinases (MMP), particularly MMP-912; EPC engraftment and possibly differentiation occur in response to stomal cell–derived factor 1> and, as has become apparent more recently, insulinlike growth factor (IGF). Although more research needs to be done to further elucidate the mechanisms of EPC recruitment and homing, it is clear that these progenitor cells are necessary for normal wound healing– associated neovasculogenesis and injury repair. In fact, key signaling intermediates responsible for coordinating/regulating wound healing angiogenesis and vasculogenesis may be dysfunctional during diabetes. Indeed, diabetic patients prone to the development of chronic wounds may exhibit deficiencies in either EPC bone marrow release or peripheral tissue homing and engraftment. Thus, therapies aimed at correcting EPC-linked deficiencies may prove beneficial for treating diabetes-induced chronic wounds.3

4. Matrix Remodeling and Scar Formation (weeks to months12)

Reestablishment of a normal blood supply provides a favorable microenvironment for epidermal and dermal cell migration and proliferation. In turn, this leads to wound re- epithelialization and restoration of epidermal integrity. Fibroblasts proliferate within the wound and synthesize extra-cellular matrix (ECM) forming granulation tissue perfused with newly

formed blood vessels. Simultaneously, provisional matrix mainly consisting of collagen III, fibrin, fibronectin, and hyaluronic acid is progressively substituted with ECM mainly containing collagen . Next, wound contraction and matrix remodeling occur. Contraction is mainly achieved by differentiated fibroblasts or myofibroblasts that, in response to TGF-A, tissue tension, and the presence of certain matrix proteins (such as ED-A fibronectin and tenascin C), acquire smooth muscle actin–containing stress fibers. Fibroblast-induced contractile forces are then transmitted to the ECM via cytoskeleton-associated and ECM receptor–dependent mechanocoupling focal adhesion complexes, that is, integrin receptors. 3

Another mechanism leading to wound contraction is fibroblast motility with consequent matrix reorganization.This dynamic and reciprocal process involves slow cycles of ECM synthesis and degradation both occurring in a stromalor fibroblastic cell–dependent manner. Here, matrix-remodeling enzymes, particularly MMPs, play important roles in remodeling the local matrix microenvironment in support of several healing responses, including cellular migration, proliferation, and angiogenic induction. Finally, apoptosis of fibroblastic cells occurs, leading to the formation of a relatively acellular scar tissue whose tensile strength is comparable with unwounded skin.3

Although the importance of apoptosis in granulation tissue remodeling and scar formation is widely accepted, the triggers of apoptosis are not well understood. It has been suggested that TGF-A, tumor necrosis factor, and surprisingly FGF-2 (that normally is considered a stimulator of cell proliferation) can lead to an increase in the number of apoptotic cells during the final phase of healing. Inability of dermal cells, particularly myofibroblasts to undergo timely apoptosis, has been linked to wound healing pathologies, including the hypertrophic scar and keloid formation.3

Figure 1. Pathophysiology of wound healing3

Non healing wound

Non-healing wounds are a significant problem in health care systems all over the world. Unlike other areas of health care, wound management has not had the benefit of evidence-based, standardised treatment and referral plans, multidisciplinary collaboration, robust evaluations of treatments, adequate knowledge of health care personnel, patients and administrative persons, and appropriate treatment structures for the patients and basic, as well as clinical, research.13

In healthy individuals with no underlying factors an acute wound should heal within three weeks with remodeling occurring over the next year or so. If a wound does not follow the normal

trajectory it may become stuck in one of the stages and the wound becomes chronic. Chronic wounds are thus defined as wounds, which have “failed to proceed through an orderly and timely process to produce anatomic and functional integrity, or proceeded through the repair process without establishing a sustained anatomic and functional result.”12

Once a wound is considered chronic it should trigger the wound care clinician to search for underlying causes, which may not have been addressed. Better yet, an understanding of the causative factors should lead us to be proactive in addressing these factors in at risk populations so that chronic wounds are prevented.12

For a wound to heal successfully, all four phases must occur in the proper sequence and time frame. Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing. 2

Factors affecting wound healing

There are multiple factors which can lead to impaired wound healing.The factors are divided into three : condition of the patient, types of wound and local factors.14

Local factors that influence healing

Table 3. Local factors that influence healing.2

Oxygenation

Oxygen is important for cell metabolism, especially energy production by means of ATP, and is critical for nearly all wound healing processes. It prevents wounds from infection, induces

angiogenesis, increases keratinocyte differentiation, migration, and re-epithelialization, enhances fibroblast proliferation and collagen synthesis, and promotes wound contraction. In addition, the level of superoxide production (a key factor for oxidative killing pathogens) by polymorphonuclear leukocytes is critically dependent on oxygen levels. Wound required adequate oxygen delivery to heal.2

Due to vascular disruption and high oxygen consumption by metabolically active cells, the microenvironment of the early wound is depleted of oxygen and is quite hypoxic. Several systemic conditions, including advancing age and diabetes, can create impaired vascular flow, thus setting the stage for poor tissue oxygenation. In the context of healing, this overlay of poor perfusion creates a hypoxic wound. Chronic wounds are notably hypoxic; tissue oxygen tensions have been measured transcutaneously in chronic wounds from 5 to 20 mm Hg, in contrast to control tissue values of 30 to 50 mm Hg .In wounds where oxygenation is not restored, healing is impaired. Temporary hypoxia after injury triggers wound healing, but prolonged or chronic hypoxia delays wound healing. In acute wounds, hypoxia serves as a signal that stimulates many aspects of the wound-healing process. Hypoxia can induce cytokine and growth factor production from macrophages, keratinocytes, and fibroblasts. Cytokines that are produced in response to hypoxia include PDGF, TGF-β, VEGF, tumor necrosis factor-α (TNF-α), and endothelin-1, and are crucial promoters of cell proliferation, migration and chemotaxis, and angiogenesis in wound healing. In normally healing wounds, ROS such as hydrogen peroxide (H2O2) and superoxide (O2) are thought to act as cellular messengers to stimulate key processes associated with wound healing, including cell motility, cytokine action (including PDGF signal transduction), and angiogenesis. Both hypoxia and hyperoxia increase ROS production, but an increased level of ROS transcends the beneficial effect and causes additional tissue damage .2

Infection

Wound infection is an imbalance between host resistance and bacterial growth. Open wound invariably become colonized by bacteria. The wound has no protective barrier to prevent bacterial adherence in the exposed dermis or subcutaneous fat and muscle. If bacterial infection occurs, the healing can be not only delayed but also stopped.15

Treatment of closed,infected wound depends on whether fluid or necrotic tissue is present. If there is no fluid is drained, antibiotic can be used. Signs of wound infection include fever, tenderness, erythema, edema, and drainage.15

Systemic factors that influence healing

Age

Increased age is a major risk factor for impaired wound healing. Delayed wound healing in the aged is associated with an altered inflammatory response, such as delayed T-cell infiltration into the wound area with alterations in chemokine production and reduced macrophage phagocytic capacity. Delayed re-epithelialization, collagen synthesis, and angiogenesis have also been observed in aged mice as compared with young mice. Overall, there are global differences in wound healing between young and aged individuals. A review of the age-related changes in healing capacity demonstrates that every phase of healing undergoes characteristic age-related changes, including enhanced platelet aggregation, increased secretion of inflammatory mediators, delayed infiltration of macrophages and lymphocytes, impaired macrophage function, decreased secretion of growth factors, delayed re-epithelialization, delayed angiogenesis and collagen deposition, reduced collagen turnover and remodeling, and decreased wound strength.2

Interestingly, exercise has been reported to improve cutaneous wound healing in older adults as well as aged mice, and the improvement is associated with decreased levels of pro-inflammatory cytokines in the wound tissue. The improved healing response may be due to an exercise-induced anti-inflammatory response in the wound.2

Sex hormones

Sex hormones play a role in age-related wound-healing deficits. Compared with aged females, aged males have been shown to have delayed healing of acute wounds. A partial explanation for this is that the female estrogens (estrone and 17β-estradiol), male androgens (testosterone and 5α-dihydrotestosterone, DHT), and their steroid precursor dehydroepiandrosterone (DHEA) appear to have significant effects on the wound-healing process. Estrogen affects wound healing by regulating a variety of genes associated with regeneration, matrix production, protease inhibition, epidermal function, and the genes primarily associated with inflammation. Studies indicate that estrogen can improve the age-related impairment in healing in both men and women.2

Stress

Studies in both humans and animals have demonstrated that psychological stress causes a substantial delay in wound healing. The hypothalamic-pituitary-adrenal and the sympathetic- adrenal medullary axes regulate the release of pituitary and adrenal hormones. These hormones include the adrenocorticotrophic hormones, cortisol and prolactin, and catecholamines (epinephrine and norepinephrine). Stress up-regulates glucocorticoids (GCs) and reduces the levels of the proinflammatory cytokines IL-1β, IL-6, and TNF-α at the wound site. Stress also reduces the expression of IL-1α and IL-8 at wound sites—both chemoattractants that are necessary for the initial inflammatory phase of wound healing. Furthermore, GCs influence immune cells by suppressing differentiation and proliferation, regulating gene transcription, and reducing expression of cell adhesion molecules that are involved in immune cell trafficking . The

GC cortisol functions as an anti-inflammatory agent and modulates the Th1-mediated immune responses that are essential for the initial phase of healing. Thus, psychological stress impairs normal cellmediated immunity at the wound site, causing a significant delay in the healing process.2

Stressors can lead to negative emotional states, such as anxiety and depression, which may in turn have an impact on physiologic processes and/or behavioral patterns that influence health outcomes. In addition to the direct influences of anxiety and depression on endocrine and immune function, stressed individuals are more likely to have unhealthy habits, which include poor sleep patterns, inadequate nutrition, less exercise, and a greater propensity for abuse of alcohol, cigarettes, and other drugs. All of these factors may come into play in negatively modulating the healing response.2

Figure 2. Effect of stress on wound healing.2

Diabetes

Chronic non-healing diabetic foot ulcers (DFUs), which are estimated to occur in 15% of all persons with diabetes. DFUs are a serious complication of diabetes, and precede 84% of all diabetes related lower leg amputations.2

Several dysregulated cellular functions are involved in diabetic wounds, such as defective T-cell immunity, defects in leukocyte chemotaxis, phagocytosis, and bactericidal capacity, and dysfunctions of fibroblasts and epidermal cells. These defects are responsible for inadequate bacterial clearance and delayed or impaired repair in individuals with diabetes The neuropathy that occurs in diabetic individuals probably also contributes to impaired wound healing. Neuropeptides such as nerve growth factor, substance P, and calcitonin gene-related peptide are relevant to wound healing, because they promote cell chemotaxis, induce growth factor production, and stimulate the proliferation of cells. A decrease in neuropeptides has been

associated with DFU formation. In addition, sensory nerves play a role in modulating immune defense mechanisms, with denervated skin exhibiting reduced leukocyte infiltration.2

In summary, the impaired healing that occurs in individuals with diabetes involves hypoxia, dysfunction in fibroblasts and epidermal cells, impaired angiogenesis and neovascularization, high levels of metalloproteases, damage from ROS and AGEs, decreased host immune resistance, and neuropathy.2

Figure 3. Effect of diabetes on wound healing. 2

Medications

Glucocorticoid Steroids

Systemic glucocorticoids (GC), which are frequently used as anti-inflammatory agents, are well-known to inhibit wound repair via global anti-inflammatory effects and suppression of cellular wound responses, including fibroblast proliferation and collagen synthesis. Systemic steroids cause wounds to heal with incomplete granulation tissue and reduced wound contraction Glucocorticoids also inhibit production of hypoxia-inducible factor-1 (HIF-1), a key transcriptional factor in healing wounds.2

Chemotherapeutic Drugs

Most chemotherapeutic drugs are designed to inhibit cellular metabolism, rapid cell division, and angiogenesis and thus inhibit many of the pathways that are critical to appropriate wound repair. These medications inhibit DNA, RNA, or protein synthesis, resulting in decreased fibroplasia and neovascularization of wounds. Chemotherapeutic drugs delay cell migration into

the wound, decrease early wound matrix formation, lower collagen production, impair proliferation of fibroblasts, and inhibit contraction of wounds. Chemotherapy induces neutropenia, anemia, and thrombocytopenia, thus leaving wounds vulnerable to infection, causing less oxygen delivery to the wound, and also making patients vulnerable to excessive bleeding at the wound site.2

Obesity

Obese individuals frequently face wound complications, including skin wound infection, dehiscence, hematoma and seroma formation, pressure ulcers, and venous ulcers. Many of these complications may be a result of a relative hypoperfusion and ischemia that occurs in subcutaneous adipose tissue. This situation may be caused by a decreased delivery of antibiotics as well. In surgical wounds, the increased tension on the wound edges that is frequently seen in obese patients also contributes to wound dehiscence.

Wound tension increases tissue pressure, reducing microperfusion and the availability of oxygen to the wound. The increase in pressure ulcers or pressure-related injuries in obese individuals is also influenced by hypovascularity, since poor perfusion makes tissue more susceptible to this type of injury. In addition, the difficulty or inability of obese individuals to reposition themselves further increases the risk of pressurerelated injuries. Moreover, skin folds harbor micro-organisms that thrive in moist areas and contribute to infection and tissue breakdown. The friction caused by skin-on-skin contact invites ulceration. Together, these factors predispose obese individuals to the development of impaired wound healing.2

The function of adipose tissue used to be considered as primarily caloric storage. However, more recent findings have documented that adipose tissue secretes a large variety of bioactive substances that are collectively named adipokines. Both adipocytes themselves as well as macrophages inside the adipose tissue are known to produce bioactive molecules including cytokines, chemokines, and hormone-like factors such as leptin, adiponectin, and resistin. Adipokines have a profound impact on the immune and inflammatory response. The negative influence of adipokines on the systemic immune response seems likely to influence the healing process, although direct proof for this is lacking. Impaired peripheral blood mononuclear cell function, decreased lymphocyte proliferation, and altered peripheral cytokine levels have been reported in obesity. Importantly, though, many of the obesityrelated changes in peripheral immune function are improved by weight loss.2

Figure 4. Effect obesity on wound healing. 2

Alcohol consumption

A recent review on alcohol-induced alterations on host defense after traumatic injury suggested that, in general, short-term acute alcohol exposure results in suppressed pro-inflammatory cytokine release in response to an inflammatory challenge. The higher rate of post-injury infection correlates with decreased neutrophil recruitment and phagocytic function in acute alcohol exposure. 2

Beyond the increased incidence of infection, exposure to ethanol also seems to influence the proliferative phase of healing. In murine models, exposure to a single dose of alcohol that caused a blood alcohol level of 100 mg/dL (just above the legal limit in most states in the US) perturbed re-epithelialization, angiogenesis, collagen production, and wound closure. Connective tissue restoration is also influenced by acute ethanol exposure, and results in decreased collagen production and alterations in the protease balance at the wound site.2

Smoking

Post-operatively, patients who smoke show a delay in wound healing and an increase in a variety of complications such as infection, wound rupture, anastomotic leakage, wound and flap necrosis, epidermolysis, and a decrease in the tensile strength of wounds.2

Nicotine stimulates sympathetic nervous activity, resulting in the release of epinephrine, which causes peripheral vasoconstriction and decreased tissue blood perfusion. Nicotine also increases blood viscosity caused by decreasing fibrinolytic activity and augmentation of platelet adhesiveness.2

In addition to the effects of nicotine, carbon monoxide in cigarette smoke also causes tissue hypoxia. Carbon monoxide aggressively binds to hemoglobin with an affinity 200 times greater than that of oxygen, resulting in a decreased fraction of oxygenated hemoglobin in the bloodstream. Hydrogen cyanide, another well-studied component of cigarette smoke, impairs cellular oxygen metabolism, leading to compromised oxygen consumption in the tissues. Beyond these direct tissue effects, smoking increases the individual’s risk for atherosclerosis and chronic obstructive pulmonary disease, two conditions that might also lower tissue oxygen tension .2

During the proliferative phase of wound healing, exposure to smoke yields decreased

fibroblast migration and proliferation, reduced wound contraction, hindered epithelial regeneration, decreased extracellular matrix production, and upset in the balance of proteases.2

Nutrition

For more than 100 years, nutrition has been recognized as a very important factor that affects wound healing. Most obvious is that malnutrition or specific nutrient deficiencies can have a profound impact on wound healing after trauma and surgery. Patients with chronic or non-healing wounds and experiencing nutrition deficiency often require special nutrients. Energy, carbohydrate, protein, fat, vitamin, and mineral metabolism all can affect the healing process.2

Protein is one of the most important nutrient factors affecting wound healing. A deficiency of protein can impair capillary formation, fibroblast proliferation, proteoglycan synthesis, collagen synthesis, and wound remodeling. A deficiency of protein also affects the immune system, with resultant decreased leukocyte phagocytosis and increased susceptibility to infection. Collagen is the major protein component of connective tissue and is composed primarily of glycine, proline, and hydroxyproline. Collagen synthesis requires hydroxylation of lysine and proline, and co-factors such as ferrous iron and vitamin C. Impaired wound healing results from deficiencies in any of these co-factors.2

Arginine is a semi-essential amino acid that is required during periods of maximal growth, severe stress, and injury. Arginine has many effects in the body, including modulation of immune function, wound healing, hormone secretion, vascular tone, and endothelial function. Arginine is also a precursor to proline, and, as such, sufficient arginine levels are needed to support collagen deposition, angiogenesis, and wound contraction. Arginine improves immune function, and stimulates wound healing in healthy and ill individuals . Under psychological stress situations, the metabolic demand of arginine increases, and its supplementation has been shown to be an effective adjuvant therapy in wound healing .2

Glutamine is the most abundant amino acid in plasma and is a major source of metabolic energy for rapidly proliferating cells such as fibroblasts, lymphocytes, epithelial cells, and macrophages. The serum concentration of glutamine is reduced after major surgery, trauma, and sepsis, and supplementation of this amino acid improves nitrogen balance and diminishes immunosuppression . Glutamine has a crucial role in stimulating the inflammatory immune response occurring early in wound healing. Oral glutamine supplementation has been shown to improve wound breaking strength and to increase levels of mature collagen .2

Lipids are used as nutritional support for surgical or critically ill patients to help meet energy demands and provide essential building blocks for wound healing and tissue repair. Polyunsaturated fatty acids (PUFAs), which cannot be synthesized de novo by mammals, consist mainly of two families, n-6 (omega-6, found in soybean oil) and n-3 (omega-3, found in fish oil).

Fish oil has been widely touted for the health benefits of omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The effects of omega-3 fatty acids on wound healing are not conclusive. They have been reported to affect pro-inflammatory cytokine production, cell metabolism, gene expression, and angiogenesis in wound sites. The true benefit of omega-3 fatty acids may be in their ability to improve the systemic immune function of the host, thus reducing infectious complications and improving survival.2

Vitamins C (L-ascorbic acid), A (retinol), and E (tocopherol) show potent anti-oxidant and anti-inflammatory effects. Vitamin C has many roles in wound healing, and a deficiency in this vitamin has multiple effects on tissue repair. Vitamin C deficiencies result in impaired healing, and have been linked to decreased collagen synthesis and fibroblast proliferation, decreased angiogenesis, and increased capillary fragility. Also, vitamin C deficiency leads to an impaired immune response and increased susceptibility to wound infection.Similarly, vitamin A deficiency leads to impaired wound healing. The biological properties of vitamin A include anti-oxidant activity, increased fibroblast proliferation, modulation of cellular differentiation and proliferation, increased collagen and hyaluronate synthesis, and decreased MMP-mediated extracellular matrix degradation .2

Vitamin E, an anti-oxidant, maintains and stabilizes cellularmembrane integrity by providing protection against destruction by oxidation. Vitamin E also has anti-inflammatory properties and has been suggested to have a role in decreasing excess scar formation in chronic wounds. Animal experiments have indicated that vitamin E supplementation is beneficial to wound healing, and topical vitamin E has been widely promoted as an anti-scarring agent.2

Several micronutrients have been shown to be important for optimal repair. Magnesium functions as a co-factor for many enzymes involved in protein and collagen synthesis, while copper is a required co-factor for cytochrome oxidase, for cytosolic anti-oxidant superoxide dismutase, and for the optimal cross-linking of collagen. Zinc is a co-factor for both RNA and DNA polymerase, and a zinc deficiency causes a significant impairment in wound healing. Iron is required for the hydroxylation of proline and lysine, and, as a result, severe iron deficiency can result in impaired collagen production.2

Conclusion

Wound healing is a complex biological process that consists of hemostasis, inflammation, proliferation, and remodeling. Large numbers of cell types,including neutrophils, macrophages, lymphocytes, keratinocytes, fibroblasts, and endothelial cells are involved in this process. 2The normal wound healing process can be divided into 4 overlapping phases: coagulation, inflammation, formation of granulation tissue (proliferative phase), and remodeling or scar formation.3 Multiple factors can cause impaired wound healing by affecting one or more phases of the process and are categorized into local and systemic factors. The influences of these factors are not mutually exclusive. Single or multiple factors may play a role in any one or more

individual phases, contributing to the overall outcome of the healing process.2

References

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