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WoundVite® 

clinical studies

There are a vast number of clinical studies over the last few decades that have shown the effectiveness of the ingredients found in WoundVite. Our clinical research team has compiled several of these studies with the results so that you can find out for yourself that the ingredients in WoundVite can help heal chronic wounds and reduce scars.*.

supplement facts
CLINICAL RESEARCH⌄CLINICAL RESEARCH⌄

Vitamin A is a fat-soluble vitamin that is required for the formation of skin cells. A deficiency of this vitamin slows the wound healing process.

Vitamin C is a water-soluble vitamin that is required for the synthesis of collagen. Vitamin C can help speed up the healing process.

Vitamin D3 helps fight off bacteria that may cause wound infections. Vitamin D3 also helps begin the repair process.

Vitamin E is a fat-soluble vitamin that possesses anti-inflammatory properties. A low amount of vitamin E can lead to slowed wound healing time and can increase the risk of scarring.

Vitamin B12 is a water-soluble B vitamin that is used to help build red blood cells which start and sustain the healing process. A deficiency in this vitamin can delay wound healing time.

Biotin is a B vitamin that helps produce more collagen and delivers more oxygen and nutrients to the site of injury.

Iron acts as a cofactor in the production of collagen. Iron also allows more oxygen to be delivered to the injury site.

Selenium is a trace element with antioxidant properties that helps minimize tissue damage.

L-Arginine is an amino acid that is used in the synthesis of collagen. Arginine also increases the blood flow to allow for faster healing times.


Bromelain is an enzyme found in pineapple that reduces swelling.

L-Glutamine is an amino acid that helps prevent infections in wounds. Glutamine is also an energy source for wound healing cells.

Copper is an essential trace element that stimulates collagen development and increases the thickness of the skin. Copper also speeds up the production of cells.

Zinc is an essential trace element that promotes immune function and improves skin healing. Zinc aids in the replication of cells which is responsible for creating new tissue.

Chlorella is a type of algae that has recently been promoted as a superfood. Chlorella stimulates cells to reproduce at a faster rate to stimulate healing.

Calendula is a plant that possesses anti-inflammatory properties. Calendula also increases blood flow and oxygen to wounds to help grow new tissue more rapidly.

Grape Seed Extract helps vitamin C enter cells and may help build new blood vessels. Grape Seed Extract also helps prevent scarring in tissues.

Turmeric has natural anti-inflammatory properties and helps fight bacteria. Turmeric also helps the wound heal and prevents scarring.

FOR HEALTHCARE PROFESSIONALS

medical cross

Independent ingredient review

Chlorella

"In Vitro Effectiveness of Microspheres Based on Silk Sericin and Chlorella vulgaris or Arthrospira platensis for Wound Healing Applications Bari E, et al. In Vitro Effectiveness of Microspheres Based on Silk Sericin and Chlorella vulgaris or Arthrospira platensis for Wound Healing Applications. Materials. 2017;10(9):983. doi:10.3390/ma10090983. Some natural compounds have recently been widely employed in wound healing applications due to their biological properties. One such compound is sericin, which is produced by Bombix mori, while active polyphenols, polysaccharides and proteins are synthetized by Chlorella vulgaris and Arthrospira platensis microalgae. Our hypothesis was that sericin, as an optimal bioactive polymeric carrier for microencapsulation process, could also improve the regenerative effect of the microalgae. A solvent-free extraction method and spray drying technique were combined to obtain five formulations, based on algal extracts (C. vulgaris and A. platensis, Chl and Art, respectively) or silk sericin (Ser) or their mixtures (Chl-Ser and Art-Ser). The spray drying was a suitable method to produce microspheres with similar dimensions, characterized by collapsed morphology with a rough surface. Art and Art-Ser showed higher antioxidant properties than other formulations. All microspheres resulted in cytocompatibility on fibroblasts until 1.25 mg/mL and promoted cell migration and the complete wound closure; this positive effect was further highlighted after treatment with Art and Art-Ser. To our surprize the combination of sericin to Art did not improve the microalgae extract efficacy, at least in our experimental conditions."


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Calendula

"Phytochemical Constituents and Pharmacological Activities of Calendula officinalis Linn (Asteraceae): A Review Muley BP, Khadabadi SS, Banarase NB. Phytochemical Constituents and Pharmacological Activities of Calendula officinalis Linn (Asteraceae): A Review. Tropical Journal of Pharmaceutical Researc. Calendula officinalis Linn. (Asteraceae) is used medicinally in Europe, China and India amongst several places in the world. It is also known as “African marigold” and has been a subject of several chemical and pharmacological studies. It is used in traditional medicine, especially for wound healing, jaundice, blood purification, and as an antispasmodic. Chemical studies have underlined the presence of various classes of compounds, the main being triterpenoids, flavonoids, coumarines, quinones, volatile oil, carotenoids and amino acids. The extract of this plant as well as pure compounds isolated from it, have been demonstrated to possess multiple pharmacological activities such as anti-HIV, cytotoxic, antiinflammatory, hepatoprotective, spasmolytic and spasmogenic, amongst others. In this review, we have explored the phytochemistry and pharmacological activities of C. officinalis in order to collate existing information on this plant as well as highlight its multi-activity properties as a medicinal agent. This is as a result of the worldwide cultivation of the plant and increasing published reports on it."


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"Antimicrobial activity of Calendula officinalis, Camellia sinensis and chlorhexidine against the adherence of microorganisms to sutures after extraction of unerupted third molars FARIA RL, et al. Antimicrobial activity of Calendula officinalis, Camellia sinensis and chlorhexidine against the adherence of microorganisms to sutures after extraction of unerupted third molars. Journal of Applied Oral Science. 2011;19(5):476-482. doi:10.1590/S1678-77572011000500007. Objective:The objective of this study was to compare the antimicrobial effect of mouthwashes containing Calendula officinalis L., Camellia sinensis (L.) Kuntze and 0.12% chlorhexidine digluconate on the adherence of microorganisms to suture materials after extraction of unerupted third molars. Material and Methods: Eighteen patients with unerupted maxillary third molars indicated for extraction were selected (n=6 per mouthwash). First, the patients were subjected to extraction of the left tooth and instructed not to use any type of antiseptic solution at the site of surgery (control group). After 15 days, the right tooth was extracted and the patients were instructed to use the Calendula officinalis, Camellia sinensis or chlorhexidine mouthwash during 1 week (experimental group). For each surgery, the sutures were removed on postoperative day 7 and placed in sterile phosphate-buffered saline. Next, serial dilutions were prepared and seeded onto different culture media for the growth of the following microorganisms: blood agar for total microorganism growth; Mitis Salivarius bacitracin sucrose agar for mutans group streptococci; mannitol agar for Staphylococcus spp.; MacConkey agar for enterobacteria and Pseudomonas spp., and Sabouraud dextrose agar containing chloramphenicol for Candida spp. The plates were incubated during 24-48 h at 37ºC for microorganism count (CFU/mL). Results: The three mouthwashes tested reduced the number of microorganisms adhered to the sutures compared to the control group. However, significant differences between the control and experimental groups were only observed for the mouthwash containing 0.12% chlorhexidine digluconate. Conclusions: Calendula officinalis L. and Camellia sinensis (L.) Kuntze presented antimicrobial activity against the adherence of microorganisms to sutures but were not as efficient as chlorhexidine digluconate."


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"Wound Healing and Anti-Inflammatory Effect in Animal Models of Calendula officinalis L. Growing in Brazil Parente L, et al. “Wound Healing and Anti-Inflammatory Effect in Animal Models of Calendula officinalis L. Growing in Brazil,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 375671, 7 pages, 2012. doi:10.1155/2012/375671 Calendula officinalis is an annual herb from Mediterranean origin which is popularly used in wound healing and as an anti-inflammatory agent. In this study, the ethanolic extract, the dichloromethane, and hexanic fractions of the flowers from plants growing in Brazil were produced. The angiogenic activity of the extract and fractions was evaluated through the chorioallantoic membrane and cutaneous wounds in rat models. The healing activity of the extract was evaluated by the same cutaneous wounds model through macroscopic, morphometric, histopathologic, and immunohistochemical analysis. The antibacterial activity of the extract and fractions was also evaluated. This experimental study revealed that C. officinalis presented anti-inflammatory and antibacterial activities as well as angiogenic and fibroplastic properties acting in a positive way on the inflammatory and proliferative phases of the healing process."


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Grape seed extract

"The topical effect of grape seed extract 2% cream on surgery wound healing Hemmati AA, et al. The topical effect of grape seed extract 2% cream on surgery wound healing. Glob J Health Sci. 2014 Oct 29;7(3):52-8. doi: 10.5539/gjhs.v7n3p52. PubMed PMID: 25948437; PubMed Central PMCID: PMC4802053. BACKGROUND: Reducing the wound healing time is crucial in wound as it lowers the chance of infection and decreases complications and cost. Grape seed extract has the ability to release endothelial growth factor and its topical application results in contraction and closure of the skin wound. Furthermore, it possesses antioxidant and antibacterial properties. In several studies it has been proved effective in animals. Therefore, due to low side effects and recognition of herbal medicine, we decided to evaluate the effect of grape seed extract 2% herbal cream on human skin lesions. MATERIALS: This study is a double blind clinical trial conducted on two groups of treatment and placebo. Surgery was performed on skin lesions such as skin tags and moles which were found on the neck, trunk and limbs (except for face). After enrollment and obtaining informed consent from participants, they were randomized into two groups of treatment and placebo. Excision of the lesions was done by surgical scissors. The lesions got restored by secondary intention method. After the first day of treatment, the patients were visited on the 3rd, 7th, 10th, 14th, and 21st day. Grape seed extract cream 2% was produced and coded by the Faculty of Pharmacy, Ahvaz University of Medical Sciences. In order to compare the two groups, T-test was used. For time assessing, analysis of variance with repeated measures was employed. RESULTS: The results showed complete repair of wounds averagely on day 8 for the treatment group and on day 14 for the placebo group, which was clearly significant in terms of statistical difference (p=0.00). CONCLUSION: Proanthocyanidins in grape seed extract trigger the release of vascular endothelial growth factor and its topical application causes wound contraction and closure. Curing skin lesions with grape seed extract caused proliferation areas with protected boundaries in epithelium, increased cell density and increased deposition of connective tissue at the wound site which in general improves cellular structure in wound. In addition, its anti-inflammatory and anti-microbial properties are effective in wound healing."


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"Grape Seed Extract Help Speed Up Wound Recovery, Study Suggests Ohio State University. ""Grape Seed Extract Help Speed Up Wound Recovery, Study Suggests."" ScienceDaily. ScienceDaily, 4 December 2002. Grape-seed extract may help skin wounds heal faster and with less scarring, a new study suggests. The extract seemed to aid wound healing in two ways: It helped the body make more of a compound used to regenerate damaged blood vessels, and it also increased the amount of free radicals in the wound site. Free radicals help clear potentially pathogenic bacteria from a wound."


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Turmeric (Curcuma Longa)

"Wound Healing Effects of Curcumin: A Short Review Tejada S, et al. Wound Healing Effects of Curcumin: A Short Review. Curr Pharm Biotechnol. 2016;17(11):1002-7. Review. PubMed PMID: 27640646. Wound healing is a complex process that consists of several phases that range from coagulation, inflammation, accumulation of radical substances, to proliferation, formation of fibrous tissues and collagen, contraction of wound with formation of granulation tissue and scar. Since antiquity, vegetable substances have been used as phytotherapeutic agents for wound healing, and more recently natural substances of vegetable origin have been studied with the attempt to show their beneficial effect on wound treatment. Curcumin, the most active component of rhizome of Curcuma longa L. (common name: turmeric), has been studied for many years due to its bio-functional properties, especially antioxidant, radical scavenger, antimicrobial and anti-inflammatory activities, which play a crucial role in the wound healing process. Moreover, curcumin stimulated the production of the growth factors involved in the wound healing process, and so curcumin also accelerated the management of wound restoration. The aim of the present review is collecting and evaluating the literature data regarding curcumin properties potentially relevant for wound healing. Moreover, the investigations on the wound healing effects of curcumin are reported. In order to produce a more complete picture, the chemistry and sources of curcumin are also discussed."


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"Protective Effects of Curcumin against Oxidative Damage on Skin Cells In Vitro: Its Implication for Wound Healing Phan T, See P, Lee S, Chan S. Protective Effects of Curcumin against Oxidative Damage on Skin Cells In Vitro: Its Implication for Wound Healing. Journal of Trauma-Injury Infection & Critical Care: November 2001 - Volume 51 - Issue 5 - pp 927-31. Background : Curcumin, isolated from turmeric, has been known to possess many pharmacologic properties. It has been proven to exhibit remarkable anticarcinogenic, anti-inflammatory, and antioxidant properties. Turmeric curcumin may be a good potential agent for wound healing. Methods : To further understand its therapeutic mechanisms on wound healing, the antioxidant effects of curcumin on hydrogen peroxide (H2O2) and hypoxanthine-xanthine oxidase induced damage to cultured human keratinocytes and fibroblasts were investigated. Cell viability was assessed by colorimetric assay and quantification of lactate dehydrogenase release. Results : Exposure of human keratinocytes to curcumin at 10 μg/mL showed significant protective effect against hydrogen peroxide. Interestingly, exposure of human dermal fibroblasts to curcumin at 2.5 μg/mL showed significant protective effects against hydrogen peroxide. No protective effects of curcumin on either fibroblasts or keratinocytes against hypoxanthine-xanthine oxidase induced damage were found in our present studies. Conclusion : The findings indicate that curcumin indeed possessed powerful inhibition against hydrogen peroxide damage in human keratinocytes and fibroblasts."


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"Role of curcumin, a naturally occurring phenolic compound of turmeric in accelerating the repair of excision wound, in mice whole-body exposed to various doses of γ-radiation Jagetia G, et al. Role of curcumin, a naturally occurring phenolic compound of turmeric in accelerating the repair of excision wound, in mice whole-body exposed to various doses of γ-radiation. Journal of Surgical Research , Volume 120 , Issue 1 , 127 - 138 The healing of irradiated wounds has always been a central consideration in medical practice because radiation disrupts normal response to injury, leading to a protracted recovery period. The quest for clinically effective wound healing agents is important in the medical management of irradiated wounds. Therefore, the present study was conceptualized to investigate the effect of curcumin (natural yellow, diferuloylmethane), a major yellow pigment and an active component of turmeric on wound healing in mice exposed to whole-body γ-radiation. A full-thickness wound was created on the dorsum of mice whole-body irradiated to 2, 4, 6, or 8 Gy. The progression of wound contraction was monitored periodically by capturing video images of the wound. The collagen, hexosamine, DNA, nitric oxide, and histological profiles were evaluated at various postirradiation days in mice treated and not treated with curcumin before exposure to 0 or 6 Gy. The whole-body exposure resulted in a dose-dependent delay in wound contraction and prolongation of wound healing time. Irradiation caused a significant reduction in collagen, hexosamine, DNA, and nitric oxide synthesis. Pretreatment with curcumin significantly enhanced the rate of wound contraction, decreased mean wound healing time, increased synthesis of collagen, hexosamine, DNA, and nitric oxide and improved fibroblast and vascular densities. This study demonstrates that curcumin pretreatment has a conducive effect on the irradiated wound and could be a substantial therapeutic strategy in initiating and supporting the cascade of tissue repair processes in irradiated wounds."


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"Curcumin-encapsulated nanoparticles as innovative antimicrobial and wound healing agent Krausz AE, et al. Curcumin-encapsulated nanoparticles as innovative antimicrobial and wound healing agent. Nanomedicine : nanotechnology, biology, and medicine. 2015;11(1):195-206. doi:10.1016/j.nano.2014.09.004. Burn wounds are often complicated by bacterial infection, contributing to morbidity and mortality. Agents commonly used to treat burn wound infection are limited by toxicity, incomplete microbial coverage, inadequate penetration, and rising resistance. Curcumin is a naturally derived substance with innate antimicrobial and wound healing properties. Acting by multiple mechanisms, curcumin is less likely than current antibiotics to select for resistant bacteria. Curcumin's poor aqueous solubility and rapid degradation profile hinder usage; nanoparticle encapsulation overcomes this pitfall and enables extended topical delivery of curcumin. In this study, we synthesized and characterized curcumin nanoparticles (curc-np), which inhibited in vitro growth of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa in dose-dependent fashion, and inhibited MRSA growth and enhanced wound healing in an in vivo murine wound model. Curc-np may represent a novel topical antimicrobial and wound healing adjuvant for infected burn wounds and other cutaneous injuries."


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Vitamin A

"Vitamin A-soaked gelfoam sponges and wound healing in steroid-treated animals Haws M, Brown RE, Suchy H, Roth A. Vitamin A-soaked gelfoam sponges and wound healing in steroid-treated animals. Ann Plast Surg. 1994 Apr;32(4):418-22. PubMed PMID: 8210163. Previous work has shown improved wound healing after the administration of systemic vitamin A in patients on chronic steroids. In contrast there have been mixed reports on the effect of topical vitamin A on wound healing in steroid-treated patients. Previous laboratory work has suggested that the topical application of vitamin A may be beneficial to wound healing in a sutured wound in a steroid-treated rat. Due to some inconsistencies in previous studies and steroid animal models, we sought to develop a better wound-healing model in a steroid-treated rat and to assess the effect of topical vitamin A as part of the wound closure. With preliminary studies, we developed a consistent and reliable wound-healing model in a steroid-treated rat using dexamethasone in contrast to cortisone acetate, which had been used in previous studies. Next, rats were randomized into 8 groups, some of which received steroids. Wounds were treated with saline or vitamin A topically or via a soaked gelfoam sponge. Rats were wounded 1 week after the commencement of steroid administration. Wounds were repaired and allowed to heal for 2 weeks. Strips of the wounds were then harvested and tested for tensile strength and breaking strength using a tensiometer. Wound edges were then fixed and wound surface area was measured using digital planimetry. Steroid treatment resulted in consistent weight loss and failure to gain weight as well as decreased breaking strength. Tensile strength was not decreased. Vitamin A applied for 10 minutes before wound closure and a gelfoam sponge alone placed before wound closure both resulted in an increased breaking strength and tensile strength.(ABSTRACT TRUNCATED AT 250 WORDS)."


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"Impaired wound healing in streptozotocin diabetes Seifter E, et al. Impaired wound healing in streptozotocin diabetes. Prevention by supplemental vitamin A. Ann Surg. 1981 Jul;194(1):42-50. PubMed PMID: 6454399; PubMed Central PMCID: PMC1345193. Goodson and Hunt showed that wound healing is impaired in streptozotocin (Sz) diabetic rats; we speculated that this impairment results from defective early inflammatory responses to wounding. Because we had shown that supplemental vitamin A stimulates the early inflammatory response to wounding in nondiabetic rats, we studied the effect of supplemental vitamin A on wound healing in rats with Sz-induced diabetes. Male Sprague-Dawley rats were fed a commercial rat chow containing twice the amount of vitamin A recommended by the NRC for healthy rats. The rats ate and drank (tap water) ad libitum. Two-thirds of the rats were injected (intravenously) with Sz 60 mg/kg body weight. All of these rats became diabetic (hyperglycemia greater than 350 mg/dl, hyperphagic, polydipsic, polyuric, glycosuric greater than 2%). Seven days later, half of the Sz-injected rats were continued on the chow (Group 2) while the other half (Group 3) were switched to the chow supplemented with 150,000 units of vitamin A/kg chow. The next day, all were wounded (7 cm skin incisions and s.c. polyvinyl alcohol sponge implants). Similarly wounded saline injected nondiabetic rats ingesting the unsupplemented chow served as controls (Group 1). The wounds of Group 2 rats healed poorly compared to Group 1 (breaking strength of skin incisions, 308 +/- 19 g vs 584 +/- 23 g, p less than 0.001; hydroxyproline of the sponge reparative tissue, 0.87 mg vs 2.40 mg/100 mg sponge p less than 0.001). Supplemental vitamin A(Group 3) did not affect the hyperglycemia, hyperphagia, polydipsia or glycosuria, but increased the breaking strengths of the incisions of the diabetic rats (468 +/- 40 g, p less than 0.001), and the sponge hydroxyproline (2.38 mg/100 mg sponge, p less than 0.001). In another experiment, in which the wounding and start of supplemental vitamin A were delayed until 28 days after streptozotocin administration (50 mg/kg body weight), similar results were obtained. Streptozotocin diabetes also caused a decrease in the cross-linking of reparative collagen as judged by the ratio of breaking strengths of skin incisions before and after formalin fixation. Supplemental vitamin A did not influence this defect. Sz also caused peripheral lymphocytopenia, adrenal hypertrophy and thymic involution which responded to the supplemental vitamin A. Based upon experimental data and theoretical considerations we conclude Sz diabetes causes two defects in wound healing: a) quantitatively (reduction in reparative collagen accumulation) and b) qualitative reduction in the degree of cross-linking of reparative woundcollagen. The action of supplemental vitamin A in correcting the impaired wound healing, adrenal enlargement, thymic involution and lymphocytopenia of Sz-diabetic rats is independent of an effect on their disturbed carbohydrate metabolism."


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"Reduction of adhesions and antrostomy stenosis with topical vitamin A after endoscopic sinus surgery Fang KM, Wang CT, Chen YW, Huang TW. Reduction of adhesions and antrostomy stenosis with topical vitamin A after endoscopic sinus surgery. Am J Rhinol Allergy. 2015 Nov-Dec;29(6):430-4. doi: 10.2500/ajra.2015.29.4235. PubMed PMID: 26637582. BACKGROUND: Prevention of adhesion formation and restoration of mucociliary mucosa are major determinants of the success of endoscopic sinus surgery (ESS). Vitamin A (VA) can promote mucociliary differentiation of respiratory epithelium. However, whether topical VA can promote sinonasal wound healing or reduce adhesion formation after ESS in humans remains unexplored. OBJECTIVE: To investigate the effect of topical VA on sinonasal wound healing and adhesion formation after ESS. METHODS: This is a within-subject control study. Patients with chronic rhinosinusitis were included. Each patient underwent ESS, and topical VA was applied over the sinonasal wound. Postoperative outcomes were assessed by using the Lund-Kennedy score, and the antrostomy size was measured. In vitro wound healing assay of fibroblasts with or without VA was evaluated. Restoration of ciliated epithelium was examined by using scanning electron microscopy. RESULTS: Thirty patients were enrolled. The mean (standard deviation {SD}) scores for scarring/adhesion in the VA-treated side at 3 and 12 months after surgery (0.20 ± 0.40 and 0.23 ± 0.42, respectively) were significantly lower than those in the controls (0.47 ± 0.50 and 0.53 ± 0.62, respectively). The mean (SD) antrostomy size in the VA treated side at 1, 3, and 12 months after surgery (0.85 ± 0.30 cm(2), 0.7 ± 0.30 cm(2), and 0.70 ± 0.27 cm(2), respectively) were significantly larger than those in the controls (0.79 ± 0.26 cm(2), 0.60 ± 0.25 cm(2), and 0.57 ± 0.24 cm(2), respectively). Wound healing assay revealed that VA significantly inhibited the proliferation and migration of fibroblasts. Scanning electron microscopy showed mature ciliated cells in the VA-treated side. CONCLUSION: Topical VA is a promising agent for sinonasal wound healing after ESS because it can promote mucociliary reepithelization, reduce adhesion, and prevent antrostomy stenosis."


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Vitamin C

"Vitamin C and human wound healing Ringsdorf WM Jr, Cheraskin E. Vitamin C and human wound healing. Oral Surg Oral Med Oral Pathol. 1982 Mar;53(3):231-6. Review. PubMed PMID: 7038579. Clinical studies provide evidence that wound healing in subjects judged not deficient in vitamin C can be significantly accelerated with supplements of this nutrient above the recommended daily allowance (RDA). The authors administered daily dosages of 500 to 3,000 mg., which is roughly 8 to 50 times the RDA of 60 mg., to subjects recovering from surgery, other injuries, decubital ulcers, and leg ulcers induced by hemolytic anemia. Genetic impairment of collagen synthesis has also been observed to be responsive to ascorbic acid supplementation in an 8-year-old boy with Type VI Ehlers-Danlos syndrome. Four grams of ascorbic acid daily produced a significant improvement in the quality of newly synthesized collagen but did not alter that formed prior to the supplementation of C. The combined evidence in this review provides a substantial base for further research, both clinical and experimental trials, concerning the interrelationships between vitamin C and the body's healing potential."


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"The Roles of Vitamin C in Skin Health Pullar JM, Carr AC, Vissers MCM. The Roles of Vitamin C in Skin Health. Nutrients. 2017 Aug 12;9(8). pii: E866. doi: 10.3390/nu9080866. Review. PubMed PMID: 28805671; PubMed Central PMCID: PMC5579659. The primary function of the skin is to act as a barrier against insults from the environment, and its unique structure reflects this. The skin is composed of two layers: the epidermal outer layer is highly cellular and provides the barrier function, and the inner dermal layer ensures strength and elasticity and gives nutritional support to the epidermis. Normal skin contains high concentrations of vitamin C, which supports important and well-known functions, stimulating collagen synthesis and assisting in antioxidant protection against UV-induced photodamage. This knowledge is often used as a rationale for the addition of vitamin C to topical applications, but the efficacy of such treatment, as opposed to optimising dietary vitamin C intake, is poorly understood. This review discusses the potential roles for vitamin C in skin health and summarises the in vitro and in vivo research to date. We compare the efficacy of nutritional intake of vitamin C versus topical application, identify the areas where lack of evidence limits our understanding of the potential benefits of vitamin C on skin health, and suggest which skin properties are most likely to benefit from improved nutritional vitamin C intake."


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"Vitamin C: a wound healing perspective Moores J. Vitamin C: a wound healing perspective. Br J Community Nurs. 2013 Dec;Suppl:S6, S8-11. Review. PubMed PMID: 24796079. Vitamin C, also known as ascorbic acid (AA), is involved in all phases of wound healing. In the inflammatory phase it is required for neutrophil apoptosis and clearance. During the proliferative phase, AA contributes towards synthesis, maturation, secretion and degradation of collagen. Deficiencies affect the maturation phase by altering collagen production and scar formation. The body strives to maintain homeostasis of AA, thereby ensuring availability for collagen synthesis. After wounding, plasma and tissue levels of AA diminish and, as a consequence, supplements may be useful for healing, although levels beyond saturation are excreted Clinicians need to be aware of both the nutritional status of patients with either acute or chronic wounds and the possibility of any AA deficiency which may hinder healing."


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"Ascorbic acid for the healing of skin wounds in rats Lima CC, et al. Ascorbic acid for the healing of skin wounds in rats. Braz J Biol. 2009 Nov;69(4):1195-201. PubMed PMID: 19967193. BACKGROUND: Healing is a complex process that involves cellular and biochemical events. Several medicines have been used in order to shorten healing time and avoid aesthetic damage. OBJECTIVE: to verify the topical effect of ascorbic acid for the healing of rats' skin wounds through the number of macrophages, new vessels and fibroblast verifications in the experimental period; and analyse the thickness and the collagen fibre organization in the injured tissue. METHODS: Male Rattus norvegicus weighing 270 +/- 30 g were used. After thionembutal anesthesia, 15 mm transversal incisions were made in the animals' cervical backs. They were divided into two groups: Control Group (CG, n = 12) - skin wound cleaned with water and soap daily; Treated Group (TG, n = 12) - skin wound cleaned daily and treated with ascorbic acid cream (10%). Samples of skin were collected on the 3rd, 7th and 14th days. The sections were stained with hematoxylin-eosin and picrosirius red for morphologic analysis. The images were obtained and analysed by a Digital Analyser System. RESULTS: The ascorbic acid acted on every stage of the healing process. It reduced the number of macrophages, increased the proliferation of fibroblasts and new vessels, and stimulated the synthesis of thicker and more organized collagen fibres in the wounds when compared to CG. CONCLUSION: Ascorbic acid was shown to have anti-inflammatory and healing effects, guaranteeing a suiTable environment and conditions for faster skin repair."


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"The effect of vitamin A and vitamin C on postoperative adhesion formation: A rat model study Keleidari B, et al. The effect of vitamin A and vitamin C on postoperative adhesion formation: A rat model study. J Res Med Sci. 2014 Jan;19(1):28-32. PubMed PMID: 24672562; PubMed Central PMCID: PMC3963320. BACKGROUND: The aim of this study is to investigate the effect of vitamin A and C, as the agents that improve wound healing, on the adhesion formation process. MATERIALS AND METHODS: Sixty male Wistar rats were used. They underwent midline laparotomy, for repair of a peritoneal injury, and were then assigned to four groups. Group 1 (Vitamin A) received 2000 units/kg intramuscular injection of vitamin A daily, post surgery, for two weeks; Group 2 (Vitamin C) received 100 mg/kg oral vitamin C daily, after laparotomy, for two weeks; Group 3 (vitamins A and C) received 2000 units/kg intramuscular injection of vitamin A and 100 mg/kg oral vitamin C daily, after laparotomy, for two weeks, and Group four (Sham) rats did not receive any drugs. The adhesion, inflammation, fibrosis scores, and wound integrity were evaluated after two weeks. RESULTS: Rats in the vitamin C group had the lowest mean adhesion formation score (1 ± 0.27) and the values of p were < 0.0001 for the vitamin A group and vitamin A and C groups and 0.003 for the sham group. Vitamin C also had the lowest fibrosis score (0.50 ± 0.17) among the study groups and the values of p were < 0.0001 for the vitamin A group and vitamin A and C groups and 0.002 for the sham group. The mean inflammation score did not differ significantly among the study groups. The wound disruption strength was the highest in the vitamin C group and the difference was statistically significant in the sham group (1188.69 ± 281.92 vs. 893.04 ± 187.46, p : 0.003). CONCLUSION: Administration of oral vitamin C reduces adhesion formation and improves wound healing."


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Vitamin D3 (as Cholecalceferol)

"Vitamin D and skin repair: a prospective, double-blind and placebo controlled study in the healing of leg ulcers Burkiewicz CJ, et al. Vitamin D and skin repair: a prospective, double-blind and placebo controlled study in the healing of leg ulcers. Rev Col Bras Cir. 2012 Sep-Oct;39(5):401-7. English, Portuguese. PubMed PMID: 23174792. OBJECTIVE: To analyze the relation between vitamin D insufficiency and wound healing in patients with venous ulcers; to correlate vitamin D insufficiency with characteristics of the ulcer (size and pain) and to evaluate if reposition of vitamin D in these subjects expedites ulcer healing. METHODS: We selected 26 patients with leg ulcers, and 26 control patients without ulcers, matched for gender, age, systemic arterial hypertension and tobacco use. The venous ulcer group was divided in two subgroups: one that received placebo (nine patients) and other receiving vitamin D, 50.000 IU per week over two months (13 patients). Blood was collected for 25 OH vitamin D dosage before and after the medication. In the ulcer group, we obtained data concerning demographics, leg ulcer size, as well as pain severity, measured by an analogical visual scale. Data was grouped in contingency and frequency tables, the tests of Fisher and chi-squared being used for nominal variables and Mann-Whitney for numerical variables. The adopted significance was of 5%. RESULTS: We found vitamin D insufficiency in the great majority of the patients. The median level in the ulcer group was 17.05 ng/dl and 22.75 ng/dl in the group without ulcer (p=0,0182) No relation was found between the ulcer size without treatment and the level of vitamin D. After treatment, the average size of the ulcer changed from 25 cm² to 18 cm² in the patients that took vitamin D and from 27 cm² to 24,5 cm² in the placebo group (p=0,7051 and p=0,7877, respectively). Considering the variability of the size of the ulcer in the treatment group versus placebo group, the average size was equal to -0,75 cm² in the first group and +4cm² in the second (p=0,0676) CONCLUSION: Patients with leg ulcers have more vitamin D deficiency. No difference in the ulcer characteristics was noted between those with and without vitamin D deficiency. There was a trend toward a better healing in those with vitamin D reposition."


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"Effect of vitamin D receptor knockout on cornea epithelium wound healing and tight junctions Elizondo RA, Yin Z, Lu X, Watsky MA. Effect of vitamin D receptor knockout on cornea epithelium wound healing and tight junctions. Invest Ophthalmol Vis Sci. 2014 Jul 24;55(8):5245-51. doi: 10.1167/iovs.13-13553. PubMed PMID: 25061117; PubMed Central PMCID: PMC4142771. PURPOSE: Our laboratory previously determined that vitamin D3, the vitamin D receptor (VDR), and 1α hydroxylase are present and active in the eye. In this study, we examined the effects of VDR knockout on wound healing, the tight junction-associated proteins occludin and ZO-1, and tight junction numbers in mouse corneas. METHODS: Epithelial wounds (2-mm) were made with an agar brush on 4-week-old and 10-week-old wild-type, heterozygous, and VDR knockout mouse corneas. Mice were on a normal or high lactose, Ca(2+), and PO₄(-) diet. Wound-healing area was measured over time. Real-time PCR was used to quantify occludin and ZO-1 message expression. Western blot was used for protein expression. Transmission electron microscopy was used to examine corneal epithelium and endothelium tight junctions. Immunofluorescence was used to examine epithelial ZO-1 distribution. RESULTS: Results showed a decreased healing rate in 10-week-old VDR knockout mice compared with wild-types. Vitamin D receptor knockout mice on the special diet had no difference in healing rate compared with wild-types. Real-time PCR showed decreased expression of occludin and ZO-1 in 10-week-old VDR knockout mice compared with wild-types. Western blot of 10-week-old knockout mouse corneas showed decreased occludin expression compared with wild-types. Transmission electron microscopy showed a significant difference in tight junction numbers in VDR knockouts versus wild-types. Immunofluorescence showed a change in ZO-1 distribution among genotypes. CONCLUSIONS: Vitamin D receptor knockout affects mouse corneal epithelium wound healing and tight junction integrity."


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"Hypertrophic Scars: Are Vitamins and Inflammatory Biomarkers Related with the Pathophysiology of Wound Healing? Correia-Sá I, Serrão P, Marques M, Vieira-Coelho MA. Hypertrophic Scars: Are Vitamins and Inflammatory Biomarkers Related with the Pathophysiology of Wound Healing? Obes Surg. 2017 Jun 1. doi: 10.1007/s11695-017-2740-4. [Epub ahead of print] PubMed PMID: 28569361. BACKGROUND: Hypertrophic scars are a consequence of wound healing. OBJECTIVE: The objective of the present study is to evaluate vitamin D and inflammatory biomarker plasma levels during wound healing. METHODS: A prospective study was performed in patients (n = 63) submitted to body contouring surgery. Blood samples were collected before (t 0) and 5 days after surgery (t 5). Blood cell count, protein inflammatory biomarkers, and circulating plasma levels of 25(OH)D, vitamin A and vitamin E were quantified. Six months after surgery, scars were evaluated and classified as normal or hypertrophic. RESULTS: At the end of the study, 73% of the patients developed a normal scar (control group, n = 46) and 27% of the patients presented hypertrophic scars (HT group, n = 17). The patients in the HT group presented higher eosinophil (0.145 × 109 /L vs. 0.104 × 109 /L, p = 0.028) and basophil count (0.031 × 109 /L vs. 0.22 × 109 /L, p = 0.049) and C-reactive protein levels (6.12 mg/L vs. 2.30 mg/L, p = 0.015) in t 0 than the patients in the control group. At t 5, the patients in the HT group showed a decrease in neutrophil (3.144 × 109/L vs. 4.03 × 109/L, p = 0.031) and an increase in basophil (0.024 × 109/L vs. 0.015 × 109/L, p = 0.005) and lymphocyte count (1.836 × 109 /L vs. 1.557 × 109/L; p = 0.028). Before surgery, vitamin D plasma levels were found to be decreased by almost 50% (23.52 ng/mL vs. 15.46 ng/mL, p = 0.031) in the patients who developed hypertrophic scars. Thirty-one percent of the patients submitted to bariatric surgery had more hypertrophic scars, versus 24% of the patients with no previous bariatric surgery. CONCLUSION: There is a different systemic inflammatory profile response in the patients during the formation of hypertrophic scars. Vitamin D plasma levels are marked reduced in these patients. Considering the powerful anti-inflammatory effect of vitamin D, these findings could be related."


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"Vitamin D and calcium regulation of epidermal wound healing Oda Y, Tu CL, Menendez A, Nguyen T, Bikle DD. Vitamin D and calcium regulation of epidermal wound healing. J Steroid Biochem Mol Biol. 2016 Nov;164:379-385. doi: 10.1016/j.jsbmb.2015.08.011. Epub 2015 Aug 14. Review. PubMed PMID: 26282157; PubMed Central PMCID: PMC4753150. Wound healing is essential for survival. This is a multistep process involving a number of different cell types. In the skin wounding triggers an acute inflammatory response, with the innate immune system contributing both to protection against invasive organisms and to triggering the invasion of inflammatory cells into the wounded area. These cells release a variety of cytokines and growth factors that stimulate the proliferation and migration of dermal and epidermal cells to close the wound. In particular, wounding activates stem cells in the interfollicular epidermis (IFE) and hair follicles (HF) to proliferate and send their progeny to re-epithelialize the wound. β-catenin and calcium signaling are important for this activation process. Mice lacking the VDR when placed on a low calcium diet have delayed wound healing. This is associated with reduced β-catenin transcriptional activity and proliferation in the cells at the leading edge of wound closure. These data suggest that vitamin D and calcium signaling are necessary components of the epidermal response to wounding, likely by regulating stem cell activation through increased β-catenin transcriptional activity."


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Bromelain

"Bromelain: a natural proteolytic for intra-abdominal adhesion prevention Sahbaz A, et al. Bromelain: a natural proteolytic for intra-abdominal adhesion prevention. Int J Surg. 2015 Feb;14:7-11. doi: 10.1016/j.ijsu.2014.12.024. Epub 2015 Jan 6. PubMed PMID: 25573606. INTRODUCTION: Peritoneal adhesions are pathological fibrous connections between peritoneal surfaces resulting from incomplete peritoneal repair. Adhesions cause various health problems ranging from pelvic pain and bowel obstruction to infertility. To date, no effective agent exists for intra-abdominal adhesion prevention. Bromelain is the crude extract of the pineapple and it has fibrinolytic, antithrombotic, and anti-inflammatory properties. Bromelain has been shown to be effective for removing necrotic tissues and has been found to be effective for treating various wounds, inflammatory conditions, and thrombotic pathologies. In the present study, we evaluated bromelain as a novel agent for preventing intra-abdominal adhesions. METHODS: Group 1 (control group): Adhesions were produced by cecal abrasion method, and no treatment was applied. Group 2 (i.p. bromelain-treated group): After adhesion formation, 10 mg/kg/BW of bromelain dissolved in 1 mL saline solution was applied intraperitoneally for 10 days. Group 3 (i.p. saline-treated group): After adhesion formation, 1 mL saline solution was applied intraperitoneally for 10 days. On postoperative day 10, all animals were sacrificed. RESULTS: All 30 rats survived surgery. Throughout the follow-up period, no complications were observed. Statistically significant differences were found between the groups with regards to macroscopic adhesion scores, inflammation, fibrosis and neo-vascularization (p < 0.001, < 0.001, p = 0.001, p = 0.002, respectively). Macroscopic and histopathologic (inflammation, fibrosis, neo-vascularization) adhesion scores were lowest in the bromelain-treated group. CONCLUSION: Bromelain, acting through its barrier, anti-inflammatory, antioxidant, and proteolytic effects and without increasing bleeding tendency or having any adverse effects on wound healing, may be a suitable agent for intra-abdominal adhesion prevention."


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"Bromelain down-regulates myofibroblast differentiation in an in vitro wound healing assay Aichele K, Bubel M, Deubel G, Pohlemann T, Oberringer M. Bromelain down-regulates myofibroblast differentiation in an in vitro wound healing assay. Naunyn Schmiedebergs Arch Pharmacol. 2013 Oct;386(10):853-63. doi: 10.1007/s00210-013-0890-z. Epub 2013 Jun 15. PubMed PMID: 23771413. Bromelain, a pineapple-derived enzyme mixture, is a widely used drug to improve tissue regeneration. Clinical and experimental data indicate a better outcome of soft tissue healing under the influence of bromelain. Proteolytic, anti-bacterial, anti-inflammatory, and anti-oedematogenic effects account for this improvement on the systemic level. It remains unknown, whether involved tissue cells are directly influenced by bromelain. In order to gain more insight into those mechanisms by which bromelain modulates tissue regeneration at the cellular level, we applied a well-established in vitro wound healing assay. Two main players of soft tissue healing—fibroblasts and microvascular endothelial cells—were used as mono- and co-cultures. Cell migration, proliferation, apoptosis, and the differentiation of fibroblasts to myofibroblasts as well as interleukin-6 were quantified in response to bromelain (36 × 10−3 IU/ml) under normoxia and hypoxia. Bromelain attenuated endothelial cell and fibroblast proliferation in a moderate way. This proliferation decrease was not caused by apoptosis, rather, by driving cells into the resting state G0 of the cell cycle. Endothelial cell migration was not influenced by bromelain, whereas fibroblast migration was clearly slowed down, especially under hypoxia. Bromelain led to a significant decrease of myofibroblasts under both normoxic (from 19 to 12 %) and hypoxic conditions (from 22 to 15 %), coincident with higher levels of interleukin-6. Myofibroblast differentiation, a clear sign of fibrotic development, can be attenuated by the application of bromelain in vitro. Usage of bromelain as a therapeutic drug for chronic human wounds thus remains a very promising concept for the future."


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Vitamin E (as D-alphatocopheryl Succinate)

"Vitamin E and wound healing: an evidence-based review Hobson R. Vitamin E and wound healing: an evidence-based review. Int Wound J. 2016 Jun;13(3):331-5. doi: 10.1111/iwj.12295. Epub 2014 Aug 14. PubMed PMID: 25124164. Vitamin E has been demonstrated to modulate cellular signalling, gene expression and affect wounds infected with methicillin-resistant Staphylococcus aureus (MRSA), thus influencing wound healing. This evidence-based review aimed to identify and evaluate current research assessing the properties of vitamin E in relation to wound healing, through its role as an antioxidant and its influence on connective tissue growth factor (CTGF), MRSA and gene transcription. Literature dated from 1996 to 2012, published in English, involving either animals or adult humans with an acute or chronic wound were included. The databases that contained relevant articles were narrowed down to four, and a total of 33 identified studies were included. The literature review revealed that there is a significant dearth of robust studies establishing the effects of vitamin E on wound healing, and further research is clearly warranted."


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"Factors Affecting Wound Healing Guo S, DiPietro LA. Factors Affecting Wound Healing. Journal of Dental Research. 2010;89(3):219-229. doi:10.1177/0022034509359125. Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling. 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. This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved. The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition. A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds. "


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"Practices in Wound Healing Studies of Plants Thakur R, Jain N, Pathak R, Sandhu SS. Practices in Wound Healing Studies of Plants. Evidence-based Complementary and Alternative Medicine : eCAM. 2011;2011:438056. doi:10.1155/2011/438056. Wounds are the result of injuries to the skin that disrupt the other soft tissue. Healing of a wound is a complex and protracted process of tissue repair and remodeling in response to injury. Various plant products have been used in treatment of wounds over the years. Wound healing herbal extracts promote blood clotting, fight infection, and accelerate the healing of wounds. Phytoconstituents derived from plants need to be identified and screened for antimicrobial activity for management of wounds. The in vitro assays are useful, quick, and relatively inexpensive. Small animals provide a multitude of model choices for various human wound conditions. The study must be conducted after obtaining approval of the Ethics Committee and according to the guidelines for care and use of animals. The prepared formulations of herbal extract can be evaluated by various physicopharmaceutical parameters. The wound healing efficacies of various herbal extracts have been evaluated in excision, incision, dead space, and burn wound models. In vitro and in vivo assays are stepping stones to well-controlled clinical trials of herbal extracts."


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Biotin

"Effects of vitamin-B complex supplementation on periodontal wound healing Neiva RF, Al-Shammari K, Nociti FH Jr, Soehren S, Wang HL. Effects of vitamin-B complex supplementation on periodontal wound healing. J Periodontol. 2005 Jul;76(7):1084-91. PubMed PMID: 16018750. BACKGROUND: Reports have demonstrated that nutrient supplements, in particular vitamin-B complex (Vit-B), can positively influence wound healing processes. However, limited information is available on the effects of Vit-B on periodontal wound healing. METHODS: A total of 30 patients (13 males, 17 females) presenting with generalized moderate to severe chronic periodontitis were enrolled in this study. All subjects presented > or = two teeth in the same sextant with probing depth (PD) > or =5 mm and bleeding upon probing (BOP) in need of access flap surgery (AFS). This study was a randomized, double-masked, placebo-controlled clinical trial. Subjects were instructed to take one capsule a day of either Vit-B (50 mg of the following: thiamine HCl, riboflavin, niacinamide, d-calcium pantothenate, and pyridoxine HCl; 50 microg each of d-biotin and cyanocobalamin; and 400 mcg of folate) or placebo for 30 days following AFS. Clinical attachment levels (CAL) and N-benzoyl-dl-arginine-2-naphthylamide (BANA) test scores were measured at baseline and at 90 and 180 days following surgical intervention. Assessments of the healing response were also performed using BOP, gingival index (GI), and plaque index (Pl) at baseline and 7, 14, 30, 90, and 180 days. The mean results of each parameter were averaged within a group. Differences between groups were analyzed by using repeated measures analysis of variance (ANOVA). RESULTS: Both groups experienced comparable levels of PD reduction following AFS (test: -1.57 +/- 0.34; control: -1.50 +/- 0.21). Changes in mean CAL were more favorable in Vit-B supplemented subjects (test: +0.41 +/- 0.12; control: -0.52 +/- 0.23; P = 0.024). Stratified data demonstrated significantly better results for the test group in both shallow (test: -0.08 +/- 0.03; control: -1.11 +/- 0.27; P = 0.032) and deep sites (test: +1.69 +/- 0.31; control: +0.74 +/- 0.23; P = 0.037). No significant differences were observed between groups regarding PI, GI, and BOP. BANA test values were significantly reduced in both groups after surgical treatment and no significant differences were noted between groups. CONCLUSION: Vitamin B-complex supplement in combination with AFS resulted in statistically significant superior CAL gains when compared to placebo."


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"Effect of therapeutic dietary biotin on the healing of uncomplicated sole ulcers in dairy cattle--a double blinded controlled study Lischer ChJ, et al. Effect of therapeutic dietary biotin on the healing of uncomplicated sole ulcers in dairy cattle--a double blinded controlled study. Vet J. 2002 Jan;163(1):51-60. PubMed PMID: 11749136. The objective of this study was to investigate the influence of orally administered biotin on the healing of uncomplicated sole ulcers in dairy cattle. In a double-blind controlled study, 24 dairy cows with a mild, uncomplicated sole ulcer on a lateral hind claw were given either 40 mg biotin per day or a placebo feed over a period of 50 days. An orthopaedic shoe was fitted to the medial claw of the affected foot. The healing process was assessed clinically and by histological examination of horn samples. In the biotin-treated animals, the newly formed epidermis covering the sole ulcers was found to be of significantly better histological quality after 50 days than at the start of the study. The significant improvement in histological horn quality found in the biotin-treated animals suggests that biotin exerts a positive influence on the healing of sole ulcers, however the study period of 50 days appears to have been too short to permit macroscopic detection of the improvement in horn quality."


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Zinc (from TRAACS® Zinc Gylcinate Chelate)

"Efficacy of vitamin supplementation in situations with wound healing disorders: results from clinical intervention studies Ellinger S, Stehle P. Efficacy of vitamin supplementation in situations with wound healing disorders: results from clinical intervention studies. Current Opinion in Clin Nutr & Metab Care. 2009 Nov; 12(6): 588-95. Purpose of review This review evaluates the efficacy of vitamin supplementations for prevention and treatment of pressure ulcer and surgical wounds on the basis of recent clinical intervention studies. Recent findings Intervention studies show that an energy and protein-rich oral nutritional supplement providing high doses of vitamin C and zinc in combination with arginine may prevent the development of pressure ulcers. This measure seems to improve the healing of pressure ulcer, which is questionable for vitamin C alone. For surgical wounds, data from randomized controlled studies are scarce, but results on the use of vitamin C in combination with pantothenic acid are promising. Summary Considerable evidence suggests that supplementation of vitamin C together with zinc by an oral nutritional supplement rich in energy, protein and arginine may be an efficient tool for pressure ulcer healing in contrast to single vitamin C. The evidence for prevention of pressure ulcer by such an oral nutritional supplement is comparably low. This fits also for single vitamin C supplementation in the healing of surgical wounds. Further, well designed and well powered studies on the benefit of antioxidant vitamins for wound healing within a diet providing adequate energy and protein are necessary."


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"ACCELERATION OF WOUND HEALING IN MAN WITH ZINC SULPHATE GIVEN BY MOUTH Pories W, et al. ACCELERATION OF WOUND HEALING IN MAN WITH ZINC SULPHATE GIVEN BY MOUTH. The Lancet, Volume 289, Issue 7482, 121-4. The need for zinc in the optimal healing of wounds was demonstrated by the acceleration of healing of granulating wounds caused by excision of pilonidal-sinus tracts in young, healthy airmen who were given zinc sulphate U.S.P., 220 mg. t.i.d. by mouth during the period of repair. The rate of healing was determined by measurements of the wound volumes and the number of days for complete repair. Ten randomly selected controls (mean age 25·0 years and wound volume 32·3 ml.) were matched against ten who were given the drug (mean age 24·6 years and wound volume 54·5 ml.). The days ±S.E. for healing averaged 80·1±13·7 in the controls and 45·8±2·6 (p < 0·02) in the trial patients. Healing-rates (ml. per day ±S.E.) were 0·44±0·009 for controls and 1·25±0·30 (p < 0·01), or nearly three times greater, in the treated group. Larger wounds healed 34·3 days or 43% sooner with orally administered zinc sulphate. Medication with zinc was carried out with due consideration for the rights and welfare of the volunteers; all patients were fully informed of the experimental nature of the trial and gave their consent freely. This was necessary because of the lack of clinical experience with zinc sulphate therapy in a dose of 220 mg. t.i.d. No toxic side-effects were observed over periods ranging from 43 to 61 days. Other clinical investigations disclosed no signs of toxicity even when zinc sulphate was continued for periods up to 22 months."


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"Factors Affecting Wound Healing Guo S, DiPietro LA. Factors Affecting Wound Healing. Journal of Dental Research. 2010;89(3):219-229. doi:10.1177/0022034509359125. Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling. 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. This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved. The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition. A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds. "


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"Treatment with supplementary arginine, vitamin C and zinc in patients with pressure ulcers: a randomised controlled trial Desneves KJ, Todorovic BE, Cassar A, Crowe TC. Treatment with supplementary arginine, vitamin C and zinc in patients with pressure ulcers: a randomised controlled trial. Clin Nutr. 2005 Dec;24(6):979-87. Epub 2005 Nov 15. PubMed PMID: 16297506. BACKGROUND & AIMS: Nutrients putatively implicated in pressure ulcer healing were evaluated in a clinical setting. METHODS: Sixteen inpatients with a stage 2, 3 or 4 pressure ulcer randomised to receive daily a standard hospital diet; a standard diet plus two high-protein/energy supplements; or a standard diet plus two high-protein/energy supplements containing additional arginine (9 g), vitamin C (500 mg) and zinc (30 mg). Nutritional status measurements (dietary, anthropometric and biochemical) and pressure ulcer size and severity (by PUSH tool; Pressure Ulcer Scale for Healing; 0=completely healed, 17=greatest severity) were measured weekly for 3 weeks. RESULTS: Patients' age and BMI ranges were 37-92 years and 16.4-28.1 k g/m2) respectively. Baseline PUSH scores were similar between groups (8.7+/-0.5). Only patients receiving additional arginine, vitamin C and zinc demonstrated a clinically significant improvement in pressure ulcer healing (9.4+/-1.2 vs. 2.6+/-0.6; baseline and week 3, respectively; P < 0.01). All patient groups presented with low serum albumin and zinc and elevated C-reactive protein. There were no significant changes in biochemical markers, oral dietary intake or weight in any group. CONCLUSIONS: In this small set of patients, supplementary arginine, vitamin C and zinc significantly improved the rate of pressure ulcer healing. The results need to be confirmed in a larger study."


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L-Arginine

"Role of Arginine and Omega-3 Fatty Acids in Wound Healing and Infection Alexander JW, Supp DM. Role of Arginine and Omega-3 Fatty Acids in Wound Healing and Infection. Advances in Wound Care. 2014;3(11):682-690. doi:10.1089/wound.2013.0469. Significance: Only a few decades ago, the primary focus of nutritional supplementation was to prevent deficiencies of essential nutrients. It is now recognized that, at higher than essential levels, selected nutrients can have a pharmacologic effect to prevent or treat disease. Recent Advances: Two of the most important pharmaconutrients, arginine, and the omega-3 polyunsaturated fatty acids in fish oil, have been shown to have profound effects on wound healing and infections. Critical Issues: Both arginine and fish oils have independent benefits, but the combination appears to be much more effective. This combination has been shown to affect outcomes involving wound healing and infections, as reviewed here, and can also affect incidence and outcomes in cardiovascular disease, diabetes, organ transplant rejection, and other inflammatory conditions. These possibilities have not yet progressed to widespread clinical application. Future Directions: The optimal combinations of immunonutrients, timing of administration, and the doses needed for best results need to be determined in preclinical and clinical studies. Also, the mechanisms involved in the administration of pharmaconutrients need to be established."


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"Factors Affecting Wound Healing Guo S, DiPietro LA. Factors Affecting Wound Healing. Journal of Dental Research. 2010;89(3):219-229. doi:10.1177/0022034509359125. Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling. 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. This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved. The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition. A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds. "


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"Treatment with supplementary arginine, vitamin C and zinc in patients with pressure ulcers: a randomised controlled trial Desneves KJ, Todorovic BE, Cassar A, Crowe TC. Treatment with supplementary arginine, vitamin C and zinc in patients with pressure ulcers: a randomised controlled trial. Clin Nutr. 2005 Dec;24(6):979-87. Epub 2005 Nov 15. PubMed PMID: 16297506. BACKGROUND & AIMS: Nutrients putatively implicated in pressure ulcer healing were evaluated in a clinical setting. METHODS: Sixteen inpatients with a stage 2, 3 or 4 pressure ulcer randomised to receive daily a standard hospital diet; a standard diet plus two high-protein/energy supplements; or a standard diet plus two high-protein/energy supplements containing additional arginine (9 g), vitamin C (500 mg) and zinc (30 mg). Nutritional status measurements (dietary, anthropometric and biochemical) and pressure ulcer size and severity (by PUSH tool; Pressure Ulcer Scale for Healing; 0=completely healed, 17=greatest severity) were measured weekly for 3 weeks. RESULTS: Patients' age and BMI ranges were 37-92 years and 16.4-28.1 k g/m2) respectively. Baseline PUSH scores were similar between groups (8.7+/-0.5). Only patients receiving additional arginine, vitamin C and zinc demonstrated a clinically significant improvement in pressure ulcer healing (9.4+/-1.2 vs. 2.6+/-0.6; baseline and week 3, respectively; P<0.01). All patient groups presented with low serum albumin and zinc and elevated C-reactive protein. There were no significant changes in biochemical markers, oral dietary intake or weight in any group. CONCLUSIONS: In this small set of patients, supplementary arginine, vitamin C and zinc significantly improved the rate of pressure ulcer healing. The results need to be confirmed in a larger study."


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L-Glutamine

"Oral L-glutamine administration attenuated cutaneous wound healing in Wistar rats Goswami S, et al. Oral L-glutamine administration attenuated cutaneous wound healing in Wistar rats. Int Wound J. 2016 Feb;13(1):116-24. doi: 10.1111/iwj.12246. Epub 2014 Apr 1. PubMed PMID: 24690128. The objective of this study was to evaluate the wound healing potential of l-glutamine in laboratory rats using excision and incision wound models. Excision wounds of size 500 mm2 and depth 2 mm were made on the dorsal portion of male Wistar rats (230–250 g) and were used for the study of oral l-glutamine (1 g/kg) treatment on the rate of contraction of wound and epithelisation. Histological evaluation of wound tissue was also performed. Six-centimetre-long two linear-paravertebral incisions in male Wistar rats (230–250 g) were used to study the effect of l-glutamine (1 g/kg, p.o.) treatment on tensile strength, total protein and hydroxyproline content in the incision model. Oral administration of l-glutamine (1 g/kg) significantly decreased wound area, epithelisation period and wound index, whereas the rate of wound contraction significantly increased (P < 0·001) when compared with vehicle control rats in the excision wound model. Tensile strength, hydroxyproline content and protein level were significantly increased (P < 0·001) in l-glutamine (1 g/kg, p.o.)-treated rats when compared with vehicle control rats in the incision wound model. Histological evaluation of wound tissue from l-glutamine (1 g/kg, p.o.)-treated rats showed complete epithelialisation with new blood vessel formation and high fibrous tissues in the excision wound model. In conclusion, oral administration of l-glutamine (1 g/kg) promotes wound healing by acting on various stages of wound healing such as collagen synthesis, wound contraction and epithelialisation."


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"Micronutrients, Arginine, and Glutamine: Does Supplementation Provide an Efficient Tool for Prevention and Treatment of Different Kinds of Wounds? Ellinger S. Micronutrients, Arginine, and Glutamine: Does Supplementation Provide an Efficient Tool for Prevention and Treatment of Different Kinds of Wounds? Adv Wound Care (New Rochelle). 2014 Nov 1;3(11):691-707. Review. PubMed PMID: 25371852; PubMed Central PMCID: PMC4217021. Significance: Wound-healing complications are a clinical problem with a considerable socioeconomic burden. Since several nutrients play a physiological role in wound healing, supplementation of these nutrients may improve wound healing. Recent Advances: Oral nutritional supplements and enteral formulas providing arginine, glutamine, and micronutrients such as ascorbic acid and zinc should improve the healing of pressure ulcers (PU) and the healing of surgical, traumatic, and burned wounds. Is their efficacy proved from clinical intervention trials? Critical Issues: Formulas that are rich in energy, protein, arginine, vitamin C, and zinc can improve PU healing, whereas their efficacy for PU prevention is less clear. High-dose supplementation of vitamin C, zinc, and pantothenic acid may improve the healing of surgical wounds in healthy subjects. Arginine lowers the risk of fistulas in patients undergoing elective surgery due to gastrointestinal cancer. However, formulations also enriched with n-3-fatty acids and ribonucleic acids lower the risk of several wound complications, thus being more effective than isolated arginine. Glutamine and antioxidant micronutrients (vitamin C and E, zinc, selenium, and copper) can improve the healing of surgical, traumatic, and burned wounds. Future Directions: Considerable evidence suggests that formulations, indicated especially for critically ill patients, support the healing of PU and the healing of surgical and burned wounds. However, their optimal composition with regard to the dose of individual components has to be determined in future studies. Further well-designed trials should investigate the impact of certain nutrients for the prevention of PU and for the healing of surgical wounds in healthy subjects."


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"The effect of glutamine supplementation in patients following elective surgery and accidental injury Wilmore DW. The effect of glutamine supplementation in patients following elective surgery and accidental injury. J Nutr. 2001 Sep;131(9 Suppl):2543S-9S; discussion 2550S-1S. Review. PubMed PMID: 11533310. The metabolic response to injury, whether a controlled elective surgical procedure or an accidental injury, is characterized by the breakdown of skeletal muscle protein and the translocation of the amino acids to visceral organs and the wound. At these sites, the substrate serves to enhance host defenses, and support vital organ function and wound repair. Glutamine (GLN) plays a major role in these processes, accounting for approximately one third of the translocated nitrogen. From available data, GLN-supplemented intravenous nutrition in patients undergoing elective surgery improves nitrogen balance, helps correct the decreased GLN concentration found in the free intracellular skeletal muscle amino acid pool and enhances net protein synthesis (particularly in skeletal muscle). Six randomized blind trials (two multicentered investigations) reported a decreased length in hospital stay in postoperative patients receiving GLN supplementation. After blunt trauma, GLN supplementation increased plasma concentrations, attenuated the immunosuppression commonly observed and decreased the rate of infection. Patients with burn injury have low GLN plasma and intramuscular concentrations; turnover and synthesis rate are accelerated, yet apparently inadequate to support normal concentrations. These data suggest that GLN supplementation has important effects in catabolic surgical patients, but the exact mechanisms to explain these events remain unknown, and more research is required to explain the apparent benefits of dietary GLN."


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"Time to wound closure in trauma patients with disorders in wound healing is shortened by supplements containing antioxidant micronutrients and glutamine: a PRCT Blass SC, et al. Time to wound closure in trauma patients with disorders in wound healing is shortened by supplements containing antioxidant micronutrients and glutamine: a PRCT. Clin Nutr. 2012 Aug;31(4):469-75. doi: 10.1016/j.clnu.2012.01.002. Epub 2012 Jan 28. PubMed PMID: 22284340. BACKGROUND & AIMS: We hypothesize that wound closure in trauma patients with disorders in wound healing is accelerated by supplementation of antioxidant micronutrients and glutamine. METHODS: In a randomized, double-blind, placebo-controlled trial, 20 trauma patients with disorders in wound healing were orally supplemented with antioxidant micronutrients (ascorbic acid, α-tocopherol, β-carotene, zinc, selenium) and glutamine (verum) or they received isoenergetic amounts of maltodextrine (placebo) for 14 days. Plasma/serum levels of micronutrients, glutamine, and vascular endothelial growth factor-A (VEGF-A) were determined before and after supplementation. In the wound, several parameters of microcirculation were measured. Time from study entry to wound closure was recorded. RESULTS: Micronutrients in plasma/serum did not change except for selenium which increased in the verum group (1.1 ± 0.2 vs. 1.4 ± 0.2 μmol/l; P = 0.009). Glutamine decreased only in the placebo group (562 ± 68 vs. 526 ± 55 μmol/l; P = 0.047). The prevalence of hypovitaminoses and the concentration of VEGF-A did not change. Considering microcirculation, only O(2)-saturation decreased in the placebo group (56.7 ± 23.4 vs. 44.0 ± 24.0 [arbitrary units]; P = 0.043). Wound closure occurred more rapidly in the verum than in the placebo group (35 ± 22 vs. 70 ± 35 d; P = 0.01). CONCLUSIONS: Time to wound closure can be shortened by oral antioxidant and glutamine containing supplements in trauma patients with disorders in wound healing."


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Iron

"The role of iron in the skin and cutaneous wound healing Wright JA, Richards T, Srai SKS. The role of iron in the skin and cutaneous wound healing. Frontiers in Pharmacology. 2014;5:156. doi:10.3389/fphar.2014.00156. In this review article we discuss current knowledge about iron in the skin and the cutaneous wound healing process. Iron plays a key role in both oxidative stress and photo-induced skin damage. The main causes of oxidative stress in the skin include reactive oxygen species (ROS) generated in the skin by ultraviolet (UVA) 320–400 nm portion of the UVA spectrum and biologically available iron. We also discuss the relationships between iron deficiency, anemia and cutaneous wound healing. Studies looking at this fall into two distinct groups. Early studies investigated the effect of anemia on wound healing using a variety of experimental methodology to establish anemia or iron deficiency and focused on wound-strength rather than effect on macroscopic healing or re-epithelialization. More recent animal studies have investigated novel treatments aimed at correcting the effects of systemic iron deficiency and localized iron overload. Iron overload is associated with local cutaneous iron deposition, which has numerous deleterious effects in chronic venous disease and hereditary hemochromatosis. Iron plays a key role in chronic ulceration and conditions such as rheumatoid arthritis (RA) and Lupus Erythematosus are associated with both anemia of chronic disease and dysregulation of local cutaneous iron hemostasis. Iron is a potential therapeutic target in the skin by application of topical iron chelators and novel pharmacological agents, and in delayed cutaneous wound healing by treatment of iron deficiency or underlying systemic inflammation."


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"Iron and skin health: iron stimulates skin function Hirobe T. (2012) Iron and skin health: iron stimulates skin function. In: Preedy V.R. (eds) Handbook of diet, nutrition and the skin. Human Health Handbooks no. 1, vol 2. Wageningen Academic Publishers Iron (Fe) and the Fe (II) and Fe (III) dimer are important for normal development of the skin and its appendages such as hair and nails. Although iron is an essential trace metal, the mechanisms regulating iron uptake from the intestinal mucosa and the skin are not well understood. The skin is involved in regulating bodily iron content. Excess iron is lost through perspiration as well as hair and nail growth, but the mechanisms controlling these actions are also not well known. The human body contains 3–5 g of iron, of which up to 75% may be bound in haemoglobin, with lesser amounts in ferritin, myoglobin and transferrin. However, the minimal levels necessary for the structure and function of the skin seem to be quite low. A normal iron concentration is required for maintaining healthy epidermis, dermis, hair and nails. Fe (II) and Fe (III) dimers such as ferrous ferric chloride are very important for regulating proliferation and differentiation of mouse and human skin cells. Low ferrous ferric chloride concentrations can stimulate mammalian skin functions. Moreover, ferrous ferric chloride can stimulate fibroblast proliferation synergistically with low-molecular-weight collagen and melanocyte differentiation in combination with herbal medicines. Most importantly, ferrous ferric chloride can stimulate proliferation and differentiation of mouse and human skin cells from a distance without being added to the culture medium. These results suggest that ferrous ferric chloride is involved in regulating skin homeostasis through the regulation of the skin-cell turnover."


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Vitamin B12 (as methylcobalamin)

"A Reversible Cause of Skin Hyperpigmentation and Postural Hypotension Cherqaoui R, et al. “A Reversible Cause of Skin Hyperpigmentation and Postural Hypotension,” Case Reports in Hematology, vol. 2013, Article ID 680459, 5 pages, 2013. doi:10.1155/2013/680459 Vitamin B12 deficiency results in neuropsychiatric, hematologic, gynecologic, cardiovascular, and cutaneous manifestations. It is seen most commonly in the elderly, malabsorption diseases  (>60% of all cases), vegans, and vegetarians. Manifestations of pernicious anemia may be similar to Addison disease and may lead to a misdiagnosis. Herein, we report two cases of vitamin B12 deficiency in which clinical features shared many similarities with Addison disease. Both patients presented with progressive darkening of hands and postural hypotension that reversed with replenishment of vitamin B12. Vitamin B12 deficiency should be considered in patients presenting with skin lesions especially with other coexisting autoimmune diseases."


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"Nutrition and Chronic Wounds Molnar JA, Underdown MJ, Clark WA. Nutrition and Chronic Wounds. Advances in Wound Care. 2014;3(11):663-681. doi:10.1089/wound.2014.0530. Significance: Nutrition is one of the most basic of medical issues and is often ignored as a problem in the management of our chronic wound patients. Unfortunately, malnutrition is widespread in our geriatric patients even in nursing homes in developed countries. Attention to basic nutrition and providing appropriate supplements may assist in the healing of our chronic wounds. Recent Advances: Recent research has revealed the epidemiology of malnutrition in developed countries, the similarities to malnutrition in developing countries, and some of the physiologic and sociologic causes for this problem. More information is now available on the biochemical effects of nutrient deficiency and supplementation with macronutrients and micronutrients. In some cases, administration of isolated nutrients beyond recommended amounts for healthy individuals may have a pharmacologic effect to help wounds heal. Critical Issues: Much of the knowledge of the nutritional support of chronic wounds is based on information that has been obtained from trauma management. Due to the demographic differences of the patients and differences in the physiology of acute and chronic wounds, it is not logical to assume that all aspects of nutritional support are identical in these patient groups. Before providing specific nutritional supplements, appropriate assessments of patient general nutritional status and the reasons for malnutrition must be obtained or specific nutrient supplementation will not be utilized. Future Directions: Future research must concentrate on the biochemical and physiologic differences of the acute and chronic wounds and the interaction with specific supplements, such as antioxidants, vitamin A, and vitamin D."


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"The effect of B vitamin supplementation on wound healing in type 2 diabetic mice Mochizuki S, et al. The effect of B vitamin supplementation on wound healing in type 2 diabetic mice. Journal of Clinical Biochemistry and Nutrition. 2016;58(1):64-68. doi:10.3164/jcbn.14-122. The aim of this study was to test the effects of B-group vitamin supplements on wound healing in diabetic mice. The mice in the experimental group were treated daily with 1 g/L B6, 1.25 mg/L B12, and 62.5 mg/L folic acid in their drinking water. Full-thickness excision wounds were created with 6-mm skin biopsy punches. Each wound closure was digitally photographed. Beginning on day 3 after wounding, the wound area in the diabetic mice was statistically larger than that of normal mice (p<0.05 vs diabetic mice). The diabetic mice treated with B vitamins displayed accelerated wound closure on day 3 (wound area 42.8 ± 11.3%, p<0.05). On day 9 after wounding, the wound area in the diabetic mice was also statistically larger than that of normal mice (p<0.05 vs diabetic mice). The diabetic mice treated with B vitamins displayed accelerated wound closure on day 3 (wound area 13.2 ± 16.8%, p<0.05). In addition, the high glucose level in the diabetic animals decreased significantly in response to B vitamin treatment. In conclusion, the results of this study indicate that B vitamin supplementation may improve wound healing in diabetic mice."


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Selenium (as L-Selenomethionine)

"Effect of selenium on connexin expression, angiogenesis, and antioxidant status in diabetic wound healing Bajpai S, et al. Effect of selenium on connexin expression, angiogenesis, and antioxidant status in diabetic wound healing. Biol Trace Elem Res. 2011 Dec;144(1-3):327-38. doi: 10.1007/s12011-011-9097-7. Epub 2011 Jun 2. PubMed PMID: 21633835. This study was done to analyze the effect of selenium on antioxidant status and expression of different connexins in diabetic wound healing. The levels of vascular endothelial growth factor, superoxide dismutase, lipid peroxide, and connexins were analyzed in wound tissues taken from diabetic and non-diabetic mice before and after sodium selenite administration. The mRNA transcript levels of Cx 26, 30.3, 31, 31.1, and 43 were significantly elevated in diabetic wounds as compared to the non-diabetic wounds. After selenium administration, the expression of connexins along with serum glucose decreases more significantly in diabetic wounds as compared to non-diabetic wounds. In diabetic wounds, the low levels of vascular endothelial growth factor and extracellular superoxide dismutase were restored to normal level following selenium administration. The lipid peroxidation decreased significantly in diabetic mice post-selenium administration. The histopathological analysis revealed that administration of selenium improves angiogenesis at the wound site. The results of this study demonstrate that selenium, acting as an essential component of the antioxidant system, normalizes the antioxidant status, and as an insulin mimetic compound, downregulates connexin expressions and induces angiogenesis. Together, these effects of selenium accelerate wound healing in diabetic conditions."


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"Time to wound closure in trauma patients with disorders in wound healing is shortened by supplements containing antioxidant micronutrients and glutamine: a PRCT Blass SC, et al. Time to wound closure in trauma patients with disorders in wound healing is shortened by supplements containing antioxidant micronutrients and glutamine: a PRCT. Clin Nutr. 2012 Aug;31(4):469-75. doi: 10.1016/j.clnu.2012.01.002. Epub 2012 Jan 28. PubMed PMID: 22284340. BACKGROUND & AIMS: We hypothesize that wound closure in trauma patients with disorders in wound healing is accelerated by supplementation of antioxidant micronutrients and glutamine. METHODS: In a randomized, double-blind, placebo-controlled trial, 20 trauma patients with disorders in wound healing were orally supplemented with antioxidant micronutrients (ascorbic acid, α-tocopherol, β-carotene, zinc, selenium) and glutamine (verum) or they received isoenergetic amounts of maltodextrine (placebo) for 14 days. Plasma/serum levels of micronutrients, glutamine, and vascular endothelial growth factor-A (VEGF-A) were determined before and after supplementation. In the wound, several parameters of microcirculation were measured. Time from study entry to wound closure was recorded. RESULTS: Micronutrients in plasma/serum did not change except for selenium which increased in the verum group (1.1 ± 0.2 vs. 1.4 ± 0.2 μmol/l; P = 0.009). Glutamine decreased only in the placebo group (562 ± 68 vs. 526 ± 55 μmol/l; P = 0.047). The prevalence of hypovitaminoses and the concentration of VEGF-A did not change. Considering microcirculation, only O(2)-saturation decreased in the placebo group (56.7 ± 23.4 vs. 44.0 ± 24.0 [arbitrary units]; P = 0.043). Wound closure occurred more rapidly in the verum than in the placebo group (35 ± 22 vs. 70 ± 35 d; P = 0.01). CONCLUSIONS: Time to wound closure can be shortened by oral antioxidant and glutamine containing supplements in trauma patients with disorders in wound healing."


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Copper (as Cupric Oxide)

"Using Copper to Improve the Well-Being of the Skin Borkow G. (2015). Using Copper to Improve the Well-Being of the Skin. Current Chemical Biology. 8. 89-102. 10.2174/2212796809666150227223857. Copper has two key properties that are being exploited in consumer and medical device products in the last decade. On the one hand, copper has potent biocidal properties. On the other hand, copper is involved in numerous physiological and metabolic processes critical for the appropriate functioning of almost all tissues in the human body. In the skin, copper is involved in the synthesis and stabilization of extracellular matrix skin proteins and angiogenesis. This manuscript reviews clinical studies that show that the use of textile consumer and medical device products, embedded with microscopic copper oxide particles, improve the well-being of the skin. These include studies showing a) cure of athlete’s foot infections and improvement in skin elasticity, especially important for individuals suffering from diabetes; b) reduction of facial fine line and wrinkles; and c) enhancement of wound healing; by copper oxide embedded socks, pillowcases and wound dressings, respectively. The manuscript also reviews and discusses the mechanisms by which the presence of copper in these products improves skin well-being. "


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Hyaluronic Acid

"Hyaluronic Acid in Inflammation and Tissue Regeneration Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T. Hyaluronic Acid in Inflammation and Tissue Regeneration. Wounds. 2016 Mar;28(3):78-88. Review. PubMed PMID: 26978861. Hyaluronic acid (HA), the main component of extracellular matrix, is considered one of the key players in the tissue regeneration process. It has been proven to modulate via specific HA receptors, inflammation, cellular migration, and angiogenesis, which are the main phases of wound healing. Studies have revealed that most HA properties depend on its molecular size. High molecular weight HA displays anti-inflammatory and immunosuppressive properties, whereas low molecular weight HA is a potent proinflammatory molecule. In this review, the authors summarize the role of HA polymers of different molecular weight in tissue regeneration and provide a short overview of main cellular receptors involved in HA signaling. In addition, the role of HA in 2 major steps of wound healing is examined: inflammation and the angiogenesis process. Finally, the antioxidative properties of HA are discussed and its possible clinical implication presented."


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"Hyaluronic acid and oxidized regenerated cellulose prevent adhesion reformation after adhesiolysis in rat models Zhang Y, Liu Q, Yang N, Zhang X. Hyaluronic acid and oxidized regenerated cellulose prevent adhesion reformation after adhesiolysis in rat models. Drug Des Devel Ther. 2016 Oct 25;10:3501-3507. eCollection 2016. PubMed PMID: 27822014; PubMed Central PMCID: PMC5087760. Postsurgical adhesion formation is the most common complication in abdominal and pelvic surgery. Adhesiolysis is the most commonly applied treatment for adhesion formation but is often followed by adhesion reformation. Therefore, an efficient strategy should be adopted to solve these problems. This study aimed to explore whether hyaluronic acid and oxidized regenerated cellulose (ORC) could prevent adhesion formation and reformation. Thirty female Sprague Dawley rats were randomly divided into three groups (n=10 each) and subjected to different treatments during the first and second surgery. The control group was treated with isotonic sodium chloride, the ORC group was treated with ORC (1.5×1 cm), and the medical sodium hyaluronate (MSH) group was treated with 1% MSH (0.5 mL). At 2 weeks after the first surgery, adhesion scores in the MSH group (1.90±0.99) and the ORC group (1.40±0.97) were significantly lower than those in the control group (3.00±0.82) (P=0.005). Similarly, 2 weeks after the second surgery, adhesion scores in the MSH group (2.00±0.82) and the ORC group (1.50±1.27) were significantly lower than those in the control group (3.50±0.53) (P=0.001). In addition, body weights in the MSH group and the ORC group did not change significantly, whereas the control group showed a consistent decrease in body weight during the experiment. Histological examination revealed that inflammatory infiltration was involved in both adhesion formation and reformation. In conclusion, hyaluronic acid and ORC were both efficient in reducing adhesion formation and reformation in the rat model."


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"A model for the role of hyaluronic acid and fibrin in the early events during the inflammatory response and wound healing Weigel PH, Fuller GM, LeBoeuf RD. A model for the role of hyaluronic acid and fibrin in the early events during the inflammatory response and wound healing. J Theor Biol. 1986 Mar 21;119(2):219-34. PubMed PMID: 3736072. A model is presented outlining the molecular and cellular events that occur during the early stages of the wound healing process. The underlying theme is that there is a specific binding interaction between fibrin, the major clot protein, and hyaluronic acid (HA), a constituent of the wound extracellular matrix. This binding interaction, which could also be stabilized by other cross-linking components, provides the driving force to organize a three-dimensional HA matrix attached to and interdigitated with the initial fibrin matrix. The HA-fibrin matrix plays a major role in the subsequent tissue reconstruction processes. We suggest that HA and fibrin have both structural and regulatory functions at different times during the wound healing process. The concentration of HA in blood and in the initial clot is very low. This is consistent with the proposed interaction between HA and fibrin(ogen), which could interfere with either fibrinogen activation or fibrin assembly and cross-linking. We propose that an activator (e.g. derived from a plasma precursor, platelets or surrounding cells) is produced during the clotting reaction and then stimulates one or more blood cell types to synthesize and secrete HA into the fibrin matrix of the clot. We predict that HA controls the stability of the matrix by regulating the degradation of fibrin. The new HA-fibrin matrix increases or stabilizes the volume and porosity of the clot and then serves as a physical support, a scaffold through which cells trapped in the clot or cells infiltrating from the peripheral edge of the wound can migrate. The HA-fibrin matrix also actively stimulates or induces cell motility and activates and regulates many functions of blood cells, which are involved in the inflammatory response, including phagocytosis and chemotaxis. The secondary HA-fibrin matrix itself is then modified as cells continue to migrate into the wound, secreting hyaluronidase and plasminogen activator to degrade the HA and fibrin. At the same time these cells secrete collagen and glycosaminoglycans to make a more differentiated matrix. The degradation products derived from both fibrin and HA are, in turn, important regulatory molecules which control cellular functions involved in the inflammatory response and new blood vessel formation in the healing wound. The proposed model generates a number of testable experimental predictions."


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