Warren L. Garner

American Burn Association consensus conference to define sepsis and infection in burns.

Because of their extensive wounds, burn patients are chronically exposed to inflammatory mediators. Thus, burn patients, by definition, already have “systemic inflammatory response syndrome.” Current definitions for sepsis and infection have many criteria (fever, tachycardia, tachypnea, leukocytosis) that are routinely found in patients with extensive burns, making these current definitions less applicable to the burn population. Experts in burn care and research, all members of the American Burn Association, were asked to review the literature and prepare a potential definition on one topic related to sepsis or infection in burn patients. On January 20, 2007, the participants met in Tucson, Arizona to develop consensus for these definitions. After review of the definitions, a summary of the proceedings was prepared. The goal of the consensus conference was to develop and publish standardized definitions for sepsis and infection-related diagnoses in the burn population. Standardized definitions will improve the capability of performing more meaningful multicenter trials among burn centers.

Correlation of the local and systemic cytokine response with clinical outcome following thermal injury.

Eighty-eight patients with acute thermal injury were evaluated. Forty-eight hours after injury, TNF, IL-6, and IL-8 were significantly present in the systemic circulation, lung, normal skin, and thermally injured skin. The presence of TNF, IL-6, and IL-8 proteins in the lung, normal skin, and thermally injured skin were associated with TNF, IL-6, and IL-8 mRNA upregulation. Logistic regression analysis controlling for the Abbreviated Burn Severity Index demonstrated that the presence of IL-8 in the lung was associated with early pulmonary physiologic dysfunction (p = 0.006) and nosocomial pulmonary infection (p = 0.040). We conclude that acute thermal injury initiates an early systemic, lung, and skin response involving TNF, IL-6, and IL-8. The TNF, IL-6, and IL-8 protein present in the lung and skin in response to acute thermal injury are generated locally and do not originate from the systemic cytokine pool. The lung cytokine response to acute thermal injury may initiate local organ failure.

Epithelial to Mesenchymal Transition in Human Skin Wound Healing Is Induced by Tumor Necrosis Factor-α through Bone Morphogenic Protein-2

Epithelial-mesenchymal transition (EMT), characterized by loss of epithelial adhesion and gain of mesenchymal features, is an important mechanism to empower epithelial cells into the motility that occurs during embryonic development and recurs in cancer and fibrosis. Whether and how EMT occurs in wound healing and fibrosis in human skin remains unknown. In this study we found that migrating epithelial cells in wound margins and deep epithelial ridges had gained mesenchymal features such as vimentin and FSP1 expression. In hypertrophic scars, EMT-related genes were elevated along with inflammatory cytokines, indicating a causal relationship. To reconstitute EMT in vitro, normal human skin and primary keratinocytes were exposed to cytokines such as tumor necrosis factor-alpha (TNF-alpha), resulting in expression of vimentin, FSP1, and matrix metalloproteinases. Moreover, TNF-alpha-induced EMT was impaired by antagonists against bone morphogen proteins (BMP) 2/4, suggesting that BMP mediates the TNF-alpha-induced EMT in human skin. Indeed, TNF-alpha could induce BMP-2 and its receptor (BMPR1A) in human skin and primary keratinocytes, and BMP2 could induce EMT features in skin explants and primary keratinocytes. In summary, we uncovered EMT features in both acute and fibrotic cutaneous wound healing of human skin. Moreover, we propose that the mesenchymal induction in wound healing is motivated by TNF-alpha, in part, through induction of BMP.

Inflammatory mediators in wound healing

This article provides much evidence that the inflammatory process has direct effects on normal and abnormal wound healing. As better understanding develops for the mechanism for these outcomes, targeted proinflammatory and anti-inflammatory interventions are likely to be successful. When inflammation is maintained as a regulated and orchestrated response, effective and normal wound healing is likely to result.

epidermal Regulation of Dermal Fibroblast Activity

&NA; Although the association between delayed burn wound healing and subsequent hypertrophic scar formation is well‐established, the mechanism for this relationship is unknown. Unhealed burn wounds lack an epidermis, suggesting a possible regulatory role for the epidermis in controlling dermal fibroblast matrix synthesis. Therefore, we examined the effect of epidermal cells and media conditioned by epidermal cells on fibroblast collagen synthesis and replication. Purified fibroblast and keratinocyte cell strains were developed from discarded normal adult human skin. Conditioned media were created by incubation of cytokine‐free and serum‐free medium with either confluent fibroblast or keratinocyte cultures for 18 hours (n = 3). Nearly confluent fibroblast cultures were exposed for 48 hours to graded concentrations of either unconditioned medium (control), conditioned medium, or varying numbers of keratinocytes. Replication was quantified by the incorporation of 3H‐thymidine. Collagen synthesis was measured by the incorporation of 3H‐proline into collagenase‐sensitive protein. Data were compared using analysis of variance (ANOVA) and linear regression. Keratinocyte conditioned medium induced a significant increase in replication (n = 3) (p = 0.004) and a decrease in collagen synthesis (n = 6) (p < 0.001). In contrast, neither fibroblast conditioned medium nor control medium had an effect on fibroblast replication or collagen synthesis. Co‐culture of fibroblast with a graded number of keratinocytes similarly decreased collagen synthesis (n = 6) (p < 0.001). Dermal fibroblast collagen synthesis appears to be regulated by a soluble keratinocyte product. This result suggests a mechanism for the clinical observation that unhealed burn wounds, which lack the epidermis, demonstrate excess collagen production and scar. Clinical strategies to decrease hypertrophic scar should include an attempt at early wound closure with skin grafting or the application of cultured epithelial autografts. (Plast. Reconstr. Surg. 102: 135, 1998.)

Matrix metalloproteinase-9 delays wound healing in a murine wound model.

BACKGROUND Metalloproteinase-9 (MMP-9) is a type IV collagenase found at elevated levels in chronic wounds. As wounds heal, MMP-9 diminishes. In this study, we investigated whether MMP-9 directly contributes to chronic wound pathogenesis. METHODS Recombinant proMMP-9 was prepared using immortalized keratinocytes transduced by a lentivirus. ProMMP-9 was purified from cell culture media and activated using 4-aminophenylmercuric acetate. Active MMP-9 was then suspended in xanthan gum to a concentration paralleling that found in human chronic wounds. Two parallel 6-mm punch biopsies were made on the backs of C57BL mice. Wounds were treated daily with MMP-9 or vehicle. Wound areas were measured and tissues examined by densitometry, real-time RT-PCR, histology, and immunohistochemistry at days 7, 10, and 12. RESULTS Exogenous MMP-9, at the level found within chronic wounds, delayed wound healing in this animal model. By 7 days, wounds in the MMP-9-injected group were 12% larger than control wounds (P = .008). By day 12, wounds in the MMP-9-injected group were 25% larger than those of the control group (P = .03). Histologic examination shows that high levels of active MMP-9-impaired epithelial migrating tongues (P = .0008). Moreover, consistent with elevated MMP-9, the collagen IV in the leading edge of the epithelial tongue was diminished. CONCLUSION MMP-9 appears to directly delay wound healing. Our data suggests that this may occur through interference with re-epithelialization. We propose that MMP-9 interferes with the basement membrane protein structure, which in turn impedes keratinocyte migration, attachment, and the reestablishment of the epidermis.

Integra in Lower Extremity Reconstruction after Burn Injury

Background: Standard care for lower extremity injuries with exposed bone or tendon is vascularized tissue transfer. In patients with deep and extensive burn injuries, these options are often not available or for various reasons are technically difficult. The advent of Integra, a permanent dermal replacement matrix, provides an important alternative to the traditional reconstructive choices. Methods: The authors report seven patients, with a total of nine lower extremity injuries, from the Los Angeles County and University of Southern California Hospital Burn Unit treated from September of 2001 to January of 2003 who presented with complex burn injuries involving their lower extremities with tendon, open joints, and/or bone exposure. Results: All seven patients were treated initially with tangential excision of the burn eschar and placement of Integra. After engraftment, epidermal coverage was restored with a thin split-thickness skin graft. This treatment provided stable wound coverage, and none of the patients have required further surgical procedures to maintain wound closure. Conclusions: The use of a bioengineered, cell-free dermal matrix expands reconstructive options and allows salvage of extremities that might otherwise have been amputated or required prolonged, staged procedures. The authors’ experience shows that Integra provides a sound alternative option for providing durable coverage of vital lower extremity structures. It should be considered as part of the lower extremity wound coverage algorithm.

An Open, Parallel, Randomized, Comparative, Multicenter Study to Evaluate the Cost-Effectiveness, Performance, Tolerance, and Safety of a Silver-Containing Soft Silicone Foam Dressing (Intervention) vs Silver Sulfadiazine Cream

An open, parallel, randomized, comparative, multicenter study was implemented to evaluate the cost-effectiveness, performance, tolerance, and safety of a silver-containing soft silicone foam dressing (Mepilex Ag) vs silver sulfadiazine cream (control) in the treatment of partial-thickness thermal burns. Individuals aged 5 years and older with partial-thickness thermal burns (2.5–20% BSA) were randomized into two groups and treated with the trial products for 21 days or until healed, whichever occurred first. Data were obtained and analyzed on cost (direct and indirect), healing rates, pain, comfort, ease of product use, and adverse events. A total of 101 subjects were recruited. There were no significant differences in burn area profiles within the groups. The cost of dressing-related analgesia was lower in the intervention group (P = .03) as was the cost of background analgesia (P = .07). The mean total cost of treatment was

HYPERTROPHIC SCAR, WOUND CONTRACTION AND HYPER-HYPOPIGMENTATION

309 vs

Migration of human keratinocytes in plasma and serum and wound re-epithelialisation

513 in the control (P < .001). The average cost-effectiveness per treatment regime was