Trauma and Wound Healing
Certain amino acids or their metabolites may provide additional benefits to wound healing aside from their role as building blocks for proteins.
Glutamine can be used as an energy source by various cells, including connective tissue and immune cells, and provides nitrogen for synthesis of other non-essential amino acids (Bellon 1995; Karna 2001; Molnar 2014). Research suggests glutamine may promote healing in trauma patients with wound-healing disorders (Blass 2012). Three randomized controlled trials that collectively enrolled 118 patients with severe burns involving 20‒80% of the body surface area were included in a research review. In all three studies, enteral formulas enriched with glutamine (0.35‒0.5 g/kg body weight daily) increased the rate of healing compared with placebo. Another study in the review reported that glutamine supplementation at 1.0 g/kg body weight for six days preceding and five days after surgery lowered the incidence of wound infections in patients with colorectal cancer undergoing surgery (Ellinger 2014).
Arginine is used to make proline, which is needed for collagen synthesis, and nitric oxide, which contributes to wound healing. It improves immune function and can stimulate wound healing (Guo 2010; Molnar 2014). Arginine in doses ranging from 6 to 30 grams daily has been found to reduce surgical wound complications in patients undergoing several types of surgery (Ellinger 2014). Along with zinc and vitamin C, arginine has been shown to promote healing of pressure ulcers (Desneves 2005; Cereda 2009).
Ornithine is a metabolite of arginine that shares many of its pharmacological properties. Mice supplemented with ornithine as 0.5% of their diet showed improved wound healing (Shi 2002). In a study of 160 elderly patients with heel pressure ulcers, 10 grams of an ornithine compound (ornithine alpha-ketoglutarate) once daily for six weeks shortened the time to ulcer closure compared with placebo (Meaume 2009).
Beta-hydroxy beta-methylbutyrate (HMB) is a metabolite of the amino acid leucine. It has anti-catabolic properties, contributing to a positive protein balance by reducing protein breakdown and stimulating protein synthesis (Landi 2016). In a small trial of amino acid supplementation, nine participants with diabetic foot ulcers received a combination of arginine, glutamine, and HMB or placebo twice daily for two weeks. Tissue hydroxyproline concentration (a measure of collagen concentration) increased by an average of almost 68% in the supplemented group, and dropped by over 78% in the control group (Jones 2014). In a larger trial in 270 diabetics, a drink containing HMB plus arginine and glutamine led to better healing than a control drink in a subgroup of participants with poor blood flow in their limbs and/or low albumin levels (Armstrong 2014).
Omega-3 Fatty Acids
Omega-3 fatty acids have been shown to promote wound healing by several mechanisms and may reduce infection during the healing process (Guo 2010). Intriguing evidence suggests omega-3 fats may have immunomodulatory effects, promoting local inflammation at the site of injury (where it is needed), while at the same time promoting recovery of physical function after surgery (Kiecolt-Glaser 2014). In a study of 40 patients with pressure ulcers, those whose enteral or parenteral food formulas were enriched with the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as copper, zinc, manganese, and vitamins A, C, and E, had decreased ulcer progression and reduced inflammatory marker levels over two weeks compared with those receiving an unenriched formula (Theilla 2012).
Copper, Selenium, and Zinc
Trace element deficiencies are associated with delayed wound healing and infections (Abdullahi 2014). Copper is a cofactor for the oxidative stress-reducing enzyme superoxide dismutase, as well as an enzyme used to synthesize collagen (Rucker 1998; Guo 2010). Selenium is a cofactor for the oxidative stress-reducing enzyme glutathione peroxidase, which protects cell membranes from free radical damage (Baker 1993; Espinoza 2008). Zinc is a cofactor for enzymes that prevent oxidative damage and are involved in cell replication and tissue repair and growth (Molnar 2014). In a systematic review of several randomized controlled clinical trials in burn patients, parenteral and enteral micronutrient preparations containing copper, selenium, and zinc have been associated with positive treatment outcomes. These include improved wound healing, decreased protein breakdown, reduced incidence of respiratory infection, increased glutathione peroxidase activity, and shorter hospital stay (Adjepong 2016).
In a controlled study of 20 healthy men with surgical wounds, those who received 150 mg of zinc (in the form of 220 mg zinc sulfate) per day had an average healing time of approximately 46 days versus 80 days in those who did not receive zinc. The greatest improvements in healing were seen during closure of the superficial skin (Pories 1967). In patients with pressure ulcers, treatment with protein-rich supplements containing 18‒30 mg zinc, 500 mg ascorbic acid, and 6‒9 grams arginine resulted in reduced ulcer surface area and ulcer severity after three to eight weeks (Desneves 2005; Cereda 2009).
Vitamin and Multi-nutrient Supplements
Vitamin A is a fat-soluble vitamin that can stimulate growth of cells involved in tissue and skin repair when applied topically (Reichrath 2007). It has an anti-inflammatory effect in wounds, and animal models suggest it can reduce the negative impact of steroid medications on wound healing (Molnar 2014).
Vitamin C lowers oxidative stress levels, has anti-inflammatory activity, and is a cofactor for collagen synthesis. Vitamin C levels fall rapidly during inflammation and low levels are associated with delayed healing (Mohammed 2015). Vitamin C deficiency results in decreased tissue growth and blood vessel formation, increased capillary fragility, impaired immune response, and increased susceptibility to infection (Guo 2010). In patients with pressure ulcers, one gram of vitamin C daily reduced healing time and ulcer surface area (Taylor 1974; ter Riet 1995). In a randomized controlled trial in 20 trauma patients with evidence of wound healing disorders, taking a multi-nutrient drink with 500 mg vitamin C twice daily reduced time to wound closure by about half compared with a placebo drink. The multi-nutrient drink also contained glutamine (20 grams), vitamin E (166 mg), beta-carotene (3.2 mg), zinc (6.6 mg), and selenium (100 mcg) (Blass 2012). Studies of protein-rich supplements containing 18‒30 mg zinc, 500 mg ascorbic acid, and 6-9 grams arginine have been shown to reduce ulcer surface area and ulcer severity scores over a period of three to eight weeks (Desneves 2005; Cereda 2009).
Diosmin and Hesperidin
Diosmin and hesperidin, citrus flavonoids that have been reported to increase venous tone and decrease capillary leakage, have been extensively studied for their effects on venous insufficiency (Shoab 1999). In a meta-analysis of five randomized controlled trials with a combined total of 723 patients with venous ulcers, the addition of 450 mg of diosmin plus 50 mg of hesperidin twice daily to conventional treatment (compression and local therapies) resulted in significantly better healing than conventional treatment alone or with placebo. Differences in healing were evident by the second month and, after six months of treatment, 32% more ulcers were healed in flavonoid-treated patients. The average time for complete healing was 16 weeks with citrus flavonoids and 21 weeks without flavonoids (Coleridge-Smith 2005).
Aloe vera gel contains several biologically active compounds, including polysaccharides, vitamins C and B complex, enzymes, minerals, and salicylic acids. These constituents give aloe vera anti-inflammatory and antimicrobial properties, as well as the ability to stimulate tissue regeneration, collagen synthesis, and new blood vessel formation (Pereira 2016). Several small studies have investigated the use of topical aloe vera in the treatment of acute and chronic wounds. A randomized controlled trial compared topical aloe prepared with olive oil to phenytoin cream for the treatment of chronic ulcers in 60 patients. Although both groups showed improvement, reduction in wound size, depth, edema, and pain scores were superior in the aloe group (Panahi 2015). In other research, treatment with aloe resulted in faster skin closure and quicker onset of pain relief in burn victims compared with 1% silver sulfadiazine cream (Shahzad 2013; Khorasani 2009).
Calendula (Calendula officinalis, commonly known as pot marigold) is a familiar garden plant with traditional application as a wound-healing agent. Constituents extracted from calendula have been shown to possess anti-inflammatory, antibacterial, antifungal, and free radical-reducing properties, and to stimulate blood vessel growth and collagen synthesis (Khairnar 2013; Schmiderer 2015; Pereira 2016). In a pilot study in 32 patients with non-infected venous leg ulcers, 17 were treated with a topical alcoholic extract of calendula, while the remaining 15 were treated with a topical antibiotic. After seven weeks, the patients treated with calendula saw a nearly 43% decrease in ulcer surface area versus almost 36% in those treated with the antibiotic. Additionally, the number of different types of bacteria isolated from healing ulcers in the calendula-treated patients was significantly lower than in the antibiotic-treated patients (Binić 2010).
Arnica (Arnica montana) is a member of the sunflower family with a history of use as a homeopathic remedy for relieving pain and bruising after physical trauma (Barkey 2012; Iannitti 2016). Post-surgical topical application of arnica cream around the nose and eyes in 36 patients following nose reconstruction significantly reduced bruising and edema at days 2, 5, and 7 post-surgery compared with 36 patients not treated with arnica cream (Simsek 2016). Topical use of a 20% arnica cream for 2 weeks reduced experimental laser-induced bruising in healthy volunteers when compared with placebo (Leu 2010).
Topical bromelain is used in the enzymatic debridement of wounds. In addition, several clinical trials have investigated the use of oral bromelain as a treatment to reduce edema, bruising, and pain following surgical or traumatic wounds (MacKay 2003). In a rat model of crush injury to the Achilles tendon, oral bromelain increased numbers of tendon structural cells (Aiyegbusi 2011).
Pycnogenol is an extract from Maritime pine bark that is rich in free radical-scavenging, anti-inflammatory polyphenolic compounds (Deger 2013; Grether-Beck 2016). A growing body of evidence suggests that pycnogenol may have positive effects on skin health, improving elasticity and hydration and protecting against damage related to sun exposure (Grether-Beck 2016). It may also have a role in supporting wound healing.
In a randomized clinical trial, 30 patients with venous ulcers were treated with surgery followed by 50 mg of pycnogenol three times daily or a flavonoid combination previously shown to enhance vascular healing for 90 days. Pycnogenol was found to be as effective as the flavonoid combination at promoting healing of surgically treated venous ulcers (Toledo 2017). In another trial, the use of both oral and topical pycnogenol worked better than oral pycnogenol alone at reducing venous ulcers and edema (fluid accumulation) in individuals with a condition called venous hypertension (Belcaro 2005). In chronic venous hypertension, high pressure in the veins causes vascular damage, inflammatory signaling, and movement of fluid out of the venous system into nearby tissues, leading to tissue damage that can result in skin ulceration (Raffetto 2014). Another clinical trial found that oral (systemic) and topical (local) pycnogenol preparations, alone and in combination, led to higher rates of complete healing of diabetic ulcers after six weeks of use compared with standard medications (Belcaro 2006).
Animal research further suggests pycnogenol may be helpful as an aid to healing various types of wounds. The use of topical 1%, 2%, and 5% pycnogenol solutions shortened wound healing time and reduced scar size compared with pycnogenol-free solution in rats subjected to experimental injury, and the benefits were amplified as pycnogenol concentration increased (Blazso 2004). Abdominal injections of a pycnogenol solution for ten days after abdominal surgery was found to reduce adhesions better than abdominal saline injections in rats that had undergone abdominal surgery (Sahbaz 2015). Another study in rats showed that a topical pycnogenol solution reduced tissue oxidative stress and improved healing of incision wounds, and a solution made with an extract from the bark of another type of pine tree had even stronger effects (Cetin 2013).
Diabetes is well known to impair skin healing, and one animal study showed that pycnogenol may counter this problem. In the study, topical treatment with pycnogenol powder reduced the size of wounds compared with no treatment three weeks after experimental skin wounding in diabetic rats (Dogan 2017). Findings from another study in rats suggest that oral pycnogenol may reverse the negative impact of prior radiation therapy on post-surgical healing time (Deger 2013).
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