Many wounds pose no challenge to the body's innate ability to heal; some wounds, however, may not heal easily either because of the severity of the wounds themselves or because of the poor state of health of the individual. Any wound that does not heal within a few weeks should be examined by a healthcare professional because it might be infected, might reflect an underlying disease such as diabetes, or might be a serious wound requiring medical treatment.
All wounds follow roughly the same healing process, which consists of an orderly progression of events that reestablish the integrity of the damaged tissue. The initial wound touches off a series of separate – yet interdependent – responses to the injury, including inflammation, epithelialization (growth of new skin), angiogenesis (blood vessel regeneration), and the accumulation of cells necessary to heal the tissue.
There are many different causes of wounds. Partial-thickness wounds penetrate the outer layers of the skin (the epidermis and the superficial dermis) and heal by regeneration of epithelial tissue (skin). Full-thickness wounds involve a loss of dermis (deeper layers of skin and fat) and of deep tissue, as well as disruption of the blood vessels; they heal by producing a scar.
Wounds are classified by 'stage'.
Ulcers are open sores on the skin (or a mucous membrane) that cause destruction of surface tissue. An ulcer can be shallow or deep and crater-shaped. Ulcers are usually inflamed and painful. Types of ulcers include traumatic ulcers, arterial ulcers (tissue death due to impaired arterial circulation), venous ulcers (caused by faulty backflow valves within veins), diabetic foot ulcers (caused by a narrowing of the small arteries), and pressure ulcers (also known as bedsores).
Burns fall into three categories:
The Stages of Wound Healing
Wounds with even edges that come together spontaneously (minor cuts) or can be brought together with sutures usually heal well with routine wound care. Wounds with rough edges and tissue deficit (a crater) may take longer to heal. When there is a crater and the edges of a wound are not brought together (left open intentionally), bumpy granulation tissue grows from the exposed tissue. The granulation tissue is eventually covered by skin that grows over the wound from the cut edges to the center. When healing is complete, the granulation tissue develops into tough scar tissue.
All wounds heal in three stages:
The Danger of Infection
Poorly healing wounds may partially be due to the types of offending organisms they harbor. Tissue is constantly in contact with pathogens which, under the proper conditions, are able to proliferate to create pathological conditions. Many different types of pathogens may be involved.
Infection of a wound with a large number of bacteria, a process known as colonization, will slow the healing process. However, all wounds contain some bacteria. This contamination usually does not affect the healing process. The difference between contamination and colonization is the concentration of bacteria. Signs of infection include red skin around the wound, discharge containing pus, swelling, warmth, foul odor, and fever.
Anaerobic bacteria such as bacteroides, clostridium and streptococcus may be active at deeper levels of the dermis, insulated from the healing influence of oxygen. Anaerobic bacteria are responsible for many devastating infections resulting in gangrene. Aerobic bacteria are more closely identified with superficial epidermal layers but may also be involved in infective processes and include staphylococcus epidermis, corynebacteria, propionibacteria.
Poor circulation plays a part in most wounds that do not heal readily. Diabetes provides an example of this, where there can be impaired circulation and altered carbohydrate metabolism. In cases where diabetes affects the peripheral circulation, tissues such as the epidermis and dermis become compromised, and thus are more prone to injuries and persistent infections. Diabetic ulcers frequently develop following simple injuries and are notoriously difficult to treat.
In a study of women being treated for venous leg ulcers, it was revealed that the women had suboptimal dietary intake of energy-providing food sources and key wound-healing nutrients such as vitamin C and zinc even though they had well-organized food habits [Wissing et al. 1997].
Wound Treatment. Hyperbaric Oxygen Therapy is used to treat very serious wounds. The patient breathes 100% oxygen in a pressurized chamber for 90-120 minutes. The oxygen dissolves into the blood and is distributed throughout the body, providing extra oxygen to the cells attempting to heal the wound. Hyperbaric oxygen treatments have been found to increase the rate of collagen deposition, angiogenesis, and bacterial clearance. Another benefit is that, if the wound environment has more oxygen, certain types of bacteria that cause serious infections cannot grow. This method has been used for many years in treating difficult or complicated, non-healing wounds. It is well recognized as a very effective treatment.
Whirlpool Therapy is used by physical therapists once or twice daily for about 20 minutes during the inflammatory stage of healing to enhance circulation and bring more oxygen into the wound area. The whirlpool also softens and loosens dead tissue and cleanses the wound. Some patients find that whirlpool therapy relieves wound pain. Whirlpool therapy should not be used on wounds that are in the proliferative stage of healing because it will damage the fragile skin cells. It should not be used on venous ulcers which result from too much blood in the area.
Ultrasound treatment uses mechanical vibration delivered at a frequency above the range of human hearing. Physical therapists report that covering the wound area with a hydrogel film and applying ultrasound during the inflammatory and proliferative stages stimulates the cells involved in wound healing and also warms the tissue, enhancing healing by improving circulation.
Electrical Stimulation mimics the body's own bioelectric system that influences wound healing by attracting repair cells, changing the permeability of cell membranes, and therefore affecting secretions and orienting cell structures. A current is generated between the skin and inner tissues when a break in the skin occurs. This current is enhanced by a moist wound environment and can be mimicked by electrical stimulation which is believed to accelerate the healing process. Electrical stimulation uses electrodes that are positioned around the wound area. It can be used on most wounds during all three stages to support, speed, and even improve wound healing. Use of this therapy results in a smoother, thinner scar. In 1994, the Agency for Health Care Policy and Research endorsed electrical stimulation therapy for treating Stage III and IV pressure ulcers, based on data from five clinical trials involving 147 patients.
Magnetic therapy has a rationale similar to that for electrical stimulation, because the body's magnetic field is related to its bioelectric system. The use of magnets has been reported to increase blood flow and enhance cell growth by transferring energy. Magnets also affect nerve signals in ways that may relieve pain. A published case study describes the complete healing of a long-standing abdominal wound by using magnet therapy for one month. [Szor et al. 1998]
Growth Factors are being studied intensively. These are biological substances that exert their influence by causing cellular growth and proliferation. In an ideal wound-healing situation, new tissue growth would replace damaged tissue resulting from a wound with no functional or cosmetic impairment. In other words, the newly-grown tissue would work as well as the previous tissue that was damaged, and it also would be identical in appearance. Understandably, research involving growth factors in wound care management is among the most intriguing research being conducted. There is hope that we are on the eve of learning how to manipulate growth factors, as well as cytokines, to control wound healing, improving function and aesthetics.
Less researched, Dilantin (Phenytoin) is a drug commonly used to treat epilepsy and seizure disorders. One of the known complications of Dilantin is gingival overgrowth (overgrowth of tissue at the gum margins in the mouth), suggesting that Dilantin might have an ability to alter and improve healing in chronic wounds by the same mechanism of encouraging tissue growth. Although no studies have been reported in the United States, Dilantin has been reviewed in Great Britain and suggested for this use [Talas et al. 1999]. In another study, topical Dilantin was compared with glucose analogs (honey) in patients with chronic leg ulcers over a 4-week period and showed superiority [Oluwatosin et al. 2000].
Research has shown that certain nutrients such as aloe vera, arginine, glutamine, zinc, copper, and vitamin C play key roles in wound healing [Vaxman et al. 1990; Worwag et al. 1999]. The typical Western diet is deficient in these nutrients.
With any type of wound – even seemingly minor injuries – there is always danger of rapid multiplication of bacteria. The elderly and persons with reduced immunity are at great risk for wound-related infections. Once bacteria escape from the primary location of a wound, they enter the blood. This condition is commonly called blood poisoning, septicemia, sepsis, or septic shock. Sepsis is always a serious, life-threatening condition, with 56% mortality. In the United States, sepsis occurs annually in some three cases per 1,000 population. In sepsis and septic shock, circulation is reduced; blood pressure is markedly reduced, causing vital organs to receive reduced blood supply; heart, kidney, and liver functions are reduced or show signs of shutdown (multiple organ failure); and abnormal bleeding can develop. Symptoms of septicemia and septic shock are sudden onset of illness, high fever, chills, rapid breathing, headache, and altered mental state. If the infection is identified promptly and the patient is treated aggressively (in an intensive care facility), full recovery from sepsis is possible.
Tetanus prophylaxis is essential in wounds. Tetanus used to be a common cause of death, but is seldom seen now because of antibiotic treatment and vaccinations. However, in an unvaccinated person over 60 who develops tetanus, mortality is in excess of 60% once the disease process begins, regardless of what treatments are begun at that time. Persons with uncomplicated wounds who have not been vaccinated for tetanus in the prior 5 years should receive a tetanus booster. In complicated wounds – those that are particularly dirty or contain a large amount of devitalized tissue – tetanus vaccination should be updated after 5 years. Symptoms of tetanus include irritability, headache, fever, and painful muscle spasms resulting in a condition called lockjaw.
Alcohol impairs wound healing and increases the likelihood of wound infection. Alcohol impairs the early inflammatory response; it inhibits wound closure, development of new blood vessels, and collagen production; it alters the protease balance at the wound site, which is needed to remove foreign matter and dead tissue; it decreases resistance to infectious microorganisms.
Smoking delays wound healing by weakening the immune system and reducing oxygen levels.
A well-balanced diet provides the body with the tools (nutrients) it needs to repair wounds.
Most chemotherapy drugs inhibit cell functions that are critical to proper wound repair.
Many medications inhibit wound healing. Examples include drugs that interfere with clot formation, platelet function, inflammatory responses, or cell proliferation; certain steroids, NSAIDs, chemotherapy drugs.
Human growth hormone (HGH) levels decline with age. HGH stimulates the production of collagen, which sticks wounds together, strengthens weakened tissue, gives skin more elasticity and helps wounds of the skin or bone heal faster and stronger.
Neutropenia and neutrophil dysfunction has been shown to play a role in poor wound healing.
Studies have shown that stressed individuals often exhibit significantly delayed wound healing.
Obese individuals often experience delayed wound healing due to a number of factors including: reduced oxygen, nutrient and blood supply to the wound site; moisture and microorganism collection in skin folds that decreases skin integrity and increases risk of infection; immobility, skin friction and skin shear impair the skin's barrier function.
Many studies have demonstrated enhanced wound and ulcer healing with oral zinc supplementation. The healing time of surgical wounds was reduced by 43% with zinc sulfate at 50mg tid. Not surprisingly, zinc deficiency is also associated with impaired wound healing. A study of patients deficient in zinc found that topically applied zinc oxide, but not zinc sulfate, enhanced the regeneration of epithelial tissue on leg ulcers. In addition, inflammation and bacterial growth were both reduced.
1. What is the use of zinc for wound healing? Int J Dermatol 1978;17: pp.568-70
2. Acceleration of healing with zinc sulfate. Ann Surg 1967;165: pp.432-6
3. Studies on zinc in wound healing. Acta Derm Venereol Suppl 1990;154: pp.1-36
Failure to provide either omega-6 or omega-3 fatty acids in the diet results in poor wound healing.
Injury significantly increases the need for the amino acid arginine, which is essential for a variety of metabolic functions. In a clinical study published in a major medical journal, arginine supplementation significantly increased the amount of reparative collagen synthesized at the site of a "standard wound" (an incision 5cm long and 1mm in diameter) made in healthy volunteers. The same study found marked enhancement of the activity and efficacy of peripheral T-lymphocytes (white blood cells in the bloodstream) [Kirk et al. 1993].
Other animal and human studies have demonstrated that arginine stimulates the cell-mediated immune response and protects against bacterial challenges [Gurbuz et al. 1998]. Arginine's ability to improve wound healing and immune-system function is thought to be related to its stimulation of the release of growth hormone. Growth hormone plays a critical role in modulating the immune system and is essential for muscle growth and development. That growth hormone secretion diminishes progressively with advancing age is one of the primary reasons for the decline in immune-system function and muscular strength as we grow older.
Under normal conditions, the 5gm per day of arginine found in the typical Western diet would be marginally sufficient to maintain tissue health. Research has demonstrated, however, that in patients undergoing gallbladder surgery, supplementing 15gm of arginine for 3 days prior to surgery significantly reduced nitrogen excretion (evidence that the patients were using, not excreting, amino acids in order to heal) when compared with patients receiving conventional nutritional support. In patients undergoing surgery for gastrointestinal cancer, supplementation with 25gm of arginine a day for 7 days improved their nitrogen balance as measured 5-7 days after surgery and led to more rapid recovery and discharge from the hospital. [Daly et al. 1995]
The amino acid glutamine is an important substrate for rapidly proliferating cells, including lymphocytes (white blood cells). It is also the major amino acid lost during muscle protein catabolism in the initial response to injury. An article documented beneficial effects from supplying burn patients with glutamine and arginine in amounts 2-7 times those found in the normal diet of healthy persons [De-Souza et al.1998].
Aloe can be applied topically to wounds and taken internally for both skin wounds and gastrointestinal ulcers. [Chithraet al. 1998] Aloe's mode of action may be through modulating macrophage function in the wound, enabling an immune response that ingests and destroys foreign pathogens. [Zhang et al. 1996] It has been suggested that aloe works as a free radical scavenger and improves blood flow to the wound. [Heggers et al. 1997]
Aloe vera provides the micronutrients required for protein synthesis. Its many components work together to reduce inflammation and pain, promote healing, and stop infection. Some of these components cause cells to divide and multiply; some stimulate the growth of white blood cells. Aloe vera also enhances cell wall permeability, increasing cell access to nutrients and facilitating the removal of toxins from the cells. Aloe vera can be used on the skin and can also be taken internally as a juice (2 ounces of concentrate in a 6-ounce beverage).
Known for its remarkable wound healing properties, centella has been found to induce levels of antioxidants in wounds and newly-formed tissue, including superoxide dismutase, glutathione peroxidase, vitamin E, and vitamin C. Centella improves collagen formation and angiogenesis [Shukla et al. 1999]. A review article of centella noted the most beneficial effects to date involved the stimulation and mutation of scar tissue by production of Type I collagen and an inhibition of the inflammatory reaction. This article reviewed seven other articles about centella, stating "Centella asiatica has been documented to aid wound healing in a large number of scientific reports" [Shukla 1999b; Widgerow et al. 2000].
Curcumin is an extract of the spice turmeric, known to have antioxidant properties and other health benefits. In Indian medicine, curcumin is used to reduce inflammation and treat wounds and skin ulcers. Topical application of curcumin encourages wound remodeling via effects on transforming growth factor-beta (TGF-b). It also improves reepitheliazation (new skin formation) and migration of cells such as myofibroblasts, fibroblasts, and macrophages, necessary for healing at the wound site.
Bromelain is found in pineapple and contains a proteolytic enzyme with the ability to break down or dissolve proteins. This mechanism of action can be helpful in chronic wounds or wounds having too much scar tissue. According to the PDR for Nutritional Supplements [2001, p. 72], bromelain speeds up healing time after surgical procedures, shows positive effects in the treatment of athletic injuries, and in at least one study has reduced swelling and pain from injuries of the musculoskeletal system.
Complications are more likely to develop in aging skin, such as the progression of a wound to a chronic non-healing state. This is related to an increased amount of elastase in the wound. Elastase is an enzyme that breaks down elastic proteins and is upregulated in impaired wound healing states. In a study [Ashcroft et al. 1999] involving 36 patients over the age of 70, half male and half female, topical estrogen was found to decrease delays in wound healing in both the male and female patients. Wound size, collagen levels, and fibronectin levels all improved with topical estrogen, indicating improved wound healing.
In this study, estrogen was delivered to the wound site for 24 hours as a patch routinely used in female estrogen replacement therapy. Fibronectin levels have been found to be deficient in chronic wounds of the aged, such as venous ulcers in humans or laboratory wounds in aged animals [Herrick et al. 1997]. Later studies have confirmed that estrogen can improve the age-related impairment in healing in both men and women [Gilliver et al. 2007].
A German physician first observed the role of copper in healing, noting that broken bones seemed to heal faster when patients were given a copper salt during convalescence. Since then, the role of copper in the biosynthesis of bone and connective tissue has been well established, although its mechanism of action is only partially known [Tenaud et al. 1999].
NOTE: Long-term high-dose copper is not recommended as a dietary supplement because there is significant evidence that it generates too much free-radical activity throughout the body. On the other hand, therapeutic, short-term supplementation of copper (8mg daily) to enhance wound healing at localized injury sites is appropriate. Copper supplementation as early as possible after serious burns has been demonstrated to replenish the copper depletion that is so typical of burn victims.
Zinc can be used topically or orally to encourage wound healing, in which it plays a well-documented and important role. Although zinc is present in the body in only a small quantity, it is found in many tissues, including bone, skin, muscle, and organs. It is a component of DNA, RNA, and numerous enzyme systems that participate in tissue growth and healing. Zinc is crucial for protein synthesis and is a key part of the thymulin molecule which enables T-lymphocytes to mature.
The immune system is adversely affected by even moderate degrees of zinc deficiency, and severe zinc deficiency depresses immune function. Relative zinc deficiencies, especially in the elderly, are common in the United States [Andrews et al. 1999]. Zinc is required for the development and activation of T-lymphocytes, a kind of white blood cell that helps fight infection. When zinc supplements are given to individuals with low zinc levels, the numbers of T-cell lymphocytes circulating in the blood increase and the ability of lymphocytes to fight infection improves.
Studies show that poor, malnourished children in India, Africa, South America, and Southeast Asia experience shorter courses of infectious diarrhea after taking zinc supplements. Amounts of zinc provided in these studies ranged from 4mg per day up to 40mg per day and were provided in a variety of forms (zinc acetate, zinc gluconate, or zinc sulfate). Zinc supplements are often given to help heal skin ulcers or bed sores, but they do not increase rates of wound healing when zinc levels are normal.
Zinc should be taken at least 2 hours after copper or the antibiotic tetracycline. Note that excess zinc can cause tissue injury and impaired wound healing [Cario et al. 2000].
During the initial phase of wound healing, immune cells are rushed to the wound site to protect against harmful invaders. They actually use free radicals to fight bacteria and to dispose of dead tissue. Once the free radicals have accomplished their job, however, they must be neutralized so the actual healing process can begin. SOD and other antioxidants such as vitamins C and D stop the free-radical oxidation process and promote the healing and repair process itself. Wounds treated with SOD have been shown to heal better and more quickly [Niwa 1989; Misaki et al. 1990; Eldad et al. 1998].
Injury can deplete SOD and other antioxidants. For certain antioxidants, depletion levels as high as 70% have been reported following injury [Ballmer et al. 1994]. SOD should be supplemented to encourage new tissue to grow, to enhance collagen, and to reduce swelling. Current research indicates that SOD taken orally is destroyed in the digestive tract. A lipid-encapsulated injectable form of SOD (LIPSOD) and a sublingually administered form currently show the most promise for direct supplementation.
Vitamin C is crucial for the proper function of the enzyme protocollagen hydroxylase which produces collagen, the primary constituent of the granulation tissue that heals a wound and the key component in blood vessel walls. A published review stated that vitamin C plays a variety of roles in the prevention and treatment of cancer, including stimulating the immune system and enhancing wound healing [Head 1998]. Wound healing requires more vitamin C than diet alone can easily provide. It must be replenished daily because it is water-soluble; any excess is excreted rather than stored.
Pantothenic acid improves healing by encouraging the migration of cells into the wounded area, thus establishing epithelialization [Weimann et al. 1999]. At the same time that new cells are migrating into the wounded area, cell division is increased and protein synthesis is increased, improving the efficiency of the healing process. Vitamin B5 also helps prevent an excess of inflammatory response in the wound and has been shown to improve surgical wound healing [Kapp et al. 1991].
Vitamin B5 has been demonstrated to speed up wound healing, increase protein synthesis, and multiply the number of repair cells available at the wound site [Aprahamian et al. 1985]. Vitamin B5 seems to have the most benefit early on in wound repair, actually increasing the distance that repair cells can travel.
French researchers examined combined supplementation with vitamins B5 and C before the removal of tattoos. One week prior to surgery, some patients were administered 200mg of vitamin B5 and 1gm of vitamin C. Scars of all patients were measured 75 days after surgery. The scars of those who had been supplemented with vitamins B5 and C were stronger and thicker and had more color. Researchers concluded that the vitamins had "recruited" more minerals to the wound areas [Vaxman et al. 1995]. These "recruited" minerals included copper, magnesium, and manganese, all proven to enhance wound repair. Vitamins B5 and C also kept iron from the wound areas, thus enhancing the healing process. The same group of researchers found that supplementation with vitamins B5 and C strengthens the healing of wounds incidental to colon surgery.
B-vitamins are needed for cell proliferation and for the replacement and maturation of red blood cells lost through bleeding. One response to a wound is a higher rate of metabolism. This leads to higher energy-level requirements in order to heal a wound, and to increased requirements for thiamine, niacin, and riboflavin.
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