David Mark Burmeister

Burn injuries impose significant healthcare and logistical burdens in both civilian and military settings. This includes infectious complications that are amplified in prolonged field care environments where surgical intervention is delayed. As such, there is a growing need for adjunctive therapies that mitigate infection and zwitterionic (ZW) hydrogels offer a promising solution for maintaining a moist wound environment and reducing bacterial colonization. This study evaluates the safety and efficacy of 2 ZW hydrogel products: CleraFlex and a ZW hydrogel loaded with polyhexamethylene biguanide (PHMB) in infected burns in swine under simulated prolonged field care conditions. Ten 5 × 5 cm contact burns were created on the dorsum of Yorkshire-cross swine (n = 3) and inoculated with Pseudomonas aeruginosa (ATCC #27853, 2.5 × 105 colony-forming units [CFUs]). Wounds were treated with saline, triple antibiotic ointment (TAO), CleraFlex, or ZW + PHMB. Photographs and biopsies were obtained. On day 7 postburn, wounds appeared infected due to greenish discoloration to varying degrees. Saline-treated wounds had the highest bacterial burden (9.38 ± 0.40 log CFU/g). Triple antibiotic ointment treatment resulted in a nonsignificant reduction to 6.95 ± 0.63 log CFU/g (P = .078), whereas CleraFlex and ZW + PHMB achieved greater significant reductions (6.39 ± 0.36 log CFU/g and 5.98 ± 0.65 log CFU/g, respectively; P < .05 and P < .01). Blinded histological analysis also showed reduced leukocyte extravasation, and potentiated removal of the necrotic eschar in burn wounds treated with ZW ± PHMB. Zwitterionic formulations ± PHMB significantly reduced bacterial burden in a porcine burn-infection model simulating prolonged field care, supporting their potential as effective adjuncts in managing infection during delayed evacuation in austere environments.

Increasing evidence implicates mitochondrial/cellular dynamics in ischemia reperfusion (I/R)-induced acute kidney injury (AKI). Sodium-glucose-co-transporter-2 inhibitors (SGLT2is, e.g., canagliflozin, CG) have been shown to mitigate I/R-induced AKI. Here, we hypothesized that CG-improved AKI was associated with altered mitochondrial dynamics and apoptosis in a previously established swine model. CG (300 mg, PO) significantly increased pro-apoptotic genes Bid, Bad, Bax, Bak1 and Casp1 expression (all p < 0.05). Pink1 (p = 0.0019), Optn (p = 0.038), and Map1lc3 (p = 0.0093) expression also increased with CG, implicating mitophagy; PINK1 protein levels were unchanged. The expression of mitochondrial fission regulator Fis1 increased with CG treatment (p = 0.0015) while fusion regulator Opa1 expression decreased (p = 0.038). TUNEL staining showed increased apoptosis primarily in damaged proximal tubular cells of CG animals. Ki67 staining revealed I/R-injury increased cell proliferation throughout the kidney, which was significantly attenuated with CG. Moreover, correlative analysis revealed that AKI severity positively correlated with cell proliferation. In this large animal model, CG reduced AKI via increased mitochondrial fission and pro-apoptotic gene expression, potentiating clearance of damaged mitochondria, and decreased cell proliferation. Future studies should evaluate other SGLT2is as a potential therapeutic for I/R AKI.

Introduction: Polytrauma is often characterised by rhabdomyolysis, hyperkalaemia and renal failure, which is treated with acute haemodialysis. Transport and storage of dialysate are expensive and cumbersome and require space that may be unavailable in resource-limited scenarios. We examined a portable, powerless dialysate generator in a porcine model of continuous renal replacement therapy (CRRT). Methods: Anaesthetised swine (n=12) underwent bilateral nephrectomy and placement of a haemodialysis catheter. Intravenous potassium and urea were infused, and animals received CRRT with either a dialysate solution prepared with tap water through a novel portable dialysate generator (PDG) or commercially available dialysate (CAD, NxStage). Both groups were dialysed with a NxStage System One through an in-line haemodialysis filter at typical flow rates. Blood samples were drawn hourly during 6 hours of CRRT. Results: There were no differences in conductivity between PDG and CAD (p=0.31), as well as no detected arsenic, lead, mercury or free chlorine in the PDG dialysate produced. After 6 hours of CRRT, total effluent fluid was 10.09±0.18 L and 10.04±0.30 L in the PDG and CAD groups, respectively (p=0.89). Urea reduction ratio was similar in the two groups (p=0.39), as were serum levels of potassium (p=0.87). All animals survived until the end of CRRT. Conclusions: A PDG machine using potable water created dialysate of similar efficacy as commercial prepackaged dialysate in a porcine CRRT model. The generated dialysate may obviate transport and storage of large quantities of dialysate in a resource-limited combat or natural disaster environments.

While radiation and burn injury have distinct local and systemic effects, they both negatively impact intestinal permeability/function. In a nuclear attack, combined thermal burns and radiation exposure (e.g., combined injury (CI)) would be a dominant injury pattern. Despite this, how burns affect gastrointestinal acute radiation syndrome, and vice versa, has been largely unstudied. Next-generation sequencing has revealed a strong bidirectional link between the liver and gut. Here, we used a porcine model to evaluate the impact of burn, radiation, and CI on the gut microbiota and liver transcriptomics to determine if this link exists in these injury patterns. Sinclair minipigs were randomly divided into three groups: burn ( n = 8), hemibody radiation ( n = 7), and CI ( n = 8). Animals were monitored for 14 days with longitudinal rectal swab and blood collection. CI increased weight loss, diarrhea, inappetence and lethargy compared to either injury pattern alone. Jejunum histology revealed increased mucosal apoptosis in burn and CI groups compared to radiation. CI led to elevated levels of NLRP3 and IL1β in the jejunum. Intestinal barrier disruption was indicated by decreasing circulating l-citrulline in CI which correlated inversely with intestinal-Fatty Acid Binding Protein. Bacteremia was elevated post-burn on day 1 and again from day 7–14 in burn and CI groups. Microbiome analysis showed phylogenetic shifts and differential abundance across groups with CI animals exhibiting distinct microbial signatures linked to intestinal dysfunction and liver injury. Liver RNA-seq revealed group-specific gene expression changes, with CI-altered pathways implicating immune responses and lipid metabolism, which were correlated with gut microbiota such as Bacteroidaceae and Lachnospiraceae . Taken together, we present a first-of-its kind large animal model of radiation combined injury to highlight the interplay between gut-liver axis disruptions and systemic injury responses.

Emerging research highlights the gut microbiota’s critical role in modulating brain activity via the gut–brain axis. This study explores whether targeted gastrointestinal irradiation induces abscopal effects on the brain proteome, revealing microbiota-mediated neurobiological changes. Male Sinclair minipigs were randomized to receive either sham treatment (n = 6) or 8 Gy lower hemibody (gut-targeted) irradiation (n = 5). Over 14 days, rectal swabs were collected to monitor microbiota dynamics, followed by frontal cortex proteomic analysis. Irradiation altered gut microbiota composition, notably reducing Chlamydiae and Firmicutes phyla, while increasing Coriobacteriaceae and Acinetobacter. Proteomic analysis identified 75 differentially abundant proteins in the frontal cortex, including a significant decrease in pannexin-1 (PANX1), suggesting modulation of the NLRP3 inflammasome pathway. Functional enrichment analysis revealed immune and neurotransmission-related changes linked to microbial shifts. These results demonstrate that gut-targeted radiation can remotely affect brain protein expression, emphasizing the microbiota’s role in neuroimmune regulation and pointing to novel therapeutic opportunities in gut–brain axis disorders.

Fluid resuscitation after thermal injury is paramount to avoid burn shock and restore organ perfusion. Both over- and under-resuscitation can lead to unintended consequences affecting patient outcomes. While many studies have examined systemic effects, limited data exist on how fluid resuscitation impacts burn wound progression in the acute period. Furthermore, the mechanisms underlying burn wound progression remain not fully understood. This study used a swine model to investigate how varying resuscitation levels affect peri-burn wound dynamics. Twenty-seven female Yorkshire pigs were anesthetized, subjected to 40% total body surface area burn and 15% hemorrhage, then randomized (n = 9) to receive decision-support-driven (adequate, 2–4 mL/kg/%TBSA), fluid-withholding (under, >4 mL/kg/%TBSA) resuscitation. Pigs were monitored for 24 h in an intensive care setting prior to necropsy. Laser Doppler Imaging (LDI) was conducted pre-burn and at 2, 6, 12, and 24 h post burn to assess perfusion. Biopsies were taken from burn, peri-burn (within 2 cm), and normal skin. RNA was isolated at 24 h for the qRT-PCR analysis of IL-6, CXCL8, and IFN-γ. At hour 2, LDI revealed increased peri-burn perfusion in over-resuscitated animals vs. under-resuscitated animals (p = 0.0499). At hour 24, IL-6 (p = 0.0220) and IFN-γ (p = 0.0253) were elevated in over-resuscitated peri-burn skin. CXCL8 showed no significant change. TUNEL staining revealed increased apoptosis in over- and under-resuscitated peri-burn skin. Differences in perfusion and cytokine expression based on resuscitation strategy suggest that fluid levels may influence burn wound progression.

BACKGROUND: Traumatic hemorrhage is the leading cause of preventable battlefield death and hemostatic agents can improve survival. We compared a novel, amorphous, silica dioxide–based fiber (SBF) hemostatic matrix to the criterion standard QuikClot Combat Gauze (QCCG) in treating a junctional arterial injury in hypocoagulable swine. METHODS: Vascular access was obtained in 16 anesthetized swine, and hemodilution was achieved with 50% blood exchange with saline. A 5-mm arteriotomy was made in the common femoral artery. After 30 seconds of free bleeding, SBF or QCCG was applied, and pressure was held for 5 minutes. After 1 hour of monitoring, an angiogram and movement test were performed. Samples were drawn for blood count, chemistry, blood gas and rotational thromboelastography at various time points. The artery and hindlimb were collected for histology. RESULTS: All animals (n = 8/group) survived. Hemodilution induced significant differences in hematocrit, platelets, clot formation time, and maximum clot firmness (p < 0.0001). There was no difference in blood counts or chemistries (p = 0.81–0.99) between groups at euthanasia. SBF required an average of 1.25 applications compared with 1.13 for QCCG (p > 0.99). SBF had significantly less blood loss (106.2 ± 66.6 mL) versus QCCG (189.6 ± 78.9 mL, p = 0.038). Angiography revealed patency with distal perfusion in all (8/8) SBF-treated animals. Alternatively, all QCCG-treated arteries were occluded without distal perfusion, which was statistically significant (p < 0.01). All animals remained hemostatic after the movement test. Blinded histopathological analysis revealed only two of eight cases of tunica intimal thickening and neutrophils in the QCCG group, which was not statistically different. CONCLUSION: SBF and QCCG had comparable hemostatic efficacy and no difference in the number of applications, despite SBF packaging containing less material. There was no evidence of significant laboratory abnormalities at the study conclusion. Taken together, SBF may be an appropriate hemostatic agent for hemorrhagic injury and is able to maintain hemostasis following stressed movement. Its improved vessel patency suggests SBF may decrease tissue ischemia and improve limb salvage in vascular injuries.

Introduction: Treating extensive burn injury requires an individually tailored resuscitation protocol that includes hourly-titrated intravenous fluid infusion to avert both hypovolemic shock and edema. Due to the complexity of burn pathophysiology and significant variability in treatment protocols, there is an ongoing effort to optimize burn resuscitation. The goal of this work is to contribute to this effort by developing a mathematical model of burn pathophysiology and resuscitation for in silico testing of burn resuscitation protocols and decision-support systems.Methods: In our previous work, we developed and validated a mathematical model consisting of volume kinetics, burn-induced perturbations, and kidney function. In this work, we expanded our previous mathematical model to incorporate novel mathematical models of cardiovascular system and hormonal system (renin-angiotensin-aldosterone (RAAS) system and antidiuretic hormone) which affect blood volume and pressure regulation. We also developed a detailed mathematical model of kidney function to regulate blood volume, pressure, and sodium levels, including components for glomerular filtration rate, reabsorption rates in nephron tubules, Tubuglomerular feedback, and myogenic mechanisms. We trained and validated the expanded mathematical model using experimental data from 15 pigs and 9 sheep with extensive burns to quantitatively evaluate its prediction accuracy for hematocrit, cardiac output, mean arterial pressure, central venous pressure, serum sodium levels, and urinary output. We then trained and tested the mathematical model using a clinical dataset of 233 human burn patients with demographic data and urinary output measurements.Results: The mathematical model could predict all tested variables very well, while internal variables and estimated parameters were consistent with the literature.Discussion: To the best of our knowledge, this is the first mathematical model of burn injury and resuscitation which is extensively validated to replicate actual burn patients. Hence, this in silico platform may complement large animal pre-clinical testing of burn resuscitation protocols. Beyond its primary purpose, the mathematical model can be used as a training tool for healthcare providers delivering insight into the pathophysiology of burn shock, and offering novel mathematical models of human physiology which can be independently used for other purposes and contexts.

Both abdominal radiotherapy and a nuclear event can result in gastrointestinal symptoms, including acute radiation syndrome (GI-ARS). GI-ARS is characterized by compromised intestinal barrier integrity increasing the risk for infectious complications. Physiologically relevant animal models are crucial for elucidating host responses and therapeutic targets. We aimed to determine the radiation dose requirements for creating GI-ARS in the Sinclair minipig. Male, sexually mature swine were randomly divided into sham (n = 6) and three lower hemibody radiation dosage groups of 8, 10, and 12 Gy (n = 5/group) delivered using linear accelerator-derived x-rays (1.9 Gy/min). Animals were monitored for GI-ARS symptoms for 14 days with rectal swab and blood collection at days 0–3, 7, 10, and 14 followed by necropsy for western blotting and histology. Dose-dependent increases in weight loss, diarrhea severity, and mortality (log-rank test, P = 0.041) were seen. Villi length was significantly reduced in all irradiated animals compared to controls (P < 0.001). Serum citrulline decreased and bacterial translocation increased after irradiation compared to controls. Increased NLRP3 levels in post-mortem jejunum were seen (P = 0.0043) as well as increased IL-1β levels in the 12 Gy group (P = 0.041). Radiation dose and survival were associated with significant gut microbial community shifts in beta diversity. Moreover, decedents had increased Porphyromonas, Campylobacter, Bacteroides, Parvimonas, and decreased Fusobacterium and decreased Aerococcus, Lactobacillus, Prevotella, and Streptococcus. Our novel Sinclair minipig model showed dose-dependent clinical symptoms of GI-ARS. These findings provide invaluable insights into the intricate interplay between GI-ARS, intestinal inflammation, and gut microbiota alterations offering potential targets for therapeutic and diagnostic interventions after radiation exposure.