Esther B. Lim

Self-propelled particles that transport cargo through flowing blood and halt hemorrhage

Simple, water-reactive particles can carry enzymes upstream through aqueous solutions and into wounds to halt severe bleeding. Delivering therapeutics deep into damaged tissue during bleeding is challenging because of the outward flow of blood. When coagulants cannot reach and clot blood at its source, uncontrolled bleeding can occur and increase surgical complications and fatalities. Self-propelling particles have been proposed as a strategy for transporting agents upstream through blood. Many nanoparticle and microparticle systems exhibiting autonomous or collective movement have been developed, but propulsion has not been used successfully in blood or used in vivo to transport therapeutics. We show that simple gas-generating microparticles consisting of carbonate and tranexamic acid traveled through aqueous solutions at velocities of up to 1.5 cm/s and delivered therapeutics millimeters into the vasculature of wounds. The particles transported themselves through a combination of lateral propulsion, buoyant rise, and convection. When loaded with active thrombin, these particles worked effectively as a hemostatic agent and halted severe hemorrhage in multiple animal models of intraoperative and traumatic bleeding. Many medical applications have been suggested for self-propelling particles, and the findings of this study show that the active self-fueled transport of particles can function in vivo to enhance drug delivery.

Effects of rapid wound sealing on survival and blood loss in a swine model of lethal junctional arterial hemorrhage.

BACKGROUND Hemostatic gauzes, which must be packed into wounds and compressed for several minutes, may be of limited use for noncompressible wounds in junctional anatomic locations. Rapid mechanical wound sealing is an alternative approach that seals the wound at the skin, allowing internal clot formation. We evaluate wound sealing for junctional hemorrhage control using a hemostatic clamp (iTClamp). METHODS Severe junctional hemorrhage was induced in anesthetized immature female swine using a 5-mm femoral arteriotomy. After 30 seconds of free bleeding, animals were randomized to one of seven hemostatic interventions: no intervention (control), direct compression for 3 minutes (compression), plain gauze packing (packing), mechanical wound seal (seal), plain gauze packing + wound seal (packing + seal), plain gauze packing + compression (packing + compression), or hemostatic gauze packing (Combat Gauze) + compression (HS-packing + compression). All animals then received one 15-mL/kg bolus of Hextend, followed by lactated Ringer’s solution for hypotension up to 100 mL/kg. Animals were monitored for 3 hours. RESULTS Survival was similar between control (3-hour survival, 0%) and compression (0%, Kaplan-Meier survival analysis and log-rank test [KM-LR], p = 1.0) but marginally improved with packing (12.5%, KM-LR, p < 0.001). Survival improved with seal (62.5%) versus control (KM-LR, p < 0.001) and with packing + seal (100%) versus packing alone (KM-LR, p < 0.001). Survival was similar between packing + compression (87.5%), HS-packing + compression (62.5%), and packing + seal (100%) (KM-LR, p ≥ 0.05). Total hemorrhage volume was decreased for seal versus control (p < 0.001) and for packing + seal versus packing (p < 0.001). Hemorrhage was similar among packing + compression, HS-packing + compression, seal, and packing + seal (analysis of variance p ≥ 0.05). Application times (mean [SD]) were significantly faster with packing + seal (125.8 [56.2] seconds) than packing + compression (236.6 [7.2] seconds) and HS-packing + compression (223.0 [6.8] seconds) (analysis of variance, all p < 0.001). CONCLUSION In this preclinical junctional hemorrhage model, rapid wound sealing improved survival and decreased hemorrhage in both packed and unpacked wounds and performed comparably with standard-of-care hemostatic bandages. Rapidly sealing junctional wounds may be a viable alternative to wound compression.

Post-translational oxidative modification of fibrinogen is associated with coagulopathy after traumatic injury

Victims of trauma often develop impaired blood clot formation (coagulopathy) that contributes to bleeding and mortality. Fibrin polymerization is one critical component of clot formation that can be impacted by post-translational oxidative modifications of fibrinogen after exposure to oxidants. In vitro evidence suggests that Aα-C domain methionine sulfoxide formation, in particular, can induce conformational changes that prevent lateral aggregation of fibrin protofibrils during polymerization. We used mass spectrometry of plasma from trauma patients to find that fibrinogen Aα-C domain methionine sulfoxide content was selectively-increased in patients with coagulopathy vs. those without coagulopathy. This evidence supports a novel linkage between oxidative stress, coagulopathy, and bleeding after injury.

Self-Propelled Dressings Containing Thrombin and Tranexamic Acid Improve Short-Term Survival in a Swine Model of Lethal Junctional Hemorrhage.

Abstract Hemorrhage is the leading cause of preventable death in trauma, and hemorrhage from noncompressible junctional anatomic sites is particularly difficult to control. The current standard is QuikClot Combat Gauze packing, which requires 3 min of compression. We have created a novel dressing with calcium carbonate microparticles that can disperse and self-propel upstream against flowing blood. We loaded these microparticles with thrombin and tranexamic acid and tested their efficacy in a swine arterial bleeding model without wound compression. Anesthetized immature female swine received 5 mm femoral arteriotomies to induce severe junctional hemorrhage. Wounds were packed with kaolin-based QuikClot Combat Gauze (KG), propelled thrombin-microparticles with protonated tranexamic acid (PTG), or a non-propelling formulation of the same thrombin-microparticles with non-protonated tranexamic acid (NPTG). Wounds were not compressed after packing. Each animal then received one 15 mL/kg bolus of hydroxyethyl starch solution followed by Lactated Ringer as needed for hypotension (maximum: 100 mL/kg) for up to 3 h. Survival was improved with PTG (3-h survival: 8/8, 100%) compared with KG (3/8, 37.5%) and NPTG (2/8, 25%) (P <0.01). PTG animals maintained lower serum lactate and higher hemoglobin concentrations than NPTG (P <0.05) suggesting PTG decreased severity of subsequent hemorrhagic shock. However, total blood loss, Lactated Ringer infusion volumes, and mean arterial pressures of surviving animals were not different between groups (P >0.05). Thus, in this swine model of junctional arterial hemorrhage, gauze with self-propelled, prothrombotic microparticles improved survival and 2 indicators of hemorrhagic shock when applied without compression, suggesting this capability may enable better treatment of non-compressible junctional wounds.

Rediscovering the wound hematoma as a site of hemostasis during major arterial hemorrhage

Treatments for major internal bleeding after injury include permissive hypotension to decrease the rate of blood loss, intravenous infusion of plasma or clotting factors to improve clot formation, and rapid surgical hemostasis or arterial embolization to control bleeding vessels. Yet, little is known regarding major internal arterial hemostasis, or how these commonly used treatments might influence hemostasis.