Suction blister lesions and epithelialization monitored by optical coherence tomography.

BACKGROUND/PURPOSE: Our objective was to assess epithelialization of suction blister lesions by optical coherence tomography (OCT) and benchmark it to histology using epidermal thickness (ET) as the primary outcome. METHODS: Thirty-two healthy volunteers were recruited to Study 1 and 2. One 10-mm suction blister was raised on each buttock, and the blister roof was excised. Lesions were covered with moisture-retaining dressing. In Study 1, the lesions were OCT-scanned on day 0 (D0), D2 and D4 and excised for histological examination. In Study 2, the progress of epithelialization and skin barrier function were monitored to D14. RESULTS: ET increased from D0 to D2 by 46 µm (P<.001) and from D2 to D4 by 19 µm (P=.004). Compared with histology, OCT overestimated the presence of the epithelium (P<.0001) and ET on D4. Reliable measurements were obtained when the ET of the lesions reached the ET of the normal epidermis from D5-D7 and onwards. The ET development was reflected in decreased transepidermal water loss. CONCLUSION: We found that the OCT technique was poorly discriminative with respect to the neoepithelium and the moist lesion surface material in the early postinjury period. In the later stages, OCT seemed valuable for estimating the advancement of epithelialization.

Growth factor and proteinase profile of Vivostat® platelet-rich fibrin linked to tissue repair.

BACKGROUND AND OBJECTIVES: Autologous platelet-rich fibrin (PRF(®)) is prepared by the automatic Vivostat(®) system. Conflicting results with Vivostat PRF in acute wound healing prompted us to examine its cellular and biomolecular composition. Specifically, platelets, selected growth factors and matrix metalloproteinase (MMP)-9 were quantified using novel analytical methods. MATERIALS AND METHODS: Ten healthy non-thrombocytopenic volunteers donated blood for generation of intermediate fibrin-I and final PRF. Anticoagulated whole blood and serum procured in parallel served as baseline controls. Leucocyte, erythrocyte and platelet counts in whole blood and fibrin-I were determined by automated haematology analyser. Platelet concentration in PRF was quantified manually by stereologic analysis of Giemsa-stained tissue sections, and the total content of five growth factors and MMP-9 by enzyme-linked immunosorbent assays. RESULTS: The number of leucocytes and erythrocytes was reduced (P < 0·001), whereas platelets increased (P < 0·001) in fibrin-I versus whole blood. PRF contained 982 ± 206 × 10(9) platelets/l representing 3·9-fold (P < 0·001) enrichment relative to whole blood. Growth factor abundance in Vivostat PRF and serum was in descending order: transforming growth factor-ß1 [5·1-fold higher in PRF than serum, P < 0·001] > platelet-derived growth factor (PDGF)-AB [2·5-fold, P < 0·01] > PDGF-BB [1·6-fold, P < 0·05] > vascular endothelial growth factor > basic fibroblast growth factor [75-fold, P < 0·001]. MMP-9 was reduced 139-fold (P < 0·001) compared with serum, reflecting leucocyte depletion in PRF. CONCLUSION: The gained knowledge on platelet enrichment and biomolecular constituents may guide clinicians in their optimal use of Vivostat PRF for tissue regenerative applications.

Effect of postoperative diclofenac on anastomotic healing, skin wounds and subcutaneous collagen accumulation: a randomized, blinded, placebo-controlled, experimental study.

BACKGROUND: Retrospective studies have drawn attention to possible detrimental effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the anastomotic leakage rate after colorectal resection. In this study, we examined the effects of the NSAID diclofenac on the breaking strength of an experimental colonic anastomosis and a skin incision as well as subcutaneous collagen accumulation. METHODS: This was a randomized, blinded, placebo-controlled experimental study in 60 male Wistar rats treated with diclofenac 4 mg/kg/day or placebo. In each rat, a colonic anastomosis was performed and an expanded polytetrafluoroethylene (ePTFE) tube was placed subcutaneously. Incisional and anastomotic wound breaking strength and hydroxyproline content in the ePTFE tubes were measured 7 days after the operation. RESULTS: We found no significant differences in any of the breaking strength measurements, but showed a median 38% reduction in hydroxyproline deposition as a result of diclofenac treatment (p = 0.03). In the placebo group, subcutaneous collagen deposition tended to correlate positively with skin incisional but negatively with anastomotic bio-mechanical strength. CONCLUSION: Postoperative diclofenac treatment significantly inhibited collagen deposition in subcutaneous granulation tissue. Anastomotic strength and skin wound strength were not significantly affected. The ePTFE model is suitable for assessing the effect of various drugs on collagen formation and thus on wound healing.

Connective tissue alteration in abdominal wall hernia.

BACKGROUND: The aetiology and pathogenesis of abdominal wall hernia formation is complex. Optimal treatment of hernias depends on a full understanding of the pathophysiological mechanisms involved in their formation. The aim of this study was to review the literature on specific collagen alterations in abdominal wall hernia formation. METHODS: A computer-assisted search of the medical databases PubMed and Embase was performed, together with a cross-reference search of eligible papers. RESULTS: Fifty-two papers were included. Collagen alteration depended on the type of hernia; there were more pronounced changes in patients with a direct inguinal hernia than in those with an indirect inguinal hernia, recurrent inguinal hernia or incisional hernia. A consistent finding was a significant increase in immature type III collagen relative to the stronger type I collagen in patients with a hernia. This resulted in thinner collagen fibres with a correspondingly diminished biomechanical strength. It has been suggested that these alterations are due to variation in the synthesis, maturation or degradation of collagen by matrix metalloproteinases, in combination or alone. CONCLUSION: Hernia formation and recurrence is associated with altered collagen metabolism manifested by a decreased type I:III collagen ratio.

S100A8/A9 deficiency in nonhealing venous leg ulcers uncovered by multiplexed antibody microarray profiling.

BACKGROUND: Knowledge on the underlying mechanisms for nonhealing chronic wounds is fragmentary. OBJECTIVES: To increase our understanding of the pathogenesis, the relationship between healing ability and a large panel of proteins was studied using a specially designed wound-healing antibody-based microarray. METHODS: Wound fluid from nondiabetic patients with nonhealing venous leg ulcers was compared with that from patients with healing open granulating acute wounds. The high-throughput method enabled simultaneous measurement of the relative levels of 48 different proteins representing major categories of wound-healing modulators. RESULTS: Unexpectedly, several of the examined proteins, including various proinflammatory cytokines, proteinases and antiproteinases, were not significantly (P>0·001) changed in chronic wound fluid. For example, levels of matrix metalloproteinase-9 and one of its substrates type IV collagen were similar in the two groups. The wound fluid samples displayed similar degrees of fragmentation of fibronectin by Western blot analysis and the total fibronectin levels were doubled (P<0·001) in chronic compared with acute wounds. The increased fibronectin originated from α-smooth muscle actin-positive myofibroblasts and not from the circulation. S100A8/A9 was the sole protein that was reduced (P<0·001) in wound fluid from venous ulcers [median 226 µg mL(-1) (interquartile range 213-278)] compared with healing wounds [455 µg mL(-1) (382-504)], probably reflecting a difference in inflammatory cell composition. CONCLUSION: The molecular anomalies in chronic wounds are more subtle than the current paradigm and neither excessive proteinase activity nor deficiencies of examined extracellular matrix proteins, growth factors or angiogenic/angiostatic factors appear to contribute significantly to the nonhealing state of venous leg ulcers.

Collagen levels are normalized after decompression of experimentally obstructed colon.

AIM: Our aim was to define the dynamics in collagen concentrations in the large bowel wall following decompression of experimental obstruction. METHOD: Colonic obstruction was created in 28 male rats by the placement of a silicone ring around the distal colon. The ring was removed after 4 days to mimic endoscopical decompression by stent deployment. Colon circumference and collagen concentration were measured proximal to the obstructed segment immediately and at 3 and 10 days after decompression. The corresponding colonic sites of 23 sham-operated and eight nonoperated control animals were subjected to identical analyses. RESULTS: Four days of obstruction resulted in a more than twofold increase in colonic circumference (20 vs 8 mm), with a concomitant 43% reduction (P = 0.001) in collagen concentration in the bowel wall proximal to the obstruction compared with sham animals. Three days after decompression, collagen concentrations remained reduced (P < 0.05), while there was no significant difference after 10 days with either sham-operated or nonoperated controls. Colonic circumference of the obstructed colon remained slightly distended (11 mm) on day 10 and tended to correlate (r(S) = 0.51, P = 0.053) with total matrix metalloproteinase activity. CONCLUSION: The marked reduction in collagen concentration in an experimentally obstructed colon is normalized 10 days after decompression. These findings may have clinical implications for the timing of surgical resection.

Effect of diclofenac on cyclooxygenase-2 levels and early breaking strength of experimental colonic anastomoses and skin incisions.

BACKGROUND: Recently, there has been a focus on the effect of the nonsteroidal anti-inflammatory drugs on the anastomotic leakage rate after colorectal surgery. METHODS: An experimental, randomized, placebo-controlled prospective study on 32 male Wistar rats was carried out. We examined the effect of diclofenac 4 mg/kg/day on the cyclooxygenase-2 (COX-2) enzyme in the anastomotic tissue and on the breaking strength of anastomotic and incisional wounds. The operation was performed with colonic resection and hand-sewn anastomosis. After 3 days, the rats were sacrificed and the breaking strength and the COX-2 content of the anastomosis were measured. RESULTS: There was a significantly reduced level of COX-2 in the rats treated with diclofenac (p = 0.001); no significant differences in any of the breaking strength measurements and no significant correlation between COX-2 levels and breaking strength of the anastomotic or incisional wounds could be found (p = 0.073 and p = 0.727). CONCLUSION: This study for the first time showed that a diclofenac dose of 4 mg/kg/24 h was sufficient to reduce the level of COX-2 enzymes in the anastomotic tissue in rats. This inhibition of the inflammatory response did not lead to reduced breaking strength of either anastomotic or incisional wounds. Whether there is a detrimental effect of COX inhibition on colorectal anastomoses in the clinical setting remains controversial.

Effects of amelogenins on angiogenesis-associated processes of endothelial cells.

OBJECTIVE: To study the effects of an amelogenin mixture on integrin-dependent adhesion, DNA synthesis and apoptosis of cultured human dermal microvascular endothelial cells and angiogenesis in an organotypic assay. METHOD: Immobilised antibodies against specific integrins (alpha-1, alpha-2, alpha-3, alpha-4, alpha-5, alpha-v, ß1, ß2, ß3, ß4, ß6, alpha-vß3, alpha-vß5 and alpha-5ß1) were used to capture treated human dermal microvascular endothelial cells, which were detected colourimetrically. DNA synthesis of the cells was monitored by 5-bromo-2'- deoxyuridine incorporation and apoptosis by a TdT-mediated dUTP nick-end labelling technique. Tubule formation from aortic arches of 13-d-old chick embryos were followed over 48h. RESULTS: The amelogenin mixture increased microvessel outgrowth by 76% (p < 0.01, n=12) from the aortic explants. Also, amelogenins increased the adhesion (p < 0.01, n = 5) by multiple angiogenesis associated integrin subunits and alpha-vß3, alpha-vß5 and alpha-5ß1 heterodimers on human dermal microvascular endothelial cells at a non-mitogenic concentration (100 µg/ml). Conversely, amelogenins at 1,000 µg/ml decreased microvessel formation possibly due to attenuation of corresponding integrins despite increasing (p < 0.001, n = 8) DNA synthesis. No significant apoptosis was detected in human dermal microvascular endothelial cells cultured on Matrigel with and without amelogenins. CONCLUSION: Increased surface expression of integrins on endothelial cells may contribute to the proangiogenic property of amelogenins.

Evaluation of a near-senescent human dermal fibroblast cell line and effect of amelogenin.

BACKGROUND: Fibroblast senescence may delay healing of chronic wounds. OBJECTIVES: To characterize a chronic human dermal fibroblast cell line (CRL-7815) with near-senescent properties, cell proliferation and production of wound-healing modulating cytokines, and biosynthesis and remodelling of collagen were compared with normal human dermal fibroblasts. Also, the response of CRL-7815 fibroblasts to the extracellular matrix protein amelogenin that is beneficial in the treatment of stalled chronic wounds was studied. METHODS: Fibroblast proliferation was monitored by time-resolved growth curves and factors secreted into the culture medium containing 10% fetal bovine serum were measured by enzyme-linked immunosorbent assays. Fibroblast-mediated reorganization was examined in three-dimensional type I collagen matrices. RESULTS: Cell proliferation over 9 days was significantly (P < 0.01) slower for CRL-7815 than for normal fibroblasts. Amelogenin at 1 mg mL(-1) increased (P < 0.01) CRL-7815 proliferation to the level of the normal fibroblasts. The neutrophil chemoattractant interleukin (IL)-8 was low while the constitutive production of monocyte chemoattractant protein (MCP)-1 was highly elevated in medium from cultured CRL-7815 fibroblasts. Amelogenin augmented IL-8 but attenuated MCP-1 secretion in CRL-7815 fibroblasts. The elevated vascular endothelial growth factor production in CRL-7815 fibroblasts was further increased with amelogenin while increased type I collagen synthesis by CRL-7815 was reduced with 0.1 mg mL(-1) amelogenin. The dramatically impaired collagen matrix remodelling with CRL-7815 fibroblasts (P < 0.001) was slightly improved with amelogenin (P = 0.0011). CONCLUSIONS: The near-senescent cell line CRL-7815 shares functional anomalies with fibroblasts isolated from nonhealing chronic cutaneous wounds. Amelogenin has the capacity to switch chronic fibroblasts into an acute-like phenotype.

Type V Collagen is Persistently Altered After Inguinal Hernia Repair.

BACKGROUND AND AIMS: Hernia formation is associated with alterations of collagen metabolism. Collagen synthesis and degradation cause a systemic release of products, which are measurable in serum. Recently, we reported changes in type V and IV collagen metabolisms in patients with inguinal and incisional hernia. The aim of this study was to determine if the altered collagen metabolism was persistent after hernia repair. MATERIAL AND METHODS: Patients who had undergone repairs for inguinal hernia (n = 11) or for incisional hernia (n = 17) were included in this study. Patients who had undergone elective cholecystectomy served as controls (n = 10). Whole venous blood was collected 35-55 months after operation. Biomarkers for type V collagen synthesis (Pro-C5) and degradation (C5M) and those for type IV collagen synthesis (P4NP) and degradation (C4M2) were measured by a solid-phase competitive assay. RESULTS: The turnover of type V collagen (Pro-C5/C5M) was slightly higher postoperatively when compared to preoperatively in the inguinal hernia group (P = 0.034). In addition, the results revealed a postoperatively lower type V collagen turnover level in the inguinal hernia group compared to controls (P = 0.012). In the incisional hernia group, the type V collagen turnover was higher after hernia repair (P = 0.004) and the postoperative turnover level was not different from the control group (P = 0.973). CONCLUSION: Patients with an inguinal hernia demonstrated a systemic and persistent type V collagen turnover alteration. This imbalance of the collagen metabolism may be involved in the development of inguinal hernias.

Biophysical effects of repetitive removal of adhesive dressings on peri-ulcer skin.

OBJECTIVE: To study the effect of repeated removal of four different adhesive dressings on peri-ulcer skin using quantitative non-invasive techniques. METHOD: Forty-five patients with open (n = 29) or healed (n = 16) venous leg ulcers were included. Peri-ulcer skin was treated for 14 days with patches of two different hydrocolloid-based adhesive dressings, one polyurethane adhesive and one soft silicone adhesive dressing. Normal skin of the patients' ventral forearm was also treated identically. Adhesive patches of the dressings were replaced every second day. The skin barrier function was assessed by measuring transepidermal water loss and stratum corneum hydration by measuring electrical conductance. RESULTS: Thirty-nine patients completed the study. The hydrocolloid adhesives increased transepidermal water loss and conductance while the polyurethane and soft silicone adhesives did not influence these parameters significantly compared with adjacent non-treated peri-ulcer skin. For normal forearm skin, similar relative effects among the four adhesives were found. CONCLUSION: Repetitive treatment with hydrocolloid-based adhesive dressings induced major functional alterations of the stratum corneum. In contrast, a polyurethane adhesive and a soft silicone adhesive dressing did not alter transepidermal water loss or conductance of peri-ulcer skin.

Collagenase in wound healing: effect of wound age and type.

Collagenase is believed to be important for cell migration and collagen remodeling during tissue repair and regeneration. We have investigated collagenase concentrations in different types of surgically inflicted wounds in pigs. Collagenase was extracted from tissue homogenates of wounds by heating to 60 degrees C for 6 min in 0.1 M CaCl2. The molecular weight of latent collagenase was about 52 kDa. Activated collagenase produced the characteristic 3/4 fragment of collagen. Collagenase was assayed by the use of radiolabeled telopeptide-free collagen. To detect maximal collagenase activity, extracts were reduced and alkylated to destroy inhibitors, then activated with aminophenylmercuric acetate. Sutured incisions showed peak collagenase content on postoperative day 1 and thereafter steadily declining concentrations. Granulation tissue from non-sutured large defect full-thickness wounds showed high collagenase content on postoperative day 5 and then a sharp decline to day 7 followed by a slowly declining curve to postoperative day 21. Partial-thickness wounds exhibited a different time course, with collagenase increasing to peak concentrations on postoperative days 3-5; however, a large proportion of the detected collagenase was due to the adherent scab. By day 7 collagenase concentrations approached the low concentrations of normal skin when epithelialization was complete and the scab rejected. In general, collagenase shows an early maximum and then declines with postoperative time, with the sharpest decline occurring when epithelialization is complete.

Proliferation and mitogenic response to PDGF-BB of fibroblasts isolated from chronic venous leg ulcers is ulcer-age dependent.

Several pathophysiologic mechanisms have been proposed to explain slow-healing leg ulcers, but little is known about the growth behavior of cells in these wounds. Platelet-derived growth factor-BB applied topically to chronic wounds has shown beneficial effects, although the effects have been less pronounced than would have been expected based on studies on acute wounds. The objective of this study was to compare fibroblasts in culture obtained from chronic wounds (non-healing chronic venous leg ulcers), acute wounds and normal dermis regarding growth, mitogenic response to platelet-derived growth factor-BB and levels ofplatelet-derived growth factor alpha-receptor and beta-receptor. Fibroblasts were obtained by an explant technique and expanded in vitro using fibroblast growth medium supplemented with 10% fetal bovine serum and used for the assays at their third passage. Growth of chronic wound fibroblasts (n = 8) was significantly (p < 0.05) decreased compared with those from acute wounds (n = 10) and normal dermis (n = 5). Fibroblasts from ulcers older than 3 y grew significantly (p < 0.01) slower than those from ulcers that had been present for less than 3 y. Morphology and size of fibroblasts from the oldest chronic wounds deviated substantially from those of acute wounds and normal dermis, and resembled in vitro aged or senescent fibroblasts. Mitogenic response of chronic wound fibroblasts to human recombinant platelet-derived growth factor-BB was also reduced with ulcer age. No significant differences were found in the amount of either platelet-derived growth factor alpha-receptor or beta-receptor among the three groups. The features decreased growth related to ulcer age, altered morphology, and reduced response to platelet-derived growth factor, indicating that fibroblasts in some chronic wounds have approached or even reached the end of their lifespan (phase III). This might provide one explanation for the non-healing state and therapy resistance to topical platelet-derived growth factor-BB of some venous leg ulcers.

Impaired function of postoperative macrophages from zinc-deficient rats decreases collagen contraction. Brief report.

Zinc deficiency impairs connective tissue contraction in the perforated rat mesentery model. Since the rat mesentery is almost avascular, free peritoneal macrophages are important for mesenteric repair. Impairment of contraction may thus be caused either by a direct effect of zinc deficiency on tissue cells or by hampered macrophage function. To further elucidate the role of macrophages in tissue contraction, we studied their effect on lattice contraction. A number of typical functions of macrophages in zinc deficiency were also investigated. Lattice contraction was significantly impaired by conditioned medium from zinc-deficient macrophages. Zinc deficiency did not influence peripheral blood leukocyte number, but postoperatively the number of peritoneal macrophages increased on days 7 and 10. A significant release of lysosomal enzymes from macrophages was recorded during phagocytosis, whilst no difference was observed between controls and zinc-deficient macrophages. Superoxide anion generation during phagocytosis was not significantly increased in zinc deficiency. Conditioned medium from zinc-deficient macrophages was shown to impair lattice contraction in vitro and the results are compatible with impaired macrophage function as a cause of decreased connective tissue contraction in vivo.

Matrix metalloproteinases and colon anastomosis repair: a new indication for pharmacological inhibition?

Excessive matrix metalloproteinase activities have been implicated in the pathogenesis of intestinal anastomotic dehiscence, a serious and potentially life-threatening complication following gastrointestinal surgery. In this review, the properties of matrix metalloproteinases are summarized followed by presentation of clinical therapeutic interventions with synthetic matrix metalloproteinase inhibitors and novel experimental data on colon anastomosis repair that warrant exploration of these drugs in surgical colorectal patients.

Matrix metalloproteinases (MMPs) are required for re-epithelialization of cutaneous wounds.

Matrix metalloproteinases (MMPs) are neutral zinc-dependent endopeptidases with substrate specificity for most extracellular matrix molecules. MMPs participate in physiological and pathological biological processes. In wound repair, several MMPs are upregulated in migrating epithelium although the biological significance of their presence is unknown. To elucidate the role of MMPs in epithelial migration of cutaneous wounds, a broad-spectrum synthetic MMP inhibitor (GM 6001, 10 mg/ml) was applied topically to partial-thickness wounds in domestic pigs to inhibit endogenous MMPs. The concentration of solubilized GM 6001 in wound fluid obtained from treated porcine wounds was 0.06 mg/ml (150 microM) as determined by high-performance liquid chromatography. Zymographic analysis showed that GM 6001 solubilized at this concentration abolished almost completely all enzymatic activity present in wound fluid. Epithelial coverage, assessed morphometrically, after 66 h of treatment was significantly decreased (P = 0.002) in GM 6001-treated wounds (50.0 +/- 29.6%, mean +/- SD, n = 6) compared with wounds treated with the vehicle (a hydrogel) alone (87.4 +/- 10.6%, n = 6). Topical GM 6001 did not influence the degree of dermal inflammatory cell infiltrate or the in vivo incorporation of 5-bromo-2'-deoxyuridine (as a measure of epithelial proliferation in the wounds) indicating that the reduced re-epithelialization with GM 6001 was not due to interference with the inflammatory response or epithelial proliferation. Our results suggest that MMPs are directly involved and necessary in epithelial resurfacing of moist skin wounds.

Collagenase during burn wound healing: influence of a hydrogel dressing and pulsed electrical stimulation.

Epithelialization of second-degree burn wounds is known to be accelerated by topical treatment with hydrogel dressings and further enhanced by pulsed electrical stimulation compared with no treatment (air exposure). Tissue collagenase has been proposed to be involved during the process of epithelialization. In the present study collagenase levels were examined in partial-thickness burn wounds in the skin of four domestic pigs. Collagenase levels, assayed on postburn days 1 to 10, were substantially reduced in deblistered and air-exposed burn wounds compared with excisional partial-thickness wounds. Early application of hydrogel dressing to the burn wounds was accompanied by elevated collagenase activities and an increased inflammatory reaction in dermis. Addition of pulsed electrical stimulation increased (p < 0.001) collagenase levels twofold above those with hydrogel alone during initiation of epithelialization (postburn days 3 and 4). These results suggest that collagenase is closely linked to wound epithelialization.

Studies on zinc in wound healing.

Topical zinc is widely used in wound treatment although the beneficial effect of zinc has only been documented in zinc-deficient patients who were given zinc orally. The main purpose of this study was to investigate the effect of topically applied zinc on leg ulcer healing and examine its effect on some mechanisms in wound healing using standardized animal models. Additionally, absorption of zinc into wounds and intact skin treated topically with zinc was studied. In a double-blind trial involving 37 leg ulcer patients with low serum zinc levels, topical zinc oxide promoted cleansing and re-epithelialization. Infections and deteriorations of ulcers were less common in zinc oxide treated patients. Re-epithelialization, an important mechanism in the closure of leg ulcers, was enhanced with zinc oxide applied topically on partial-thickness wounds in pigs with normal zinc status. Zinc sulfate at three different concentrations did not, however, result in this beneficial effect on the resurfacing of wounds. The inflammatory reaction was diminished in zinc treated wounds except when a high zinc sulfate concentration was applied. Bacterial growth and concomitant diseases such as diabetes can complicate wound healing. In normal rats, bacterial growth in full-thickness wounds was reduced with topical zinc oxide but not in hyperglycemic diabetic rats. The anti-bacterial mechanism of zinc oxide seemed to be more indirect and to be mediated via local defense systems rather than being directly toxic to the bacteria. Healing of 21-day-old skin incisions was impaired in zinc deficiency, as measured by a significantly decreased wound breaking strength in zinc-deficient rats compared with that of pair-fed controls. The decreased breaking strength did not seem to be due to differences in collagen concentration of the wounds. Zinc oxide was slowly but continuously solubilized when applied on open wounds in rats. On the other hand, with zinc sulfate, the zinc concentrations, either locally or systemically, did not maintain a constant level for the 48-hour post-operative treatment period as they did with zinc oxide. Zinc absorption in and through normal human forearm skin was demonstrated after treatment with a zinc oxide medicated occlusive dressing by increased zinc levels in epidermis, interstitial fluid and dermis compared with the non-zinc control dressing. In conclusion, topical zinc may stimulate leg ulcer healing by enhancing re-epithelialization, decreasing inflammation and bacterial growth. When zinc is applied on wounds it not only corrects a local zinc deficit but also acts pharmacologically.(ABSTRACT TRUNCATED AT 400 WORDS)

Causes and effects of the chronic inflammation in venous leg ulcers.

The pathogenesis of venous leg ulcers is multifactorial. In this review article new physiological, molecular and cellular abnormalities in venous ulcers related to the chronic inflammation are presented and discussed. Venous hypertension causes disturbed microcirculation and pathological changes of the capillaries, which eventually locks the condition in a self-amplifying, detrimental cascade with persistent elevated levels and activities of pro-inflammatory cytokines and proteases preventing progress into a healing phase. As a consequence fibroblasts senescence and become less responsive to growth factors the older the ulcers become. Current data imply there is no deficiency but rather an unfavorable distribution of growth factors in venous ulcers. An imbalance in proteolytic enzymes and their endogenous inhibitors is a common finding in chronic venous leg ulcers. Variation in disease severity and concomitant ailments in this heterogeneous patient group may explain the contradictory results in the literature. Thus, to advance the areas of research further, longitudinal studies involving larger number of patients are required to identify the major pathogenic factors.