Review                                            Wound Healing
                                            Nutritional Support
                                             for Wound Healing
                                                                                      Douglas MacKay, ND,
                                                                                     and Alan L. Miller, ND
                Abstract                                            Introduction
                Healing of wounds, whether from accidental                  Wound healing involves a complex series
                injury or surgical intervention, involves the       of interactions between different cell types,
                activity of an intricate network of blood cells,    cytokine mediators, and the extracellular matrix.
                tissue types, cytokines, and growth factors.        The phases of normal wound healing include he-
                This results in increased cellular activity, which  mostasis, inflammation, proliferation, and remod-
                causes an intensified metabolic demand for          eling. Each phase of wound healing is distinct,
                nutrients. Nutritional deficiencies can impede      although the wound healing process is continu-
                wound healing, and several nutritional factors      ous, with each phase overlapping the next. Be-
                required for wound repair may improve healing       cause successful wound healing requires adequate
                time and wound outcome. Vitamin A is required       blood and nutrients to be supplied to the site of
                for epithelial and bone formation, cellular         damage, the overall health and nutritional status
                differentiation, and immune function. Vitamin       of the patient influences the outcome of the dam-
                C is necessary for collagen formation, proper       aged tissue. Some wound care experts advocate a
                immune function, and as a tissue antioxidant.       holistic approach for wound patients that consid-
                Vitamin E is the major lipid-soluble antioxidant    ers coexisting physical and psychological factors,
                in the skin; however, the effect of vitamin E on    including nutritional status and disease states such
                surgical wounds is inconclusive. Bromelain                                                       1
                reduces edema, bruising, pain, and healing          as diabetes, cancer, and arthritis. Keast and Orsted
                time following trauma and surgical procedures.      wittily state, “Best practice requires the assess-
                Glucosamine appears to be the rate-limiting         ment of the whole patient, not just the hole in the
                substrate for hyaluronic acid production in the     patient. All possible contributing factors must be
                wound. Adequate dietary protein is absolutely       explored.”
                essential for proper wound healing, and tissue              Wound repair must occur in a physiologic
                levels of the amino acids arginine and              environment conducive to tissue repair and regen-
                glutamine may influence wound repair and            eration. However, several clinically significant
                immune function. The botanical medicines            factors are known to impede wound healing, in-
                Centella asiatica and Aloe vera have been used      cluding hypoxia, infection, tumors, metabolic dis-
                for decades, both topically and internally, to      orders such as diabetes mellitus, the presence of
                enhance wound repair, and scientific studies        debris and necrotic tissue, certain medications, and
                are now beginning to validate efficacy and
                explore mechanisms of action for these              Douglas J. MacKay, ND – Technical Advisor, Thorne
                botanicals. To promote wound healing in the         Research, Inc; Senior Editor, Alternative Medicine Review;
                shortest time possible, with minimal pain,          private practice, Sandpoint, ID.
                                                                    Correspondence address: Thorne Research, PO Box 25,
                discomfort, and scarring to the patient, it is      Dover, ID 83825  E-mail: duffy@thorne.com
                important to explore nutritional and botanical      Alan L. Miller, ND – Technical Advisor, Thorne Research,
                influences on wound outcome.                        Inc; Senior Editor, Alternative Medicine Review.
                (Altern Med Rev 2003;8(4):359-377)                  Correspondence address: Thorne Research, PO Box 25,
                                                                    Dover, ID  83825  E-mail: alanm@thorne.com
                                        
            Alternative Medicine Review ◆  Volume 8, Number 4 ◆ 2003                                                               Page 359
          Wound Healing                                                  Review
               a diet deficient in protein, vitamins, or minerals.         tissue. The neutrophils engulf debris and
               In addition, increased metabolic demands are                microorganisms, providing the first line of defense
               made by the inflammation and cellular activity in           against infection. Neutrophil migration ceases
               the healing wound, which may require increased              after the first few days post-injury if the wound is
               protein or amino acids, vitamins, and minerals.2            not contaminated. If this acute inflammatory phase
                        The objective in wound management is               persists, due to wound hypoxia, infection,
               to heal the wound in the shortest time possible,            nutritional deficiencies, medication use, or other
               with minimal pain, discomfort, and scarring to the          factors related to the patient’s immune response,
                                                                                                                              3
               patient. At the site of wound closure a flexible and        it can interfere with the late inflammatory phase.
               fine scar with high tensile strength is desired.                     In the late inflammatory phase, monocytes
               Understanding the healing process and nutritional           converted in the tissue to macrophages, which di-
               influences on wound outcome is critical to suc-             gest and kill bacterial pathogens, scavenge tissue
               cessful management of wound patients. Research-             debris and destroy remaining neutrophils. Mac-
               ers who have explored the complex dynamics of               rophages begin the transition from wound inflam-
               tissue repair have identified several nutritional           mation to wound repair by secreting a variety of
               cofactors involved in tissue regeneration, includ-          chemotactic and growth factors that stimulate cell
               ing vitamins A, C, and E, zinc, arginine, glutamine,        migration, proliferation, and formation of the tis-
               and glucosamine. Botanical extracts from Aloe               sue matrix.
               vera, Centella asiatica, and the enzyme brome-                       The subsequent proliferative phase is
               lain from pineapple have also been shown to im-             dominated by the formation of granulation tissue
               prove healing time and wound outcome. Eclectic              and epithelialization. Its duration is dependent on
               therapies, including topical application of honey,          the size of the wound. Chemotactic and growth
               sugar, sugar paste, or Calendula succus to open             factors released from platelets and macrophages
               wounds, and comfrey poultices and hydrotherapy              stimulate the migration and activation of wound
               to closed wounds are still in use today. Although           fibroblasts that produce a variety of substances
               anecdotal reports support the efficacy of these             essential to wound repair, including glycosami-
               eclectic therapies, scientific evidence is lacking.         noglycans (mainly hyaluronic acid, chondroitin-
                                                                           4-sulfate, dermatan sulfate, and heparan sulfate)
                                                                                         2
               The Four Phases of Wound Healing                            and collagen.  These form an amorphous, gel-like
                        Tissue injury initiates a response that first      connective tissue matrix necessary for cell migra-
               clears the wound of devitalized tissue and foreign          tion.
               material, setting the stage for subsequent tissue                    New capillary growth must accompany
               healing and regeneration. The initial vascular re-          the advancing fibroblasts into the wound to pro-
               sponse involves a brief and transient period of             vide metabolic needs. Collagen synthesis and
               vasoconstriction and hemostasis. A 5-10 minute              cross-linkage is responsible for vascular integrity
               period of intense vasoconstriction is followed by           and strength of new capillary beds. Improper
               active vasodilation accompanied by an increase              cross-linkage of collagen fibers has been respon-
               in capillary permeability. Platelets aggregated             sible for nonspecific post-operative bleeding in
               within a fibrin clot secrete a variety of growth fac-       patients with normal coagulation parameters.4
               tors and cytokines that set the stage for an orderly        Early in the proliferation phase fibroblast activity
               series of events leading to tissue repair.                  is limited to cellular replication and migration.
                        The second phase of wound healing, the             Around the third day after wounding the growing
               inflammatory phase, presents itself as erythema,            mass of fibroblast cells begin to synthesize and
               swelling, and warmth, and is often associated with          secrete measurable amounts of collagen. Collagen
               pain. The inflammatory response increases                   levels rise continually for approximately three
               vascular permeability, resulting in migration of            weeks. The amount of collagen secreted during
               neutrophils and monocytes into the surrounding              this period determines the tensile strength of the
                                                                           wound.
                                                                                              
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                 Review                                            Wound Healing
                        Figure 1.  Nutrient Impacts on the Phases of Wound Healing
                          Wounding
                                     Calendula succus – topical antimicrobial
                          Hemostasis
                                     Drugs, herbs, vitamins, amino acids, or minerals that effect blood-clotting 
                                      mechanisms should be avoided prior to surgery.
                          Inflammatory Phase
                                     Vitamin A – enhances early inflammatory phase
                                     Bromelain and adequate protein intake – prevent prolonging inflammatory phase 
                                     Vitamin C – enhances neutrophil migration and lymphocyte transformation
                          Proliferative Phase
                                     Vitamin C – necessary for collagen synthesis
                                     Centella asiatica – promotes type-1 collagen synthesis
                                     Glucosamine – enhances hyaluronic acid production
                                     Vitamin A – promotes epithelial cell differentiation
                                     Zinc – required for DNA synthesis, cell division, and protein synthesis
                                     Calendula succus and Aloe vera – support formation of granulation tissue
                          Remodeling
                                     Protein deficiency – inhibits wound remodeling
                        The final phase of wound healing is                    Figure 1 summarizes the phases of wound
                wound remodeling, including a reorganization of        healing and nutrients that impact the various
                new collagen fibers, forming a more organized lat-     phases.
                tice structure that progressively continues to in-
                crease wound tensile strength. The remodeling
                process continues up to two years, achieving 40-
                70 percent of the strength of undamaged tissue at
                four weeks.2
                                         
             Alternative Medicine Review ◆  Volume 8, Number 4 ◆ 2003                                                               Page 361
         Wound Healing                                                  Review
              Vitamins and Minerals Essential to                  with fractures, tendon damage, or vitamin A defi-
              Wound Healing                                       ciency may also benefit from perioperative vita-
              Vitamin A                                           min A supplementation. Additional research is
                                                                  necessary to establish the effectiveness of univer-
                     Vitamin A is required for epithelial and     sal perioperative vitamin A supplementation in
              bone tissue development, cellular differentiation,  healthy individuals.
              and immune system function. Substantial evidence            Concern among some practitioners re-
              supports the use of vitamin A as a perioperative    garding the potential toxicity of higher doses of
              nutritional supplement.5
                                     In addition to facilitating  vitamin A has led to uneasiness about using it
              normal physiological wound repair, Ehrlich and      perioperatively. The vast majority of toxicity cases
              Hunt have shown vitamin A reverses the cortico-     have occurred at daily vitamin A dosages of
              steroid-induced inhibition of cutaneous and fas-    50,000-100,000 IU in adults over a period of
                               6-8                                               15
              cial wound healing.  Vitamin A has also corrected   weeks to years.  Short-term supplementation of
              non-steroid induced, post-operative immune de-      25,000 IU daily appears to be safe for most non-
                     9
              pression  and improved survival in surgically-in-   pregnant adults. Caution must be exercised in
              duced abdominal sepsis.10 Levenson et al suggest    supplementing vitamin A in patients for whom the
              vitamin A benefits the wound by enhancing the       anti-inflammatory effect of steroids is essential,
              early inflammatory phase, including increasing the  such as in rheumatoid arthritis or organ transplants,
              number of monocytes and macrophages at the          as well as in pregnant women and women of child-
              wound site, modulating collagenase activity, sup-   bearing age.5
              porting epithelial cell differentiation, and improv-
              ing localization and stimulation of the immune      Vitamin C
              response.10,11                                              Ascorbic acid is an essential cofactor for
                     Animal studies show vitamin A may in-        the synthesis of collagen, proteoglycans, and other
              crease both collagen cross-linkage and wound-       organic components of the intracellular matrix of
              breaking strength. Greenwald et al inflicted sur-   tissues such as bones, skin, capillary walls, and
              gical flexor profundus damage and immediate re-     other connective tissues. Ascorbic acid deficiency
              pair on adult chickens. They found chickens that    causes abnormal collagen fibers and alterations
              ate a diet supplemented with vitamin A (150,000     of the intracellular matrix that manifests as cuta-
              IU/kg chicken chow) demonstrated wound-break-       neous lesions, poor adhesion of endothelium cells,
              ing strength more than double that of controls fed                                              16
              standard chicken chow.12 In addition, rats with     and decreased tensile strength of fibrous tissue.
              dorsal skin incisions and concurrent comminuted     Clinical manifestations of ascorbic acid deficiency
              femoral fractures exhibited delayed cutaneous       include bleeding gums, poor immunity, easy bruis-
              healing. Supplemental vitamin A enhanced wound      ing and bleeding, and slow healing of wounds and
                                                                           17
              healing in these animals, demonstrated by in-       fractures.  Ascorbic acid is necessary for the hy-
              creased breaking strength of the dorsal skin inci-  droxylation of proline and lysine residues in
              sions in rats fed supplemental vitamin A compared   procollagen, which is necessary for its release and
              to the non-supplemented group. The authors be-      subsequent conversion to collagen. Hydroxypro-
              lieve the improved wound healing is a result of an  line also stabilizes the collagen triple-helix struc-
                                                                       18
                                                   13             ture.  In addition to collagen production, ascor-
              increased rate of collagen cross-linkage.                                              19
                     Levenson and Demetrio recommend vi-          bic acid enhances neutrophil function,  increases
                                                                               20
              tamin A supplementation of 25,000 IU daily be-      angiogenesis,  and functions as a powerful anti-
                                                                  oxidant.21
              fore and after elective surgery.14 Research supports        Although ascorbic acid is required for
              perioperative vitamin A supplementation in pa-      reparation of damaged tissue, researchers have
              tients known to be immune depleted or steroid       demonstrated the benefit of vitamin C only in vi-
              treated. Surgical patients with sepsis and those    tamin C-deficient individuals using low doses of
                                                                                   
          Page 362                                                           Alternative Medicine Review ◆  Volume 8, Number 4 ◆ 2003