Adrian Barbul

GENERAL PRINCIPLES OF WOUND HEALING

Wound healing is a complex process involving different biologic and immunologic systems. Despite improvements in diagnostics and therapy, wound failures remain a clinical problem. The approach to a nonhealed wound is an interdisciplinary challenge that should not be underestimated. Better understanding of the complex wound-healing cascade helps our approach to wound healing and its possible failure. Manipulations of the involved immunologic features offer future therapeutic strategies.

Understanding the role of immune regulation in wound healing

The immune system plays an integral role in successful wound healing. In addition to contributing to host defenses and inflammation, immune cells are critical regulators of wound healing through the secretion of cytokines, lymphokines, and growth factors. We review the mechanisms by which the immune system regulates wound healing.

HEALING IN THE GASTROINTESTINAL TRACT

Healing in the GI tract is rapid when free of complications: Unlike cutaneous healing, in which progress can be observed on a daily basis and intervention instituted early if necessary, healing of the intestinal anastomosis is anatomically obscured from inspection, allowing the surgeon only the patients parameters of general well-being to judge the success of the operation. For the same reason, complications usually require re-operation, with the associated morbidity of a laparotomy and additional general anesthetic. This places a great responsibility on the surgeon to be cognizant of all the preoperative, intraoperative, and postoperative factors relating to anastomotic healing that might compromise the healing process. Bearing these in mind, along with attention to technical detail, should limit complications to an acceptable level. Patients most at risk are (1) those who perioperatively develop physiologic problems that lead to shock, hypoxia, and resultant anastomotic ischemia, (2) those with radiation-induced tissue injury, (3) those with sepsis, and (4) those with preoperative bowel obstruction. Malnourishment, malignancy, diabetes, steroids, and age also influence outcome to varying degrees. Future advancement in the field of GI healing lies in our ability to manipulate the early struggle between collagen synthesis and collagen breakdown. A profound understanding of the molecular and biochemical pathways and the factors that control them will bring us closer to this goal. Clinically, this may be accomplished by the introduction of wound healing enhancers into the anastomotic site, possibly by incorporating them into suture materials, biofragmentable anastomotic rings, or staple materials. Already much is known about the influence of different cytokines and growth factors on collagen regulation, knowledge that will help resolve many of the long-standing problems associated with GI surgery.

Arginine physiology and its implication for wound healing

Arginine is a basic amino acid that plays several pivotal roles in cellular physiology. Like any amino acid, it is involved with protein synthesis, but it is also intimately involved with cell signaling through the production of nitric oxide and cell proliferation through its metabolism to ornithine and the other polyamines. Because of these multiple functions, arginine is an essential substrate for wound healing processes. Numerous studies have shown that arginine supplementation can lead to normalization or improvement of healing. This article reviews the basic biochemistry and cell signaling within which arginine performs its functions. In particular, the requirement for this amino acid in tissue repair is highlighted. (WOUND REP REG 2003;11:419–423)

Diabetes-impaired healing and reduced wound nitric oxide synthesis : A possible pathophysiologic correlation

BACKGROUND Nitric oxide (NO) is synthesized in wounds, but its role in the healing process is not fully understood. The inhibition of NO production during wound healing is accompanied by decreased wound reparative collagen deposition. To further define the role of NO in reparative collagen accumulation, we studied its production during diabetes-induced wound healing impairment. METHODS Male Sprague-Dawley rats (290 to 310 gm) were rendered diabetic by intraperitoneal streptozotocin administration. Seven days after induction of diabetes (blood glucose greater than 300 mg/dl), the rats underwent dorsal skin incision and subcutaneous implantation of polyvinyl alcohol sponges. Beginning on the day of wounding, 21 diabetic animals were treated with 3 units/day insulin via intraperitoneally implanted miniosmotic pumps. Ten days after injury, wound breaking strength was determined, and wound collagen accumulation and types I and III collagen gene expression were measured in subcutaneously implanted polyvinyl alcohol sponges. NO-synthesis, as measured by nitrite/nitrate accumulation, was determined in wound fluid and in supernatants of wound cell cultures. RESULTS Streptozotocin-induced diabetes markedly impaired wound breaking strength and collagen deposition. A parallel decrease occurred in wound NO synthesis as reflected by decreased nitrite/nitrate concentration in wound fluid and in diminished ex vivo NO production by wound cells. Insulin treatment partially but significantly improved wound mechanical strength (p < 0.01) and collagen accumulation (p < 0.001). Decreased wound NO accumulation and ex vivo NO production by wound cells were also partially restored by insulin treatment. CONCLUSIONS Impaired diabetic wound healing is paralleled by decreased wound NO synthesis, supporting the hypothesis that NO plays a significant role in wound reparative collagen accumulation.

Guidelines for the treatment of pressure ulcers

1. Co-chaired this panel 2. University of Washington, Seattle, WA 3. University of Texas Medical Branch Galveston, Galveston, TX 4. Sinai Hospital, Baltimore, MD 5. Johns Hopkins Medical Institutions, Baltimore, MD 6. University of Southern Denmark, Odense University Hospital, Odense, Denmark 7. University of South Florida, Tampa, FL 8. University of Virginia Health System, Charlottesville, VA 9. St. Louis Medical Center, St. Louis, MO, and 10. University of San Francisco, San Francisco, CA

The effect of in vivo T helper and T suppressor lymphocyte depletion on wound healing.

The role of T lymphocytes in wound healing is still not well-defined. Because it had been previously shown that in vivo depletion of T cells leads to impaired wound healing, the effect of depleting T cell subsets on subsequent fibroplasia was studied. T helper/effector cells were depleted by the use of the monoclonal antibody GK1.5, reactive against the L3T4 antigen (CD4). T suppressor/cytotoxic lymphocytes were depleted by using the 2.43 monoclonal antibody reactive against the Lyt 2 antigen (CD8). In the first experiment, Balb/c mice were treated with the antibodies starting at 24 hours before wounding was performed, and weekly thereafter. Depletion of the T helper/effector cells had no effect on wound-breaking strength or hydroxyproline deposition in sponge granulomas, whereas depletion of T suppressor/cytotoxic cells significantly enhanced both of these healing parameters. In a second experiment, T cell subset depletion was started on Days 0, 3, 7, 10, and 14 postwounding, and treatments were continued weekly thereafter. Once again, depletion of T helper/effector cells had no effect on wound healing, whereas depletion of T suppressor/cytotoxic cells markedly increased both wound-breaking strength and collagen synthesis. In conclusion, the data show that T suppressor/cytotoxic cells have a counter-regulatory role in wound healing, whereas the T cell subset responsible for up-regulating wound healing remains to be identified.

Nutrition and wound healing

The relationship between nutrition and wound healing--after injury or surgical intervention--has been recognized for centuries. There is no doubt 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 healing. 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 nutritional support in postoperative and wounded patients. The experimental evidence for the use of arginine, glutamine, vitamins, and micronutrient supplementation 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 patients plan of care must be individualized to optimize the relationship between nutrition and wound healing.

Nitric Oxide and Wound Healing

Nitric oxide is a short-lived free radical that acts at the molecular, cellular, and physiologic level. Since its discovery almost 20 years ago it has proven itself as an important element in wound healing. This review highlights many of the important aspects of nitric oxide in wound healing, including a review of the basic biology of nitric oxide, its role as part of the cytokine cascade and as a promoter of angiogenesis, as well as its more recently elucidated role in apoptosis.

Intravenous hyperalimentation with high arginine levels improves wound healing and immune function

The purpose of this study was to evaluate the effect of increased arginine levels in intravenous hyperalimentation (IVH) therapy on wound healing and thymic immune function. Groups of SD rats, 275-325 g, underwent placement of internal jugular catheter, 7-cm dorsal skin wounding, insertion of polyvinyl alcohol sponges subcutaneously, and closure of wounds with stainless-steel sutures. Twenty-four hours later, rats were started on IVH at a rate of 0.8-1 ml/100 g body wt/hr. All IVH solutions contained 20% dextrose, adequate amounts of minerals and vitamins, and two different amino acid mixtures: (A) Fre III (4.05 g ARG/liter) (n = 13); (B) experimental (7.50 g ARG/liter) (n = 11). Solutions were isonitrogenous, and contained similar amounts of essential amino acids. After 7 days of IVH, weight gain did not differ between the two groups; however, cumulative N balance was superior in group A. Wound healing was improved in group B as assessed by fresh wound strip breaking strength, fixed breaking strength, and the amount of reparative collagen deposition as assessed by the hydroxyproline content of the implanted sponges. Group B animals also had improved thymic function as assessed by thymic weight, the total number of thymic lymphocytes/gland and mitogenic reactivity of thymic lymphocytes to PHA and Con A. The experiments indicate that high arginine levels in IVH solutions improve wound healing and thymic immune function following injury.