RECONSTRUCTIVE

Nutrition and Wound Healing

Meghan Arnold, M.D.
Summary: The relationship between nutrition and wound healing–-after injury
Adrian Barbul, M.D. or surgical intervention–-has been recognized for centuries. There is no doubt
Baltimore, M.D. that adequate carbohydrate, fat, and protein intake is required for healing to
take place, but research in the laboratory has suggested that other specific
nutritional interventions can have significant beneficial effects on wound heal-
ing. Successful translation into the clinical arena, however, has been rare. A
review of normal metabolism as it relates to wound healing in normoglycemic
and diabetic individuals is presented. This is followed by an assessment of the
current literature and the data that support and refute the use of specialized
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nutritional support in postoperative and wounded patients. The experimental

evidence for the use of arginine, glutamine, vitamins, and micronutrient sup-
plementation is described. Most of the experimental evidence in the field
supporting the use of specialized nutritional support has not been borne out by
clinical investigation. A summary of the clinical implications of the data is
presented, with the acknowledgment that each patient’s plan of care must be
individualized to optimize the relationship between nutrition and wound
healing. (Plast. Reconstr. Surg. 117 (Suppl.): 42S, 2006.)

W
ound healing and nutrition have an in- In the 1930s, Ravdin showed the specific rela-
timate relationship that has been recog- tionship between protein malnutrition and the
nized by physicians for hundreds of incidence of laparotomy wound dehiscence in
years. Malnutrition or nutrient deficiencies can dogs.4 – 6 Ravdin concluded that poor nutritional
have a severe impact on the outcome of trau- intake or lack of certain essential nutrients sig-
matic and surgical wounds. Wound failure, as nificantly altered the body’s ability to heal
reflected by wound infections and/or delayed wounds. Interest has since swung from under-
healing, significantly contributes to the financial standing the basic physiologic mechanisms of
burden imposed on health care systems world- wound healing to attempting to modulate or
wide. enhance the process. The dynamic and complex
The critical role of nutrition to healing has been cascade of wound healing has proved responsive
recognized since the beginning of medicine as a to the external manipulation of metabolic and
discipline. Some of the earliest known writings nutritional factors, but concrete changes to clin-
identifying this synergy date to roughly 2300 years ical management have been more elusive.
ago, when Hippocrates warned of underestimat-
ing the vital role that nutrition played in health NUTRITIONAL FACTORS IN WOUND
and human disease.1 In the late 1800s, Coleman, REPAIR
Shaffer, and DuBois investigated the meta-
bolic changes occurring in disease.2 Later, Malnutrition
Cuthbertson3 further defined these biochemi- Malnutrition after injury results from multiple
cal responses to injury in studying patients and factors, including poor nutritional intake to a
animals with long bone fractures by demonstrating host’s perturbed metabolic equilibrium. Studies
significant alterations in physiologic electrolyte lev- over the past century have shown that changes in
els, increased nitrogen turnover, and stimulation energy, carbohydrate, protein, fat, vitamin, and
of the overall host metabolism. mineral metabolism affect the healing process.7
Loss of protein from protein-calorie malnutrition,
From the Department of Surgery, Sinai Hospital of Baltimore, the most common form of malnutrition in the
and the Johns Hopkins Medical Institutions. world, leads to decreased wound tensile strength,
Received for publication November 19, 2005; revised April decreased T-cell function, decreased phagocytic
5, 2006. activity, and decreased complement and antibody
Copyright ©2006 by the American Society of Plastic Surgeons levels, ultimately diminishing the body’s ability
DOI: 10.1097/[Link].0000225432.17501.6c to defend the wound against infection. These im-

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Volume 117, Number 7S • Nutrition and Wound Healing

mune compromises correlate clinically with in- caloric intake by 50 percent results in decreased
creased wound complication rates and increased collagen synthesis, matrix protein deposition, and
wound failure after clean surgical procedures.8 –10 granulation tissue formation.27,28 In other animal
In elderly nursing home patients, malnutrition is models, severe or prolonged protein-calorie malnu-
also associated with increased mortality, an in- trition is necessary to impair the healing responses.
creased risk of developing pressure ulcers, and a In humans, however, only modest protein-calorie
lower quality of life.11–14 malnutrition impairs fibroplasia.29 Finally, brief pre-
Malnutrition may predate wounding or may operative illness or decreased nutritional intake in
be secondary to the catabolism resulting from the the prewounding period has a significant effect on
injury itself. Wounding increases metabolic rates, collagen synthesis. Preoperative food intake, then,
catecholamine levels, loss of total body water, and may be more important to the wound-healing pro-
cellular protein turnover, resulting in an overall cess than the patient’s overall nutritional status.30
state of catabolism.15 During this time of increased Conversely, brief nutritional intervention by enteral
energy demand, muscle breakdown occurs pref- or parenteral routes can overcome or prevent these
erentially to the use of existing fat stores, thus impairments in the healing process.31,32
providing amino acids for gluconeogenesis.16 The Although the current literature is laden with
host’s catabolic response to injury is proportional studies attempting to delineate the exact role that
to the severity of the injury.17,18 In fact, healing may nutrition and nutritional supplements play in the
be prioritized by metabolic activity. Levenson and wound-healing process, most wounds heal un-
others,19 –22 for example, have shown significantly eventfully, including those that occur in the set-
slower cutaneous wound healing, but increased ting of significant malnutrition. Patients under-
liver regeneration, in burned and traumatized an- going oncologic operations, for example, often
imals. These disparities in the overall anabolic or present with preoperative weight loss and malnu-
catabolic state between various organs after ther- trition but generally heal without infection or
mal injury suggest that vital structures are pre- wound dehiscence. Albina,33 however, noted that
served at the expense of others. severe protein-calorie malnutrition and symptom-
In a society where malnutrition is thought to atic specific nutrient deficiencies can impair
have been eliminated, a significant proportion of wound healing by delaying the healing process
medical and surgical patients have preexisting itself. These discrepant results underscore the im-
malnutrition from decreased nutritional intake. A portance and preeminence of healing in the post-
study of orthopedic patients, including post- traumatic response and should not lead clinicians
trauma patients and individuals undergoing total to ignore the need for optimal nutrition. The pri-
hip replacement, found that 42 percent of those mary goal, therefore, should be to provide every
studied were malnourished.23 In a separate anal- patient with optimal nutrition so that this priori-
ysis, 12 percent of noncancer patients were found tization of wound healing can occur within an
to be malnourished at preoperative evaluation.24 ideal host environment.
Another cross-sectional study demonstrated that
approximately 50 percent of medical and surgical
patients in an urban hospital showed evidence of Carbohydrates
malnutrition.25 Although the exact parameters Carbohydrates, together with fats, are the pri-
used to define clinical malnutrition may vary, an mary source of energy in the body and, conse-
assessment of preexisting malnutrition should be quently, in the wound-healing process. Wounds
performed when evaluating a wound or a patient require energy mainly for collagen synthesis. Es-
about to undergo operative intervention. Identi- timates of caloric requirements for a particular
fication of the potential risk imposed by malnu- wound can be determined knowing that (1) pro-
trition is especially important in populations with tein synthesis requires 0.9 kcal/g and (2) a 3-cm2
other risk factors for impaired wound healing. ⫻ 1-mm-thick section of granulation tissue con-
An understanding of normal metabolism is tains 10 mg of collagen. As such, simple wounds
critical when planning a surgical procedure in have little energy impact on overall metabolism,
malnourished patients. One of the critical ele- but thermal injuries or large complicated wounds
ments required for healing is energy, which in the can divert a disproportionate amount of energy to
human host is derived from carbohydrates, pro- the healing milieu.34
tein, and fat. Dietary carbohydrates and protein Glucose is the major source of fuel used to
provide approximately 4 kcal of energy per kilo- generate cellular energy in the form of adenosine
gram, and fats provide 9 kcal/kg.26 In rats, reducing triphosphate, which in turn powers the wound-

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 Plastic and Reconstructive Surgery • June Supplement 2006

healing process. The use of glucose to generate brane transport may explain this mechanism, as
adenosine triphosphate is relatively inefficient, glucose and ascorbic acid are structurally similar.46
but the caloric contribution from glucose is es- This effect of hyperglycemia, specifically as it re-
sential in preventing the depletion of other amino lates to leukocytes, is thought to explain the de-
acid and protein substrates. The liver, triggered by creased early inflammatory response and im-
the catecholamine and cortisol surge that occurs paired wound healing seen in diabetic patients.
after wounding, initiates gluconeogenesis using The importance of controlling serum glucose lev-
amino acids from degraded muscle protein. Un- els in diabetics around the time of injury, opera-
checked, and in the presence of inadequate car- tion, and wound healing cannot be overempha-
bohydrate and fat stores, this increased glucone- sized. The alteration in a diabetic’s metabolism
ogenesis can significantly deplete amino acids and after injury or elective surgery can significantly
protein. Although carbohydrates play an impor- affect wound healing by any of the mechanisms
tant role in providing the energy essential for op- discussed above. In addition, diabetic patients are
timal healing, little is known about the functions more susceptible to infection because of de-
that different sources of carbohydrates play in this creased host resistance. It is crucial that physicians
process. As mentioned, gluconeogenesis is a rel- recognize and anticipate the needs of diabetic
atively inefficient pathway for glucose production patients early, before the encumbering effects of
that can result in the production of excess diabetes lay hold to the wound-healing process. In
amounts of glucose. This excess may subsequently summary, the most important factor affecting
complicate wound healing, especially in diabetic wound healing in diabetic patients involves achiev-
patients with poor glycemic control. ing and maintaining normal glucose control.46,47
Diabetic patients have a significantly impaired
ability to heal wounds and, therefore, exhibit in-
creased complication rates compared with their Fats
euglycemic counterparts. The mechanisms at In contrast to carbohydrates, the role of fats
work are multifactorial and yet to be clearly de- has not been studied widely, although it is recog-
lineated, but they may be related to a build-up of nized that the demand for essential fatty acids
advanced glycation endproducts in body tissues.35 increases after injury.48,49 Linoleic and arachi-
Diabetics exhibit a diminished early inflammatory donic acid are among the unsaturated fatty acids
response and inhibition of fibroblast and endo- that must be supplied in the diet to allow for
thelial cell activity.35–37 When inflammatory cells prostaglandin synthesis. Although both fatty acids
eventually arrive at the site of injury, they initiate can be synthesized from linoleic acid, the rate of
a prolonged inflammatory phase that results in synthesis is inadequate for basic metabolic needs.
delayed deposition of matrix components, wound Deficiencies in these lipids can occur as early as 2
remodeling, and closure.38 Delayed epithelializa- weeks after their removal from the diet, although
tion of open wounds and decreased collagen ac- clinical manifestations may not be apparent for 2
cumulation deep within the wound have been re- to 7 months.36,50 As components or precursors of
ported in models of streptozotocin-induced phospholipids and prostaglandins, free fatty acid
diabetes.37 Decreased reendothelialization of mi- deficiency impairs wound healing in animals and
croarterial anastomoses has also been demon- humans,51–54 primarily because phospholipids are
strated, an effect that was not corrected by insulin key constituents of cellular basement membranes
administration at the time of surgery and that while prostaglandins play critical roles in cellular
extended into the early postoperative period.39 metabolism and inflammation.
Work by Weringer and associates using a mouse Deficiencies of dietary essential fatty acids
model demonstrated that, in addition to hyper- were rarely seen clinically until the introduction of
glycemia, the lack of insulin itself seems to impair prolonged parenteral feedings that did not con-
wound healing.40 – 42 Topical application of insulin tain fat. Total parenteral nutrition is the most
to infected skin wounds or systemic administration common cause of essential fatty acid deficiency; its
in diabetic mice can improve healing,43 but to administration results in rapid onset of essential
achieve normal healing insulin must be started fatty acid deficiency, which can manifest within 10
soon after wounding.44 days of starting an entirely fat-free diet.55 This, in
Hyperglycemia interferes with the cellular turn, leads to elevated insulin levels, which block
transport of ascorbic acid into fibroblasts and leu- both lipolysis and essential fatty acid release.56
kocytes and decreases leukocyte chemotaxis.45 Additional research has sought to define ben-
Competitive inhibition of ascorbic acid mem- efits to wound healing of specific lipid types. The

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␻-3 fatty acids, which exhibit anti-inflammatory lease, and T-lymphocyte stimulation and is in-
properties by inhibiting the production of eico- volved in the metabolic pathways that
sanoids and other mediators, such as platelet-ac- synthesize urea, nitric oxide, and creatine
tivating factor, interleukin-1, and tumor necrosis phosphate.69,70 Arginine is absorbed from the
factor-␣,57– 62 are among the most widely investi- intestine by a transport system shared with ly-
gated. Animals consuming diets enriched with ␻-3 sine, ornithine, and cysteine in an energy-
fatty acids have weaker wounds because of poor dependent and sodium-dependent fashion with
quality, cross-linking, and spatial orientation of substrate specificity. Although arginine is syn-
collagen fibrils.57 The true benefit of ␻-3 fatty ac- thesized in adequate quantities to sustain mus-
ids, therefore, may be in their immune modula- cle and connective tissue mass, in situations of
tion of the host rather than in improved wound stress or injury, body stores of arginine de-
healing per se. Studies of healing burns in humans crease rapidly. It is during these times, in which
and guinea pigs, however, have demonstrated im- its synthesis is insufficient to meet the demands
proved immune function, improved survival, and of increased protein turnover, that arginine be-
reduced infectious complications after the admin- comes an indispensable amino acid in the pro-
istration of a diet rich in ␻-3 fatty acids to this cess of wound healing and in the maintenance
specific subset of injured patients.63,64 of a positive nitrogen balance.71,72
The role of arginine in wound healing was first
Protein shown in the 1970s using an animal model, when
The importance of protein in wound healing it was hypothesized that, following injury, the
has been recognized and researched since the amino acid requirements of the adult organism
early 1930s. Experimentally, severe protein depri- would revert to those of the growing infant. Based
vation leads to impaired healing through im- on this hypothesis, the effect of arginine on wound
paired collagen synthesis and deposition, de- healing in young adult rats was studied. Animals
creased skin and fascial wound-breaking strength, were fed an arginine-deficient diet for 4 to 6 weeks
and increased wound infection rates.28,65 In the before wounding. When animals were subjected to
clinical setting, however, pure protein deficiencies the minor trauma of a dorsal skin incision and
are rarely encountered; most patients exhibit com- closure, they demonstrated increased postopera-
bined protein-energy or protein-calorie malnutri- tive weight loss, an increased mortality rate to ap-
tion. proximately 50 percent, and a notable decrease in
wound-breaking strength as well as wound colla-
gen accumulation compared with animals fed a
Amino Acids
diet containing arginine (Fig. 1).72 Subsequent
Because wound healing can be impaired by experiments revealed that chow-fed rats that were
deficiencies in a variety of nutrients, there has not arginine-deficient and were then fed a diet
been a rising interest over the last several decades containing an additional 1% arginine had en-
in the use of individual nutrients to promote hanced wound healing, as assessed by wound-
wound healing.34 Partial resolution of healing de- breaking strength and collagen synthesis, com-
fects in protein-deficient rats was noted with the pared with chow-fed controls (Fig. 1).72 Similar
administration of single sulfur-containing amino findings were observed in parenterally fed rats
acids, such as methionine and cysteine, although given an amino acid mixture containing high
the clinical relevance of these findings has never doses (7.5 g/liter) of arginine. These animals ex-
been pursued.66,67 Arginine and glutamine, on the hibited increased wound-breaking strength, in-
other hand, have been the most extensively stud- creased collagen accumulation, and enhanced im-
ied amino acids in the wound-healing process. mune function.73 Likewise, mature or old rats fed
diets supplemented with a combination of argi-
Arginine nine and glycine had enhanced rates of wound
In the late 1940s and early 1950s, Rose68 collagen deposition compared with controls.74
classified arginine as one of two semiessential Twenty years ago a micromodel was described
amino acids in mammalian metabolism. Argi- that has made it possible to study the human fi-
nine is a dibasic amino acid synthesized endo- broblastic response.75 In this model, collagen ac-
genously from ornithine through citrulline and cumulation occurs in subcutaneously placed seg-
is a precursor for proline during collagen ments (5 to 7 cm long) of polytetrafluoroethylene
synthesis.36 Arginine also has roles in maintain- tubing that can be removed for analysis. Two stud-
ing positive nitrogen balance, growth factor re- ies in healthy human volunteers examined the

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 Plastic and Reconstructive Surgery • June Supplement 2006

Fig. 1. Effect of supplemental dietary arginine added to an arginine-free (defined) diet or normal laboratory
chow (1.8% arginine content) on wound healing in rats. Statistical comparison by Student’s t test. FBS, fresh
breaking strength of scar, g; FxBS, formalin-fixed breaking strength, g; OHP, hydroxyproline content of subcu-
taneously implanted polyvinyl alcohol sponges, ␮g/100 mg sponge dry weight.

effects of arginine supplementation using this

model. In the first study, 36 young, healthy human
volunteers (ages 25 to 35 years) were randomized
to one of three groups: (1) 30-g arginine hydro-
chloride daily supplements (24.8 g of free argi-
nine); (2) 30 g of arginine aspartate (17 g of free
arginine); or (3) placebo. The supplements were
given for 2 weeks, after which the polytetrafluo-
roethylene catheters were removed and the hy-
droxyproline content (index of reparative colla-
gen synthesis) was determined. Arginine
supplementation at both doses significantly in-
creased the amount of hydroxyproline and total
protein deposition at the wound site (Fig. 2).76
The second study evaluated 30 elderly volunteers
(age ⬎70 years) who received 30 g of arginine
aspartate or placebo. In addition to evaluating the
fibroblastic wound response using the catheters,
this study also examined epithelialization after
creation of a split-thickness wound on the upper
thigh of each subject. The catheters in this study
were analyzed for ␣-amino nitrogen content (as-
sessment of total protein accumulation), DNA ac- Fig. 2. Effect of 2 weeks of arginine supplementation on hy-
cumulation (index of cellular infiltration), and droxyproline accumulation in subcutaneously implanted poly-
hydroxyproline content.77 There was no enhanced tetrafluoroethylene catheters in young human volunteers (mean
DNA present in the wounds of the arginine-sup- ⫾ SEM). Groups of 12 volunteers each received a placebo (con-
plemented group, suggesting that the effect of trol), 30 g of arginine aspartate (Arg Asp; 17 g of free arginine) per
arginine is not mediated by an inflammatory day, or 30 g of arginine hydrochloride (AG HCl; 24.8 g free argi-
mode of action (Fig. 3). Arginine supplementa- nine) per day for 2 weeks.

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Fig. 3. Effect of arginine on wound-healing parameters in healthy elderly human volunteers. Accumulation of
hydroxyproline (OHP), total ␣-amino N, and DNA in subcutaneously implanted polytetrafluoroethylene catheters
was measured at the end of 2 weeks (mean ⫾ SEM). Controls (n ⫽ 15) received placebo syrup; the arginine group
(n ⫽ 30) received 30 g of arginine aspartate.

tion had no effect on the rate of epithelialization bumin. Patients treated with arginine, however,
of the skin defect, indicating that the predomi- had lower rates of fistula formation and, conse-
nant effect of arginine is on wound collagen quently, shorter hospital stays. Nursing home pa-
deposition.78 tients with pressure ulcers have been the most
Oral arginine supplementation is well toler- recent patient population studied with regard to
ated and has been the focus of recent studies of arginine supplementation. One study sought to
wound healing and medical outcomes. A recent determine the tolerance of oral arginine admin-
randomized trial in healthy volunteers demon- istration and effectiveness in improving mitogen-
strated improved collagen synthesis after dietary induced lymphocyte proliferation and interleu-
supplementation with arginine, glutamine, and kin-2 production, two in vitro parameters of
␤-hydroxy-␤-methylbutyrate.79 Despite improve- immune function.81 Subjects tolerated the argi-
ments in markers of collagen biosynthesis, how- nine supplementation well, but no improvement
ever, clinical evidence of improved wound healing in immune function was observed. Prior work in
has not been reported in most of the studies pub- volunteers and patients had shown that arginine
lished to date. In a study by de Luis et al., patients supplementation increased mitogen-induced lym-
undergoing resection for oral or laryngeal cancer phocyte proliferation,78,82,83 but other studies
were randomized to receive an enteral dietary sup- found no effect.84 – 86
plement containing either fiber or fiber and Several mechanisms have been postulated to
arginine.80 Postoperative infectious complications explain the positive effect of arginine on wound
were similar in the two groups, as were plasma healing. First, the beneficial effects of supplemen-
protein levels of albumin, transferrin, and preal- tal arginine on wound healing are similar to the

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 Plastic and Reconstructive Surgery • June Supplement 2006

effects seen with growth hormone.87– 89 In a study thus emphasizing its essential nature in wound
exploring this observation, hypophysectomized healing.77 The inducible isoform of nitric oxide
and normal pituitary-bearing animals were di- synthase, iNOS, is most active in response to in-
vided into two groups–-one receiving growth hor- flammatory stimuli (e.g., wounding) and gener-
mone and one receiving placebo–-with half the ates more nitric oxide than the constitutive
animals in each group also supplemented with 1% isoforms.70 Supranormal collagen deposition has
dietary arginine. After wounding, the intact, argi- been observed after transfection of iNOS DNA
nine-supplemented animals demonstrated in- into wounds,101 while mice lacking the iNOS gene
creased wound-breaking strength and collagen ac- experience delayed closures of excisional wounds,
cumulation, whether growth hormone was given an impairment that is remedied by adenoviral
or not. In the hypophysectomized animals, argi- transfer of the iNOS gene into the wound bed.102
nine had no effect on these wound-healing pa- Functional loss of the iNOS gene abrogates the
rameters, again regardless of the administration of beneficial effect of arginine in wound healing,
growth hormone. This result suggests that, in rats, whereas wild-type mice fed arginine-supple-
the effects of arginine on wound healing require mented diets exhibit improved incisional wound
an intact hypothalamopituitary axis.90 In humans, healing as assessed by breaking strength and col-
arginine supplementation in doses that have been lagen deposition. This finding suggests that the
shown to improve wound healing also increases iNOS pathway is at least partially responsible for
plasma insulin-like growth factor, the peripheral the enhancement of wound healing observed with
mediator of growth hormone activity.78 the administration of arginine.69
Second, supplemental arginine has a unique Arginine supplementation may play an es-
effect on T-cell function by stimulating T-cell re- pecially important role in the wound healing of
sponses and reducing the inhibitory effect of in- diabetic patients. As previously described, dia-
jury and wounding on T-cell function.73,91–93 T lym- betic patients exhibit an impaired inflamma-
phocytes are known to be essential for normal tory response to injury. This abnormal response
wound healing, as evidenced by decreased wound- is characterized by delayed neutrophil chemo-
breaking strength in animals treated with mono- taxis and impaired phagocytosis and leads to
clonal antibodies against all T lymphocytes. In decreased concentrations of nitric oxide and
addition, T lymphocytes can be detected immu- growth factors as well as inadequate collagen
nohistochemically in distinctive patterns through- synthesis. Animal models of diabetes, however,
out the various phases of wound healing. Further- have demonstrated that arginine supplementa-
more, specific T-cell types have modulating roles tion leads to greater wound-breaking strength
on different stages of cutaneous healing. T lym- resulting from increased levels of hydroxypro-
phocytes interact within the dynamics of each line and collagen.103,104
phase of healing to accomplish a specific task,
which, when considered collectively, leads to nor- Glutamine
mal repair of the wound.94 The exact mechanisms Glutamine is the most abundant amino acid
are not fully understood, but it is thought that one in the body; it accounts for approximately 20
manner in which arginine may enhance wound percent of the total circulating free amino acid
healing is by stimulating the host’s T-cell response, pool and 60 percent of the free intra-
which in turn increases fibroplasia.95–97 cellular amino acid pool.105,106 In addition to
Third, arginine has been identified as a being a major respiratory fuel source, glutamine
unique substrate for the generation of nitric ox- serves as a nitrogen donor for the synthesis of
ide, a highly reactive radical that may play a critical amino acids and amino sugars.107,108 Glutamine
role in wound healing. Inhibitors of nitric oxide is also an important precursor for the synthesis
have been shown to significantly impair the heal- of nucleotides in cells, including fibroblasts and
ing of cutaneous incisional wounds and colonic macrophages.109,110 Gluconeogenesis involves
anastomoses in rodents.98,99 In vitro studies have the shuttling of alanine and glutamine to the
noted increased collagen synthesis in cultured liver for conversion to glucose, which is used
dermal fibroblasts exposed to exogenous nitric peripherally as fuel for certain aspects of wound
oxide.100 Arginine is catabolized in wounds healing. Glutamine is also an energy source for
through two separate pathways, one involving ni- lymphocytes and is essential for lymphocyte pro-
tric oxide synthases and the other by arginase.70 liferation.111,112 Finally, glutamine has a crucial
Both pathways have been shown to deplete the role in stimulating the inflammatory immune
wound environment of extracellular arginine, response occurring early in wound healing.105

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Given the abundant roles of glutamine in the Although the recommended dietary allow-
cells involved in wound healing, it is not surprising ance for vitamin C is 60 mg/d, the clinical spec-
that there is a rapid fall in plasma and muscle trum of its administration varies widely. In major
glutamine levels after injury.113,114 Although effi- burn victims, the requirement may be as much as
cacy of supplemental glutamine administration 2 g per day to restore urine and tissue levels to
has been shown in some clinical situations,115 it has normal.123 In animal models, the wounds of
not proved to have any noticeable effect on wound burned guinea pigs bore histologic resemblance
healing specifically.116 Most of glutamine’s benefit to those of scorbutic unburned animals. These
appears to involve improvements in gut perme- changes were prevented when supplemental vita-
ability, normalization of serum levels, improved min C was given. Although the dose needed in
protein synthesis, and decreased hospital length different settings may vary, there is no evidence to
of stay.117–119 suggest that massive doses of ascorbic acid provide
any substantial benefit to wound healing. There
also is no evidence that excess vitamin C is toxic.124
Vitamins Vitamin C deficiency, in addition to impairing
The vitamins most closely associated with wound healing, has been associated with an in-
wound healing are vitamin C (ascorbic acid) and creased susceptibility to wound infection. If
vitamin A. Vitamin C deficiency is well known be- wound infection does occur in the setting of vita-
cause of its historical significance in relation to min C deficiency, it is apt to be more severe. These
scurvy (scorbutus). The earliest accounts of this effects are thought to be attributable to impaired
deficiency were in sailors and field armies who collagen synthesis and a subsequent inability to
consumed a diet lacking in fresh fruits and vege- wall off bacteria and localize infection, as well an
tables and who subsequently developed scurvy. In impairment of neutrophil function and comple-
the late 1800s, Osler120 categorized and eloquently ment activity.34
described the manifestations of this condition, McCollum and Davis initially discovered vita-
noting that it had virtually disappeared as a clinical min A in the early 1900s. Since that time it has been
entity, owing in large part to the work of Lind.
shown to be beneficial to the wound-healing pro-
Scurvy has as its central element a failure in col-
cess by stimulating epithelialization and collagen
lagen synthesis and cross-linking.121 The symptoms
deposition by fibroblasts. Brandaleone and
of scurvy reflect this impaired synthesis of collagen
Papper125 were the first to demonstrate that
and connective tissue and include bleeding into
the gingiva, skin, joints, peritoneum, pericardium, wound healing was impaired by vitamin A defi-
and adrenal glands. More generalized symptoms ciency. Ehrlich and Hunt126 subsequently de-
include weakness, fatigue, and depression. During scribed the benefits of supplemental vitamin A on
the time that Osler was describing the symptoms wound healing in nondeficient humans and ani-
of scurvy, the underlying defect in collagen was mals by showing that vitamin A can reverse the
not understood. Crandon and colleagues122 first anti-inflammatory effects of corticosteroids on
revealed the significance of this “intracellular sub- wound healing. The administration of vitamin A,
stance” (collagen) and the temporal aspects of topically or systemically, also can correct the im-
vitamin C deficiency. In 1940, while working as a paired wound healing of patients on long-term
surgical resident, Crandon consumed a diet lack- steroid therapy.127,128 Finally, vitamin A has been
ing vitamin C. After 3 months on this diet, a skin used to restore the impaired wound healing
incision healed normally and a biopsy sample 10 caused by diabetes, tumor formation, cyclophos-
days after the injury was normal. After 6 months on phamide, and radiation.129 –132
this diet, however, a second incision healed As alluded to earlier, vitamin A increases the
poorly, and a 10-day biopsy sample revealed a lack inflammatory response in wounds. This in-
of “intracellular substance.” After resuming a diet creased response is thought to occur by an en-
supplemented with 1 g of ascorbic acid per day, hanced lysosomal membrane lability, increased
healing improved, and a final biopsy sample macrophage influx and activation, and stimula-
showed increased collagen and capillary forma- tion of collagen synthesis.36 In vitro studies have
tion. These early histologic descriptions are con- shown increased collagen synthesis of fibroblast
sistent with the findings now known to be associ- cell cultures in the presence of vitamin A.133,134
ated with vitamin C deficiency: minimal collagen These mechanisms still are not well understood,
deposition, decreased angiogenesis, and signifi- but it is clear vitamin A plays in important role
cant hemorrhage. in wound healing.

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Serious injury or stress leads to increased vi- toma formation within a wound, which can impair
tamin A requirements. Large doses of corticoste- healing and predispose to infection. It is this he-
roids can also deplete hepatic stores of vitamin A. mostatic capacity of vitamin K that most influences
Decreased serum levels of vitamin A, retinol-bind- wound healing.15
ing protein, retinyl esters, and ␤-carotene have
been noted after burns, fractures, and elective
surgery.135–137 In the severely injured, doses of vi- Micronutrients
tamin A of 25,000 IU/d (five times the recom- Micronutrients are essential components of
mended daily dose) have been advocated and cellular function and can be divided into organic
used without any significant side effects. Larger compounds, such as the vitamins already dis-
doses of vitamin A do not improve further wound cussed, and inorganic compounds or trace ele-
healing, and prolonged excessive intake can be ments. Although these nutrients comprise only a
toxic.138 small portion of the body’s overall nutritional
The fat-soluble vitamin A and the water-solu- needs, they are relied on heavily by the cellular
ble vitamin C are the predominant vitamins at machinery that carries out wound healing. It is
work in the wound-healing process. The other difficult to associate deficits in specific minerals
water-soluble vitamin is vitamin B complex, which and trace elements to impairments in wound heal-
may have an indirect role in wound healing ing, because micronutrient deficiencies almost al-
through its influence on host resistance. The re- ways are accompanied by other coexisting meta-
maining fat-soluble vitamins, D, E, and K, do not bolic or nutritional disturbances. Most of these
contribute significantly to wound healing. minerals and trace elements do not influence
Vitamin E maintains and stabilizes cellular wound healing directly; rather they serve as co-
membrane integrity, primarily by protection factors or part of an enzyme that is essential to
against destruction by oxidation.139 Vitamin E pos- healing and homeostasis. Clinicians became more
sesses anti-inflammatory properties, similar to aware of deficiencies of these elements after the
those of steroids, as shown by the reversal of introduction of long-term parenteral nutritional
wound-healing impairment imposed by vitamin E solutions, which did not include supplemental
after administration of vitamin A in the first days minerals and trace elements. As such, it is often
after wounding.140 Vitamin E also has been shown easier to prevent these deficiencies than to diag-
to affect various host immune functions. As an nose them clinically.34
antioxidant, vitamin E may reduce injury to the Magnesium is essential for wound repair and
wound by scavenging excess free radicals.141 The functions as a cofactor for many enzymes involved
liberation of free radicals from inflammatory cas- in protein and collagen synthesis.15,139 The pri-
cades in necrotic tissue, tissue colonized with mi- mary role of magnesium is to provide structural
crobial flora, ischemic tissue, and chronic wounds stability to adenosine triphosphate, which powers
can result in depletion of free radical scavengers many of the processes used in collagen synthesis,
such as vitamin E.142,143 This process is believed to thus making it a factor essential to wound
be at work in patients with chronic lower extremity repair.127,139
wounds. In these patients it is not known if their Of the numerous trace elements present in the
relative lack of vitamin E is due to consumption of body, copper, zinc, and iron have the closest re-
vitamin E in its antioxidant capacity or overall lationship to wound healing. Copper is a required
vitamin E deficiency, either of which could impair cofactor for cytochrome oxidase, the cytosolic an-
healing. Some authors have suggested that, in tioxidant superoxide dismutase, and for the opti-
chronic wounds of the lower extremity, vitamin E mal functioning of lysyl oxidase, an enzyme that
may have a role in decreasing excess scar forma- catalyzes the cross-linking of collagen and
tion, which is known to occur in chronic wounds.15 strengthens the collagen framework.138,139 Exper-
While two studies in animal models have sug- imentally, impaired healing has been noted sec-
gested a beneficial effect of vitamin E supplemen- ondary to decreased copper stores in patients with
tation on wound healing,144,145 supplementation in Wilson’s disease and in animals after the admin-
humans has not been shown to have a beneficial istration of penicillamine.148,149
effect on wound healing.36,146,147 Zinc is the most well-known element in wound
Vitamin K is required for the carboxylation of healing and has been used empirically in derma-
glutamate in clotting factors II, VII, IX, and X and tologic conditions for centuries. Zinc is a cofactor
contributes little to direct wound healing. Its ab- for both RNA and DNA polymerase and, there-
sence or deficiency, however, may lead to hema- fore, is involved in DNA synthesis, protein synthe-

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Volume 117, Number 7S • Nutrition and Wound Healing

sis, and cellular proliferation. Zinc deficiency im- clearing wound infection. The immune system is
pairs the crucial roles each of these processes play tied to overall host nutrition and specific nutri-
in wound healing and leads, ultimately, to delayed tional entities, such as arginine and its related
wound healing.150 In zinc deficiency, fibroblast metabolic pathways. In critically ill patients, it is
proliferation and collagen synthesis are de- crucial that nutritional status be optimized to pro-
creased, leading to decreased wound strength and vide increased substrate availability to meet the
delayed epithelialization. These defects are readily demands of tissue repair and immune function
reversed with repletion of zinc to normal levels.34 and to prevent wounds from succumbing to in-
Both cellular and humoral immune functions are fection and delayed healing.156
impaired in zinc deficiency, resulting in an in-
creased susceptibility to wound infection and a
resultant increased probability of delayed healing. Evaluation of Overall Nutritional State
Zinc levels can be depleted in settings of severe Clinicians must be aware of nutritional distur-
stress151 and in patients receiving long-term bances in wounded patients before these nutri-
steroids.15 In these settings, it is recommended tional deficits can be corrected. The severity of the
that patients receive vitamin A and zinc supple- deficit must be assessed and the caloric require-
mentation to improve wound healing152 ; the cur- ments for healing to ensue should be estimated.
rent recommended daily allowance for zinc is 15 Kinney157 outlined the metabolic adjustments ex-
mg. No studies have shown improvement in perienced after injury as follows: (1) uncompli-
wound healing after the administration of zinc to cated intra-abdominal surgery increases the met-
patients who are not already zinc deficient.153 abolic rate approximately 10 percent; (2)
Iron is required for the hydroxylation of pro- uncomplicated injuries, such as femoral fracture,
line and lysine, and as a result, severe iron defi- increase metabolism about 20 percent; (3) peri-
ciency can result in impaired collagen production. tonitis increases metabolism 20 percent to 40 per-
Iron is also a component of the oxygen transport cent; (4) third-degree burns increase metabolism
system and can affect wound healing in this ca- 50 percent to 100 percent; and (5) fever increases
pacity, but only in settings of severe iron-defi- metabolism 10 percent for each 1ºC above nor-
ciency anemia. In the clinical environment, iron mothermia. Historically, the sine qua non of linear
deficiency is common and can result from blood nutritional status measurements over time has
loss, infection, malnutrition, or an underlying he- been serial weight measurements. This commonly
matopoietic disorder. In contrast to other defi- used marker for malnutrition can be misleading,
ciencies of trace elements, iron deficiency is easily however, if the presence of abnormal amounts of
detected and treated.15,128 body water is not taken into account. Total body
water increases at approximately the same rate
OTHER FACTORS AFFECTING WOUND that body protein decreases.158 Body water also can
HEALING influence the anthropometric measurements
used to estimate body fat from skin-fold thickness
Infection and predetermined nomograms.
The complex cascade of events that comprise Other markers predictive of nutritional state
the body’s response to tissue injury with the pur- include serum albumin, prealbumin, retinol-bind-
pose of restoring cutaneous integrity occurs in the ing protein and transferrin levels, total lympho-
presence of various environmental factors. Any of cyte count, anergy-delayed hypersensitivity, uri-
these factors can impair the wound-healing pro- nary nitrogen, and respiratory minute volume.
cess if they are not effectively managed or pre- One of the least expensive and practical ways to
vented. estimate simple caloric requirements of seriously
Sepsis, whether present as local bacterial col- ill patients is respiratory minute volume. In the
onization of the wound site or as a systemic in- absence of metabolic acidosis or alkalosis, with
flammatory response, is one of the most formida- normal breathing, the respiratory minute volume
ble obstacles to successful wound healing. gives a close correlation to the patient’s metabolic
Experimentally, the crucial inoculum of microor- rate. This value can then be used to guide nutri-
ganisms that significantly inhibits healing is 105 tional care. Serum albumin levels and total lym-
colony-forming units per square centimeter of phocyte count also are useful nutritional prognos-
wound surface or gram of tissue.154,155 In addition ticators. In a study of nutritional status as a
to appropriate antibiotic therapy, an intact, func- predictor of wound healing after amputation, nor-
tioning immune system is vital to preventing and mal albumin and total lymphocyte levels corre-

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 Plastic and Reconstructive Surgery • June Supplement 2006

lated with increased rates of healing.9 These values least 7 days preoperatively.160 –163 Total parenteral
can be misinterpreted, however, if factors such as nutrition has many associated risks, however, not
liver dysfunction, sepsis, or infection are present the least of which is infection. Total enteral nu-
and not taken into account. A depressed hyper- trition has associated risks as well, but there is
sensitivity reaction to intradermally injected anti- growing experimental evidence that it is superior
gens has also been established as an indicator of to total parenteral nutrition as a feeding modality.
nutritional status.159 Studies evaluating the route of nutrition and
wound healing in rats showed that total enteral
Feeding nutrition particularly influences the early stages of
Wound healing has been described repeatedly wound healing. In these studies, total enteral nu-
in this article as a complex series of cellular and trition significantly increased collagen deposition
biochemical events that are dependent on energy and wound-breaking strength when measured
availability. The substrates for wound-healing en- within 5 days after wounding when compared with
ergy are protein, carbohydrate, fat, amino acids, total parenteral nutrition (Fig. 4). This beneficial
and micronutrients. Specifically, it has been rec- influence seems to disappear during the period of
ommended that the calorie-to-nitrogen ratio be maximal fibroplasias, which occurs 5 to 10 days
120 to 150:1 during the early weeks of wound after injury. Total enteral nutrition maintains local
healing after severe injury; it should then be raised and systemic immune responses, improves protein
to 200 to 225:1 as the body shifts to a period of metabolism and survival, and preserves gut integrity,
positive nitrogen balance.138 thereby decreasing bacterial translocation.164 –167 As
Patients who are malnourished before injury already alluded to, total enteral nutrition seems to
have increased rates of wound infection and ex- exert a greater influence over the early cellular, in-
hibit delayed wound healing. There seems to be flammatory phase of wound healing than total par-
ample evidence that nutritional repletion before enteral nutrition. This cellular phase is exquisitely
planned elective operations in malnourished pa- sensitive to nutrient availability. The influence total
tients significantly reduces these complications. enteral nutrition has on systemic immune function
The exact route of administration, whether en- contributes to the function and number of inflam-
teral or parenteral, may be important, but the data matory cells present during early healing, ultimately
are conflicting. affecting wound repair.168
Total parenteral nutrition has been shown to Specific feeding regimens, however, should be
reduce postoperative complications when admin- tailored to individual patients. In patients who are
istered to severely malnourished patients for at malnourished, preoperative repletion should be

Fig. 4. Wound-breaking strength (g, mean ⫾ SEM) and hydroxyproline content (␮g/100 mg sponge, mean ⫾ SEM)
of the sponge granulomas in enterally [total enteral nutrition (open square)] and parenterally [total parenteral
nutrition (striped square)] fed animals.

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Volume 117, Number 7S • Nutrition and Wound Healing

accomplished by the route that exposes the pa- rations and its use is generally only indicated
tient to the least risk, and if possible, elective op- for less than 7 days.173
erations should be delayed until the patient is Serum protein markers are the best way to
satisfactorily supplemented. In patients who are assess the adequacy of nutritional supplementa-
not likely to take nutrition orally, total parenteral tion, as conventional methods, such as daily
nutrition should be initiated early. The nutritional weight, may not be accurate in critically ill pa-
supplement should be as specific as possible to the tients. While albumin is commonly used as a pre-
patient’s perceived nutritional deficiency, and operative marker of nutritional, its half-life of 18
substrates that are turned over rapidly (e.g., argi- to 21 days precludes its use as an effective daily
nine) should be included. Because even brief pe- indicator of improvements in nutritional status.
riods of malnutrition can have significant negative Prealbumin (half-life, 3 to 5 days) and transferrin
effects on wound healing, nutritional deficiencies (half-life, 7 to 10 days) should be monitored
must be recognized early and repletion initiated as
weekly in patients receiving enteral or parenteral
soon as possible.
nutritional support.
CLINICAL IMPLICATIONS Beyond the basic understanding that general
The clinical significance of nutrition and nutritional support is critical for optimal wound
wound healing involves individual patients with healing, many questions remain about the specific
unique needs. The goal of the physician, then, is type of supplementation that should be used. Al-
to determine whether, when, and how nutritional though glutamine and arginine have been shown
supplementation is needed. There are few con- to have beneficial effects on wound healing in
crete answers. Although the benefits of perioper- animal models and in healthy volunteers, their
ative nutritional support are apparent, the risk clinical significance has yet to be proven. We can-
complications and increased cost need to be con- not, therefore, recommend their general use in
sidered as well. severely injured or postsurgical patients. Supple-
Preoperative nutritional support is generally mental vitamin C appears to have beneficial effects
recommended for patients with moderate (10 to in burn healing, whereas vitamin A is best reserved
20 percent weight loss; serum albumin ⬍3.2 g/dl for those patients who have required long-term
to ⬎2.5 g/dl) to severe malnutrition (⬎20 percent corticosteroid therapy. Zinc and iron supplemen-
weight loss; serum albumin ⬍2.5 g/dl)169 and who tation, on the other hand, are best reserved for
can tolerate waiting at least 7 days for an elective those with preexisting deficiency states.
operation. If intestinal function is maintained in
a patient, enteral nutritional support is generally
preferred, as it is associated with the maintenance SUMMARY
of gut mucosal barrier function, the decreased The relationship between host nutrition and
activation of gut-associated lymphoid tissue, and wound healing has been the subject of study and
lower costs of administration than parenteral experimentation for centuries. Despite the many
nutrition.170,171 While the only absolute contrain- years of study and substantial knowledge base of
dication to enteral feeding is complete intestinal the specific processes and factors involved, wound
obstruction, a variety of relative contraindications healing remains enigmatic. There is still much to
(e.g., high-output intestinal fistulas, acute pancre- learn about the wound-specific nutritional inter-
atitis, acute inflammatory bowel disease, severe
ventions that are available to improve wound heal-
diarrhea) must be considered. Enteral nutritional
ing. Nutrition profoundly influences the process
support may be achieved via nasogastric, nasoen-
teric, gastrostomy, jejunostomy, or gastrojejunal of wound healing, such that depletion exerts an
tubes, and a variety of commercial nutrition prod- inhibitory effect and nutritional supplementation
ucts are available for use in specialized patient has a positive effect. Within this paradigm, the
populations.172 Parenteral nutritional support is physician should be able to recognize patients who
often used as the sole source of caloric intake in may be expected to have wound-healing difficul-
hospitalized patients, but there are some instances ties and offer early intervention to avoid wound
in which its use is best as a supplement to enteral failure.
feeding. Although peripheral parenteral nutrition Adrian Barbul, M.D.
may be easier to implement because it does not 2401 W. Belvedere Avenue
require central venous access, its nutritive value Baltimore, Md. 21215
is substantially less than that of central prepa- abarbul@[Link]

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 Plastic and Reconstructive Surgery • June Supplement 2006

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Volume 117, Number 7S • Nutrition and Wound Healing

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