A novel, reverse-phase-shifting, thermoreversible foaming hydrogel containing antibiotics for the treatment of thermal burns in a swine model - A pilot study.

BACKGROUND: This study compared a novel topical hydrogel burn dressing (CI-PRJ012) to standard of care (silver sulfadiazine) and to untreated control in a swine thermal burn model, to assess for wound healing properties both in the presence and absence of concomitant bacterial inoculation. METHODS: Eight equal burn wounds were created on six Yorkshire swine. Half the wounds were randomized to post-burn bacterial inoculation. Wounds were subsequently randomized to three treatments groups: no intervention, CI-PRJ012, or silver sulfadiazine cream. At study end, a blinded pathologist evaluated wounds for necrosis and bacterial colonization. RESULTS: When comparing CI-PRJ012 and silver sulfadiazine cream to no treatment, both agents significantly reduced the amount of necrosis and bacteria at 7 days after wound creation (p < 0.01, independently for both). Further, CI-PRJ012 was found to be significantly better than silver sulfadiazine (p < 0.02) in reducing bacterial colonization. For wound necrosis, no significant difference was found between silver sulfadiazine cream and CI-PRJ012 (p = 0.33). CONCLUSIONS: CI-PRJ012 decreases necrosis and bacterial colonization compared to no treatment in a swine model. CI-PRJ012 appeared to perform comparably to silver sulfadiazine. CI-PRJ012, which is easily removed with the application of room-temperature water, may provide clinical advantages over silver sulfadiazine.

Thermoreversible Reverse-Phase-Shift Foam for Treatment of Noncompressible Torso Hemorrhage, a Safety Trial in a Porcine Model.

INTRODUCTION: Noncompressible torso hemorrhage is the leading cause of exsanguination on the battlefield. A self-expanding, intraperitoneal deployed, thermoreversible foam has been developed that can be easily administered by a medic in austere settings to temporarily tamponade noncompressible torso hemorrhage. The purpose of this study was to assess the long-term safety and physical characteristics of using Fast Onset Abdominal Management (FOAM; Critical Innovations LLC) in swine. MATERIALS AND METHODS: Yorkshire swine (40-60 kg) were sedated, intubated, and placed on ventilatory support. An external jugular catheter was placed for sampling of blood. Continuous heart rate, temperature, saturation of peripheral oxygen, end-tidal carbon dioxide, and peak airway pressures were monitored for a 4-hour period after intervention (i.e., FOAM agent injection or a sham introducer without agent delivery). The FOAM agent was injected to obtain an intra-abdominal pressure of 60 mmHg for at least 10 minutes. After 4 hours, the animals were removed from ventilatory support and returned to their housing for a period of 7-14 days. Group size analysis was not performed, as this was a descriptive safety study. Blood samples were obtained at baseline and at 1-hour post-intervention and then on days 1, 3, 7, and 14. Euthanasia, necropsy, and harvesting of samples for histologic analysis (from kidneys, terminal ilium, liver, pancreas, stomach, spleen, and lungs) were performed upon expiration. Histologic scoring for evidence of ischemia, necrosis, and abdominal compartment sequela was blinded and reported by semi-quantitative scale (range 0-4; 0 = no change, 1 = minimal, 2 = mild, 3 = moderate, and 4 = marked). Oregon Health & Science University's Institutional Animal Care and Use Committee, as well as the U.S. Army Animal Care and Use Review Office, approved this protocol before the initiation of experiments (respectively, protocol numbers IP00003591 and MT180006.e002). RESULTS: Five animals met a priori inclusion criteria, and all of these survived to their scheduled endpoints. Two animals received sham injections of the FOAM agent (one euthanized on day 7 and one on day 14), and three animals received FOAM agent injections (one euthanized on day 7 and two on day 14). A transitory increase in creatinine and lactate was detected during the first day in the FOAM injected swine but resolved by day 3. No FOAM agent was observed in the peritoneal cavity upon necropsy at day 7 or 14. Histologic data revealed no clinically relevant differences in any organ system between intervention and control animals upon sacrifice at day 7 or 14. CONCLUSIONS: This study describes the characteristics, survival, and histological analysis of using FOAM in a porcine model. In our study, FOAM reached the desired intra-abdominal pressure endpoint while not significantly altering basic hematologic parameters, except for transient elevations of creatinine and lactate on day 1. Furthermore, there was no clinical or histological relevant evidence of ischemia, necrosis, or intra-abdominal compartment syndrome. These results provide strong support for the safety of the FOAM device and will support the design of further regulatory studies in swine and humans.

Efficacy of past, present, and future fluid strategies in an improved large animal model of non-compressible intra-abdominal hemorrhage.

BACKGROUND: Noncompressible hemorrhage is a leading cause of potentially survivable combat death, with the vast majority of such deaths occurring in the out-of-hospital environment. While large animal models of this process are important for device and therapeutic development, clinical practice has changed over time and past models must follow suit. Developed in conjunction with regulatory feedback, this study presents a modernized, out-of-hospital, noncompressible hemorrhage model, in conjunction with a randomized study of past, present, and future fluid options following a hypotensive resuscitation protocol consistent with current clinical practice. METHODS: We performed a randomized controlled experiment comparing three fluid resuscitation options in Yorkshire swine. Baseline data from animals of same size from previous experiments were analyzed (n = 70), and mean systolic blood pressure was determined, with a permissive hypotension resuscitation target defined as a 25% decrease from normal (67 mm Hg). After animal preparation, a grade IV to V liver laceration was induced. Animals bled freely for a 10-minute "time-to-responder" period, after which resuscitation occurred with randomized fluid in boluses to the goal target: 6% hetastarch in lactated electrolyte injection (HEX), normal saline (NS), or fresh whole blood (FWB). Animals were monitored for a total simulated "delay to definitive care" period of 2 hours postinjury. RESULTS: At the end of the 2-hour study period, 8.3% (1 of 12 swine) of the HEX group, 50% (6 of 12 swine) of the NS group, and 75% (9 of 12 swine) of the FWB had survived (p = 0.006), with Holm-Sidak pairwise comparisons showing a significant difference between HEX and FWB and (p = 0.005). Fresh whole blood had significantly higher systemic vascular resistance and hemoglobin levels compared with other groups (p = 0.003 and p = 0.001, respectively). CONCLUSION: Survival data support the movement away from HEX toward NS and, preferably, FWB in clinical practice and translational animal modeling. The presented model allows for future research including basic science, as well as translational studies of novel diagnostics, therapeutics, and devices.

Thermoreversible Reverse-Phase-Shift Foam for Treatment of Noncompressible Torso Hemorrhage.

BACKGROUND: Noncompressible torso hemorrhage (NCTH) is a leading cause of traumatic exsanguination, requiring emergent damage control surgery performed by a highly trained surgeon in a sterile operating environment. A self-expanding, intraabdominally deployed, thermoreversible foam is one proposed method to potentially task shift temporizing hemostasis to earlier providers and additional settings. The purpose of this study was to assess the feasibility of using Fast Onset Abdominal Management (FOAM) in a lethal swine model of NCTH. METHODS: This was a proof-of-concept study comparing FOAM intervention in large Yorkshire swine to historical control animals in the established Ross-Burns model of NCTH. After animal preparation, a Grade IV liver laceration was surgically induced, followed by a free bleed period of 10 min. FOAM was then deployed to a goal intraabdominal pressure of 60 mm Hg for 5 min, followed by a total 60-min observation period following injury. RESULTS: At the end of the experiment, the FOAM agent was found to be distributed throughout the peritoneal cavity in all animals, without signs of iatrogenic injury. The FOAM group demonstrated a significantly higher mean arterial pressure compared with historical controls and a trend toward improved survival: 82% (9/11) compared with 50% for controls (7/14; P = 0.082). CONCLUSIONS: This is the first study to describe the use of a thermoresponsive foam to manage NCTH and successfully demonstrated proof-of-concept feasibility of FOAM deployment. These results provide strong support for future, higher-powered studies to confirm improved survival with this novel intervention.

Use of black light traps to monitor the abundance, spread, and flight behavior of Halyomorpha halys (Hemiptera: Pentatomidae).

Monitoring the distribution and abundance of an invasive species is challenging, especially during the initial years of spread when population densities are low and basic biology and monitoring methods are being investigated. Brown marmorated stink bug (Halyomorpha halys (Stål)) is an invasive agricultural and urban pest that was first detected in the United States in the late 1990s. At the time of its detection, no method was available to effectively track H. halys populations, which are highly mobile and polyphagous. One possible solution was the utilization of black light traps, which are nonspecific traps attractive to night flying insects. To determine if black light traps are a reliable monitoring tool for H. halys, a state-wide network of 40-75 traps located on New Jersey farms were monitored from 2004 to 2011 for H. halys. This proved to be a highly effective method of monitoring H. halys populations and their spread at the landscape level. The total number of brown marmorated stink bug caught in New Jersey increased exponentially during this period at a rate of 75% per year. Logistic regression estimates that 2.84 new farms are invaded each year by H. halys. The results indicate that black light traps are attractive to early season populations as well as at low population densities. Weekly trap catch data are being used to generate state-wide population distribution maps made available to farmers in weekly newsletters and online. While no economic threshold currently exists for brown marmorated stink bug, the maps provide farmers with a tool to forecast pest pressure and plan management.

A novel high-throughput screening assay for sickle cell disease drug discovery.

Although the pathophysiology and molecular basis of sickle cell disease (SCD) were described more than half a century ago, an effective and safe therapy is not yet available. This may be explained by the lack of a suitable high-throughput technique that allows rapid screening of thousands of compounds for their antisickling effect. The authors have thus developed a novel high-throughput screening (HTS) assay based on detecting the ability of red blood cells (RBC) to traverse a column of tightly packed Sephacryl chromatography beads. When deoxygenated, sickle RBC are rigid and remain on the top of the column. However, when deoxygenated and treated with an effective antisickling agent, erythrocytes move through the Sephacryl media and produce a red dot on the bottom of the assay tubes. This approach has been adapted to wells in a 384-well microplate. Results can be obtained by optical scanning: The size of the red dot is proportional to the antisickling effect of the test molecule. The new assay is simple, inexpensive, reproducible, requires no special reagents, and should be readily adaptable to robotic HTS systems. It has the potential to identify novel drug candidates, allowing the development of new therapeutic options for individuals affected with SCD.

The effects of a soluble polymer and bone wax on sternal healing in an animal model.

PURPOSE: This study compares the effects of a soluble polymer hemostatic material and bone wax on sternal bone healing. DESCRIPTION: Median sternotomies were performed on 20 New Zealand White rabbits, and sufficient polymer (Ostene; Ceremed Inc, Los Angeles CA) or bone wax (Bone Wax; Ethicon Inc, Somerville, NJ) was applied to achieve bone hemostasis. After 6 weeks, sternal healing was assessed using roentgenograms, histology, and mechanical strength testing. EVALUATION: Roentgenograms revealed normal bone healing in the polymer-treated group and nonunion in the bone wax group. Histology showed normal bone healing in the polymer group, with fibrotic scar tissue and the absence of new bone formation in the bone wax group. Mechanical strength testing showed that polymer-treated sternal segments were twice as strong as those treated with bone wax. They had a significantly higher flexural strength (2.53 +/- 0.43 vs. 1.29 +/- 0.37 megapascal [MPa]; p < 0.001) and Young's modulus (0.315 +/- 0.056 vs 0.146 +/- 0.031 MPa; p < 0.001). CONCLUSIONS: The application of the polymer hemostatic material to the sternum resulted in significantly stronger union compared with the use of bone wax.

Ostene, a new water-soluble bone hemostasis agent.

Traditional formulations of bone wax are composed largely of beeswax and are well known to interfere with bone healing and cause inflammatory reactions. Ostene, a newly available bone hemostasis agent made of water-soluble alkylene oxide copolymers, was evaluated. The soft tissue response to Ostene was compared with bone wax and a polyethylene control after implantation into the paravertebral muscles of three rabbits. After 2 weeks, Ostene elicited no fibrous response, the polyethylene elicited a thin (less than 0.5 mm) fibrous response, and the bone wax was encased in a fibrous capsule 0.6 to 1.0 mm thick infiltrated with inflammatory cells. The effects of Ostene were compared with bone wax in a femur defect model in eight rabbits. Ostene showed no evidence of an adverse response in the cortical defect site, medullary cavity, or the surrounding tissue at 4 and 8 weeks. In contrast, bone wax at both time intervals elicited a foreign body response consisting of fibrous tissue infiltrated by macrophages, giant cells, and lymphocytes at the sites of the bone defects. Bone wax also displaced the bone marrow and interfered with bone ingrowth into the defects. Ostene provides the clinician a water-soluble bone hemostasis material that does not demonstrate the adverse tissue response or the interference with bone healing seen with the use of bone wax.