Subcutaneous Anti-inflammatory Therapies to Prevent Burn Progression in a Swine Model of Contact Burn Injury.

INTRODUCTION: If left untreated, burn injuries can deepen or progress in depth within the first 72 hours after injury as a result of increased wound inflammation, subsequently worsening healing outcomes. This can be especially detrimental to warfighters who are constrained to resource-limited environments with delayed evacuation times to higher roles of care and more effective treatment. Preventing this burn progression at the point of injury has the potential to improve healing outcomes but requires a field-deployable therapy and delivery system. Subcutaneous therapies known to treat inflammation delivered local to the wound site may prove to be one such avenue for success. MATERIALS AND METHODS: Seven Yorkshire-cross swine received partial-thickness burn injuries using a previously established contact burn model. Each animal received one of the seven therapies: (1) saline, (2) heparin, (3) ibuprofen, (4) erythropoietin, (5) resolvin, (6) rapamycin, and (7) placental extract, all of which are either currently employed or are experimental in field use and indicated to treat inflammation. Treatments were delivered subcutaneously on the day of injury and 24 hours post-injury to simulate a prolonged field care scenario, before potential evacuation. Animals and wound development were observed for 28 days before euthanasia. Throughout the course of the study, wounds were observed macroscopically via non-invasive imaging. Histological analyses provided the critical metric of burn progression. Treatment success criteria were designated as the ability to prevent burn progression past 80% of the dermal depth in two of the three treated wounds, a clinically relevant metric of burn progression. RESULTS: It was determined that the applied model successfully created reproducible partial-thickness burn injuries in this porcine study. No significant differences with regard to lateral wound size or the rate of lateral wound closure were observed in any treatments. Several treatments including resolvin, rapamycin, ibuprofen, and erythropoietin successfully reduced burn progression to less than 80% of the dermal depth in two of the three wounds, 24 hours after injury. CONCLUSIONS: This report employs an established model of porcine contact burn injury in order to test the ability of local subcutaneous delivery of therapeutics to prevent burn progression at the point of injury, via what is believed to be the inhibition of inflammation. Several treatments successfully prevented burn progression to a full-thickness injury, potentially improving wound healing outcomes in a simulated battlefield scenario. Subcutaneously administered therapies combating burn-induced inflammation at the point of injury may serve as a field-deployable treatment modality to improve warfighter recovery and return to duty.

The Role of Vitamin E in Thermal Burn Injuries, Infection, and Sepsis: A Review.

Thermal burn injuries are still a serious public health concern in the United States, due to the initial insult and resulting comorbidities. Burned patients are increasingly susceptible to colonization by endogenous and exogenous microorganisms after having lost skin, which acts as the primary protective barrier to environmental contaminants. Furthermore, the onset of additional pathophysiologies, specifically sepsis, becomes more likely in burned patients compared to other injuries. Despite improvements in the early care of burn patients, infections, and sepsis, these pathophysiologies remain major causes of morbidity and mortality and warrant further investigation of potential therapies. Vitamin E may be one such therapy. We aimed to identify publications of studies that evaluated the effectiveness of vitamin E as it pertains to thermal burn injuries, infection, and sepsis. Several investigations ranging from in vitro bench work to clinical studies have examined the impact on, or influence of, vitamin E in vitro, in vivo, and in the clinical setting. To the benefit of subjects it has been shown that enteral or parenteral vitamin E supplementation can prevent, mitigate, and even reverse the effects of thermal burn injuries, infection, and sepsis. Therefore, a large-scale prospective observational study to assess the potential benefits of vitamin E supplementation in patients is warranted and could result in clinical care practice paradigm changes.

Advances in Immunomodulation and Immune Engineering Approaches to Improve Healing of Extremity Wounds.

Delayed healing of traumatic wounds often stems from a dysregulated immune response initiated or exacerbated by existing comorbidities, multiple tissue injury or wound contamination. Over decades, approaches towards alleviating wound inflammation have been centered on interventions capable of a collective dampening of various inflammatory factors and/or cells. However, a progressive understanding of immune physiology has rendered deeper knowledge on the dynamic interplay of secreted factors and effector cells following an acute injury. There is a wide body of literature, both in vitro and in vivo, abstracted on the immunomodulatory approaches to control inflammation. Recently, targeted modulation of the immune response via biotechnological approaches and biomaterials has gained attention as a means to restore the pro-healing phenotype and promote tissue regeneration. In order to fully realize the potential of these approaches in traumatic wounds, a critical and nuanced understanding of the relationships between immune dysregulation and healing outcomes is needed. This review provides an insight on paradigm shift towards interventional approaches to control exacerbated immune response following a traumatic injury from an agonistic to a targeted path. We address such a need by (1) providing a targeted discussion of the wound healing processes to assist in the identification of novel therapeutic targets and (2) highlighting emerging technologies and interventions that utilize an immunoengineering-based approach. In addition, we have underscored the importance of immune engineering as an emerging tool to provide precision medicine as an option to modulate acute immune response following a traumatic injury. Finally, an overview is provided on how an intervention can follow through a successful clinical application and regulatory pathway following laboratory and animal model evaluation.

TWO-LAYER MATHEMATICAL MODELING OF GENE EXPRESSION: INCORPORATING DNA-LEVEL INFORMATION AND SYSTEM DYNAMICS.

High-throughput genome sequencing and transcriptome analysis have provided researchers with a quantitative basis for detailed modeling of gene expression using a wide variety of mathematical models. Two of the most commonly employed approaches used to model eukaryotic gene regulation are systems of differential equations, which describe time-dependent interactions of gene networks, and thermodynamic equilibrium approaches that can explore DNA-level transcriptional regulation. To combine the strengths of these approaches, we have constructed a new two-layer mathematical model that provides a dynamical description of gene regulatory systems, using detailed DNA-based information, as well as spatial and temporal transcription factor concentration data. We also developed a semi-implicit numerical algorithm for solving the model equations and demonstrate here the efficiency of this algorithm through stability and convergence analyses. To test the model, we used it together with the semi-implicit algorithm to simulate a Drosophila gene regulatory circuit that drives development in the dorsal-ventral axis of the blastoderm-stage embryo, involving three genes. For model validation, we have done both mathematical and statistical comparisons between the experimental data and the model's simulated data. Where protein and cis-regulatory information is available, our two-layer model provides a method for recapitulating and predicting dynamic aspects of eukaryotic transcriptional systems that will greatly improve our understanding of gene regulation at a global level.