Clinics in Dermatology (2010) 28, 432–439

Nutrition and wound healing

Katherine L. Brown, MD, Tania J. Phillips, MD, FRCPC ⁎
Department of Dermatology, Boston University School of Medicine, 609 Albany St, Boston MA 02118, USA

Abstract Nutrition is an important component of wound healing. Several studies have indicated that
nutrient deficiencies are more prevalent and cause delayed healing in patients with wounds. The
exact role for nutrition and nutritional supplementation in the management of wounds remains
uncertain, however. This contribution reviews available data regarding possible roles for nutrition in
wound healing.
© 2010 Elsevier Inc. All rights reserved.

Introduction Nutrient deficiencies have been found in some in patients

Adequate nutrition is important for wound healing.
Several biologic processes in the skin require nutrients for
proliferation and maintenance. Wound healing requires
competency in cellular repair mechanisms, chemotactic
factors (eg, cytokines and growth factors), and a local
environment that promotes cell division, movement, and
differentiation.1,2 Adequate amounts of nutrients are needed
for synthesis of nucleic acids (DNA and RNA), proteins,
and other factors involved in functional tissue maturation
and differentiation.3
Depletion of protein and minerals, through diet or
associated with malabsorption syndromes, or due to
substances that limit nutrient bioavailability, can impair
wound healing and increase the risk of developing chronic
ulcers, rough or thin skin, alopecias, and nail dystro-
phies.4-8 This is evidenced by skin diseases caused by
nutrient deficiencies, (among them beriberi, acrodermatitis,
and enteropathica), as well as by numerous published
studies indicating that deficiencies in protein, amino acids,
and minerals impair wound repair and tensile strength.
⁎ Corresponding author. Tel.: +1 617 848 1613.
E-mail address: tphill@bu.edu (T.J. Phillips).
with skin wounds; however, the role of nutritional supple-
mentation in wound healing is relatively unexplored. This is
partly because nutrition is not an exact science. There is
significant variation across health status, age, and sex, as well
as geographic, socioeconomic, and racial factors. 3 In
addition, there remains a paucity of good data on appropriate
screening of patients, supplementation protocols, and their
efficacies. This contribution reviews available data regarding
the roles of nutrients required for biologic processes in the
skin (Table 1) and their involvement in wound healing.
Macronutrients
Macronutrients are nutritional dietary components re-
quired in relatively large amounts and include proteins,
carbohydrates, and fats.
Protein and amino acids
Proteins provide the main building blocks for tissue
growth, cell renewal, and repair after injury. 9 They
significantly affect multiple phases of wound healing—
hemostasis, inflammation and granulation tissue formation,

0738-081X/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.clindermatol.2010.03.028
Nutrition and wound healing
Table 1 Nutrients that may affect wound healing
Macronutrients
• Proteins and amino acids
• Carbohydrates
• Lipids and essential fatty acids
Micronutrients
• Vitamins: A, B complex, C, E, and K
• Minerals: copper, iron, zinc
cell proliferation, tissue reorganization, and normalization—
by their roles in RNA and DNA synthesis, collagen and
elastic tissue formation, nutrition of the immune system,
epidermal growth, and keratinization. With prolonged
protein malnutrition, skin becomes thinner and wrinkled,
and immunity wanes.10 Diabetic patients with protein
malnutrition are at higher risk for amputations.11,12
Nitrogen balance is important in wound healing due to
increased protein synthesis.10 Deficiencies in cysteine and
proline adversely affect neoangiogenesis, fibroblastic re-
sponse, collagen synthesis, and wound remodeling, often
resulting in thin fragile skin with decreased tensile
strength.10,13,14 Collagen formation is particularly affected
by proline deficiency,15 whereas cysteine, cystine, methio-
nine, argentine, tyrosine, histidine, and glycine deficiencies
can contribute to delayed wound healing.16 Arginine, a
nonessential amino acid, becomes a conditionally essential
substrate in stressed adults.
Protein uptake, metabolism, and usage depend on
vitamins and trace metals that act as cofactors for enzymes,
for example, copper in lysyl oxidase and zinc in metallo-
proteinases. Although kwashiorkor due to protein-calorie
malnutrition is prevalent in underdeveloped countries,17
deficiencies in vitamins, amino acids, and trace metals are
more widely distributed causes of kwashiorkor.18
The negative effects of protein deficiency and the
advantage of nutritional supplementation in undernourished
surgical and trauma patients are well established. The role for
supplementation in outpatients and those with chronic
wounds has yet to be determined.19 A recent prospective
study found a higher prevalence of protein deficiency among
ambulatory outpatients with leg ulcers (27%) than in those
without (2%), and 55% of the malnourished patients also had
a concomitant inflammatory syndrome (as measured by
C-reactive protein), suggesting a catabolic mechanism for
protein deficiency. Protein deficiency was strongly associ-
ated with a poor healing prognosis, whereas the presence of a
concomitant inflammatory syndrome was associated with the
occurrence of wound complications.20 Other studies have
shown that arginine supplementation enhances collagen
deposition and wound strength in animals and humans.21,22
Carbohydrates
Carbohydrates are the principle source of energy for the
body and help sustain the high metabolic activity required for
433
regeneration. 23 Fibroblast proliferation is sensitive to
glucose deficiencies.24 Significantly lower glucose levels
(range, 0.3-5.9 mM/I) have been recorded in the wound fluid
of chronic wound patients.3,24,25
Lipids and essential fatty acids
Fats provide energy for proliferation and are building
blocks for epidermal and dermal tissues. They are important
for cell membrane synthesis, epidermal phospholipids,
inflammatory reactions, and intracellular matrix synthesis.
Micronutrients
At least 20 vitamin type substances and at least 16 mineral
and trace elements are required for normal health and
physiologic functions. Excess concentrations of some are
toxic, having deleterious dermatologic effects.3 Although
excess amounts of water-soluble substance typically are
renally excreted, particular caution should be taken for fat-
soluble substances, such as vitamins A, D, E, and K.
Vitamin A
Vitamin A is a fat-soluble vitamin derived from carote-
noids in vegetables. At appropriate doses, it is essential for
epidermal proliferation and reepithelialization through the
binding of retinol (the active form of vitamin A) to cell surface
receptors. Vitamin A is important in the inflammatory phase
of wound healing, which is typically prolonged in chronic
wounds,26 and can reverse corticosteroid-induced inhibition
of wound healing.27 It participates in regulating glycoprotein
and glycolipid synthesis, prostaglandin production, and cell
membrane metabolism.3 Vitamin A also appears to influence
dermal growth by inhibiting collagenase. Study data,
however, have demonstrated that excessive retinoate can
inhibit collagen and fibroblast production in vitro.28
Vitamin A deficiency delays collagen synthesis and
reepithelialization, decreases collagen stability, and increases
susceptibility to infection.29,30 Zinc deficiency can impair
absorption, transport, and metabolism of vitamin A because
it is essential for the synthesis of vitamin A transport proteins
and the oxidation of retinol to retinal.31
Multiple studies report low levels of vitamin A in chronic
wound patients.26,32 In animal models, supplementation
restored impaired wound healing.27 Vitamin A (25,000 IU/d)
supplementation has been recommended for chronic corti-
costeroid users, diabetic patients, seriously injured patients,
and those undergoing chemotherapy or radiotherapy.10,33
Vitamin B complex
Vitamin B complex consists of eight water-soluble
vitamins found in meat, dairy, vegetables, fish, brewer's
434
yeast (beer), and cereals.3 Vitamin B complex helps to
promote cell proliferation, maintain healthy skin and muscle
tone, support and increase metabolic rate, and enhance
immune and nervous system function.34
Deficiencies in vitamin B can impair wound healing35 and
are associated with several disorders, many of which have
skin manifestations (Table 2). In particular, thiamine is
associated with decreased wound healing and breaking
strength.36 In a study of elderly wound patients, researchers
found that 25% consumed less than two-thirds of the
recommended daily allowance for vitamin B6, and less than
7% for folate and vitamin B12.26 More research is needed to
assess possible benefits of vitamin B supplementation.
Vitamin C (ascorbic acid)
Vitamin C is a water-soluble vitamin with a multitude of
roles, including being a cofactor for collagen synthesis, a
powerful reducing agent for reactive oxygen species, and an
electron donor for multiple enzymes. Some of these
enzymatic processes involve lysine and proline hydroxyl-
ation needed for collagen to assume a triple-helical
structure, carnitine synthesis essential in fatty acid transport
into mitochondria for adenosine triphosphate generation,
and modulating tyrosine metabolism. Vitamin C also
contributes to metabolism of trace metals, iron uptake and
metabolism, calcium metabolism for epidermal gradients,
and immune response.3,37-39
Systemic deficiency can lead to scurvy, and local vitamin
C depletion in injured skin can lead to impaired collagen
synthesis, white cell production, use of oxygen free radicals
for killing bacteria, immune responsiveness, and γ-globulin
Table 2 Vitamin B deficiencies
B Vitamin Deficiency
B1 (thiamine) Beriberi
Wernicke encephalopathy (acute)
Korsakoff syndrome (chronic)—
psychosis with amnesia and
confabulation
B2 (riboflavin) Ariboflavinosis—angular cheilitis,
pharyngitis, glossitis, seborrheic
dermatitis, photosensitivity
B3 (niacin) Pellagra—dermatitis, dementia,
diarrhea, death
B5 (pantothenic acid) Acne and paresthesia
B6 (pyridoxine) Anemia, depression, dermatitis,
hypertension, elevated homocysteine
B7 (biotin) Impaired growth and neurological
disorders in infants
B9 (folate) Birth defects, macrocytic anemia,
elevated homocysteine
B12 (cobalamin) Macrocytic anemia, peripheral
neuropathy, dementia, elevated
homocysteine
K.L. Brown, T.J. Phillips
production.10 Vitamin C deficiency also is associated with
collagen defects, defective fibroblast responses, and abnor-
mal scar tissue formation.3,40
Although vitamin C deficiency is most often attributed
to decreased food intake, there are mixed reports regarding
the normalcy of serum vitamin C levels in leg ulcer
patients.26,32,41 There are no specific guidelines for vitamin
C in wound healing; however, supplemental vitamin C (1-
2 mg/d) has been recommended for severely ill patients
until recovered.10
Vitamin D
Vitamin D constitutes a group of fat-soluble prohormones
obtained from sunlight (290-320 nm), fatty fish, whole egg,
beef liver, mushrooms, fortified foods, and supplements.
Vitamin D is involved in calcium uptake and metabolism by
inhibiting secretion of calcitonin and parathyroid hormone.
These hormones are involved in cartilage and bone
remodeling, neuromuscular function, and immune func-
tion.42 Deficiency in vitamin D leads to rickets in children,
and osteomalacia and osteoporosis in adults. The role of
vitamin D in wound healing is unclear.
Vitamin E
Vitamin E is a fat-soluble vitamin present in asparagus,
avocado, eggs, seeds, nuts, and spinach. It serves an antioxidant
role by interacting with selenium-dependent glutathione
oxidase to inhibit degradation of cell membrane fatty acids.3
Low levels of vitamin E have been reported in chronic
wound patients.26,43 In chronic wounds, ischemia, necrotic
tissue, and microbial flora trigger inflammatory cascades that
enhance free radical formation.44 Supplementation remains
controversial. Some reports indicate that vitamin E may
impair collagen synthesis and wound healing in animals,45,46
whereas other authors report enhanced healing in irradiated
rat skin and patients with postthrombotic leg ulcers.47,48
Vitamin K
Vitamin K refers to a group of fat-soluble vitamins
present in leafy green vegetables, parsley, avocado, kiwi,
meat, eggs, and dairy. Vitamin K is needed for posttrans-
lational modification of certain proteins that are mainly
required for coagulation and bone metabolism.49 As a result,
it is important in the hemostasis phase of wound healing.
Vitamin K deficiency can result in hemorrhage, impaired
wound repair, and infection.50,51
Calcium
Calcium constitutes 99% of the body's total mineral
content and is a cofactor and regulator in many soft tissues,
including skin. Calcium gradients in the epidermis regulate
Nutrition and wound healing
basal cell proliferation. There is a paucity of data on the role
of calcium in wound healing. A steep increase in calcium
occurs after skin injury that is sustained into the normaliza-
tion phase of wound healing. Calcium ions in wound
exudates contribute to hemostasis.3
Copper
Copper is an essential trace element in all living cells and
a cofactor for several enzyme systems, including those for
cross-linking reactions that strengthen scars.26 High levels of
copper and zinc are associated with increased wound
elasticity and resistance.52,53
Features of copper deficiency include hair and nail
deformities, as seen in Menkes kinky hair syndrome, an X-
linked inherited copper deficiency resulting in impaired
keratin formation in hair papillae, retarded growth, and
reduced vasculature.4 Low serum copper leads to defective
collagen and elastic tissue formation, resulting in impaired
wound healing and reduced tensile strength.54,55 Studies
investigating sufficiency of copper levels in chronic wound
patients, however, have yielded mixed results.26,56
Iron
Iron is important in hemoglobin formation and oxygen
transport, uptake and metabolism of free radicals, oxidation-
reduction processes, mitochondrial respiration, and hydrox-
ylation of collagen precursors.3 Iron deficiency interferes
with healing through tissue hypoxia and decreased bacteri-
cidal ability by leukocytes.13,57 Deficiencies in iron or
vitamin C (involved in iron metabolism), or both, are
evidenced by follicular and perifollicular inflammation, hair
loss, abnormal keratinization, and decreased wound tensile
strength.3 Some patients with iron-deficiency anemia present
with nail deformities (Beau's lines) and eczema.58
Iron supplementation is recommended for pressure ulcer
patients, especially those associated with hemolytic ane-
mia.39 Some studies of chronic ulcer patients reported low
iron levels,26,59 but the role of supplementation in this setting
is uncertain.
Selenium
As a key component of glutathione peroxidase, selenium
acts as a free radical scavenger for protecting biologic
membranes.60 In animals, deficiency is immunosuppressive
and supplementation appears to increase immunity.26
Zinc
Zinc is a cofactor for at least 70 major enzyme systems
important in wound healing, including DNA and RNA
polymerases, proteases, and carbonic anhydrase.3,59 Other
proposed roles include cell membrane stabilization, carbo-
435
hydrate metabolism, and mobilization of vitamins (particu-
larly, A and C). Acrodermatitis enteropathica exemplifies the
importance of zinc in the skin through its association with
dermatitis, alopecia, thin skin, and impaired wound healing.61
Cutaneous zinc levels usually are proportional to levels of
mitotic activity, with zinc concentrations rising at least 15%
after acute skin injury. 3 Many studies have reported
significantly lower zinc levels in chronic wound patients
compared with presumably healthy controls.26,32,41,52,56
Because zinc deficiency impairs wound healing, zinc
repletion may increase healing rates52,56; however, there is
no strong clinical evidence that oral zinc sulfate aids healing
of arterial and venous ulcers.62,63 Topical zinc acts as a mild
antiseptic and anti-inflammatory agent in wound care. In
addition, one study showed that 1% zinc oxide cream
increased mitosis and reepithelialization rates.3
Water
Water is a cytoplasmic component of epidermal and
dermal cells and provides a medium for upward maturation
of epidermal cells and for enzymatic repair processes.3
Water balance regulation is crucial for optimal healing.
Hydration promotes cell proliferation and migration along
chemotactic gradients created by metal ions (eg, zinc and
calcium), cytokines, and growth factors. Dehydration leads
to epidermal hardening and dermal necrosis that delays
wound healing and adds to patient discomfort.64,65 Under
normal conditions, epidermal phospholipids “waterproof”
the skin, minimizing dehydration and penetration of foreign
substances. Occlusive dressings help minimize dehydration
in wounded skin and retain enzyme-rich wound exudates that
promote wound autolysis and healing. Little information is
available regarding recommendations for water intake during
wound healing.
Wound patients at increased risk
for malnutrition
Several studies indicate that certain populations of wound
patients are at particular risk of undernutrition. These include
institutionalized, hospitalized, and elderly patients,26,41,66-70
as well as patients with chronic ulcers, diabetes, burns,
malabsorption issues, and nutrient-imbalanced diets.
Elderly patients
Common reasons for malnutrition in the elderly include
decreased appetite (including drugs that reduce appetite),
psychosocial factors such as depression and isolation,
dependency on help for eating, teeth and chewing problems,
poor positioning, impaired cognition, frequent acute ill-
nesses resulting in poor gastrointestinal absorption, higher
436
nutrient requirements, and monotony of diet. 71,72 A
nutritional status survey of elderly patients found 50%
consumed less than two-thirds of the recommended daily
allowance for zinc, 25% for vitamin B6, and less than 7%
for folate and vitamin B12.26
Chronic ulcer patients
Compared with other elderly persons, those with chronic
ulcers have significantly lower levels of vitamins A, E, zinc,
and carotenes.26 A recent prospective study20 found a higher
prevalence of protein deficiency among ambulatory out-
patients with chronic leg ulcers than those without (27% vs
2%, respectively). Of these malnourished patients, 55% had
a concomitant inflammatory syndrome (as measured by C-
reactive protein), suggesting increased catabolism contri-
butes to protein deficiency. Protein deficiency was strongly
associated with a poor healing prognosis, while the presence
of a concomitant inflammatory syndrome was associated
with the occurrence of wound complications.
Diabetic patients
Studies indicate that diabetic patients with low protein
levels have a higher incidence of nonhealing wounds,
infection, and necrosis leading to possible amputation.11,12
Burn patients
Burns involving more than 20% of the body's surface area
result in extensive metabolic, inflammatory, endocrine, and
immune responses that can predispose patients to malnutri-
tion, poor wound healing, and frequent infections. This
highly catabolic state results in energy requirements
exceeding as much as 100% of the basal energy requirements
of healthy persons, resulting in weight loss and negative
nitrogen balance through increased proteolysis and lipolysis.
Burns wounds also have significant exudative losses of
proteins and micronutrients.73-75 Artificial skin may the
decrease nutritional requirements in wound patients.76
Nutritional support entails high-protein, high-energy diets
starting soon after injury. Enteral supplementation is
preferred because this maintains tropism of the gastrointes-
tinal tract,77 whereas patients receiving parenteral feedings
typically experience more infectious complications.78,79
Treatment of critically ill patients with dietary components
like glutamine, arginine, and (n-3) fatty acids and related
compounds added in quantities of two to seven times that of
normal intake (referred to as “immune-enhancing diets”)
have resulted in reduced infections and hospital length of
stay.80-84 Several of these studies have design flaws,
however, and differ in amounts of consumed nitrogen,79,80,82
energy,81 or lipid.85-87 Studies also suggest that supplemen-
tation with copper, selenium, and zinc results in earlier
normalization of antioxidant enzymes and glutathione in the
K.L. Brown, T.J. Phillips
skin, a reduction in surgical grafting requirements, and a
significantly better index of skin graft acceptance.75,88
Patients with impairments in nutrient bioavailability
These include patients with diseases that influence
nutrient uptake and metabolism (eg, genetic disorders,
malabsorption issues, pernicious anemia) and those who
consume substances (eg, medications) that impair nutrient
bioavailability. Penicillamine, a powerful chelator of metal
ions, should be avoided in patients with wounds.3
Screening for nutritional deficiencies
Simply identifying wound patient populations at high risk
for nutritional deficiencies is insufficient for advancing
wound care. More information is needed regarding appro-
priate screening tests, laboratory monitoring frequencies, and
their cost-effectiveness.
Studies indicate that anthropomorphic measurements,
such as body mass index and weight loss, are less sensitive
markers of malnutrition in leg ulcer patients, where the
proportion of obese patients reaches 20% to 30%.89,90
Although low body mass index values and recent weight loss
are associated with hypoalbuminemia, such measures can
miss more than half of patients with protein deficiency. As
such, anthropomorphic measures likely are insufficient for
identifying patients that might benefit from a laboratory
nutritional assessment.20
Currently, there is no standard regimen for testing or
monitoring nutritional deficiencies in wound patients. Some
researchers suggest that systematic laboratory nutritional
assessments and C-reactive protein levels may be appropri-
ate.20 Moreover, there is a dearth of information for testing local
wound nutritional deficiencies outside the research setting.
Treatment
In general, it is important to counsel undernourished
patients about ways to improve their diets. Providing
nutritional supplements in addition to regular food intake
seems a logical means of replenishing nutrients and
supplying extra nutrients for increased tissue resistance and
wound repair.95,91 Nutrition and nutritional supplementation
in wound care is not yet standard of care, however, and
remains controversial.
Oral nutritional supplements
Guidelines from the European Pressure Ulcer Advisory
Panel and the Pressure Management Guideline of the
National Institute for Health and Clinical Excellence are
Nutrition and wound healing
among those that have addressed the importance of nutrition
in pressure ulcer care.92-94 According to a systematic review,
an oral nutritional supplementation for pressure ulcers that
contained containing 250 kcal, 20 g of total protein, 3 g of
arginine, 250 mg of vitamin C, 38 mg of vitamin E, 9 g of
zinc, and other micronutrients showed positive effects on
pressure ulcer healing and possible preventative effects in
patients at risk for pressure ulcers.95 Unfortunately, many of
the practice-based studies that showed positive effects of oral
nutritional studies on ulcer healing and potentially preven-
tative effects on ulcer development were of limited size, short
duration, and were not randomized controlled trials.96,97
Aside from efficacy data, information regarding health
care practitioner endorsement, patient compliance (including
acceptability and tolerance), and cost-effectiveness will be
important for assessing a role for nutritional supplementation
in the standard of care. Data do show that nutritional
screening and interventions are conducted more frequently in
institutions where guidelines are in place.68 Patient compli-
ance is optimistic given that one large open intervention study
of oral nutritional supplements for pressure ulcers reported
that 80% of patients did not complain about supplements
being prescribed at three servings daily. 98 Finally, a
mathematic cost-effectiveness analysis of adding an oral
nutritional supplement containing protein, arginine, vitamin
C, vitamin E, zinc, and other micronutrients to regular care
resulted in cost savings, provided that the duration of more
intensive nursing care was reduced by as little as 1 day.99
In addition to traditional oral nutritional supplements,
herbal and plant extracts also could be considered oral
nutritional supplements. Many oral plant extracts have been
used for adjunctive treatment of venous stasis and ulcers—
including horse chestnut extract (Aesculus hippocastanum
L), rutoside extracts, and Pycnogenol (French maritime pine
bark extract)—although little data exist on the exact
mechanisms or benefits of these extracts in wound care,
particularly when added to standard therapy.100
Other nutritional supplements
Maintaining good nutrition with adequate circulating
levels of nutrients is important for overall health and wound
healing. It seems plausible, however, for local wound nutrient
depletions to occur in the absence of major changes in normal
laboratory ranges, leading one to question the possible
efficacy of more local routes of administration for nutritional
supplementation. Unfortunately, there are few efficacy trials
for oral and intravenous nutritional supplements, and even less
information for nutritional supplements by alternate routes.
Conclusions
Nutrition and hydration are important in wound heal-
ing.4 Although it is impractical to consider individual
437
nutrients in isolation, several nutrients appear particularly
important for wound healing. Proteins and amino acids
provide the main building blocks for tissue growth,
renewal, and repair after injury. Fats provide energy and
substrates for proliferation, maturation, and hemostasis in
epidermal and dermal tissues. The body also relies on at
least 20 vitamin-like substances and 16 minerals and trace
elements for normal health and physiologic functions.3
Several studies have found deficiencies of multiple
nutrients in various groups of wound patients.
Although nutritional supplementation may seem intuitive
for enhancing wound healing in patients with documented
deficiencies, many questions about supplementation in
routine wound care are left unanswered. To date, most
studies have been of small size and short duration. More
randomized clinical control trials and larger studies are
needed to establish the bioavailability of oral and topical
nutrients for healing wounds, their efficacies, potential risks
(ie, safety), and information for therapeutic dosing regimens.
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