Alternative Medicine Review 2003 (Nov); 8 (4): 359–377 ~ FULL TEXT
MacKay D, Miller AL
Thorne Research, Inc.,
PO Box 25, Dover, ID 83825, USA.
Healing of wounds, whether from accidental injury or surgical intervention, involves the activity of an intricate network of blood cells, tissue types, cytokines, and growth factors. This results in increased cellular activity, which causes an intensified metabolic demand for nutrients. Nutritional deficiencies can impede wound healing, and several nutritional factors required for wound repair may improve healing time and wound outcome. Vitamin A is required for epithelial and bone formation, cellular differentiation, and immune function. Vitamin C is necessary for collagen formation, proper immune function, and as a tissue antioxidant. Vitamin E is the major lipid-soluble antioxidant in the skin; however, the effect of vitamin E on surgical wounds is inconclusive. Bromelain reduces edema, bruising, pain, and healing time following trauma and surgical procedures. Glucosamine appears to be the rate-limiting substrate for hyaluronic acid production in the wound. Adequate dietary protein is absolutely essential for proper wound healing, and tissue levels of the amino acids arginine and glutamine may influence wound repair and immune function. The botanical medicines Centella asiatica and Aloe vera have been used for decades, both topically and internally, to enhance wound repair, and scientific studies are now beginning to validate efficacy and explore mechanisms of action for these botanicals. To promote wound healing in the shortest time possible, with minimal pain, discomfort, and scarring to the patient, it is important to explore nutritional and botanical influences on wound outcome.
Wound healing involves a complex series of interactions between different cell types, cytokine mediators, and the extracellular matrix. The phases of normal wound healing include hemostasis, inflammation, proliferation, and remodeling.
Each phase of wound healing is distinct, although the wound healing process is continuous, with each phase overlapping the next. Because successful wound healing requires adequate blood and nutrients to be supplied to the site of
damage, the overall health and nutritional status of the patient influences the outcome of the damaged tissue. Some wound care experts advocate a holistic approach for wound patients that considers coexisting physical and psychological factors,
including nutritional status and disease states such as diabetes, cancer, and arthritis. Keast and Orsted  wittily state, “Best practice requires the assessment of the whole patient, not just the hole in the patient. All possible contributing factors must be explored.”
Wound repair must occur in a physiologic environment conducive to tissue repair and regeneration. However, several clinically significant factors are known to impede wound healing, including hypoxia, infection, tumors, metabolic disorders
such as diabetes mellitus, the presence of debris and necrotic tissue, certain medications, and a diet deficient in protein, vitamins, or minerals. In addition, increased metabolic demands are made by the inflammation and cellular activity in the healing wound, which may require increased protein or amino acids, vitamins, and minerals. 
The objective in wound management is to heal the wound in the shortest time possible, with minimal pain, discomfort, and scarring to the patient. At the site of wound closure a flexible and fine scar with high tensile strength is desired.
Understanding the healing process and nutritional influences on wound outcome is critical to successful management of wound patients. Researchers who have explored the complex dynamics of tissue repair have identified several nutritional
cofactors involved in tissue regeneration, including vitamins A, C, and E, zinc, arginine, glutamine, and glucosamine. Botanical extracts from Aloe vera, Centella asiatica, and the enzyme bromelain from pineapple have also been shown to improve healing time and wound outcome. Eclectic therapies, including topical application of honey, sugar, sugar paste, or Calendula succus to open wounds, and comfrey poultices and hydrotherapy to closed wounds are still in use today. Although
anecdotal reports support the efficacy of these eclectic therapies, scientific evidence is lacking.
The Four Phases of Wound Healing
Tissue injury initiates a response that first clears the wound of devitalized tissue and foreign material, setting the stage for subsequent tissue healing and regeneration. The initial vascular response involves a brief and transient period of vasoconstriction and hemostasis. A 5-10 minute period of intense vasoconstriction is followed by active vasodilation accompanied by an increase in capillary permeability. Platelets aggregated within a fibrin clot secrete a variety of growth factors and cytokines that set the stage for an orderly series of events leading to tissue repair.
The second phase of wound healing, the inflammatory phase, presents itself as erythema, swelling, and warmth, and is often associated with pain. The inflammatory response increases vascular permeability, resulting in migration of neutrophils and monocytes into the surrounding tissue. The neutrophils engulf debris and microorganisms, providing the first line of defense against infection. Neutrophil migration ceases after the first few days post-injury if the wound is not contaminated. If this acute inflammatory phase persists, due to wound hypoxia, infection, nutritional deficiencies, medication use, or other factors related to the patient’s immune response, it can interfere with the late inflammatory phase. 
In the late inflammatory phase, monocytes converted in the tissue to macrophages, which digest and kill bacterial pathogens, scavenge tissue debris and destroy remaining neutrophils. Macrophages begin the transition from wound inflammation to wound repair by secreting a variety of chemotactic and growth factors that stimulate cell
migration, proliferation, and formation of the tissue matrix.
The subsequent proliferative phase is dominated by the formation of granulation tissue and epithelialization. Its duration is dependent on the size of the wound. Chemotactic and growth factors released from platelets and macrophages stimulate the migration and activation of wound fibroblasts that produce a variety of substances essential to wound repair, including glycosaminoglycans (mainly hyaluronic acid, chondroitin-4-sulfate, dermatan sulfate, and heparan sulfate) and collagen.  These form an amorphous, gel-like connective tissue matrix necessary for cell migration.
New capillary growth must accompany the advancing fibroblasts into the wound to provide metabolic needs. Collagen synthesis and cross-linkage is responsible for vascular integrity and strength of new capillary beds. Improper cross-linkage of collagen fibers has been responsible for nonspecific post-operative bleeding in patients with normal coagulation parameters.  Early in the proliferation phase fibroblast activity is limited to cellular replication and migration.
Around the third day after wounding the growing mass of fibroblast cells begin to synthesize and secrete measurable amounts of collagen. Collagen levels rise continually for approximately three weeks. The amount of collagen secreted during
this period determines the tensile strength of the wound.
The final phase of wound healing is wound remodeling, including a reorganization of new collagen fibers, forming a more organized lattice structure that progressively continues to increase wound tensile strength. The remodeling process continues up to two years, achieving 40-70 percent of the strength of undamaged tissue at four weeks.  Figure 1 summarizes the phases of wound healing and nutrients that impact the various phases.