Factors Affecting Wound Healing

Dr.Simona Naik

09/02/2011

• Wound healing is normal biological process in human body, is achieved through 4 precisely and highly programmed phases:

-:Hemostasis-:Inflammation-:Proliferation-:Remodelling• These phases and their functions must occur in proper

sequence, at specific time, continue for a specific duration at an optimal intensity

The wound healing process

• Interuptions, abberrancies, or prolongation in the process can lead to delayed wound healing or a non healing chronic wound

• There are many factors that can affect wound healing which interfere with one or more phases , thus causing improper or impaired tissue repair

• This article reviews the recent literature on most significant factors that affect wound healing

Factors affecting wound healing

• Multiple factors can lead to impaired wound healing

• In general terms the factors that influence wound healing are categorized into local and systemic.

• Local factors are that directly influence the characteristics of the wound, while systemic factors are the overall health and disease state of the individual that affect his or her ability to heal

Factors affecting wound healing• Local factors Systemic factors• 1.Oxygenation 1. Age and gender• 2.Infection 2. sex hormones• 3.foreign body 3. Stress• 4.Venous 4. Ischemia sufficiency 5. Diabetes, 6 .Obesity 7 .Medication 8 . Alcoholism and smoking 9 . nutrition

Oxygenation

• Oxygen is important for cell metabolism, especially energy production by means of ATP

• It prevents wound from infection, induce angiogenesis, increases keratinocyte differenciation, migration, and re-epithelialization, enhances fibroblast proliferation and collagen synthesis and promotes wound contraction.

• Due to vascular disruptions and high oxygen consumption by metabolically active cells, the microevironment of the early wound is depleted of oxygen and is quite hypoxic

• Temporary hypoxia induces cytokine and growth factor production which are crucial promoters which help in wound healing

• In normal wound after the initial hypoxia progressive microcapillary neovascularization takes place and oxygen supply is restored

• But in case of injury or any systemic condition , including advancing age and diabetics can create impaired vascular flow, thus setting the stage for poor tissue oxygenation resulting in impaired healing

• Due to this prolonged hypoxia delays healing process chronic wounds are formed. Tissue oxygen tension have been measured transcutaneously in chronic wound are found to be 5 to 20 mm Hg in contrast to control tissue values of30 to 50 mm Hg (Tandara and viastoe, 2004)

• In summary, proper oxygen level is crucial for optimal wound healing

• Hypoxia stimulates wound healing such as release of growth factors and angiogenesis, while oxygen is needed to sustain the healing process.

• One therapeutic option that can sometimes overcome the influence of tissue hypoxia is hyperbaric oxygen therapy(HBOT)

• While HBOT can be effective treatment for hypoxic wound s, its availability is limited.

Infections

• Once skin is injured microorganisms that are normally sequestered at the skin surface obtain access to the underlying tissues

• Inflammation is normal part of wound healing and is important to removal of contaminating microorganisms

• In absence of effective decontamination inflammation is prolonged,since microbial clearance is incomplete

• Both bacteria and endotoxins can lead to prolonged elevation of proinflammatory cytokines such as interlukin-1 and TNF-α and elongate the inflammatory phase

• If this continues ,the wound may enter chronic state and fail to heal

• This prolonged inflammation also leads to increased levels of matrix metalloproteases (MMPs) a family of proteases that can degrade ECM.

• Also these bacteria in infected wounds occur in the form of biofilms, complex communities of aggregated bacteria embedded in a self secreted extracellular polysaccharide matrix (EPS)

• Mature biofilms develop protected microenvironment and are more resistant to conventional antibiotic treatment.

Systemic Factors- Age

• The elderly population (people over 60 years) is growing faster than any other age group.(World Health Organisation)and increased age is a major risk for impaired wound healing

• Many clinical and animal studies have been done and concluded that aging causes temporal delay in healing but not an actual impairment in terms of quality of healing

• Delayed wound healing in aged is associated with an altered inflammatory response , such as delayed T-cell infiltration into wound area with alterations in chemokine production and reduced macrophage phagocytic capacity (Swift et al., 2001)

- Intrestingly, exercise has been reported to

improve cutaneous wound healing in older adults

- The improved healing response may be due to an exercise induced anti inflammatory response in the wound (Emery et al,. 2005; Keylock et al,.2008)

Sex hormones in aged individuals

• Sex hormones play arole in age related wound healing deficits

• Compared with aged females aged males have been shown to have delayed healing of acute wounds

• Female estrogens and male androgens have significant effect on wound healing process(Giliver et al., 2007)

• Estrogen affects wound healing by regeneration matrix production, protease inhibiton, epidermal function associated with inflammation (Hardman and Ashcroft, 2008)

• Studies indicate that estrogen can improve age related impairment in healing in both men and women while androgens regulate cutaneous wound healing negetively (Gulliver etal.,2007)

Stress

• Stress has great impact on human health and social behaviour• Many diseases – such as cardiovascular disease, cancer,

compromised wound healing, and diabetes- are associated with stress

• Studies in both humans and animals have demonstrated that psychological stress causes a substantial delay in wound healing.

• Caregivers of persons with Alzheimer’s and students undergoing academic stress during examination demonstrated delayed wound healing (Kiecolt- Glaser et al., 1995; Marucha et al 1998)

• Stress up regulates glucocorticoids(GC’s) and reduces level of proinflammatory cytokines at the wound site

• Stress also reduces the expression of IL-1α and IL-8 at wound site – both chemoattractants that are necessary for the initial inflammatory phase of wound healing.

• GC cortisol functions as an anti-inflammatory agent and modulates the immune responses that are essential for initial phase of healing

• Stress can lead anxiety and depression,which may lead to unhealthy habbits like poor sleep patterns, inadequate nutrition, less exercise and a greater propensity for abuse of alchohol, cigrattes and other drugs

• All of these may come into play in negatively modulating the healing process

Diabetes

• Diabetes affects hundreds of millions of people worldwide• Diabetic individuals exibit a documented impairment in

healing of acute wounds.• Moreover diabetics are prone to develop chronic

nonhealing diabetic foot ulcers which is serious complication of diabetics and precede 84% of all diabetic related lower leg amputations.(Brem and Tomic-Canic, 2007)

• The influence of following factors on wound healing are

ImpairedWound healing

hypoxia

Keratinocyte dysfunction

Higher MMP’s

Impaired angiogenesisDecreased host

immunity

Neuropathy

hyperglycemia

• The impaired wound in diabetics involves multiple complex pathophysiological mechanism which is always associated with hypoxia

• The situation of prolonged hypoxia , which may be derived from both insufficient perfusion and insufficient angiogenesis is detrimental for wound healing

• Hyperglycemia, is also responsible for impaired wound healing in diabetics

• High levels of metalloproteases which are a feature of Diabetic foot ulcer and also levels of which are 60 times higher in chronic wound supports tissue destruction and inhibits normal repair process(Woo et al.,2007)

• 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 fibroblast and epidermal cells

• These defects are responsible for inadequate bacterial clearance and delayed or impaired repair in individuals with diabetes

• Neuropathy that occurs in diabetic individuals probably also contributes to impaired wound healing

Medications

• Many medications, such as those which interfere with clot formation or platelet function, or inflammatory responses and cell proliferation have the capacity to affect wound healing.

• Here commonly used medications that have significant impact on healing are:

1.Glucocorticoid Steroids:

• Systemic glucocorticoids (GC) which are frequently used as antiinflammatory agents inhibit wound repair

• Systemic steroids cause wounds to heal with incomplete granulation tisssue and reduced wound contraction(Franz et al.,2007)

• Beyond effects on repair systemic corticosteroids may increase the risk of wound infection

• But topical low dosage corticosteroid treatment on chronic wounds accelerate wound healing, reduce pain, and suppress hypergranulation tissue formation in 79% cases

Non-steroidal Anti-inflammatory Drugs

• NSAID’s such as ibuprofen are widely used for treatment of inflammation and for pain management.

• There are few data to suggest that short term NSAID’s have negative impact on healing.

• Systemic use of ibuprofen has demonstrated an anti proliferative effect on wound healing resulting in decrased numbers of fibroblasts, reduced wound contraction, delayed epithelialization and impaired angiogenesis

• Whereas topical application of NSAID’s on chronic wound provides moist wound healing, reduces persistant pain and benefits

Chemotherapeutic Drugs

• Most chemotherapeutic drugs inhibit cellular metabolism, rapid cell division, and angiogenesis and thus inhibit pathways critical for wound repair

• These medications result in decrease fibroplasia and neovascularization. They also delay cell migration into the wound, ↓ Wound matrix formation, lower collagen production, impair fibroblast and inhibit contraction of wounds

• They also weaken immune functions of patients thus increase risk of infection

• Impaired wound healing due to chemotherapeutic drugs such as adriamycin is most common

• A new generation of tumour chemotherapeutics are angiogenesis inhibitors such as bevacizumab which limit blood supply to tumour but may result in many wound healing complications.

Obesity

• Obesity is well known to increase risk of many diseases and these individuals frequently face wound complication.

• There is higher rate of surgical site infection in obese patients.

• Many of these complications may be result of relative hypoperfusion and ishemia that occurs in subcutaneous adipose tissue.

• Also increased tension on wound edges increases tissue pressure, reducing microperfusion and availability of oxygen to the wound

• Increase in pressure ulcers or pressure related injuries due to hypoascularity and poor perfusion makes tissue more suseptible to this type of injury

• Moreover skin folds harbour microorganisms that thrive on moist areas that contribute to infections and tissue breakdown

• Systemic factors also contribute in impaired wound healing in obese as obesity is commonly associated with diabetes, hypertension,dyslipidemia, stress, anxiety, depression.

• More recent findings have documented that adipose tissue secretes large variety of bioactive substances collectively named adipokines and have profound effect on immune and inflammatory response

• The negative influence of adipokines on systemic immune response seems likely to influence healing process , although direct proof for this is lacking

Alcohol consumption

• Clinical evidence and animal experiments have shown that exposure to alcohol

impairs wound healing increases the incidence of infectiondiminishes host resistance.• A recent review on alcohol induced alterations on host

defence after traumatic injury suggested that short term acute alcohol exposure results in suppressed pro-inflammatory cytokine release in response to an inflammatory challenge

• The most significant impairment seems to be in wound angiogenesis which is reduced by upto 61% following alcohol exposure

• Thus acute alcohol exposure can lead to impaired wound healing by impairing early inflammatory response , inhibiting wound closure, angiogenesis, collagen production and altering protease balance at wound site

• Analysis of clinical data indicates chronic alcohol exposure causes impaired wound healing and enhanced host suseptibility to infections.

Smoking

• Negative effects of smoking on wound healing outcomes have been known for a long time

• Postoperatively, patients who smoke show delay in wound healing and variety of complications such as infection, wound rupture, decrease in strength of wound.

• Also impaired healing has been noticed in both oral surgery and in placement of dental implants

• Substances in tobacco smoke Nicotine, carbon monoxide, hydrogen cyanide have been identified and have shown to have negative impact on healing

• They cause tissue hypoxia, peripheral vasocontriction, increase in blood viscosity which in turn results in impaired wound

• In inflammatory phase smoking causes impaired white blood cell migration resulting in lower number of monocytes and macrophages in wound site resulting in poor wound healing and increased risk of oppurtunistic wound infection

• During proliferative phase exposure to smoke yield decreased fibroblast migration , reduced wound contraction decreased ECM production and upset in balance of proteases

• Thus smoking cesation leads to improved repair and reduces wound infection( Sorensen et al; 2003;Lauerman, 2008)

Nutrition

• Malnutrition or specific nutrient deficiencies can have a profound impact on wound healing

• Energy, carbohydrate, fat, vitamin, and mineral metabolism all can affect healing process

• Carbohydrate, protein, amino acids: glucose is a major source that provides energy for angiogenesis and deposition of new tissues

• Protein is important nutrient factor affecting wound healing

• A deficiency of protein can impair capillary formation, fibroblast proliferation, proteoglycan synthesis, collagen synthesis, and wound remodelling

• It also affects immune system which increases suceptibility to infections

• Amino acids like arginine and glutamine by their deficiency affect wound healing process

• Fatty acids: 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

• They have also reported to affect proinflammatory cytokine production, cell metabolism, gene expression, and angiogenesis in wound sites

Vitamins,Micronutrients and Trace Elements

• VitaminC deficiency -impaired healing decreased collagen synthesis, fibroblast proliferation, decreased angiogenesis, increased capillary fragility impaired immune response• Vitamin A deficiency also leads to impaired wound healing• Vitamin E has anti-inflammatory properties and has been

suggested to to have a role in decreasing excess scar formation in chronic wounds

• Several micronutrients have been shown to be important for optimal repair:

Magnesium -protein and collagen synthesisCopper -crosslinking of collagen Zinc deficiency causes significant impairment

in wound healingSevere iron deficiency also leads to impaired

collagen production

Conclusion

• Wound healing is a complex process that consist of hemostasis, inflammation, proliferation and remodelling.

• Large number of cell types – including neutrophils, macrophages, lymphocytes, keratinocytes, fibroblast and endothelial cells- are involved in process

• Multiple factors cause impaired wound healing by affecting one or phases of the process

• The influences of these factors are not mutually exclusive• Single or multiple factors may play a role in one or more

individual phases , contributing to overall outcome of healing process.

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