Healing of incisional wounds in stomach and duodenum: The influence of experimental diabetes

The present study was performed to evaluate the effect of experimental diabetes mellitus on the mechanical properties and collagen content of healing wounds in rat stomach and duodenum. Furthermore, the effect of insulin treatment was investigated. Diabetes was induced by streptozotocin, and protamine zinc insulin was used in the treated diabetes group. Wounds were made in the nonglandular part (rumen) and the glandular oxyntic part (corpus) of the stomach and in the duodenum. The wounds were tested 7 and 20 days after operation. Experimental diabetes impaired the mechanical strength of healing wounds in stomach and duodenum. The reduction was most pronounced for breaking energy (energy absorption), while only duodenum showed a decrease for breaking strength (maximal force) of the tissues. The impairment became more pronounced by increasing healing time. A relation between mechanical strength and total collagen content was shown. Insulin treatment prevented these retardations and normalized the mechanical strength. These findings indicate that the increase of mechanical strength and collagen content in wounds in stomach and duodenum is impaired by experimental diabetes. The effects are probably a real impairment of the healing process. Insulin treatment prevented these changes.     

Healing of incisional wounds in stomach and duodenum: Collagen distribution and relation to mechanical strength

The present study was performed to determine the changes in and distribution of collagen concentration around a healing incision in rat stomach and duodenum. These concentrations were related to the mechanical properties presented previously. Wounds were made in the nonglandular (rumen) and the glandular oxyntic parts (corpus) of the stomach and in duodenum. Specimens were cut parallel to the incision line and hydroxyproline contents and dry defatted weight were measured. Wounds were investigated 5 to 40 days after operation.Of the intact tissues the nonglandular part of the stomach had twice the collagen concentration of the glandular oxyntic part and duodenum, which did not differ from each other. The healing wounds in the glandular oxyntic part of the stomach and duodenum showed the most rapid increase in collagen concentration in the incision line and 40 days postoperatively both had collagen concentrations significantly greater than those of intact tissues. Wounds in the nonglandular part of the stomach only reached the level of intact tissue after 40 days. The dimensions of the biochemically active zones around incisions in stomach and duodenum remain essentially unchanged for 40 days after operation. A relation between the development of collagen concentration and mechanical strength was shown.These findings indicate that wound healing in stomach and duodenum is rapid, that collagen is the primary factor in the mechanical properties and that the highest activity is limited to a zone close to the incision line. The width of the biochemical zone remains constant.     

Healing of incisional wounds in stomach and duodenum: A biomechanical study

The healing pattern of incisional wounds in the rat stomach and duodenum was determined. A model allowing the biomechanical determinations of complete load-deformation curves is described. Wounds were made in the nonglandular (rumen) and glandular oxyntic (corpus) parts of the stomach and in duodenum. The wounds were tested 5 to 40 days after operation.Of the intact tissues the nonglandular part of the stomach was found to be more extensible and required more energy to be ruptured than the glandular part of the stomach and duodenum. The healing wounds in the glandular part of the stomach and duodenum showed the most rapid increase in mechanical strength, and after 40 days both required more energy to be ruptured than intact tissue. Wounds in the nonglandular part of the stomach reached only 75 percent of intact strength value after 40 days. The process of wound healing resulted in an increase in tissue stiffness.These findings indicate that wound healing in stomach and duodenum is more rapid than that in most other tissues and that the load-strain data give a detailed picture of the healing process. The energy required to rupture a wound represents the most informative assessment of wound healing.     

Healing of incisional wounds in stomach and duodenum: Functional interaction between normal and wounded tissue

The development of mechanical strength in healing wounds in rat stomach and duodenum was correlated with changes in the morphologic characteristics of the wounds and adjacent tissue. Wounds were made in the nonglandular (rumen) and the glandular oxyntic (corpus) parts of the stomach and in duodenum. The wounds were tested 5 to 40 days after operation. Biomechanical analysis showed that in intact tissues the nonglandular part of the stomach was more extensible and required more energy to rupture than the glandular part of the stomach and duodenum. The wounds tested together with adjacent tissue had less mechanical strength, but a pattern of strength development similar to that found in earlier studies where isolated wound tissue was investigated. Morphologic analysis showed that with healing time the point of maximal weakness moved laterally from the incision line, and that the rupture pattern was the same in all types of tissues postoperatively. These findings indicate that suture materials and technique are important throughout the early period of wound healing in stomach and duodenum, while the influence of sutures becomes negligible later on, when the weakest point of the healing wound is outside the tissue enclosed by the sutures.     

Epidermal growth factor increases tensile strength in intestinal wounds in pigs

Growth factors enhance tensile strength, angiogenesis and collagen synthesis in skin wounds. The effects were studied of a continuous intraperitoneal infusion of epidermal growth factor (EGF) on the mechanical properties of healing in linear full-thickness wounds of the stomach, ileum and colon of young pigs (n = 16, mean(s.d.) body-weight 20.1(1.9)kg). In half the animals an osmotic minipump was implanted into the peritoneal cavity to deliver recombinant human EGF at a rate of 0.5 micrograms kg-1 24 h-1. Animals were killed at 5 days and the integrity of a 20-mm ring of intestine was tested for tensile strength. Breaking strength (g mm-2) of the intestinal wounds in untreated pigs (n = 8) was: stomach 28.0(2.0), ileum 46.8(4.8), colon 85.6(4.2). Intestinal wounds in pigs (n = 8) receiving supplemental EGF had significantly increased breaking strength: stomach 32.4(2.2) (P less than 0.05), ileum 56.8(5.4) (P less than 0.05), colon 96.0(3.8) (P less than 0.01) compared with untreated animals. At 5 days after the initial injury intraperitoneal EGF increases the tensile strength of intestinal wounds in pigs.     

Fascial incisions heal faster than skin: a new model of abdominal wall repair

BACKGROUND: Optimal healing of the fascial layer is a necessary component of complete abdominal wall repair. The majority of acute wound healing studies have focused on the dermis. We designed a model of abdominal wall repair that, to our knowledge, for the first time simultaneously characterizes differences in the wound healing trajectories of the fascia and skin. METHODS: Full-thickness dermal flaps were raised on the ventral abdominal walls of rats, and midline fascial celiotomies were completed. The dimensions of the flap were developed so as to have no detrimental effect on skin healing. The dermal flaps were replaced so that the fascial incisions would heal separately from the overlying skin incisions. Animals were killed 7, 14, and 21 days after operation and fascial and dermal wounds were harvested and tested for breaking strength. Fascial and dermal wounds were also compared histologically for inflammatory response, fibroplasia, and collagen staining. RESULTS: Fascial wound breaking strength exceeded dermal wound breaking strength at all time points (9.16 +/- 2.17 vs 3.51 +/- 0.49 N at 7 days, P <.05). Fascial wounds also developed greater fibroblast cellularity and greater collagen staining 7 days after the incision. There was no difference in wound inflammatory response. CONCLUSIONS: Fascial incisions regain breaking strength faster than simultaneous dermal incisions. The mechanism for this appears to involve increased fascial fibroplasia and collagen production after acute injury.     

Effect of bFGF on the inhibition of contraction caused by bacteria

Bacterial contamination of open wounds significantly inhibits wound contraction required in the healing process. Basic fibroblast growth factor (bFGF) has been shown to overcome contraction inhibition in wound-healing models impaired by diabetes or steroids. This study was designed to determine the effect of bFGF on wound contraction inhibition in an area contaminated with bacterial overgrowth. The topically applied bFGF reversed inhibition to wound contraction that normally occurs with bacterial contamination. This reversal does not appear to be due to increased collagen synthesis since bFGF has been shown to decrease collagen synthesis and the treated wounds showed no increase in breaking strength. The use of bFGF significantly decreased the number of days required for wound healing (P less than 0.01) despite active bacterial invasion and may be of value in the treatment of human contaminated wounds.     

Interleukin 2 enhances wound healing in rats

Antigen-stimulated lymphocytes secrete lymphokines which have been shown to enhance in vitro fibroblast migration, proliferation, and protein synthesis. In the present experiments, the effect of human recombinant interleukin 2 (RIL-2) on wound healing was assessed in vivo. Groups of male Lewis rats, 225-250 g, underwent intraperitoneal insertion of osmotic pumps and a 7-cm dorsal skin incision with subcutaneous placement of polyvinyl alcohol sponges under anesthesia. The dorsal wounds were closed with stainless-steel sutures. The dose of RIL-2 administered was 60,000 u/rat/day for 7 days in experiment I, and 140,000 u/rat/day for 7 days in experiment II. Controls received equal volumes of excipient. Animals were sacrificed 10 days post wounding and wound healing was assessed by fresh breaking strength, fixed breaking strength (following 72 hr of Formalin fixation which maximally crosslinks the collagen present), and sponge hydroxyproline content (an index of reparative collagen accumulation). In vivo RIL-2 administration significantly augmented wound fresh and fixed breaking strength and wound collagen synthesis. Higher doses of RIL-2 (experiment II) did not result in further increases in the parameters studied. The data suggest that lymphocytes participate directly in the process of wound healing.     

Erythropoietin stimulates wound healing and angiogenesis in mice.

Erythropoietin exerts hematopoietic effects by stimulating proliferation of early erythroid precursors. Nonhematopoietic effects of erythropoietin have also been shown. It may act as a new angiogenic factor in wound healing. This study aimed to investigate the effect of systemic administration of recombinant human erythropoietin on wound healing in mice. Dorsal incisional wounds were performed in mice, which were then divided into two groups; a group treated for 7 days with recombinant human erythropoietin, and a control group. Sacrificing animals on day 7, the wound tissues were collected for analysis of wound breaking strength, malondialdehyde, a marker of lipid peroxidation, hydroxyproline, an index of reparative collagen deposition, reduced glutathione levels, and for histological evaluation. The immunohistochemical determination of vascular endothelial growth factor (VEGF) which is believed to be the most prevalent angiogenic factor throughout the skin repair process, was also studied. The treatment significantly increased wound breaking strength by decreasing malondialdehyde and increasing hydroxyproline levels on day 7 after wounding. No statistically meaningful change was observed in reduced glutathione content. VEGF was immunostained significantly more on wound tissue of treated animals compared to the control group. Recombinant human erythropoietin treatment may be effective in wound healing due to inhibition of lipid peroxidation, deposition of collagen, and VEGF expression in wound area.     

In vivo characterization of interleukin-4 as a potential wound healing agent

Interleukin-4 increases the synthesis of extracellular matrix proteins, including types I and III collagen and fibronectin, by both human and rat fibroblasts. Because fibroblasts are the final common effector cells of most phases of tissue repair, this study set out to investigate the effects of interleukin-4 on the healing of three different types of wounds. Acute excisional and chronic granulating wounds inoculated with Escherichia coli and incisional wounds in streptozotocin-induced diabetic Sprague-Dawley rats were used. Recombinant murine or human interleukin-4 was applied topically to the open wounds at doses of 0.1, 1.0, or 10.0 microg/cm(2)/wound for 5 or 10 days. Incisional wounds received the same doses once-at the time of wounding. The time taken to achieve wound closure or wound breaking strength measurements of wounds was recorded and compared with relevant untreated control groups. Wound contraction was impaired in the presence of bacteria, and this was reversed by all doses of recombinant murine interleukin-4. Recombinant murine interleukin-4 had no effect on the wound closure of noncontaminated wounds; it reduced wound breaking strength in acute excisional wounds, except in a contaminated setting when wounds were treated with 1.0 pg/cm(2)/wound. Recombinant interleukin-4 (1.0 microg) improved breaking strength of both diabetic and normal incisional wounds. The apparent pleiotropic effect of interleukin-4 on wound breaking strength under different wound conditions may be related not only to the activity of the fibroblast but also the ratio of cross-linked collagen/total collagen content of wounds. This study suggests that interleukin-4 may be a useful agent for accelerating closure of wounds, particularly where healing is impaired.     

Delayed primary closure: Collagen synthesis and content in healing rat skin incisions

The rate of collagen synthesis was determined by measuring the specific activity of [³H]hydroxyproline 10, 20, and 60 days postoperatively in order to elucidate differences previously found in the mechanical strength of delayed primary closure (DPC) and primary closure (PC) wounds in rat skin. The rate of collagen synthesis was significantly higher in the DPC wounds than in the PC wounds during the time period studied. At the same time, the collagen content was lower in the DPC wounds on the 10th postoperative day. There were no differences in collagen content on the 20th or on the 60th postoperative day. These data suggest that there is more degradation of collagen in DPC wounds, starting at the 20th postoperative day. Differences in the rates of collagen synthesis in DPC and PC wounds are compatible with previously found differences in the gains of mechanical strength. It is suggested that the superior mechanical strength of DPC wounds is a result of a higher remodeling activity of collagen in DPC wounds.     

Healing of experimental colonic anastomoses. II. Breaking strength of the colon after left colon resection and anastomosis.

Mechanical strength of the left colon with anastomosis and the intact transverse colon was studied by breaking strength tests performed from four to twenty-eight days after standardized left colon resection in the rat. Two different single layer inverting suture technics were used, continuous and interrupted.Breaking strength of the colon in unoperated rats paralleled to a certain extent the collagen concentration of the colonic wall, with highest values of strength in the left colon where collagen concentration is highest.Both types of anastomoses showed a rapid and equal gain in strength between days 4 and 10, after which time the increase in strength occurred at a much slower rate. After ten days the anastomosis had gained approximately 50 per cent of the strength of the left colon in unoperated control rats. Four weeks after the operation the anastomoses made of continuous suture had reached 75 per cent of normal breaking strength and were significantly stronger than those made of interrupted sutures, which had gained only about 55 per cent of normal strength.Breaking strength test measured the strength of the anastomosis throughout the four week period of investigation, since the rupture always occurred in the anastomotic line.Breaking strength determinations of the intact transverse colon did not show any alterations from normal during the healing course as did determinations of bursting strength reported in a previous study.In skin wounds breaking strength showed a constant development of strength during the four week investigation period, while the gain in strength of the anastomosis slowed down after ten days, although it had only reached 50 per cent of normal.     

Inhibition of tumor necrosis factor-alpha attenuates wound breaking strength in rats.

Exogenous administration of tumor necrosis factor-alpha has been shown to both enhance and attenuate cutaneous healing in a dose-dependent manner. We examined the effects of tumor necrosis factor inhibition in the healing wound by both systemic and local administration of tumor necrosis factor-binding protein. Male Balb/C mice underwent dorsal skin incision with subcutaneous implantation of 20 mg polyvinyl alcohol sponges (4 per animal). In Experiment I, one group (n = 20) received intraperitoneal injections of tumor necrosis factor-binding protein (3 mg/kg) at the time of wounding, while another group (n = 20) received saline. Four animals from each group were euthanized on days 1, 3, 5, 7, and 14 postwounding. In Experiment II, one group (n = 10) received an intraperitoneal injection of tumor necrosis factor-binding protein (3 mg/kg) at the time of wounding and every third day thereafter. Another group (n = 10) received an intraperitoneal injection of saline at the time of wounding and every third day thereafter. In Experiment III, one group received a single intraperitoneal injection of tumor necrosis factor-binding protein (3 mg/kg) at the time of wounding (n = 7), or on postwounding day 4 (n = 7), or day 7 (n = 7). Another group received saline injections at the time of wounding (n = 7), or on postwounding days 4 or 7 (n = 7, respectively). All animals in Experiments II and III were killed at postwounding day 14. Wound breaking strengths were assessed using a tensiometer. Wound fluid collected from the implanted sponges was assayed for tumor necrosis factor-alpha and tumor necrosis factor-binding protein levels using a biological assay and enzyme-linked immunosorbent assay, respectively. Collagen gene expression in sponge granulomata was assessed by Northern analysis. Collagen deposition in sponges was quantified by measuring hydroxyproline content. Wounds were significantly weaker in the animals that received repeated injections of tumor necrosis factor-binding protein with a mean wound breaking strength of 93.1 g vs. 186.6 g in controls (p < 0.05). Wound breaking strength in groups that received a single injection of tumor necrosis factor-binding protein on either day 0, 4, or 7 postwounding were no different than their respective controls. There was no difference in the mean hydroxyproline content of sponges between any of the tumor necrosis factor-binding protein groups and their respective controls. Northern analysis for collagen I and III expression also revealed no differences. These data indicate that continued systemic administration of tumor necrosis factor-binding protein resulted in significantly weaker wounds with no corresponding differences in wound collagen content, and collagen gene expression. This suggests that tumor necrosis factor-alpha inhibition throughout healing leads to a qualitatively impaired wound without a quantitative alteration in collagen deposition.     

Inhibition of matrix metalloproteinases enhances breaking strength of colonic anastomoses in an experimental model

BACKGROUND: The breaking strength of colonic anastomoses declines after operation to a minimum at days 3-4, with a subsequent risk of anastomotic dehiscence. The mechanism is thought to be collagen degradation by matrix metalloproteinases (MMPs). This study examined the pathogenic role of MMPs on the mechanical strength of colonic anastomoses by giving the synthetic broad-spectrum MMP inhibitor BB-1101 systemically. METHODS: Forty-eight male Sprague-Dawley rats were treated daily for 7 days with BB-1101 30 mg/kg or vehicle alone (control) starting 2 days before operation. The breaking strength of standardized left-sided colonic anastomoses was measured on postoperative days 1, 3 and 7. RESULTS: Serum BB-1101 levels were increased at 100 nmol/l in BB-1101-treated rats. The anastomotic breaking strength was 48 per cent higher (P = 0.02) in BB-1101-treated animals compared with controls on postoperative day 3. Neither collagen accumulation nor infiltration of neutrophils in the anastomotic area was influenced by BB-1101 treatment. Net deposition of new collagen in subcutaneous sponges was unaffected by the BB-1101. CONCLUSION: The enhanced breaking strength of colonic anastomoses during the critical early postoperative phase found after administration of a broad-spectrum MMP inhibitor implies that MMPs might increase the risk of anastomotic dehiscence. Presented in part to the third joint meeting of the European Tissue Repair Society and the Wound Healing Society in Bordeaux, France, 24-28 August 1999, and published in abstract form in Wound Repair Regen 1999; 7: A321     

Growth hormone does not attenuate the inhibitory effects of sepsis on wound healing

Chronic abdominal sepsis is associated with impaired tissue repair. Treatment of burn patients with growth hormone results in improved healing of skin graft donor sites. The goal of this study was to determine whether administration of growth hormone could attenuate the inhibitory effects of sepsis on cutaneous wound healing. Four groups of male Sprague Dawley rats were studied: control, control + growth hormone, sepsis, and sepsis + growth hormone. Sepsis was caused by implantation of a bacterial focus in the peritoneal cavity. Control animals underwent sham laparotomy, and polyvinyl alcohol sponge implants were placed in subdermal pockets in all animals. Saline or growth hormone (400 microg) was injected subcutaneously every 12 hours. On day 5, the incisional wounds and polyvinyl alcohol sponge implants were harvested. The breaking strength of abdominal incisions was measured. Granulation tissue penetration and quality were determined by scoring polyvinyl alcohol sponge implant histology from 1 to 4 in a blinded fashion. Collagen deposition in polyvinyl alcohol sponge implants was quantitated by hydroxyproline assay. Septic mortality was not altered by growth hormone administration. Septic animals showed a reduction in food consumption for 2 days after surgery (p < 0.05 vs. controls), which was not affected by growth hormone administration. The breaking strength of incisional wounds and hydroxyproline content of polyvinyl alcohol sponge implants was reduced in septic rats (p < 0.001 vs. controls) but administration of growth hormone for 5 days did not improve breaking strength or collagen deposition in either group. We conclude that the administration of growth hormone for 5 days did not improve collagen deposition or breaking strength in cutaneous wounds from control or septic animals. The results suggest that growth hormone treatment is unlikely to improve tissue repair in sepsis-induced catabolic illness.     

Wound healing in normal and analbuminemic (NAR) rats

It has been suggested by several investigators that hypoalbuminemia results in impaired wound healing. In most studies, however, hypoalbuminemia is a manifestation of malnutrition or underlying liver disease. In this study, we examined the effect of isolated hypoalbuminemia on wound healing. Analbuminemic (NAR) rats which are Sprague-Dawley mutants with trace levels of plasma albumin due to a defect in albumin synthesis were studied. Adult NAR and Sprague-Dawley rats (n = 10 each) underwent a 7 cm dorsal skin incision and implantation of a polyvinyl alcohol sponge subcutaneously under pentobarbital anesthesia. Seven days postoperatively all rats were killed with ether, the wounds were excised, and breaking strength was measured. Sponge hydroxyproline content was determined colorimetrically. There were no significant differences in wound breaking strength (fresh or formalin fixed) or sponge collagen content between the Sprague-Dawley and analbuminemic rats. We conclude that isolated hypoalbuminemia has no detrimental effect on would healing in rats.     

The influence of experimental diabetes and insulin treatments on the biochemical properties of rat skin incisional wounds

The mechanical properties (tensile strength, extensibility, relative failure energy) of skin incisional wounds were analyzed after 7, 10 and 20 days of healing in normal rats, diabetic rats treated with insulin from the day of wound infliction and diabetic rats treated with insulin from the 5th preoperative day. Untreated diabetes resulted in a reduction of the failure energy of skin wounds during the 20 days of wound healing. After 7 days of wound healing, insulin treatment starting on the day of wound infliction or on the 5th preoperative day did not eliminate this reduction in failure energy of wounds induced by diabetes. However, a positive correlation was found between the duration of the insulin treatment and the failure energy of the wounds. After 10 and 20 days of wound healing, the mechanical parameters of wounds from diabetic rats treated with insulin from the day of wound infliction or from the 5th preoperative day did not differ from those of the control wounds. The experiment demonstrates that insulin treatment is essential for adequate wound healing in diabetes. Insulin treatment from the day of wound infliction or from the 5th preoperative day is not, however, sufficient to prevent the inhibitory effects of diabetes in the early phase of wound healing.     

Raxofelast, a hydrophilic vitamin E-like antioxidant, stimulates wound healing in genetically diabetic mice

BACKGROUND. Impaired wound healing is a well-documented phenomenon in experimental and clinical diabetes. Emerging evidence favors the involvement of free radicals in the pathogenesis of diabetes-related healing deficit. This study assessed the effect of systemic administration of raxofelast, a protective membrane antioxidant agent, on wound healing by using healing-impaired (db/db) mice. METHODS. The wound healing effect of raxofelast was investigated by using an incisional skin-wound model produced on the back of female diabetic C57BL/KsJ db+/db+ mice and their healthy littermates (db+/+m). Animals were then randomized to the following treatment: raxofelast (15 mg/kg/d intraperitoneally) or its vehicle (dimethyl sulfoxide/sodium chloride 0.9%, 1:1, vol/vol). The animals were killed on different days, and the wounded skin tissues were used for histologic evaluation and for analysis of malondialdehyde (MDA) level and myeloperoxidase (MPO) activity, wound breaking strength, and collagen content. RESULTS. Diabetic mice showed delayed wound healing together with low collagen content, breaking strength, and increased MDA levels and MPO activity when compared with their healthy littermates. The administration of raxofelast did not modify the process of wound repair in healthy (db/+) mice, but significantly improved impaired wound healing in diabetic mice through the stimulation of angiogenesis, reepithelialization, synthesis, and maturation of extracellular matrix. Furthermore, raxofelast treatment significantly reduced MDA levels, MPO activity, and increased the breaking strength and collagen content of the wound. CONCLUSIONS. The current study provides evidence that raxofelast restores wound healing to nearly normal levels in experimental diabetes-impaired wounds and suggests that an increased lipid peroxidation in diabetic mice may have a role in determining a defect of wound repair.     

The effect of relative bowel rest on healing of colonic anastomoses. Breaking strength and collagen in the colonic wall following left colon resection and anastomosis in the rat

The breaking strength of anastomoses in the left colon in the early phase of healing was studied in rats fed low residue diet (Biosorbin MCT) and the results were compared to those from rats fed standard laboratory diet. Further, eventual correlation between mechanical strength development and collagen content in the colonic wall around the anastomosis was evaluated. The anastomotic strength with sutures in place decreased by approximately 30% of the immediate postoperative value during the first two days in both groups of animals. There was no correlation between changes in anastomotic strength and collagen content at that time. After the second day there was a gradual increase of anastomotic strength, reaching the strength at day 0 after 7 days. The regain of strength was mainly due to collagen deposition in the anastomosis. Despite more collagen deposition in animals on standard laboratory diet the anastomoses had comparable strength development in the two groups. It was concluded that low residue diet does not impair the suture holding capacity or the anastomotic strength. Instead there was some evidence for a more uncomplicated healing when the bowel content was diminished.     

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.