Bleeding complications arising from trauma, surgery, and as congenital, disease-associated, or drug-induced blood disorders can cause significant morbidities and mortalities in civilian and military populations. Therefore, stoppage of bleeding (hemostasis) is of paramount clinical significance in prophylactic, surgical, and emergency scenarios. For externally accessible injuries, a variety of natural and synthetic biomaterials have undergone robust research, leading to hemostatic technologies including glues, bandages, tamponades, tourniquets, dressings, and procoagulant powders. In contrast, treatment of internal noncompressible hemorrhage still heavily depends on transfusion of whole blood or blood's hemostatic components (platelets, fibrinogen, and coagulation factors). Transfusion of platelets poses significant challenges of limited availability, high cost, contamination risks, short shelf-life, low portability, performance variability, and immunological side effects, while use of fibrinogen or coagulation factors provides only partial mechanisms for hemostasis. With such considerations, significant interdisciplinary research endeavors have been focused on developing materials and technologies that can be manufactured conveniently, sterilized to minimize contamination and enhance shelf-life, and administered intravenously to mimic, leverage, and amplify physiological hemostatic mechanisms. Here, a comprehensive review regarding the various topical, intracavitary, and intravenous hemostatic technologies in terms of materials, mechanisms, and state-of-art is provided, and challenges and opportunities to help advancement of the field are discussed.

Bioremediation is an important approach to waste reduction that relies on biological processes to break down a variety of pollutants. This is made possible by the vast metabolic diversity of the microbial world. To explore this diversity for the breakdown of plastic, we screened several dozen endophytic fungi for their ability to degrade the synthetic polymer polyester polyurethane (PUR). Several organisms demonstrated the ability to efficiently degrade PUR in both solid and liquid suspensions. Particularly robust activity was observed among several isolates in the genus Pestalotiopsis, although it was not a universal feature of this genus. Two Pestalotiopsis microspora isolates were uniquely able to grow on PUR as the sole carbon source under both aerobic and anaerobic conditions. Molecular characterization of this activity suggests that a serine hydrolase is responsible for degradation of PUR. The broad distribution of activity observed and the unprecedented case of anaerobic growth using PUR as the sole carbon source suggest that endophytes are a promising source of biodiversity from which to screen for metabolic properties useful for bioremediation.Tremendous increases in the manufacture and consumption of plastics over recent decades have led to numerous ecological and economic concerns. The persistence of synthetic polymers introduced into the environment by human industry poses a major threat to natural ecological systems. The low cost and ease of manufacture have increased global plastic demand more than 150-fold, with the production of 1.5 million tons in 1950 and 245 million tons as of 2006 (21). Despite recognition of the persistent pollution problems posed by plastic, global production is still increasing, with the largest increases expected in developing nations. The sheer volume of plastics produced each year presents a problem for waste disposal systems. The scale of this problem and the recalcitrance of some polymers to degradation necessitate investigation into effective methods for biodegradation of plastics. By gaining an understanding of the mechanisms of polymer degradation, a more efficient technique for the biodegradation of plastic waste can be achieved. To accomplish this goal, researchers need greater knowledge of how compounds are metabolized by existing organisms, an investigation of new organisms with bioremediation potential, and the characterization of novel metabolic capabilities.

Intravascular administration of plasminogen activators is a clinically important thrombolytic strategy to treat occlusive vascular conditions. A major issue with this strategy is the systemic off-target drug action, which affects hemostatic capabilities and causes substantial hemorrhagic risks. This issue can be potentially resolved by designing technologies that allow thrombus-targeted delivery and site-specific action of thrombolytic drugs. To this end, leveraging a liposomal platform, we have developed platelet microparticle (PMP)-inspired nanovesicles (PMINs), that can protect encapsulated thrombolytic drugs in circulation to prevent off-target uptake and action, anchor actively onto thrombus via PMP-relevant molecular mechanisms and allow drug release via thrombus-relevant enzymatic trigger. Specifically, the PMINs can anchor onto thrombus via heteromultivalent ligand-mediated binding to active platelet integrin GPIIb-IIIa and P-selectin, and release the thrombolytic payload due to vesicle destabilization triggered by clot-relevant enzyme phospholipase-A. Here we report on the evaluation of clot-targeting efficacy, lipase-triggered drug release and resultant thrombolytic capability of the PMINs in vitro, and subsequently demonstrate that intravenous delivery of thrombolytic-loaded PMINs can render targeted fibrinolysis without affecting systemic hemostasis, in vivo, in a carotid artery thrombosis model in mice. Our studies establish significant promise of the PMIN technology for safe and site-targeted nanomedicine therapies in the vascular compartment.

Bleeding from traumatic injury is the leading cause of death for young people across the world, but interventions are lacking. While many agents have shown promise in small animal models, translating the work to large animal models has been exceptionally difficult in great part because of infusion-associated complement activation to nanomaterials that leads to cardiopulmonary complications. Unfortunately, this reaction is seen in at least 10% of the population. We developed intravenously infusible hemostatic nanoparticles that were effective in stopping bleeding and improving survival in rodent models of trauma. To translate this work, we developed a porcine liver injury model. Infusion of the first generation of hemostatic nanoparticles and controls 5 min after injury led to massive vasodilation and exsanguination even at extremely low doses. In naïve animals, the physiological changes were consistent with a complement-associated infusion reaction. By tailoring the zeta potential, we were able to engineer a second generation of hemostatic nanoparticles and controls that did not exhibit the complement response at low and moderate doses but did at the highest doses. These second-generation nanoparticles led to cessation of bleeding within 10 min of administration even though some signs of vasodilation were still seen. While the complement response is still a challenge, this work is extremely encouraging in that it demonstrates that when the infusion-associated complement response is managed, hemostatic nanoparticles are capable of rapidly stopping bleeding in a large animal model of trauma.

Traumatic non-compressible hemorrhage is a leading cause of civilian and military mortality and its treatment requires massive transfusion of blood components, especially platelets. However, in austere civilian and battlefield locations, access to platelets is highly challenging due to limited supply and portability, high risk of bacterial contamination and short shelf-life. To resolve this, we have developed an I.V.-administrable ‘synthetic platelet’ nanoconstruct (SynthoPlate), that can mimic and amplify body’s natural hemostatic mechanisms specifically at the bleeding site while maintaining systemic safety. Previously we have reported the detailed biochemical and hemostatic characterization of SynthoPlate in a non-trauma tail-bleeding model in mice. Building on this, here we sought to evaluate the hemostatic ability of SynthoPlate in emergency administration within the ‘golden hour’ following traumatic hemorrhagic injury in the femoral artery, in a pig model. We first characterized the storage stability and post-sterilization biofunctionality of SynthoPlate in vitro. The nanoconstructs were then I.V.-administered to pigs and their systemic safety and biodistribution were characterized. Subsequently we demonstrated that, following femoral artery injury, bolus administration of SynthoPlate could reduce blood loss, stabilize blood pressure and significantly improve survival. Our results indicate substantial promise of SynthoPlate as a viable platelet surrogate for emergency management of traumatic bleeding.

Summary Background Platelet transfusion applications face severe challenges due to the limited availability and portability, high risk of contamination and short shelf-life of platelets. Therefore there is significant interest in synthetic platelet substitutes that can render hemostasis while avoiding these issues. Platelets promote hemostasis by injury site-selective adhesion and aggregation, and propagation of coagulation reactions on their membrane. Based on these mechanisms, we have developed a synthetic platelet technology (SynthoPlateTM) that integrates platelet-mimetic site-selective ‘adhesion’ and ‘aggregation’ functionalities via heteromultivalent surface-decoration of lipid vesicles with Von Willebrand Factor-binding, collagen-binding and active platelet integrin GPIIb-IIIa-binding peptides. Objective SynthoPlateTM was evaluated for its effects on platelets and plasma in vitro, and for systemic safety and hemostatic efficacy in severely thrombocytopenic mice in vivo. Methods In vitro, SynthoPlateTM was evaluated using aggregometry, fluorescence microscopy, microfluidics, and thrombin and fibrin generation assays. In vivo, SynthoPlateTM was evaluated for systemic safety using prothrombin and fibrin assays on plasma and for hemostatic effect on tail-transection bleeding time in severely thrombocytopenic (TCP) mice. Results SynthoPlateTM did not aggregate resting platelets or spontaneously promote coagulation in plasma, but could amplify recruitment and aggregation of active platelets at the bleeding site and thereby site-selectively enhance fibrin generation. SynthoPlateTM dose-dependently reduced bleeding time in TCP mice, to levels comparable to normal mice. SynthoPlateTM has a reasonable circulation residence time and is cleared mostly by the liver and spleen. Conclusion The results demonstrate the promise of SynthoPlateTM as a synthetic platelet substitute in transfusion treatment of platelet-related bleeding complications.

Transfusion of SynthoPlate particles reduces blood loss in a murine model of liver injury, and SynthoPlates may represent a viable transfusion product for the mitigation of blood loss in acute, severe hemorrhagic shock.

Background Trauma‐associated hemorrhage and coagulopathy remain leading causes of mortality. Such coagulopathy often leads to a hyperfibrinolytic phenotype where hemostatic clots become unstable because of upregulated tissue plasminogen activator (tPA) activity. Tranexamic acid (TXA), a synthetic inhibitor of tPA, has emerged as a promising drug to mitigate fibrinolysis. TXA is US Food and Drug Administration‐approved for treating heavy menstrual and postpartum bleeding, and has shown promise in trauma treatment. However, emerging reports also implicate TXA for off‐target systemic coagulopathy, thromboembolic complications, and neuropathy. Objective We hypothesized that targeted delivery of TXA to traumatic injury site can enable its clot‐stabilizing action site‐selectively, to improve hemostasis and survival while avoiding off‐target effects. To test this, we used liposomes as a model delivery vehicle, decorated their surface with a fibrinogen‐mimetic peptide for anchorage to active platelets within trauma‐associated clots, and encapsulated TXA within them. Methods The TXA‐loaded trauma‐targeted nanovesicles (T‐tNVs) were evaluated in vitro in rat blood, and then in vivo in a liver trauma model in rats. TXA‐loaded control (untargeted) nanovesicles (TNVs), free TXA, or saline were studied as comparison groups. Results Our studies show that in vitro, the T‐tNVs could resist lysis in tPA‐spiked rat blood. In vivo, T‐tNVs maintained systemic safety, significantly reduced blood loss and improved survival in the rat liver hemorrhage model. Postmortem evaluation of excised tissue from euthanized rats confirmed systemic safety and trauma‐targeted activity of the T‐tNVs. Conclusion Overall, the studies establish the potential of targeted TXA delivery for safe injury site‐selective enhancement and stabilization of hemostatic clots to improve survival in trauma.