Adam Rago

The biocompatibility of rapidly degrading polymeric stents in porcine carotid arteries.

The goal of this study was to evaluate the biocompatibility of materials for use in fully bioabsorbable vascular stents. 10:90 poly(L-lactic-co-glycolic acid) (10:90 L-PLGA), 85:15 poly(L-lactic-co-glycolic acid) (85:15 L-PLGA), polydioxanone (PDO), and poly-L-lactic acid (L-PLA) polymers were chosen as materials. Polymeric fibers were woven into a braided structure with a mass equivalent to or greater than that expected for a vascular stent, secured to balloon-expandable bare metal stents and implanted into porcine carotid arteries. The in vivo response was analyzed at 30 and 90 days by angiography, histopathology, and histomorphometry. All vessels were patent at 30 and 90 days. Injury score and neointima formation was mild for all samples. The faster-degrading 10:90 L-PLGA had the highest inflammatory response at 30 days, but was completely absorbed with minimal inflammation and neointimal formation at 90 days. PDO showed signs of partial absorption at 90 days, while 85:15 L-PLGA and L-PLA demonstrated minimal absorption at 30 and 90 days. The inflammatory response to these three groups was similar over the experimental period. Using a robust materials-testing platform, we demonstrated long-term patency and intravascular biocompatibility of bioabsorbable polymers with varying rates of resorption. The data point to biocompatibility of a polymeric stent in the vascular space that is fully absorbable in less than a year.

Self-expanding polyurethane polymer improves survival in a model of noncompressible massive abdominal hemorrhage.

BACKGROUND Intracavitary noncompressible hemorrhage remains a significant cause of preventable death on the battlefield. Two dynamically mixed and percutaneously injected liquids were engineered to create an in situ self-expanding polymer foam to facilitate hemostasis in massive bleeding. We hypothesized that intraperitoneal injection of the polymer could achieve conformal contact with sites of injury and improve survival in swine with lethal hepatoportal injury. METHODS High grade hepatoportal injury was created in a closed abdominal cavity, resulting in massive noncoagulopathic, noncompressible hemorrhage. Animals received either standard battlefield fluid resuscitation (control, n = 12) or fluid resuscitation plus intraperitoneal injection of hemostatic foam (polymer, n = 15) and were monitored for 3 hours. Blood loss was quantified, and all hepatoportal injuries were inspected for consistency. RESULTS Before intervention, all animals initially experienced severe, profound hypotension and near-arrest (mean arterial pressure at 10 minutes, 21 [5.3] mm Hg). Overall survival at 3 hours was 73% in the polymer group and 8% in the control group (p = 0.001). Median survival time was more than 150 minutes in the polymer group versus 23 minutes (19–41.5 minutes) in the control group (p < 0.001), and normalized blood loss in the polymer group was 0.47 (0.30) g/kg per minute versus 3.0 (1.3) g/kg per minute in the controls (p = < 0.001). All hepatoportal injuries were anatomically similar, and the polymer had conformal contact with injured tissues. CONCLUSION Intraperitoneal polymer injection during massive noncompressible hemorrhage reduces blood loss and improves survival in a lethal, closed-cavity, hepatoportal injury model. Chronic safety and additional efficacy studies in other models are needed.

Self-expanding foam for prehospital treatment of severe intra-abdominal hemorrhage: dose finding study.

BACKGROUND Noncompressible abdominal bleeding is a significant cause of preventable death on the battlefield and in the civilian trauma environment, with no effective therapies available at point of injury. We previously described the development of a percutaneously administered, self-expanding, poly(urea)urethane foam that improved survival in a lethal Grade V hepatic and portal vein injury model in swine. In this study, we hypothesized that survival with foam treatment is dose dependent. METHODS A high-grade hepatoportal injury was created in a closed abdominal cavity, resulting in massive noncompressible hemorrhage. After injury, the animals were divided into five groups. The control group (n = 12) was treated only with fluid resuscitation, and four polymer groups received different dose volumes (Group 1, n = 6, 64 mL; Group 2, n = 6, 85 mL; Group 3, n = 18, 100 mL; and Group 4, n = 10, 120 mL) in addition to fluids. Ten minutes after injury, the foam was percutaneously administered, and animals were monitored for 3 hours. RESULTS Survival with hepatoportal injury was highest in Group 4 (90%) and decreased in a dose-dependent fashion (Group 3, 72%; Group 2, 33%; Group 1, 17%). All polymer groups survived significantly longer than the controls (8.3%). Hemorrhage rate was reduced in all groups but lowest in Group 4 versus the control group (0.34 [0.052] vs. 3.0 [1.3] mL/kg/min, p < 0.001). Increasing foam dose volume was associated with increased peak intra-abdominal pressure (88.2 [38.9] in Group 4 vs. 9.5 [3.2] in the controls, p < 0.0001) and increased incidence of focal bowel injuries. CONCLUSION The self-expanding foam significantly improves survival in a dose-dependent fashion in an otherwise lethal injury. Higher doses are associated with better survival but resulted in the need for bowel resection.

Development of a lethal, closed-abdomen grade V hepato-portal injury model in non-coagulopathic swine

BACKGROUND Hemorrhage within an intact abdominal cavity remains a leading cause of preventable death on the battlefield. Despite this need, there is no existing closed-cavity animal model to assess new hemostatic agents for the preoperative control of intra-abdominal hemorrhage. METHODS We developed a novel, lethal liver injury model in non-coagulopathic swine by strategic placement of two wire loops in the medial liver lobes including the hepatic and portal veins. Distraction resulted in grade V liver laceration with hepato-portal injury, massive bleeding, and severe hypotension. Crystalloid resuscitation was started once mean arterial pressure (MAP) fell below 65 mm Hg. Monitoring continued for up to 180 min. RESULTS We demonstrated 90% lethality (9/10) in swine receiving injury and fluid resuscitation, with a mean survival time of 43 min. Previous efforts in our laboratory to develop a consistently lethal swine model of abdominal solid organs, including preemptive anticoagulation, a two-hit injury with controlled hemorrhage prior to liver trauma, and the injury described above without resuscitation, consistently failed to result in lethal injury. CONCLUSION This model can be used to screen other interventions for pre hospital control of noncompressible.

Self-expanding foam improves survival following a lethal, exsanguinating iliac artery injury.

BACKGROUND Noncompressible abdominal bleeding is a significant cause of preventable death on the battlefield and in the civilian setting, with no effective therapies available at point of injury. We previously reported that a self-expanding polyurethane foam significantly improved survival in a lethal hepatoportal injury model of massive venous hemorrhage. In this study, we hypothesized that foam treatment could improve survival in a lethal iliac artery injury model in noncoagulopathic swine. METHODS In swine with a closed abdomen, an iliac artery transection was created, resulting in massive noncompressible exsanguination. After injury, animals were treated with damage-control fluid resuscitation alone (n = 14) or foam treatment in addition to fluids. Two doses of foam treatment were studied: 100 mL (n = 12) and 120 mL (n = 13); all animals were monitored for 3 hours or until death. RESULTS Foam treatment at both doses resulted in a significant survival benefit and reduction in hemorrhage rate relative to the control group. Median survival time was 135 minutes and 175 minutes for the 120-mL and 100-mL doses, compared with 32 minutes in the control group (p < 0.001 for both groups). Foam resulted in an immediate, persistent improvement in mean arterial pressure and a transient increase in intra-abdominal pressure. The median hemorrhage rate was 0.27 g/kg per minute in the 120-mL group and 0.23 g/kg per minute in the 100-mL group, compared with 1.4 g/kg per minute in the control group (p = 0.003 and 0.006, respectively, as compared with the control). CONCLUSION Self-expanding foam treatment significantly improves survival in an otherwise lethal, noncompressible, massive, arterial injury. This treatment may provide a prehospital intervention for control of noncompressible abdominal hemorrhage.

Development of a lethal, closed-abdomen, arterial hemorrhage model in noncoagulopathic swine

BACKGROUND Prehospital treatment for noncompressible abdominal bleeding, particularly due to large vascular injury, represents a significant unmet medical need on the battlefield and in civilian trauma. To date, few large animal models are available to assess new therapeutic interventions and hemostatic agents for prehospital hemorrhage control. METHODS We developed a novel, lethal, closed-abdomen injury model in noncoagulopathic swine by strategic placement of a cutting wire around the external iliac artery. The wire was externalized, such that percutaneous distraction would result in vessel transection leading to severe uncontrolled abdominal hemorrhage. Resuscitation boluses were administered at 5 and 12 min. RESULTS We demonstrated 86% mortality (12/14 animals) at 60 min, with a median survival time of 32 min. The injury resulted in rapid and massive hypotension and exsanguinating blood loss. The noncoagulopathic animal model incorporated clinically significant resuscitation and ventilation protocols based on best evidenced-based prehospital practices. CONCLUSION A new injury model is presented that enables screening of prehospital interventions designed to control noncompressible arterial hemorrhage.

Efficacy of a prehospital self-expanding polyurethane foam for noncompressible hemorrhage under extreme operational conditions.

BACKGROUND Noncompressible abdominal hemorrhage is a significant cause of battlefield and civilian mortality. We developed a self-expanding polyurethane foam intended to provide temporary hemorrhage control and enable evacuation to a definitive surgical capability, for casualties who would otherwise die. We hypothesized that foam treatment would be efficacious over a wide range of out-of-hospital operational conditions. METHODS The foam was tested in an established lethal, closed-cavity hepatoportal injury model in four groups as follows. Group 1 involved baseline conditions, wherein foam was deployed from a pneumatically driven, first-generation delivery device at room temperature (n = 6). Group 2 involved foam deployment from a field-relevant, handheld delivery prototype (n = 12). Group 3 involved foam components that were conditioned to simulate 1-year shelf-life (n = 6). Group 4 involved foam that was conditioned to a range of temperatures (10°C and 50°C; n = 6 per group). In all studies, survival was monitored for up to 180 minutes and compared with an ongoing and accumulating control group with no intervention (n = 14). RESULTS In Group 1 with a first-generation delivery system, foam treatment resulted in a significant survival advantage relative to the control group (p < 0.001), confirming previous results. In Group 2 with a handheld delivery system, survival was also improved, 83% at 3 hours, compared with 7% in the control group (p < 0.001). In Group 3, survival was 83% at 3 hours (p = 0.002). In Group 4 at temperature extremes, 3-hour survival was 83% (p = 0.002) and 67% (p = 0.014) in the low- and high-temperature groups, respectively. Temperature extremes did not result in hypothermia, hyperthermia, or thermal injury. In all studies, the bleeding rate in foam groups was significantly lower than in the control group (p < 0.05). CONCLUSION Under a range of military operational conditions, foam treatment resulted in a survival advantage relative to the control group. This supports the feasibility of foam treatment as a prehospital hemostatic bridge to surgery for severely bleeding causalities.

Self-expanding foam for prehospital treatment of intra-abdominal hemorrhage: 28-day survival and safety.

BACKGROUND Intracavitary noncompressible hemorrhage remains a significant cause of preventable death on the battlefield and in the homeland. We previously demonstrated the hemostatic efficacy of an in situ self-expanding poly(urea)urethane foam in a severe, closed-cavity, hepatoportal exsanguination model in swine. We hypothesized that treatment with, and subsequent explantation of, foam would not adversely impact 28-day survival in swine. METHODS Following a closed-cavity splenic transection, animals received either fluid resuscitation alone (control group, n = 6) or resuscitation plus foam treatment at doses of 100 mL (n = 6), 120 mL (n = 6), and 150 mL (n = 2). Foam was allowed to polymerize in situ and was explanted after 3 hours. The animals were recovered and monitored for 28 days. RESULTS All 18 animals in the 100-mL, 120-mL, and control groups survived to the 28-day endpoint without complications. The 150-mL group was terminated after the acute phase (n = 2). En bloc explantation of the foam took less than 2 minutes and was associated with millimeter-sized remnant particles. All foam animals required some level of enteric repair (imbrication or resection). Excluding the aborted 150-mL group, all animals survived, with no differences in renal or hepatic function, serum chemistries, or semiquantitative abdominal adhesion scores. Histologic analysis demonstrated that remnant particles were associated with a fibrotic capsule and mild inflammation, similar to that of standard suture reaction. In addition, safety testing (including genotoxicity, pyrogenicity, and cytotoxicity) was performed consistent with the ISO-10993 standard, and the materials passed all tests. CONCLUSION For a distinct dose range, 28-day recovery after foam treatment and explantation for noncompressible, intra-abdominal hemorrhage is not associated with significant physiologic or biochemical evidence of end-organ dysfunction. A foam volume exceeding the maximum tolerable dose was identified. Bowel repair is required to ensure survival.

Human dose confirmation for self-expanding intra-abdominal foam: A translational, adaptive, multicenter trial in recently deceased human subjects.

BACKGROUND Noncompressible abdominal bleeding accounts for significant mortality in both military and civilian populations. There is an emergent need for a temporary hemostatic intervention whenever surgical care is not immediately available. Our team previously described a self-expanding polyurethane foam for the treatment of exsanguinating abdominal hemorrhage. The objective of this study was to translate a safe and effective swine dose into an appropriate human dose through foam administration in recently deceased humans with representative tissue compliance. METHODS With institutional review board oversight and informed consent at three centers, terminal patients were identified. Within 3 hours of death, the abdomen was accessed, and fluid was added to simulate hemorrhage. Foam was percutaneously administered using a prototype delivery system at multiple doses (45, 55, 65, 75, and 100 mL). Intra-abdominal pressure was monitored for 15 minutes, and then, foam was removed via laparotomy to assess abdominal tissue contact. RESULTS Twenty-one recently deceased patients ranging in age from 20 years to 92 years and body mass index from 18 kg/m2 to 39 kg/m2 were enrolled in the study. Foam was administered at a mean (SD) of 146 (34) minutes after death. Three subjects were screen failures, and three subjects were excluded from the analysis because of experimental errors. Change in intra-abdominal pressure and semiquantitative organ contact were used as surrogates to compare findings between humans and swine. Doses of 45, 55, and 65 mL resulted in peak pressures of 37 (20), 28 (8.1), and 33 (20) mmHg, respectively, within the acceptable range established in swine studies. Foam deployments of 75 mL and 100 mL exceeded acceptable pressures defined in swine. Higher foam doses tended to improve contact with the diaphragm, paracolic gutters, and liver. CONCLUSION The use of recently deceased humans demonstrates a novel approach to device evaluation in representative human anatomy, particularly when tissue compliance is critical. Sixty-five milliliters was determined to be the clinically appropriate dose for foam treatment in bleeding human patients.

Diagnosis and deployment of a self-expanding foam for abdominal exsanguination: Translational questions for human use.

BACKGROUND We have previously described the hemostatic efficacy of a self-expanding polyurethane foam in lethal venous and arterial hemorrhage models. A number of critical translational questions remain, including prehospital diagnosis of hemorrhage, use with diaphragmatic injury, effects on spontaneous respiration, the role of omentum, and presence of a laparotomy on foam properties. METHODS In Experiment 1, diagnostic blood aspiration was attempted through a Veress needle before foam deployment during exsanguination (n = 53). In Experiment 2: a lethal hepatoportal injury/diaphragmatic laceration was created followed by foam (n = 6) or resuscitation (n = 10). In Experiment 3, the foam was deployed in naïve, spontaneously breathing animals (n = 7), and respiration was monitored. In Experiments 4 and 5, the foam was deployed above (n = 6) and below the omentum (n = 6) and in naïve animals (n = 6). Intra-abdominal pressure and organ contact were assessed. RESULTS In Experiment 1, blood was successfully aspirated from a Veress needle in 70% of lethal iliac artery injuries and 100% of lethal hepatoportal injuries. In Experiment 2, in the presence of a diaphragm injury, between 0 cc and 110 cc of foam was found within the pleural space. Foam treatment resulted in a survival benefit relative to the control group at 1 hour (p = 0.03). In Experiment 3, hypercarbia was observed: mean (SD) Pco2 was 48 (9.4) mm Hg at baseline and 65 (14) mm Hg at 60 minutes. In Experiment 4, abdominal omentum seemed to influence organ contact and transport in two foam deployments. In Experiment 5, there was no difference in intra-abdominal pressure following foam deployment in the absence of a midline laparotomy. CONCLUSION In a series of large animal studies, we addressed key translational issues surrounding safe use of foam treatment. These additional data, from diagnosis to deployment, will guide human experiences with foam treatment for massive abdominal exsanguination where no other treatments are available.