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Hemorrhage is the primary cause of trauma-related death. Of patients that survive, polymicrobial infection occurs in 39% of traumatic wounds within a week of injury. Moreover, traumatic wounds are susceptible to hospital-acquired and drug-resistant bacterial infections. Thus, hemostatic dressings with antimicrobial properties could reduce morbidity and mortality to enhance traumatic wound healing. To that end, p-coumaric acid (PCA) was incorporated into hemostatic shape memory polymer foams by two mechanisms (chemical and physical) to produce dual PCA (DPCA) foams. DPCA foams demonstrated excellent antimicrobial and antibiofilm properties against native Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis; co-cultures of E. coli and S. aureus; and drug-resistant S. aureus and S. epidermidis at short (1 h) and long (7 days) time points. Resistance against biofilm formation on the sample surfaces was also observed. In ex vivo experiments in a porcine skin wound model, DPCA foams exhibited similarly high antimicrobial properties as those observed in vitro, indicating that PCA was released from the DPCA foam to successfully inhibit bacterial growth. DPCA foams consistently showed improved antimicrobial properties relative to those of clinical control foams containing silver nanoparticles (AgNPs) against single and mixed species bacteria, single and mixed species biofilms, and bacteria in the ex vivo wound model. This system could allow for physically incorporated PCA to first be released into traumatic wounds directly after application for instant wound disinfection. Then, more tightly tethered PCA can be continuously released into the wound for up to 7 days to kill additional bacteria and protect against biofilms.

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Phenolic acids (PAs) are natural antioxidant agents in the plant kingdom that are part of the human diet. The introduction of naturally occurring PAs into the network of synthetic shape memory polymer (SMP) polyurethane (PU) foams during foam fabrication can impart antioxidant properties to the resulting scaffolds. In previous work, PA-containing SMP foams were synthesized to provide materials that retained the desirable shape memory properties of SMP PU foams with additional antimicrobial properties that were derived from PAs. Here, we explore the impact of PA incorporation on SMP foam antioxidant properties. We investigated the antioxidant effects of PA-containing SMP foams in terms of in vitro oxidative degradation resistance and cellular antioxidant activity. The PA foams showed surprising variability; p-coumaric acid (PCA)-based SMP foams exhibited the most potent antioxidant properties in terms of slowing oxidative degradation in H2O2. However, PCA foams did not effectively reduce reactive oxygen species (ROS) in short-term cellular assays. Vanillic acid (VA)- and ferulic acid (FA)-based SMP foams slowed oxidative degradation in H2O2 to lesser extents than the PCA foams, but they demonstrated higher capabilities for scavenging ROS to alter cellular activity. All PA foams exhibited a continuous release of PAs over two weeks. Based on these results, we hypothesize that PAs must be released from SMP foams to provide adequate antioxidant properties; slower release may enable higher resistance to long-term oxidative degradation, and faster release may result in higher cellular antioxidant effects. Overall, PCA, VA, and FA foams provide a new tool for tuning oxidative degradation rates and extending potential foam lifetime in the wound. VA and FA foams induced cellular antioxidant activity that could help promote wound healing by scavenging ROS and protecting cells. This work could contribute a wound dressing material that safely releases antimicrobial and antioxidant PAs into the wound at a continuous rate to ideally improve healing outcomes. Furthermore, this methodology could be applied to other oxidatively degradable biomaterial systems to enhance control over degradation rates and to provide multifunctional scaffolds for healing.

RESUMEN

The leading cause of trauma-related death before arrival at a hospital is uncontrolled blood loss. Upon arrival at the hospital, microbial infections in traumatic wounds become an additional factor that increases mortality. The development of hemostatic materials with antimicrobial and antioxidant properties could improve morbidity and mortality in these wounds. To that end, phenolic acids (PAs) were successfully incorporated into the network of shape memory polymer (SMP) polyurethane foams by reacting them with isocyanates. Resulting PA-containing SMP foam shape memory properties, antimicrobial and antioxidant activity, and blood and cell interactions were characterized. Results showed that p-coumaric, vanillic, and ferulic acids were successfully incorporated into the SMP foams. The PA-containing SMP foams retained the antimicrobial and antioxidant properties of the incorporated PAs, with ∼20% H2O2 scavenging and excellent antimicrobial properties again E. coli (∼5X reduction in CFUs vs. control foams), S. aureus (∼4.5X reduction in CFUs vs. control foams, with comparable CFU counts to clinical control), and S. epidermidis (∼25-120X reduction in CFUs vs. control foams, with comparable CFU counts to clinical control). Additionally, appropriate thermal and shape memory properties of PA foams could enable stable storage in low-profile secondary geometries at temperatures up to ∼55°C and rapid expand within ∼2 min after exposure to water in body temperature blood. PA foams had high cytocompatibility (>80%), non-hemolytic properties, and platelet attachment and activation, with improved cytocompatibility and hemocompatibility in comparison with clinical, silver-based controls. The incorporation of PAs provides a natural non-antibiotic approach to antimicrobial SMP foams with antioxidant properties. This system could improve outcomes in traumatic wounds to potentially reduce bleeding-related deaths and subsequent infections.

RESUMEN

Although there are many hemostatic agents available for use on the battlefield, uncontrolled hemorrhage is still the primary cause of preventable death. Current hemostatic dressings include QuikClot® Combat Gauze (QCCG) and XStat®, which have inadequate success in reducing mortality. To address this need, a new hemostatic material was developed using shape memory polymer (SMP) foams, which demonstrate biocompatibility, rapid clotting, and shape recovery to fill the wound site. SMP foam hemostatic efficacy was examined in a lethal, noncompressible porcine liver injury model over 6 h following injury. Wounds were packed with SMP foams, XStat, or QCCG and compared in terms of time to bleeding cessation, total blood loss, and animal survival. The hemostatic material properties and in vitro blood interactions were also characterized. SMP foams decreased blood loss and active bleeding time in comparison with XStat and QCCG. Most importantly, SMP foams increased the 6 h survival rate by 50% and 37% (vs. XStat and QCCG, respectively) with significant increases in survival times. Based upon in vitro characterizations, this result is attributed to the low stiffness and shape filling capabilities of SMP foams. This study demonstrates that SMP foams have promise for improving upon current clinically available hemostatic dressings and that hemostatic material properties are important to consider in designing devices for noncompressible bleeding control. STATEMENT OF SIGNIFICANCE: Uncontrolled hemorrhage is the leading cause of preventable death on the battlefield, and it accounts for approximately 1.5 million deaths each year. New biomaterials are required for improved hemorrhage control, particularly in noncompressible wounds in the torso. Here, we compared shape memory polymer (SMP) foams with two clinical dressings, QuikClot Combat Gauze and XStat, in a pig model of lethal liver injury. SMP foam treatment reduced bleeding times and blood loss and significantly improved animal survival. After further material characterization, we determined that the improved outcomes with SMP foams are likely due to their low stiffness and controlled shape change after implantation, which enabled their delivery to the liver injuries without inducing further wound tearing. Overall, SMP foams provide a promising option for hemorrhage control.

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Shape memory polymer foam hemostats are a promising option for future hemorrhage control in battlefield wounds. To enable their use as hemostatic devices, they must be optimized in terms of formulation and architecture, and their safety and efficacy must be characterized in animal models. Relevant in vitro models can be used for device optimization to help mitigate the excess use of animals and reduce costs of clinical translation. In this work, a simplified gunshot wound model and a grade V liver injury model were constructed. The models were used to characterize the effects of shape memory polymer foam hemostat geometry on wall pressures, application/removal times, hemorrhage (fluid loss), and fluid absorption in comparison with clinical controls. It was found that there is no benefit in over-sizing the hemostatic device relative to wound volume and that geometry effects are dependent upon the wound type. These models provide a rapid means for elucidation of promising hemostat geometries and formulations for use in future in vivo testing.

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