July 2008 Issue

Healing From the Inside Out
By Dale Ames Kline, MS, RD, CNSD, LD
Today’s Dietitian
Vol. 10 No. 7 P. 12

Suggested CDR Learning Codes: 5170, 5380; Level 2

The body responds to wounding—whether from traumatic injury or surgery—in an ordered and predictable series of events. Many factors influence healing: age, general health, infection, and especially nutritional status. This article will explain how the body heals and the importance of sound nutrition in the healing process.

To heal, the body must remove nonviable tissue, control infection, revascularize an injured area, and secrete the products necessary for tissue repair. It accomplishes this by sending messages locally and systemically via hormones, cytokines, eicosanoids, and other messengers and producing appropriate metabolic substrates, including oxygen. When an individual is ill or stressed, alterations in metabolism and the production of hormones and cytokines make healing more difficult, especially in the presence of malnutrition or an inadequate vitamin and mineral intake.

The Skin
When we think of wounds, we usually think first of lacerated skin. The skin is the body’s first line of defense against infection, extremes in temperature, injury, ultraviolet radiation, and foreign objects. One aspect of that defense is avoidance: The skin is sensitive to painful stimuli, heat, touch, and pressure—for example, we jerk our hand away from a hot stove before damage is done. Another aspect is skin’s incredible ability to maintain its integrity and heal rapidly to protect the tissue it encloses.

Skin has three main layers:

• The epidermis is itself made of several layers. The outermost is composed of dead cells that have been keratinized (hardened) to produce a tough protective layer; the living cells in the basal cell layer beneath divide continuously, replacing the outer layer cells. It takes about three to four weeks for a cell production-loss cycle. There are no nerve endings or blood vessels in the epidermis, but the keratinization process allows for the closure (epithelialization) of wounds.

• The dermis supports and provides blood circulation to the epidermis. The dermis is composed of individual skin cells, collagen and elastin fibers, and a matrix of support tissue, made primarily of mucopolysaccharides such as chondroitin sulfate.

Within the dermis are the nerve cells that produce sensation, the lymph vessels that deal with infection, the sweat glands that regulate temperature, and the sebaceous glands that help maintain integrity by keeping the skin moist and soft. The cells of the dermis include fibroblasts, which are responsible for collagen synthesis, and macrophages, which regulate the inflammatory response and respond to infection.1

• The subcutaneous layer contains fatty tissue, blood and lymphatic vessels, nerves, and connective tissue. It serves as an insulator, shock absorber, and protector of underlying tissues. Between this layer and the tissues beneath is the fascia, which attaches skin to muscle.2

The Healing Process
When the epidermis is penetrated, a multistage healing process leading to complete tissue repair is triggered, beginning with a “coagulation cascade”—platelet aggregation to form a clot to stop blood flow. As this occurs, various substances to mediate the wound healing process are released from the injured skin cells and the first phase of the actual healing process begins.

• The inflammatory phase generally lasts four to six days. This response includes the small blood vessel dilation, increased capillary permeability, and the migration of leukocytes to the injury site. This migration is induced by the release of substances that mediate inflammation, such as cytokines. Increases in proinflammatory cytokines, such as platelet-derived growth factor, tumor necrosis factor-alpha, interleukin (IL)-1, and IL-2, orchestrate the inflammatory response.

Initially, neutrophils enter the wound, releasing the enzymes that break down damaged tissue and begin the process of removing it. Oxygen is required for neutrophils to function, so anything that interferes with the delivery of oxygen to tissues, such as anemia or poor vascularization, will interfere with healing.

Monocytes soon follow and are transformed into macrophages, which phagocytize debris and destroy bacteria. The macrophages also play a role in the induction of collagen synthesis. Tissue macrophages are the cells that produce growth factors, including fibroblast growth factor, insulinlike growth factor, and epidermal growth factor, which are important in mediating cell migration and proliferation and in producing the skin matrix. These processes allow for the induction of angiogenesis, the formation of new blood vessels, and the formation of granulation tissue during the proliferation phase.3

• The proliferation phase typically lasts four to 24 days. One of the major goals of wound healing is to reestablish the skin’s role as a barrier. This complex process is usually described as scarring, and it begins with a change in the cell structure closest to the wound. The skin looks shiny and granular and is not very strong. Fibroblasts, macrophages, immature collagen, blood vessels, and growth substances are found in the granulated wound.

After the injury, the nearby epidermal cells elongate and flatten to send tonguelike projections into the wound. New blood vessels sprout from intact blood vessels in the dermis and elongate into the developing granulation tissue. Without the new blood vessels, the wound could not receive nutrients and would be unable to heal.

The fibroblasts in the dermis produce fibronectin, which forms a matrix for the proliferation of skin cells. As the fibroblasts migrate into the wound, they begin to differentiate and increase the synthesis of connective tissue.4 The fibronectin matrix not only allows for the migration of fibroblasts into the wound but also forms the base for the collagen fibers. Once the fibroblasts are in place, the cells begin to produce large amounts of matrix materials, proteoglycans, collagen, and elastin.3

In normal dermis, the collagen fiber bundles are organized in a basket-weave pattern; in granulation tissue, the bundles are parallel to one another and therefore are not very strong.

• The remodeling phase develops scar tissue from granulation tissue produced in the proliferation phase. Granulation tissue is highly active, with cell production, blood vessel generation, carbon dioxide production, and protein synthesis. It has a high density of capillaries, leukocytes, and fibroblasts.

Collagen is the major connective tissue in wound repair. The strength and integrity of the repair depends on the deposition and cross-linkage of collagen. During the remodeling phase, the collagen molecules are cross-linked to other collagen molecules, which provides strength and integrity to the wound.

During this stage, the cell density of fibroblasts and macrophages is reduced. Blood flow to the area is reduced, the level of metabolic activity declines, and the collagen becomes stronger. The remodeling phase usually lasts from one month to one year, but it can continue for several years after the injury in the case of major wounds or if delayed by factors such as age, illness, or malnutrition.5

• Wound contraction is the final closing of the wound. Wounds close from the outer edges inward, and the skin is pulled together as the scar gets stronger. Unfortunately, scar tissue has reduced tensile strength—at best, 80% of original tissue—leaving it vulnerable to future injury and breakdown.

Stress, Illness, and Wound Healing
During illness or after trauma or surgery, alterations in the body’s metabolic demands have implications for wound healing (eg, alterations in glucose, protein, fat metabolism).

Most of these changes are initiated by the immune system, which, when stimulated, causes the body to undergo a series of physiologic and metabolic changes known as the acute phase response. This is characterized by fever, skeletal muscle catabolism, liver synthesis of acute phase proteins (complement, fibrinogen, C-reactive protein), alterations in hormone production, increases in neutrophils, and changes in serum levels of trace elements and antioxidants.

The liver reacts to the acute phase response by increasing protein uptake, which can be broken down and resynthesized into acute phase proteins or used for energy. The source of this protein is albumin, muscles, skin, and the gastrointestinal tract.

Therefore, you will see a decline in serum albumin (even if nutrition intake is adequate), as the body will make acute phase proteins instead of albumin. Once the illness’ intensity begins to wane, protein metabolism will normalize and serum albumin and prealbumin begin to rise.

The body becomes hypermetabolic as the need for energy increases. The demand for glucose increases, although hyperglycemia is a common response to stress and injury. Insulin levels increase, but hyperglycemia often persists due to increased insulin resistance in peripheral tissues.

An increase in the breakdown of stored fat (triglycerides) is seen during illness. The fatty acids are used to produce ketones, and the glycerol is used for glucose. There may be a buildup of fats in the blood until the internal hormonal environment returns to normal.

When a wound on a patient who was ill or underwent surgery is trying to heal, there is an increased need for calories and energy. If the individual is unable to eat food and/or drink nutritional supplements to meet those needs, wound healing will be slower and complicated.

Role of Diet and Nutrition
Every nutrient is important to maintain skin integrity and promote the healing process, although some are more important in efficient healing. All wounds will heal eventually, but in a healthy individual, wounds heal quickly without intervention. In an individual with malnutrition, healing is delayed. The nutrients critical for healing are the following:

• fluid;

• energy;

• protein (total, arginine, glutamine);

• fats (total and type);

• vitamins (A, C, E, K); and

• minerals (zinc, iron, copper).

• Hydration of the tissues impacts wound healing. Too little fluid impairs wound healing, as does too much. Dehydration reduces the supply of oxygen and nutrients to the wound and decreases skin turgor. Edema (overhydration) compromises the integrity of the skin and slows the inflammatory phase of wound healing.6

• Adequate energy must be available to fuel the healing process and ensure that the available protein is used for tissue synthesis and not as an energy source. Carbohydrates should comprise 50% to 55% of total calories to achieve protein-sparing. Inadequate amounts of carbohydrates compromise the inflammatory and proliferation phases of wound healing. Glucose is essential for fibroblast migration, macrophage activity, cellular proliferation, and preventing amino acid degradation for gluconeogenesis.

• Fat is an essential component of cell membranes and required for the absorption and function of fat-soluble vitamins. Fatty acid deficiency disrupts skin integrity, resulting in delayed wound healing. Fat intake should comprise 25% to 30% of the total energy requirements, as they are a concentrated energy source and provide essential linoleic and linolenic fatty acids.7

Supplementing with high levels of omega-3 fatty acids may interfere with wound healing since they are anti-inflammatory. In individuals with slow-closing wounds, careful supplementation with omega-3 fatty acids is advisable.8

• Protein is a vital element of all components of wound healing. The cytokines that initiate the process are composed of protein, fibroblasts and leukocytes depend on a source of protein for cell production, and angiogenesis is limited by inadequate protein. The synthesis, accumulation, and remodeling of collagen are impaired in protein deficiency. Immune function is decreased by protein malnutrition.

Protein needs are generally 1 to 1.5 grams per kilogram of body weight per day. In the presence of protein malnutrition, protein may need to be as high as 1.8 grams per kilogram of body weight per day.9 Protein above this level may not improve wound healing and may exacerbate any renal or liver dysfunction. Also remember, as protein intake increases, there is an increased need for fluid to rid the body of excess nitrogen.

• Arginine is classified as a conditionally essential amino acid. During growth and metabolic stress, the body is unable to produce enough to meet the tissue demands. Arginine plays a role in lymphocyte production, RNA synthesis, collagen disposition, improved tensile wound strength, and bacterial killing by macrophages.10

Studies have found that in healthy volunteers, arginine supplementation in the range of 17 to 24.8 grams per day for two weeks improves the wound strength and collagen deposition in artificial wounds.10 However, there is concern over the use of arginine supplementation in the critically ill and those with renal and/or liver dysfunction.

In individuals with poor wound healing, supplemental arginine may be worth a try, as long as energy and protein needs are being met.

• Glutamine comprises two thirds of the total amino acid pool in the body, with most of it stored in the muscles. Under normal circumstances, glutamine is a nonessential amino acid. However, in the presence of an illness or injury, the body dramatically increases the use of glutamine, and the skeletal muscles are unable to produce an adequate amount. Under these conditions, an exogenous supply of glutamine must be provided.

Glutamine plays a central role in many of the metabolic pathways involved in wound healing, acting as a building block or substrate for many rapidly proliferating cells in the healing process. It is a direct fuel for both the fibroblast and the macrophage.11 When there is an illness in addition to a wound and the wound is slow to heal, it may be beneficial to supplement glutamine to preserve muscle mass and allow the glutamine to be used in healing. The recommended dose is 0.57 grams per kilogram of body weight per day in divided doses.11 If there is any renal or liver impairment, the supplement should not be given.

• Vitamin C, a critical nutrient for wound healing, is required for the function of neutrophils in the immune response to injury and infection and aids in preventing infections. During the inflammatory phase of wound healing, free radical production and oxidative stress increase. Vitamin C is responsible for antioxidant activity in response to wounding, so a deficiency would lower the antioxidant capacity of the body.12

Ascorbic acid is an essential cofactor in the formation of collagen. Inadequate quantities of vitamin C cause decreased tensile wound strength, fragile capillaries, and delayed wound healing.

Those at risk for inadequate vitamin C include smokers (who need at least 35 milligrams per day more vitamin C than nonsmokers), alcoholics, drug abusers, those who are medically stressed/injured, and older adults. A deficiency of vitamin C will delay wound healing and increase the risk of wound infection and dehiscence (a previously closed wound reopening).

The current dietary reference intake for vitamin C is 75 milligrams per day for women and 90 milligrams per day for men. Supplemental vitamin C in the range of 100 to 200 milligrams per day is recommended for individuals with a deficiency, while 1,000 to 2,000 milligrams is recommended for those with serious pressure wounds, who are highly stressed or injured, or who have pressure wounds and malnutrition. The maximum supplemental vitamin C recommended for people with renal disease is 60 to 100 milligrams, as it increases the risk of renal stone formation.

• Vitamin A, a fat-soluble vitamin, is required for epithelialization, fibroblast proliferation, fibronectin synthesis, and collagen production. It enhances the early inflammatory response and increases the tensile strength of the healed wound. Vitamin A supplementation has been shown to reduce the inhibitory effects of corticosteroids.13

Vitamin A deficiency is associated with decreased collagen synthesis, decreased epithelialization, and increased occurrence of infection. As is the case with vitamin C, vitamin A and its precursor beta-carotene ameliorate the oxidative stress caused by wounding and infection.7

The recommended intake for vitamin A is 2,300 international units (700 RAE) for women and 3,000 international units (900 RAE) for men. This amount is sufficient for most people with wounds. In those individuals taking steroids, doses of 10,000 to 15,000 international units per day for one week are recommended to help with wound healing and to counteract the anti-inflammatory effects of the steroids.13

• Iron is a cofactor in the hydroxylation of proline and lysine in collagen. It is also involved in many enzyme systems, such as the electron transport chain, several other enzymatic reactions, and the oxidative burst in phagocytosis. Iron, as a part of hemoglobin, transports oxygen to tissues. Inadequate iron reduces energy production by the mitochondria, decreases the oxygen delivery to tissues, and impairs the ability of leukocytes to kill bacteria, increasing the risk of wound infection.14

Iron-deficiency anemia is a common nutritional problem in the United States, especially among children and older adults. The recommended daily allowance for iron in men and postmenopausal women is 8 milligrams per day and 18 milligrams per day in premenopausal women. A multivitamin/mineral can supply adequate iron to reverse iron deficiency anemia.

Iron supplementation should not be given to individuals with an active infection since it can make the infection worse. Bacteria will use the iron, making it more difficult to fight the infection.

• Zinc is a cofactor in more than 200 enzymes in the body. Numerous reactions in the body, including those of RNA and DNA production, cell production, protein synthesis, collagen synthesis, and the immune response, require zinc. Rapidly dividing cells are most affected by an inadequate supply. In wound healing, fibroblast proliferation and epithelialization are impaired when there is a zinc deficiency.

It now appears that individuals with wounds who have zinc deficiency benefit from supplementation. Zinc supplementation in individuals without a deficiency does not appear to improve wound healing.15 In fact, an excess of zinc may impair immunity and contribute to delayed wound healing. The recommended level of supplement for zinc is a maximum of 50 milligrams of elemental zinc until the wound is epithelialized. Higher doses of zinc should not be given for longer than two or three weeks. For many individuals, a multiple vitamin and mineral, with zinc at or close to the recommended daily allowance (15 milligrams for men and 12 milligrams for women), is sufficient.

• Copper is necessary for the enzyme involved in collagen synthesis and the cross-links in the collagen that give it its tensile strength. A deficiency of copper will delay wound healing, and excess zinc supplementation will interfere with copper absorption.

• Vitamin E is an important antioxidant, maintaining the integrity of cell membranes. Its exact role in wound healing is still under investigation.

• Vitamin K is involved in the formation of blood clots, so it is necessary in the initial stage of wounds when a clot is forming. A vitamin K deficiency is rare.

A multiple vitamin and mineral preparation should have adequate amounts of these last three nutrients, so added supplementation is unnecessary.
 
Nutrient deficiencies impact all aspects of wound healing, as we’ve seen. Protein and protein-calorie malnutrition result in decreased synthesis of protein and cell production, reduced immune function, and delayed progression of all phases of wound healing. Vitamin and mineral deficiencies impair tissue synthesis, energy production, oxygen transportation, immune function, and all phases of wound healing.
 
Nutritional needs increase in individuals with an illness, with an infection, or postoperatively. Failure to meet those needs negatively impacts wound healing, along with aging, disease, medication, blood circulation, and infection.

There are additional factors that affect wound healing, including the following:

• nutritional status: protein-energy malnutrition and lack of individual vitamins and minerals;

• aging;

• diabetes;

• renal disease;

• vascular disease;

• medication;

• obesity;

• infection; and

• illness or surgery.

It is well documented that wound repair declines with age. As we age, many changes in the skin become evident. The skin becomes thinner and produces less oil and moisture, due to a reduced number of sweat and sebaceous glands, resulting in increased dryness. Skin becomes wrinkled due to less subcutaneous fat.

With age, the phases of wound repair tend to proceed more slowly. Collagen synthesis takes more time, resulting in a delay in wound healing. Immune function is diminished due to reduced immune cell production, resulting in a reduced inflammatory phase response. Reduced blood circulation can result in reduced perfusion of the wound.

Some of the healing processes affected by age are compounded by nutrition-related conditions. Long-term complications of diabetes mellitus impact wound repair. There are changes in the large blood vessels due to chronic hyperglycemia, and atherosclerosis occurs more frequently in people with diabetes. The occlusion of blood vessels leads to reduced blood flow to the tissues, which impairs wound healing.

Peripheral vascular disease is more common with diabetes and contributes to the occurrence of nonhealing diabetic ulcers in the lower extremities, as the supply of blood and nutrients to the tissues is decreased. Peripheral neuropathy leads to decreased pain and temperature sensation, which contributes to increased occurrence of wounds to the extremities and poor healing of those wounds.

Impaired renal function resulting from chronically elevated blood sugar often leads to elevated blood urea levels, which are noted to reduce fibroblast activity and collagen production. Hemoglobin that is glycosylated has been shown to have reduced oxygen delivery capacity. The functions of other proteins may also be impaired due to high blood glucose levels.16

Obesity makes it more difficult to heal a wound. There is an increased incidence of postoperative infection in obese individuals, and the greater the body mass index, the higher the risk for complications with wounds.17 The development of pressure ulcers may be increased in patients who are bedridden or recovering from illness or surgery. With increasing body weight, the pressure on the skin is increased, leading to skin breakdown.18

However, a recent study found just the opposite: Increasing body fat reduced the risk of pressure ulcers in older hospitalized patients.19

Numerous drugs affect wound healing, including nonsteroidal anti-inflammatory drugs, corticosteroids, immunosuppressive agents, anticoagulants, antineoplastic agents, and antiprostaglandins. Many of these medications are taken in response to illnesses that also impact wound healing, further impairing the body’s ability to heal. Besides the drugs taken during an illness, many drugs that are routinely prescribed for treatment of many medical conditions can interfere with or delay wound healing.

— Dale Ames Kline, MS, RD, CNSD, LD, is president of Nutrition Dimension, Inc. A former hospital chief clinical dietitian and nutrition educator in the Women, Infants, and Children program, she has written and edited continuing education home study courses since 1984.

References
1. Pillsbury DM, Heaton CL. Anatomical, physiological and chemical factors in diseases of the skin. In: A Manual of Dermatology, 2nd Edition. Philadelphia: WB Saunders; 1980.

2. Hess CT. Fundamental strategies for skin care. Ostomy/Wound Manage. 1997;43(8):32-41.

3. Kirsner RS, Eaglstein WH. The wound healing process. Dermatology Clin. 1993;11(4):629-640.

4. Leaper DJ, Harding KG (eds). The biology of wound healing. In: Wounds: Biology and Management. Oxford Medical Publication; 1998.

5. Carrico TJ, Mehrhof AI Jr, Cohen IK, et al. Biology of wound healing. Surg Clin N Am. 1984;64(4):721-733.

6. Whitney JD, Heitkemper MM. Modifying perfusion, nutrition and stress to promote wound healing in patients with acute wounds. Heart and Lung. 1999;28(2):123-133.

7. Kiy AM. Nutrition in wound healing. A bio-psychosocial perspective. Nurs Clin North Am. 1997;32(4):849-862.

8. Stechmiller JK, Cowan L, Johns P. Wound healing. In: The A.S.P.E.N. Nutrition Support Core Curriculum: A Case-Based Approach—The Adult Patient. Silver Spring, Md.: American Society of Parenteral and Enteral Nutrition; 2007.

9. Telfer NR, Moy RL. Drug and nutrient aspects of wound healing. Dermat Clin. 1993;11(4):729-737.
10. Kirk SJ, Harsom M, Regan MC, et al. Arginine stimulates wound healing and immune function in elderly human beings. Surgery. 1993;114(3):115-160.

11. Smith RJ, Wilmore DW. Glutamine nutrition and requirements. JPEN. 1990;14(4 Suppl):94S-99S.

12. Ruberg RL. The role of nutrition in wound healing. Surg Clin N Am. 1984;64(4):705-713.

13. Phillips JD. Effects of chronic corticosteroids and vitamin A on the healing of intestinal anastomeses. Am J Surg. 1992;163(1):71-77.

14. Levenson SM, Demetriou AA. Metabolic factors. In: Wound Healing: Biochemical and Clinical Aspects. Philadelphia: WB Saunders; 1992.

15. Stadelmann WK, Digenis AG, Tobin GR. Impediments to wound healing. Am J Surg. 1998;176(Suppl 2A):42S-47S.

16. Powers MA. Complications of diabetes mellitus and implications for nutrition therapy. In: Handbook of Diabetes Medical Nutritional Therapy. Gaithersburg, Md.: American Society of Parenteral and Enteral Nutrition; 1996.

17. Wilson JA, Clark JJ. Obesity: Impediment to postsurgical wound healing. Adv Skin Wound Care. 2004:17(8):426-435.

18. Baugh N, Zuelzer H, Meador J, Blankenship J. Wound wise: Wounds in surgical patients who are obese. Am J Nurs. 2007;107(6):40-50.

19. Compher C, Kinosian BP, Ratcliffe SJ, Baumgarten M. Obesity reduces the risk of pressure ulcers in elderly hospitalized patients. J Gerontol Biol Sci Med Sci. 2007;62(11):1310-1312.

Learning Objectives
After completing this article, the student will be able to:

1. Discuss the various layers of the skin and their function.

2. Explain the phases of wound healing and the physical changes that take place during each phase.

3. List the nutrients critical to wound healing and the function of each nutrient in wound healing.

4. Explain the relationship of stress and illness to wound healing, including any changes in nutrient needs.

5. Discuss how aging, diabetes, vascular disease, medication, and surgery affect wound healing.

Examination
1. The primary function of the epidermis is to:
a. provide blood circulation to the dermis.
b. produce a tough protective layer of skin.
c. regulate body temperature.
d. attach the skin to muscle.

2. The inflammatory phase of the wound healing process is characterized by:
a. a constriction of small blood vessels and decreased capillary permeability.
b. an increase in the number of fibroblasts and production of platelets.
c. the migration of leukocytes and neutrophils to the injury site and a release of cytokines and enzymes.
d. a wound that is shiny in appearance and not very strong, referred to as scarring.

3. The strength and integrity of a wound is dependent on:
a. the amount of collagen and the cross-linkage with other collagen molecules.
b. the number of blood vessels and their ability to supply the wound with nutrients.
c. the dietary intake of all nutrients involved in the wound healing process.
d. the ability of immune cells to clean out the wound and prepare it for the healing process.

4. Why does serum albumin decrease in an ill individual with adequate protein intake who is trying to heal a wound?
a. The protein recommendations are too low.
b. The acute phase response causes catabolism of albumin.
c. The body cannot make enough albumin, despite adequate intake.
d. Albumin is used for energy, even when energy intake is adequate.

5. What impact will dehydration have on the healing of wounds?
a. No impact, since fluid status is not involved in wound healing.
b. Minimal impact, as it does not interfere with wound healing.
c. It will delay wound healing by decreasing the nutrient supply to the tissues.
d. It will delay wound healing by slowing the inflammatory phase of wound healing.

6. Which of the following nutrient deficiencies will delay wound healing and increase the risk of wound infection and dehiscence?
a. Vitamin E
b. Energy
c. Iron
d. Vitamin C

7. Which of the following nutrients needs to be supplemented in an individual with a wound who is taking steroids?
a. Vitamin C
b. Copper
c. Vitamin A
d. Arginine

8. Which of the following individuals with a wound would benefit from a zinc supplement?
a. Everyone, since zinc is essential for wound healing.
b. Older adults with an intake of less than 85% of normal.
c. Individuals with chronic illnesses such as diabetes.
d. Individuals with a zinc deficiency.

9. In what circumstance is an iron supplement contraindicated in individuals with inadequate iron intake and anemia who are trying to heal a wound?
a. Individuals with medications that interact with iron
b. If zinc is given as a supplement
c. If the need for oxygen in the tissues decreases
d. If an individual has an active infection

10. Which of the following complications of diabetes will interfere with wound healing?
a. Peripheral vascular disease
b. Retinopathy
c. Hyperglycemia
d. Proteinuria